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Secondary | infection, febrile illness | INFECTION, FEBRILE ILLNESS |
To estimate the relative and absolute rate reduction (derived from the same model) of symptomatic culture-confirmed S. Typhi infection among participants in vaccine clusters compared to participants in non-vaccine clusters (overall effect)To estimate the relative and absolute rate reduction of symptomatic culture-confirmed To estimate the relative and absolute rate reduction of febrile illness resulting in healthcare visits in vaccinated participants in vaccine clusters compared to unvaccinated participants in non-vaccine clustersTo describe safety outcomes associated with TyphiBEV® vaccination within the study population | PMC10399005 |
Exploratory | infection | INFECTION |
To estimate the relative and absolute rate reduction of symptomatic culture-confirmed S. Typhi infection in TyphiBEV® unvaccinated participants in vaccine clusters compared to unvaccinated participants in non-vaccine clusters (indirect effect)To estimate the relative and absolute rate reduction of the incidence of hospitalised culture-confirmed S. Typhi infection in TyphiBEV®-vaccinated participants in vaccine clusters compared to unvaccinated participants in non-vaccine clusters | PMC10399005 |
Design | Our study is an observer-blinded, cluster-randomised trial set up among the population of 30 wards in Vellore that are part of the Vellore Health and Demographic Surveillance System (VDSS). Data from the VDSS will be updated with a door-to-door survey and individual residents between the ages of 1 and 30 years will be recruited into the study after informed consent. The wards will be divided into 60 geographically contiguous areas (Fig. Ward map of Vellore city highlighting the trial clusters within the 4 randomisation strataFlow diagram of the study processes | PMC10399005 | ||
Comparator | Hepatitis A | HEPATITIS A, JAPANESE B ENCEPHALITIS | No control vaccine will be used. All those in the no-intervention arm will receive the vaccine after the study ends. Potential comparator vaccines, i.e. Hepatitis A and Japanese B Encephalitis, were considered to have non-compelling risk-to-benefit ratios by the Christian Medical College (CMC) Vellore’s Institutional Review Board (IRB), since Hepatitis A seroprevalence is high among children in India [ | PMC10399005 |
Methods and analysis | PMC10399005 | |||
Healthcare provider network | fever illness, fever, febrile | We invited the most utilised healthcare providers in the study area (determined by previous surveys) to participate in the fever surveillance based on their ability to follow a standard fever illness management protocol, i.e. to conduct a blood culture prior to the start of antimicrobial treatment in febrile patients. The locations of healthcare providers that have agreed to participate are highlighted in Fig. | PMC10399005 | |
Eligibility and recruitment | typhoid | RECRUITMENT, TYPHOID | Field Research Assistants (FRAs) will survey all households in the study area to identify individuals listed in the VDSS and those that may have migrated in or out. They will then approach individuals between the ages of 1 and 30 years for informed consent, and those who consent and do not plan to leave the study area within the next 2 years will be recruited. We will exclude those who have medical conditions that would prevent them from complying with our study’s requirements, which include follow-ups and investigations during illness. A monthly follow-up will be conducted for all participants to check for any changes in residence. A ‘mop-up’ recruitment drive 6 months after the initial process will recruit new migrants into the area and those that are newly age eligible.FRAs will also collect baseline data from participants after enrolment, which includes socio-demographic details, typhoid vaccination history, healthcare facility preferences, etc. | PMC10399005 |
Fever surveillance | febrile, illness, fever | EVENTS, ENTERIC FEVER | To capture febrile events, all participants will be asked to call a 24/7 helpline number before they visit a healthcare facility for an illness. In case the illness is febrile, our helpline operators will raise a unique digital token that the fever surveillance team will use (via an online dashboard) to track the patient. If the patient visits a facility partnered with this study, the team will contact the patient and study personnel at the facility to ensure that appropriate investigations are conducted, including automated blood cultures (CMC Vellore’s Microbiology laboratory will conduct this if the facility is unable to do so), and collect details and the outcomes of illness. We will also cover the patient’s cost of care and transportation to and from the healthcare facility. In case the patient visits a non-partnered hospital, the team will contact the patient directly to collect details of their illness and outcomes. This approach is likely to encourage reporting of febrile episodes by the participants as previous surveys have found that most febrile illnesses are treated at private facilities and paid for out of pocket.Additionally, surveillance teams will be stationed at the major hospitals listed previously, to check for febrile in-patient (IP) cases at IP wards and emergency departments that may not have contacted the helpline or been missed by them. Further, their microbiology laboratory registers will be monitored for any enteric fever cases. At the end of each month, all participants will be contacted by the surveillance team to collect details about any illness episodes and remind them to contact the helpline prior to a healthcare facