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RACIONAL: | A pesquisa em cirurgia robótica assistida cresceu dramaticamente nas últimas
duas décadas e as vantagens sobre a videolaparoscopia tradicional têm sido
amplamente debatidas. Para as hérnias, o sistema robótico pode aumentar as
estratégias intraoperatórias, principalmente em hérnias complexas ou hérnias
incisionais. | PMC9831626 | ||
OBJETIVOS: | Comparar as diferenças de custo direto entre a hernioplastia incisional
robótica e a laparoscópica e determinar cada fonte de gasto que pode estar
relacionada ao aumento de custos em um programa de robótica na perspectiva
de uma instituição pública brasileira. | PMC9831626 | ||
MÉTODOS: | hérnia | Investigar as diferenças nos custos diretos dos dados gerados a partir de um
protocolo de ensaio clínico (ReBEC: RBR-5s6mnrf). Pacientes com hérnia
incisional foram aleatoriamente designados para serem submetidos a reparo
robótico ou laparoscópico (RVIHR). Os custos foram descritos na moeda
brasileira (R$). | PMC9831626 | |
RESULTADOS: | exames diagnósticos | UTI | Dezenove pacientes submetidos à cirurgia robótica foram comparados com
dezoito submetidos à cirurgia laparoscópica. O valor gasto com tempo de
centro cirúrgico (Robótica: 2.447,91±644,79; Robótica: 1.989,67±763,00;
p=0,030), gases medicinais inalados em centro cirúrgico (Robótica:
270,57±211,51; Robótica: 84,55±252,34; p=0,023), recursos humanos em centro
cirúrgico (Robótica: 3.164,43±894,97; Laparoscópica: 2.120,16±663,78;
p<0,001), recursos materiais (Robótica : 3.204,32±351,55; Robótica:
736,51±972,32; p<0,001) e medicamentos (Robótica: 823,40±175,47;
Robótica: 288,50 ± 352,55; p<0,001) para cirurgia robótica foi maior que
cirurgia laparoscópica, implicando em maior custo total para cirurgia
robótica (Robótica: 14.712,24±3.520,82; Laparoscópica: 10.295,95±3.453,59;
p<0,001). Não foi observada diferença significativa nos custos
relacionados à permanência hospitalar, recursos humanos em UTI e enfermaria,
exames diagnósticos e telas. | PMC9831626 |
CONCLUSÕES: | O sistema robótico adiciona um custo global significativo à hernioplastia
incisional laparoscópica tradicional. O custo dos dispositivos médicos e
robóticos, além de tempos cirúrgicos mais prolongados, são os principais
fatores que impulsionam a diferença nos custos. | PMC9831626 | ||
HEADINGS | PMC9831626 | |||
DESCRITORES: | PMC9831626 | |||
INTRODUCTION | ventral hernia | Robotic-assisted surgery research has grown dramatically in the past two decades,
leveraged by top Gross Domestic Product (GDP) countriesSeveral comparative studies of robotic-assisted primary, inguinal, or incisional
ventral hernia repair versus laparoscopy found no significant differences in
postoperative outcomesThe first robotic systems acquired in Brazil date back to 2007, covering private
institutions. In 2012, public hospitals in Brazil acquired this system, making
surgical technology available to patients treated in the public health system | PMC9831626 | |
METHODS | PMC9831626 | |||
Study design and participants | hernia | This study investigated the differences in direct costs from the data generated
from a randomized trial protocol (Brazilian Registry of Clinical Trials, ReBEC;
ID: RBR-5s6mnrf). The clinical outcomes of this protocol were previously reportedAll hernia repairs took place at | PMC9831626 | |
Ethical aspects | The local Ethics Committee approved the study protocol (CAAE:
40789014.3.0000.0065), and all patients signed a written informed consent
form. | PMC9831626 | ||
Costs estimation | hernia | MAY | The direct medical costs of hernia treatment are described from the Institute’s
perspective. A mixed methodology of micro-costing and apportionment of the
macro-costing was used. The estimate for daily costs related to hospitalization
and surgery (OR time, medical and multidisciplinary consultations, daily charges
in hospital wards, intensive care units [ICUs], and ambulatory visits) were
valued by apportioning fixed and variable costs (of human resources, material
resources, and infrastructure) to assess the respective unit values of the
Institute health care service costs used. Drugs, medical devices, nutrition,
blood, laboratory, and imaging studies were valued by micro-costing calculation
according to individual patient consumption multiplied by the respective
acquisition cost. The OR time was measured from entry until the patient’s
departure from the OR, including the anesthesia and surgery. The mean cost of
laparoscopic ventral incisional hernia repair (LVIHR) and robotic ventral
incisional hernia repair (RVIHR) was calculated by averaging patient costs for
each group. Costs were expressed in the Brazilian currency (Real, R$). In May
2015, R$1.00=US$ 0.33. | PMC9831626 |
Interventional and control groups | hernia | Patients with an incisional hernia were randomly assigned to receive any
interventions: LVIHR or RVIHR, with either an intraperitoneal onlay mesh (IPOM)
or a Rives-Stoppa procedure. All robotic-assisted procedures performed in this
study used the da Vinci Si platforms. When possible, any defect was closed using
a unidirectional suture. An intraperitoneal-coated macroporous multifilament
polyester mesh was placed at least 5 cm overlap in all directions to cover the
original hernia size. | PMC9831626 | |
Statistical analysis | Qualitative variables were described as counts and percentages. Continuous
variables were described as mean, median, standard deviation, and 95% confidence
intervals (95%CIs). Differences between groups were assessed by the Mann-Whitney
U test for continuous variables and Fisher’s exact test or chi-square test for
categorical variables. Statistical analyses were performed with the STATA
software, version 16.0 (StataCorp LLC). | PMC9831626 | ||
RESULTS | In the study, 19 patients submitted to LVIHR were compared with 18 patients submitted
to RVIHR.No significant difference was noted in costs related to hospital stay (RVIHR:
1,641.50±767.85; LVIHR: 1,749.61±1,130.48; p=0.738), inhaled medical gases (ICU)
(RVIHR: 0.00; LVIHR: 10.83±44.92; p=0.331), inhaled medical gases (ward) (RVIHR:
0.00; LVIHR: 10.79±44.75; p=0.331), human resources (ICU) (RVIHR: 0.00; LVIHR:
104.60±433.68; p=0.331), human resources (ward) (RVIHR: 1,320.43±632.22; LVIHR:
1,443.11±948.26; p=0.648), diagnostic tests (RVIHR: 48.69±80.10; LVIHR 82.81±157.66;
p 0.421), and prosthesis, meshes, and special devices (RVIHR: 1,790.98±2,023.45;
LVIHR: 1,674.82±594.17; p=0.810). Meantime, the amount spent on operation room time
(RVIHR: 2,447.91±644.79; LVIHR: 1,989.67±763.00; p=0.030), inhaled medical gases
(OR) (RVIHR: 270.57±211.51; LVIHR: 84.55±252.34; p | PMC9831626 | ||
Total costs per patient (mean and standard deviation) between robotic
ventral incisional hernia repair and laparoscopic ventral incisional hernia
repair. | PMC9831626 | |||
Mean costs differences between robotic ventral incisional hernia repair
and laparoscopic ventral incisional hernia repair. | hernia | Costs were expressed as Real (R$), the monetary unit of Brazil.
RVIHR=robotic ventral incisional hernia repair; LVIHR=laparoscopic
ventral incisional hernia repair; OR: operation room; ICU: intensive
care unit; SD: standard deviation.To investigate the medications costs difference between RVIHR and LVIHR, we analyzed
the drug vials consumed per patient ( | PMC9831626 | |
Drug vials consumed per patient. | hernia | NEUROMUSCULAR BLOCKADE | SD=standard deviation; RVIHR=robotic ventral incisional hernia repair;
LVIHR=laparoscopic ventral incisional hernia repair.Regarding drug vials consumed per patient, no significant difference was noted in
routine medications (RVIHR: 8.6±7.62 vials; LVIHR: 8.53±6.92 vials; p=0.888),
intravenous fluids (RVIHR: 17.8±11.01 vials; LVIHR: 24.11±17.79 vials; p=0.089),
electrolyte replacement (RVIHR: 1.8±1.94 vials; LVIHR: 2.37±1.8 vials; p=0.191),
neuromuscular blockade reversal agents (RVIHR: 1.4±0.6 vials; LVIHR: 2.21±2.25
vials; p=0.612), vasoactive drugs (RVIHR: 0.3±0.57 vials; LVIHR: 0.68±0.95 vials;
p=0.144), antibiotics (RVIHR: 2.47±7.78 vials; LVIHR: 4.6±1.35 vials; p=0.497),
analgesics (RVIHR: 24.7±13.5 vials; LVIHR: 25.58±19.61 vials; p=0.966), antiemetics
(RVIHR: 5.6±5.79 vials; LVIHR: 6.53±6 vials; p=0.24), and other (RVIHR: 1.5±1.19
vials; LVIHR: 3.53±7.28 vials; p=0.885). On the other hand, there was a significant
difference in the consume of anesthetics (RVIHR: 5.55±1.54 vials; LVIHR: 4.26±1.88
vials; p=0.016), local anesthetic agents (RVIHR: 4.5±1.19 vials; LVIHR: 1.68±1.42
vials; p<0.001), and neuromuscular blocking agents (RVIHR: 3.25±1.21 vials;
LVIHR: 2.21±1.44 vials; p=0.016). | PMC9831626 |
DISCUSSION | STERILE, NEUROMUSCULAR BLOCKADE | The outcome of the present study showed that comparing RVIHR and LVIHR, there is a
significantly higher average cost in robotic-assisted use. These costs are mainly
associated with prolonged surgical time, higher consumption of anesthetics, high
mobilization of human resources, and, evidently, material devices related to the
robotic machine. Knowing the costs of each variable related to the surgical
intervention is essential to better allocate resources and to depict a detailed and
precise budget impact analysis before implementing a robotic program in a public
health institution.Beyond material resources, the robotic system demands higher costs related to human
resources. In theory, the robotic system demands only one surgeon for each surgery,
decreasing the need for other surgeons during the procedures. In the United States,
the physician assistant, a mid-level health care provider, may act as a bedside
assistant and helps position the patient and docking, decreasing the costs related
to robot-assisted proceduresDue to the prolonged OR time and the complexity of the procedure, there is a demand
for more number and more qualified professionals during robotic surgery. Nurses in
robot-assisted surgery need to have high technical proficiency and active attitudes.
Their roles include scheduling, checking for supplies, system operating,
administration of circulating nurses, patient and console positioning, placing
robotic arms, robotic arm sterile draping, configuring equipment and instruments,
docking, and undockingProlonged surgical time implicates higher demand for more professionals in OR and
expenditure with the OR time. Besides, prolonged surgical time implies more use of
anesthetics and neuromuscular blockade agents. Anesthesia costs usually represent a
minority proportion of the perioperative costsRecent studies demonstrated the higher costs of the RVIHR compared with LVIHR.
Nationwide American studiesAll the studies quoted in the last paragraph were North American, and worldwide
extrapolations are questionable. The present study gives a picture of a robotic
program from a public institution in a middle-income country. Nonetheless, this
study has several limitations. First, it was conducted in a single center, lacking
external validity from other middle and low-income countries. In addition, only
direct costs were accounted for, and costs related to the rehabilitation facility,
days off work after surgery, and their impact on quality of life were not
considered. Another inherent issue with any cost-analysis study is due to the
fluctuation of the exchange rate over time, making it difficult to obtain a
definitive analysis of the costs involved in any longitudinal study. Well-designed
future cost-effectiveness and cost-utility studies can answer whether the high costs
of robot-assisted approach are justifiable for all countries. Economic studies
evaluating the robotic systems’ budgetary impact on health systems are crucial for
determining their utility in public programs in developing or underdeveloped
countries.The present study’s findings raise the question: “Is there a role for the RVIHR in a
public health system?” The answer is “yes.” If a robotic program does not root in
assistance, there will be a significant delay in the dissemination of trained
robotic teams and experienced surgeons and professionals worldwide, and
consequently, expenses lowering tend to linger. Nayeemuddin et al. | PMC9831626 | |
CONCLUSIONS | hernia | A robotic system adds a significant overall cost to traditional laparoscopic hernia
repair. The cost of the medical and robotic devices and longer operative times are
the main factors driving the difference in costs. These costs should be well known
before starting any robotic public program. | PMC9831626 | |
Central Message | hernias | CAVITY, ADHESIONS | Robotic-assisted surgery research has grown dramatically in the past two decades
and the advantages over traditional videolaparoscopy have been extensively
debated. For hernias, the robotic system can increase intraoperative strategies,
especially in complex hernias or incisional hernias. The benefits comprise
high-quality 3D visualization of the abdominal cavity, gain in movement allowing
easier dissection of multiple adhesions, the release of the rectus muscle,
intraperitoneal mesh suturing, and complex reconstruction of the abdominal
wall. | PMC9831626 |
Perspectives | hernia | A robotic system adds a significant overall cost to traditional laparoscopic
hernia repair. The cost of the medical and robotic devices and longer operative
times are the main factors driving the difference in costs. These costs should
be well known before starting any robotic public program.How to cite this article: Costa TN, Tustumi F, Ferros LSM, Colonno BB, Abdalla
RZ, Ribeiro-Junior U, et al. Robotic-assisted versus laparoscopic incisional
hernia repair: differences in direct costs from a Brazilian public institute
perspective. ABCD Arq Bras Cir Dig. 2022;35:e1714.
https://doi.org/10.1590/0102-672020220002e1714
| PMC9831626 | |
REFERENCES | PMC9831626 | |||
Objectives | DISORDERS | Integrating vocational rehabilitation and mental healthcare has shown effects on vocational outcomes during sick leave with common mental disorders. In a previous paper, we showed that a Danish integrated healthcare and vocational rehabilitation intervention (INT) had a surprisingly negative impact on vocational outcomes compared to service as usual (SAU) at 6- and 12-month follow-up. That was also the case with a mental healthcare intervention (MHC) tested in the same study. This article reports the 24-month follow-up results of that same study. | PMC10713989 | |
Method | A randomized, parallel-group, three-arm, multi-centre superiority trial was conducted to test the effectiveness of INT and MHC compared to SAU. | PMC10713989 | ||
Results | In total, 631 persons were randomized. Contrary to our hypothesis, SAU showed faster return to work than both INT [hazard rate (HR) 1.39, P=0.0027] and MHC (HR 1.30, P=0.013) at 24-month follow-up. Overall, no differences were observed regarding mental health and functional level. Compared to SAU, we observed some health benefits of MHC, but not INT, at 6-month follow-up but not thereafter, and lower rates of employment at all follow-ups. Since implementation problems might explain the results of INT, we cannot conclude that INT is no better that SAU. The MHC intervention was implemented with good fidelity and did not improve return to work. | PMC10713989 | ||
Conclusion | This trial does not support the hypothesis that INT lead to faster return to work. However, implementation failure may explain the negative results. | PMC10713989 | ||
Key terms | Long-term sick leave is a risk factor for exclusion from the labor market ( | PMC10713989 | ||
Methods | Methods are reported elsewhere ( | PMC10713989 | ||
Statistical analyses | REGRESSION, SENSITIVITY | Proportion-in-work outcomes were analyzed using logistic regression and time-to-RTW outcomes using Cox-regression. Self-reported outcomes were analyzed using linear mixed-effects models. Throughout, we adhered to the intention-to-treat principle. Due to multiple testing, P-values <0.017 were considered statistically significant and those <0.05 borderline (the latter was a post-hoc decision). Subgroup analyses were performed according to selected baseline values and time. Sensitivity analyses were conducted by imputing all missing data in best/worst case scenarios, and regarding return to stable work outcomes with different thresholds for what minimal duration constituted “stable” RTW (1, 4, 8 or 12 weeks). | PMC10713989 | |
Results | DELETION | Analyses included 636 participants in total. Participant flow. [INT=IBBIS integrated intervention; MHC=mental healthcare; SAU=service as usual; RCT=randomized controlled trial]. *Due to European data legislation, complete deletion of data was possible and was requested after randomization by 8 participants. | PMC10713989 | |
Vocational outcomes at 24-month follow-up: | PMC10713989 | |||
Limitations | Implementation issues severely limit both the internal and external validity of the study. Furthermore, due to the nature of the interventions, participants could not be blinded, and the study may be limited by some effects of the allocation procedure in itself. | PMC10713989 | ||
Implications | Complex interventions involving co-location and integration of multidisciplinary teams are generally difficult to implement ( | PMC10713989 | ||
Concluding remarks | This trial compared INT and MHC to SAU. Contrary to our initial hypothesis, both INT and MHC consistently showed significantly lower RTW rates across all follow-ups, compared with SAU. MHC yielded some short-term health benefits, but they were not sustained beyond six months. However, as we cannot rule out implementation failure in INT, and because BP-MH may not have constituted an equally or more qualified mental health service than SAU, we cannot conclude solidly on the results. | PMC10713989 | ||
Ethics | The trial was registered at | PMC10713989 | ||
Supplementary material | PMC10713989 | |||
Supplementary material | PMC10713989 | |||
Acknowledgements | RECRUITMENT | The Danish Agency for Labour Market and Recruitment sponsored most of the IBBIS project, which was conducted in collaboration with the Mental Health Services in the Capital Region of Denmark. The four collaborating municipalities partly financed the salary of the employment consultants. The Danish Agency for Labour Market and Recruitment had a say in the design of the study (decisions regarding target population and selected interventions modalities). The funding agency has not taken part of any decisions regarding analysis, interpretation of the data or publication of results. | PMC10713989 | |
References | PMC10713989 | |||
CONFLICT OF INTEREST | The authors declare no conflicts of interest.To the editor,The effect on adherence of a self‐administration medication programme was tested in a randomized controlled trial involving 60 cardiac inpatients by Hajialibeigloo et al. ( | PMC9748058 | ||
DR MORISKY AND THE MMAS | Dr Morisky has received attention over the last few years for asserting copyright over the MMAS. We counted at least six Retraction Watch posts related to Dr Morisky and his adherence scale (see, e.g. Marcus, | PMC9748058 | ||
WAS DR MORISKY GIFTED AUTHORSHIP? | Dr Morisky is listed as an author in the Hajialibeigloo et al. ( | PMC9748058 | ||
CONFLICT OF INTEREST? | The authors of the Hajialibeigloo et al. ( | PMC9748058 | ||
WHY GIFTING AUTHORSHIP MATTERS | The gifting of authorship is common; authors of an observational study of three general medical journals found that up to 20% of papers reviewed had honorary authors (Bates et al., It would be informative to understand from the trial authors why Dr Morisky was included as an author on their paper. If he made the required substantial contribution to the research, then the author contribution statement in the paper should be corrected, as should the conflict‐of‐interest section of the manuscript. Dr Morisky would then probably also then have a claim to authorship on the second paper (Haji Ali Beigloo et al., | PMC9748058 | ||
RECOMMENDATIONS | The Hajialibeigloo et al. ( | PMC9748058 | ||
DATA AVAILABILITY STATEMENT | Data sharing not applicable to this article as no data sets were generated or analysed during the current study. | PMC9748058 | ||
REFERENCES | PMC9748058 | |||
Summary | PMC7614834 | |||
Background | debilitating sequelae | ADENOVIRUS, RVF, RIFT VALLEY FEVER | Rift Valley Fever (RVF) is a viral epidemic illness prevalent in Africa that can be fatal or result in debilitating sequelae in humans. No vaccines are available for human use. We evaluated the safety and immunogenicity of a non-replicating simian adenovirus (ChAdOx1)-vectored RVF vaccine in humans. | PMC7614834 |
Methods | We conducted a phase 1 first-in-human open-label dose-escalation trial in healthy adults in the United Kingdom aged 18 to 55 years ( | PMC7614834 | ||
Findings | Between 11 | PMC7614834 | ||
Interpretation | RVF | ChAdOx1 RVF vaccine was safe, well-tolerated and immunogenic when administered as a single dose in this study population. The data support further clinical development of ChAdOx1 RVF for human use. | PMC7614834 | |
Funding | UK Department of Health and Social Care through the UK Vaccines Network; Oak Foundation; Wellcome Trust | PMC7614834 | ||
Introduction | RVF, VIRUS, ZOONOSIS, RIFT VALLEY FEVER | Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that primarily affects domestic livestock (sheep, goats, cattle) and humans in Africa and the Arabian Peninsula.Natural exposure to RVF generates long-lived protective neutralising antibody (nAb) in both humans and livestock, with a modest declining of titres over many years in the absence of re-exposure.Two RVF vaccine candidates have previously been evaluated in humans. The first is an inactivated vaccine, TSI-GSD-200, which had a good safety profile but even after an initial three-dose regime, approximately 10% of vaccinees failed to seroconvert.ChAdOx1 RVF has shown remarkable safety, immunogenicity and 100% efficacy against wild-type RVF virus challenge in sheep, goats, and cattle in Kenya. | PMC7614834 | |
Methods | PMC7614834 | |||
Study design and participants | RVF, RECRUITMENT | We conducted a phase I, first-in-human, dose-escalation, open-label, non-randomised clinical trial of ChAdOx1 RVF vaccine at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Healthy adult volunteers aged 18-55 years were recruited from the local Oxfordshire area using ethically approved advertising materials. Potential volunteers initially completed an online questionnaire covering major exclusion criteria. They were then invited for an in-person screening visit where written informed consent for the study was obtained followed by a medical history assessment, physical examination, urinalysis, and clinical blood tests. Medical histories were corroborated using medical records obtained from the general practitioner (GP) of each volunteer prior to enrolment. Volunteers that had previously been vaccinated with a ChAdOx1 vaccine (e.g. ChAdOx1 nCoV-19) were excluded from the study. Additionally, volunteers with a history of travel to countries endemic for RVF were screened with a commercial RVF ELISA (ID Screen® Multispecies RVFV ELISA, ID.vet) as per manufacturer’s instructions and excluded if seropositive. Results of all screening assessments were reviewed by a trial investigator before enrolment or exclusion. Full eligibility criteria for the trial are detailed in the trial protocol (Supplementary Appendix).The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Regulatory approval was granted by the UK Medicines and Healthcare Products Regulatory Agency (CTA 21584/0438/001-0001) and ethics approval by National Health Service (NHS) East of England – Cambridge East Research Ethics Committee (reference: 20/EE/0262). Use of ChAdOx1 RVF for this clinical trial was authorised by the Oxford University Hospital NHS Trust Genetic Modification Safety Committee (GM462.18.103). The trial was registered, prior to recruitment, at clinicaltrials.gov (NCT04754776). | PMC7614834 | |
Procedures | toxicity | ADVERSE EVENTS, RVF, EVENTS, BLOOD | The ChAdOx1 RVF vaccine (formerly known as ChAdOx1 GnGc) has been described previously and was manufactured by Advent Srl in accordance with current Good Manufacturing Practices as described in the Investigational Medicinal Product Dossier.Following vaccination, participants attended a series of follow-up visits at the following nominal timepoints: day 2, 7, 14, 28, 56 and 84. Participants also completed a daily online symptom diary for 28 days following vaccination. Solicited adverse events were collected for 7 days and unsolicited adverse events (all other events not defined as solicited) for 28 days post-vaccination. Occurrence of serious adverse events was assessed at all follow up visits. Clinical laboratory blood tests including full blood count, liver function, renal function and electrolytes were performed at day 0 (immediately prior to vaccination), day 2, day 7 and day 28. Laboratory adverse events were graded by use of toxicity tables, which were adapted from the United States Food and Drug Administration toxicity grading scale. Unsolicited adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 24·0 and assessed by investigators for causality with ChAdOx1 RVF. Blood samples for immunology assays were taken on day 0 and at days 7, 14, 28, 56 and 84. The schedule of timepoints for all immunogenicity measures was specified in a laboratory analysis plan prior to the enrolment of the first participant. Four timepoint related protocol deviations occurred relating to attendance of visits outside of the planned schedule including 3 participants attending the day 28 visit between 6 and 11 days later and 1 participant attending the day 56 timepoint 17 days earlier than scheduled.Electronic data capture and clinical data management were carried out using OpenClinica open-source software, version 4·0. | PMC7614834 |
Outcomes | VIRUS, ADVERSE EVENTS, RVF, SECONDARY, APPENDIX | The primary objective of the study was assessment of safety and tolerability of the vaccine in a healthy adult population. Primary outcome measures were: occurrence of local and systemic solicited adverse events for 7 days after vaccination, occurrence of unsolicited adverse events for 28 days after vaccination, changes in clinical laboratory measures from baseline to day 28, and occurrence of serious adverse events (SAEs) throughout the trial period. The secondary objective was humoral and cellular immunogenicity of the vaccine. Secondary outcome measures were: RVF nAb titres measured against live RVF virus, IgG binding antibody titres measured by enzyme-linked immunosorbent assay (ELISA) against recombinant Gn and Gc proteins, and cellular responses to overlapping peptides spanning the Gn-Gc polyprotein measured by ex-vivo interferon-γ (IFNγ) enzyme-linked immunospot (ELISpot) assay. Exploratory outcomes measures were: IgG1-4 subclass antibody ELISA titres against Gn and Gc proteins, and analysis of correlations between immune parameters. Full details of the immunological assay procedures are in the Supplementary Appendix. | PMC7614834 | |
Statistical analysis | ADVERSE EVENTS, RVF | This phase I first-in-human trial aimed to describe the safety, tolerability, and immunogenicity of ChAdOx1 RVF. The number of participants in each vaccine dose group allowed a descriptive analysis of the frequency and magnitude of adverse events following vaccination, rather than statistical significance testing for safety differences between individuals. Immunological data were visualised and analysed using non-parametric tests on GraphPad Prism version 9 (GraphPad Software Inc., California, USA), with a two-sided alpha of 0·05 for statistical significance. | PMC7614834 | |
Role of the funding source | The authors designed, executed, analysed, and reported the study. The funders had no role in these activities other than review of the proposed study design during the funding application. | PMC7614834 | ||
Results | sore throat, feverishness, upper respiratory tract symptoms, cough | ADVERSE REACTIONS, SORE THROAT, ADVERSE EVENTS, COVID-19 INFECTION, RVF | Between 2ChAdOx1 RVF was determined to have an acceptable safety and tolerability profile during interim safety reviews, allowing dose-escalation to proceed as planned. No serious adverse events occurring in any of the participants following vaccination. Mild local reactions were common, with 14 of the 15 participants reporting solicited local adverse reactions (No participants in the low dose group reported any systemic solicited adverse events. However, 4 of the 6 participants in the intermediate dose group and all participants in the high dose group reported systemic symptoms that were mostly mild in intensity (All unsolicited adverse events reported within 28 days of vaccination were either mild or moderate in severity and are detailed within (Mild COVID-19 occurred in 2 participants within 28 days of vaccination, both in the high dose group. The first of these tested positive on a COVID-19 lateral flow device following mild feverishness on day 1 post-vaccination. Their symptoms resolved by day 2 and they were otherwise well. The second volunteer tested positive for COVID-19 after experiencing mild to moderate upper respiratory tract symptoms (sore throat, sneezing, cough) at day 20 which resolved by day 27. Neither of their immune responses to RVFV Gn and Gc was remarkable in comparison to other participants and it is unclear how, if at all, their COVID-19 infections impacted upon this.Laboratory adverse events are described in ChAdOx1 RVF was highly immunogenic, with 12 of the 15 vaccinees mounting a detectable RVF nAb response that peaked at day 28 post-vaccination and persisted to the final follow-up visit at day 84 ( | PMC7614834 |
Discussion | miscarriage, TTS | ADVERSE EVENTS, RVF, MISCARRIAGE, CORONAVIRUS, THROMBOSIS WITH THROMBOCYTOPENIA SYNDROME | There are currently no vaccines for use against RVF in humans, leaving the world vulnerable to public health emergencies associated with RVF epidemics. For this reason, the WHO has prioritised development of RVF countermeasures and compiled a target product profile to guide vaccine development.A scalable manufacturing process for ChAdOx1-vectored vaccines has been developed and successfully used for the ChAdOx1 nCoV-19 (AZD1222) COVID-19 vaccine that is now deployed in over 180 countries globally,Post-marketing surveillance of adenovirus-vectored COVID-19 vaccines, including ChAdOx1 nCoV-19, uncovered a very rare association with thrombosis with thrombocytopenia syndrome (TTS). The biological mechanism underlying TTS is incompletely understood and it remains unknown whether it may also affect adenovirus-vectored vaccines that do not deliver coronavirus antigens.In keeping with our previous livestock studies,The short follow-up duration of this first-in-human trial precluded durability assessments of immune responses generated by vaccination. However, the high nAb titres and the robust IFNγ cellular response detected within 2 weeks post-vaccination augur well for reactive use of the vaccine during RVF outbreaks where rapid induction of immunity is necessary to protect individuals at highest risk of exposure.This first-in-human trial had several limitations, including the small sample size which was sufficient for informing decisions on further evaluation in phase 2 trial but not for detection of any rare adverse events. Subsequent trials will allow assessment of any rare adverse events associated with vaccination. Long-term durability of the immune response could not be determined due to the short follow-up duration. In addition, the study participants were predominantly of white ethnicity, in a population where RVF is not endemic. The four visits conducted outside of the planned trial visit schedule may also have added variability to the measured immune responses. To generalise vaccine performance to populations at most risk, ChAdOx1 RVF and other candidate human RVF vaccines will need evaluation in the target populations in RVF-endemic regions and including adults, children and adolescents, who are all involved in animal husbandry, and in pregnant women where risk of RVF-associated miscarriage is high. | PMC7614834 |
Supplementary Material | PMC7614834 | |||
Acknowledgements | PMF | MARION, VIRUS | This study was supported through the UK Vaccines Network by the UK Department of Health and Social Care (projects 16/107/02 and 16/107/03). The views expressed in this publication are those of the author(s) and not necessarily those of the Department of Health and Social Care. GMW was supported by an Oak foundation fellowship and a Wellcome Trust grant (203077_Z_16_Z). The authors are grateful for the skilled input of the following individuals from the University of Oxford, Centre for Clinical Vaccinology and Tropical Medicine: Nicholas Byard, Hannah Preston-Jones, Syona Neeraj, Nicola Greenwood, Merin Thomas, Celia Mitton, Dina Pena Suarez, Megan Baker, Marion Watson, Jack Quaddy, and Oliver Conway. We also thank Brian Angus for acting as our local safety monitor. We thank Jeroen Kortekaas and Paul Wichgers Schreur at Wageningen Bioveterinary Research, Netherlands for providing the RVFV-4s_eGFP virus used for neutralising antibody assays. GMW, SCG, BC and AVSH are Jenner Investigators.
Methodology: PMF, AVSH, GMW, DJ, DW, AL; Validation: JNG, HKK, DM, DW; Formal analysis: DW, DJ; Investigation: DJ, PMF, AP, IP, DW, JNG, HKK, DM; Resources: KJE; Data Curation: DJ, DW, CT; Writing - Original Draft: DJ, DW, GMW; Writing - Review & Editing: All authors contributed to the reviewing and editing of the report and approved the final version; Visualization: DJ, DW; Supervision: TAB, SCG, GMW; Project administration: AL, AB, NT; Funding acquisition: GMW, AVSH, BC, PK; All data in the manuscript was accessed and verified by DW and DJ.
PMF reports funding from the Brazilian Government (CAPES) for PhD work and consulting fees from Vaccitech, a company developing ChAdOx1 vectored vaccines; KJE is a named contributor to a patent relating to ChAdOx1 MERS; TAB reports grant funding from the Medical Research Council UK; SCG is named as an inventor on the patent covering ChAdOx1 use as a vaccine vector and holds stock in Vaccitech; AVSH has recieved royalties from the COVID-19 vectored ChAdOx1 vaccine to both his institution and self, and is named as an inventor on the patent covering ChAdOx1 use as a vaccine vector; DJ, DW, AP, IP, AL, NT, AB, CT, JNG, HKK, DM, BC, PK, and GMW declare no interests. | PMC7614834 |
Data Sharing Statement | Deidentified participant data will be made available upon requests directed to the chief investigator. Proposals will be reviewed and approved by the sponsor, chief investigator, and collaborators on the basis of scientific merit. After approval of a proposal, data can be shared through a secure online platform after signing a data access agreement. The trial protocol is included in the supplementary materials. | PMC7614834 | ||
Research in context | PMC7614834 | |||
Evidence before this study | RVF, RIFT VALLEY FEVER | Both the WHO and African Union have identified vaccine development for RVF in humans as an urgent priority owing to its potential to cause a public health emergency with devastating health consequences and major economic impacts. The goal of RVF vaccinology has been to design vaccines that are safe and highly immunogenic for neutralizing antibody (nAb) - which are associated with protection - in addition to other optimal product characteristics defined by the WHO. We conducted a search for RVF vaccine trials on ClinicalTrials.gov (using: (Rift Valley Fever) AND (vaccine) with no date restrictions). Two candidate vaccines, the inactivated TSI-GSD-200 vaccine, and the live-attenuated MP-12 vaccine, have previously been evaluated in humans and shown to safely elicit nAb. TSI-GSD-200 has been registered on ClinicalTrials.gov as currently recruiting for phase 2 trial but there have been no further updates on the clinical development of MP-12 for human use since completion of a phase 2 trial in 2009. ChAdOx1 RVF, which is described in this manuscript is also listed as undergoing a separate phase 1b trial in Uganda (registration number:NCT04672824). As with TSI-GSD-200 and MP-12, further evaluation of ChAdOx1 RVF in humans follows demonstration of safety, immunogenicity and efficacy against RVF in livestock. | PMC7614834 | |
Added value of this study | ADENOVIRUS, RVF, DISEASE, ADVERSE EVENTS | This study describes a first-in-human trial of ChAdOx1 RVF, a chimpanzee adenovirus vectored RVF vaccine that has been shown to be highly immunogenic and efficacious against RVF in all major livestock species affected by the disease. While the ChAdOx1 platform is widely deployed for use against COVID-19 (Oxford/AstraZeneca AZD1222 vaccine) in over 180 countries globally, this is the first clinical evaluation of its use for RVF in humans. We assessed the safety and immunogenicity of a single intramuscular dose of ChAdOx1 RVF among adults in the UK. ChAdOx1 RVF was well tolerated with no serious adverse events. High RVF nAb titres were detected within 2 weeks of vaccination, peaking at 28 days post-vaccination. A strong RVF viral glycoprotein-specific IFNγ response, peaking 2 weeks post-vaccination, was also detected. Both humoral and cellular responses persisted over the 3 months follow up period of the study. | PMC7614834 | |
Implications of all the available evidence | RVF | A vaccine for use against RVF in humans remains an urgent unmet need. ChAdOx1 has been shown to be a scalable vaccine platform for COVID-19, but this is the first use of the platform for RVF in humans. ChAdOx1 RVF was well tolerated and generated strong humoral and cellular immune responses. Further evaluation of the vaccine in populations at most risk for RVF is warranted. | PMC7614834 | |
Trial Profile | PMC7614834 | |||
Humoral and cellular responses generated by ChAdOx1 RVF vaccination | RVF | ChAdOx1 RVF vaccine immunogenicity kinetics are shown for all participants (n=15) by dose allocation and at all immunology sampling timepoints during the 3 months of follow up. RVF nAb titres are shown in (A), summed Gn and Gc IFN γ ELISpot responses in (B), and total IgG response against Gc (C) and Gn (D) are shown as fold change from baseline (D0). Symbols represent mean values from three replicates, while connecting lines represent median values. Four samples were obtained out of the defined timepoint windows: 2.5x10 | PMC7614834 | |
Baseline Characteristics | PMC7614834 | |||
Solicited adverse events within 7 days of vaccination with ChAdOx1 RVF | PMC7614834 | |||
Abstract | tumor, death, breast cancer, toxicity, PD‐L1 | CPS, TUMOR, BREAST CANCER | Pembrolizumab plus chemotherapy improved progression‐free survival (PFS) and overall survival (OS) compared with placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic triple‐negative breast cancer with tumor programmed cell death ligand 1 (PD‐L1) combined positive score (CPS) ≥10 in the global, phase 3, randomized controlled trial KEYNOTE‐355. We report results for patients enrolled in Japan. Patients were randomized 2:1 to pembrolizumab 200 mg or placebo Q3W for 35 cycles plus chemotherapy (nab‐paclitaxel, paclitaxel, or gemcitabine–carboplatin). Primary endpoints were PFS per RECIST version 1.1 by blinded independent central review and OS in patients with PD‐L1 CPS ≥10, PD‐L1 CPS ≥1, and the intention‐to‐treat (ITT) population. No alpha was assigned to this exploratory analysis. Eighty‐seven patients were randomized in Japan (pembrolizumab plus chemotherapy, Overall survival was prolonged with pembrolizumab plus chemotherapy compared with placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple‐negative breast cancer enrolled in the global, phase 3 randomized controlled trial KEYNOTE‐355. In this analysis of outcomes in patients in KEYNOTE‐355 who were enrolled in Japan, pembrolizumab plus chemotherapy improved overall survival versus placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic triple‐negative breast cancer with manageable toxicity.
Clinical trial registration: | PMC10225213 |
INTRODUCTION | cancer, Breast cancer, death | CANCER, BREAST CANCER, BREAST CANCER | Breast cancer was the leading cause of cancer among women in 2020, both globally and in Japan.Evidence has suggested that Japanese patients may have better survival outcomes following treatment than American patients with breast cancer.Pembrolizumab, a humanized anti‐programmed cell death protein 1 (PD‐1) antibody, has demonstrated efficacy in patients with TNBC.Among the 847 patients enrolled in KEYNOTE‐355 worldwide, 87 patients were from Japan. Given the potential for differences in response to treatment among Japanese patients, it is important to assess outcomes in this setting. Here, we report results for the subset of patients in KEYNOTE‐355 enrolled in Japan. | PMC10225213 |
MATERIALS AND METHODS | PMC10225213 | |||
Patient eligibility | Eligibility criteria for KEYNOTE‐355 have been previously published.The trial protocol was approved by an institutional review board or independent ethics committee at each site, and the trial was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Written informed consent was obtained from all patients. | PMC10225213 | ||
Study design | As previously described,Eligible patients were randomized 2:1 in a double‐blind manner to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. Pembrolizumab 200 mg IV or saline placebo was administered every 3 weeks for up to 35 cycles (approximately 2 years). Chemotherapy comprised the investigator's choice of nab‐paclitaxel 100 mg/m | PMC10225213 | ||
Assessments | PD‐L1, tumor, Tumor, Cancer | ADVERSE EVENT, TUMOR, TUMOR, ADVERSE EVENT, CPS, CANCER | Tumor imaging was performed at baseline, at weeks 8, 16, and 24 from randomization, then every 9 weeks for the first year and every 12 weeks thereafter. Responses were assessed by RECIST version 1.1 by blinded independent central review. Survival was assessed every 12 weeks until withdrawal of consent or end of study. Adverse events (AEs) were monitored from the time of randomization through 30 days following cessation of treatment (90 days for serious AEs) and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Baseline tumor PD‐L1 expression was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies) at a central laboratory and reported as CPS, defined as the number of PD‐L1‐positive tumor cells, lymphocytes, and macrophages divided by the total number of tumor cells multiplied by 100. | PMC10225213 |
Endpoints | tumors, PD‐L1 | CPS, TUMORS | The dual primary endpoints were PFS per RECIST version 1.1 as assessed by blinded independent central review and OS in patients in the intention‐to‐treat population, patients with PD‐L1 CPS ≥10 tumors, and patients with PD‐L1 CPS ≥1 tumors. The primary endpoints were amended to include PFS and OS in patients with PD‐L1 CPS ≥10 tumors following the completion of enrollment and the first interim analysis based on data from other studies that reported increased clinical benefit with PD‐L1 enrichment. | PMC10225213 |
Statistical analysis | Statistical considerations for the global KEYNOTE‐355 study have been previously described. | PMC10225213 | ||
RESULTS | PMC10225213 | |||
Patients | death | CPS, DISEASE CHARACTERISTIC, ONCOLOGY | Among 847 patients enrolled in the global study,Demographics and baseline disease characteristics in the intention‐to‐treat population.
Abbreviations: CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; IVRS, interactive voice‐response system; PD‐L1, programmed cell death ligand 1.In Japanese patients, the median time from randomization to the database cutoff date of June 15, 2021 (i.e., the same database cutoff date as the protocol‐specified final analysis for the global KEYNOTE‐355 population reported previouslyPatient disposition in the Japan subset. Median duration of treatment (for any component of study medication) in the pembrolizumab plus chemotherapy group and placebo plus chemotherapy group was 7.4 months (range, 0.3–44.3 months) and 7.1 months (range, 1.2 to 25.8 months), respectively. A summary of on‐study treatment exposure is provided in Table | PMC10225213 |
Efficacy | Tumors, death, tumors, PD‐L1 | EVENT, DISEASE, TUMORS, CPS, TUMORS | Among the 87 patients in the Japan subset, 69 (79%) had died at the time of data cutoff. In the 28 patients with PD‐L1 CPS ≥10 tumors, the median OS was 25.9 months (95% CI, 17.1 months–not reached) in the pembrolizumab plus chemotherapy group and 18.2 months (95% CI, 3.0–26.5 months) in the placebo plus chemotherapy group (HR, 0.36 [95% CI, 0.14–0.89]). The 18‐month OS rates were 74% and 56%, respectively (Figure Overall survival in (A) patients with PD‐L1 CPS ≥10 tumors, (B) patients with PD‐L1 CPS ≥1 tumors, and (C) the intention‐to‐treat population. CPS, combined positive score; HR, hazard ratio; NR, not reached; PD‐L1, programmed cell death ligand 1.Among all 87 patients in the Japan subset, 70 (80%) had experienced a PFS event at the time of data cutoff. Among patients with PD‐L1 CPS ≥10 tumors, the median PFS was 11.7 months (95% CI, 3.7–27.8 months) in the pembrolizumab plus chemotherapy group and 5.6 months (95% CI, 2.0–9.7 months) in the placebo plus chemotherapy group (HR, 0.52 [95% CI, 0.20–1.34]). The 12‐month PFS rates were 44% and 13%, respectively (Figure Progression‐free survival per RECIST version 1.1 by blinded independent central review in (A) patients with PD‐L1 CPS ≥10 tumors, (B) patients with PD‐L1 CPS ≥1 tumors, and (C) the intention‐to‐treat population. CPS, combined positive score; HR, hazard ratio; PD‐L1, programmed cell death ligand 1.Among patients with PD‐L1 CPS ≥10 tumors, the ORR per RECIST version 1.1 by blinded independent central review was 42% (95% CI, 20–67) in the pembrolizumab plus chemotherapy group and 33% (95% CI, 7–70) in the placebo plus chemotherapy group. The median duration of response was 19.3 months (range, 6.0–40.3+ months) in the pembrolizumab plus chemotherapy group and 7.3 months (range, 3.4–15.4 months) in the placebo plus chemotherapy group. In patients with PD‐L1 CPS ≥1 tumors, the ORR was 43% (95% CI, 28–59) and 50% (95% CI, 28–72) and the median duration of response was 14.9 months (range, 3.5–42.8+ months) and 6.0 months (range, 2.3–28.5 months), respectively. In the intention‐to‐treat population, the ORR was 43% (95% CI, 30–56) in the pembrolizumab plus chemotherapy group and 46% (95% CI, 27–67) in the placebo plus chemotherapy group. The median duration of response was 12.6 months (range, 3.0+ to 42.8+ months) and 6.0 months (range, 2.3–28.5 months), respectively. The disease control rates were similar between the treatment groups across all 3 populations (Table Summary of confirmed ORR per RECIST Version 1.1 by blinded independent central review.
Abbreviations: CPS, combined positive score; ORR, overall response rate; PD‐L1, programmed cell death ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors.Not evaluable includes subjects with insufficient data for assessment of response per RECIST version 1.1.No assessment includes subjects without postbaseline assessment on the data cutoff date.From product‐limit (Kaplan–Meier) method for censored data.No progressive disease by the time of last disease assessment. | PMC10225213 |
Safety | hypothyroidism, nausea, decreased white blood cell count, anemia | HYPOTHYROIDISM, ADVERSE EVENT, ANEMIA, INFUSION REACTION | Treatment‐related AEs occurred in all 61 patients (100%) and 26 patients (100%) in the pembrolizumab plus chemotherapy and placebo plus chemotherapy groups, respectively. The most common treatment‐related AEs in both treatment groups were decreased white blood cell count (pembrolizumab plus chemotherapy, 75%; placebo plus chemotherapy, 85%), decreased neutrophil count (72% and 81%), anemia (66% and 62%), and nausea (52% and 62%). Grade 3 or 4 treatment‐related AEs occurred in 52 patients (85%) in the pembrolizumab plus chemotherapy group and 22 (85%) in the placebo plus chemotherapy group. The most frequently occurring grade 3 or 4 treatment‐related AEs in the pembrolizumab plus chemotherapy group versus placebo plus chemotherapy group were decreased neutrophil count (59% vs. 62%), decreased white blood cell count (49% vs. 58%), and anemia (26% vs. 23%). Nineteen patients (31%) in the pembrolizumab plus chemotherapy group and four patients (15%) in the placebo plus chemotherapy group discontinued any treatment due to a treatment‐related AE. No patients in either group died due to a treatment‐related AE.Immune‐mediated AEs and infusion reactions of any grade occurred in 20 patients (33%) in the pembrolizumab plus chemotherapy group and four patients (15%) in the placebo plus chemotherapy group. The most frequently occurring immune‐mediated AEs (incidence ≥5%) in the pembrolizumab plus chemotherapy group were hypothyroidism (Summary of AEs in all treated patients.
Abbreviation: AE, adverse event.There were no grade 5 treatment‐related AEs, immune‐mediated AEs, or infusion reactions in either treatment group. | PMC10225213 |
DISCUSSION | toxicity, TNBC | CPS, DISEASE | In this subset analysis of patients in the phase 3 KEYNOTE‐355 study enrolled in Japan, pembrolizumab plus chemotherapy improved outcomes versus placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC. Baseline characteristics were generally consistent among Japanese patients and those enrolled in the global population.The magnitude of treatment benefit with pembrolizumab plus chemotherapy versus placebo plus chemotherapy appeared greater in Japanese patients than in the global study across each of the PD‐L1 CPS populations (i.e., PD‐L1 CPS ≥10, PD‐L1 CPS ≥1, and the intention‐to‐treat population).The ORRs and disease control rates were generally similar between the treatment groups in the Japan subset and the global study in each of the PD‐L1 CPS populations.The toxicity profile was generally consistent with the profile reported for the global study.In a subgroup analysis of Japanese patients (A limitation of this study is that the Japanese subset comprises a portion of patients enrolled globally in KEYNOTE‐355 (87 of 847 patients) and no alpha was allocated to this analysis. Secondly, given the small number of patients in this analysis, we were not able to perform any meaningful subset analyses, including assessments of clinical benefit with different routinely used chemotherapy regimens, assessment of the influence of differences in clinical characteristics on outcomes, or differences in treatment patterns. In the current study, the allocation of patients to nab‐paclitaxel, paclitaxel, or gemcitabine–carboplatin was by investigator's choice. At the time of writing, there is no unequivocal evidence for whether either of these chemotherapy regimens provides more clinical benefit than the other in this setting.In Japanese patients enrolled in KEYNOTE‐355, pembrolizumab plus chemotherapy tended to show improvements in OS and PFS with manageable toxicity versus placebo plus chemotherapy, consistent with the global population. These findings provide support for the use of pembrolizumab plus chemotherapy in Japanese patients with previously untreated locally recurrent inoperable or metastatic TNBC. | PMC10225213 |
AUTHOR CONTRIBUTIONS | PMC10225213 | |||
FUNDING INFORMATION | Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. | PMC10225213 | ||
CONFLICT OF INTEREST STATEMENT | Breast Cancer | ONCOLOGY, BREAST CANCER | Masaya Hattori has received honoraria from Eli Lilly and Daiichi Sankyo. Norikazu Masuda has provided leadership to Japan Breast Cancer Research Group Association (JBCRG); has received honoraria from AstraZeneca, Chugai Pharma, Eisai, Lilly Japan, and Pfizer; and has received research funding (all to institution) from AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Eli‐Lilly, Kyowa‐Kirin, MSD, Novartis, Pfizer, and Sanofi. Toshimi Takano has received honoraria from Daiichi‐Sankyo, Chugai, Eisai, Eli Lilly, and Celltrion and has received research funding (all to institution) from MSD, Daiichi‐Sankyo, Chugai, Eisai, and Ono. Koichiro Tsugawa has received manuscript fees from Pfizer and Eli Lilly; has received research funding from Konica Minolta, Inc; and has received scholarship endowments/research grants from Taiho Pharmaceutical Co., ltd and Chugai Pharmaceutical Co., ltd. Kenichi Inoue has received research funding (all to institution) from Astellas, AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eli‐Lilly, MSD, Novartis, Ono, Pfizer, Sanofi, Takeda, and Taiho. Koji Matsumoto has received honoraria from Kyowa‐Kirin and Chugai and has received research funding from MSD, Eli Lilly, Daiichi‐Sankyo, Chugai, Eisai, and ICON‐Japan. Takashi Ishikawa has received honoraria from Daiichi Sankyo, Kyowa Kirin, Pfizer, and Chugai. Mitsuya Itoh has no conflicts of interest. Hiroyuki Yasojima has no conflicts of interest. Yuko Tanabe has received research funding from MSD. Keiko Yamamoto is an employee of MSD K.K., Tokyo, Japan. Masato Suzuki is an employee of MSD K.K., Tokyo, Japan. Wilbur Pan is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder in Merck & Co., Inc., Rahway, NJ, USA. Javier Cortes has been a consultant/advisor for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, and Reveal Genomics; has received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi Sankyo; has received research funding (all to institution) from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman‐La Roche, Guardant health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; has stock in MedSIR, Nektar Pharmaceuticals, and Leuko (relative); and has received travel/accommodation expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, and Gilead. In addition, Javier Cortes holds the following patents: (1) Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A and (2) Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/ 0338368 A1. Hiroji Iwata has no conflicts of interest. The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors had access to the data from the study and had final responsibility for the decision to submit for publication. | PMC10225213 |
ETHICS STATEMENT | The trial protocol was approved by an institutional review board or independent ethics committee at each site, and the trial was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. | PMC10225213 | ||
PATIENT CONSENT STATEMENT | Written informed consent was obtained from all patients. | PMC10225213 | ||
PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES | Not applicable. | PMC10225213 | ||
Supporting information |
Table S1.
Click here for additional data file. | PMC10225213 | ||
ACKNOWLEDGMENTS | Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD). We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel. Medical writing assistance was provided by Christabel Wilson, MSc, of ICON plc (Blue Bell, PA, USA). This assistance was funded by MSD. | PMC10225213 | ||
DATA AVAILABILITY STATEMENT | Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: | PMC10225213 | ||
REFERENCES | PMC10225213 | |||
Purpose | PCOS | Does follicular homocysteine predict the reproductive potential of oocytes following FSH stimulation in PCOS women? Can it be modulated by dietary interventions? | PMC10371946 | |
Methods | PCOS | This was a prospective, randomized, interventional clinical study. Forty-eight PCOS women undergoing in vitro fertilization at a private fertility clinic were randomized for a dietary supplementation providing micronutrients involved in homocysteine clearance or no treatment. The supplement was assumed 2 months before stimulation until pick-up day. Monofollicular fluids were collected and frozen. After embryo transfer, the fluids from the follicles generating the transferred embryos were thawed and analyzed. | PMC10371946 | |
Results | Follicular homocysteine showed a negative correlation with clinical pregnancy both in the whole population ( | PMC10371946 |
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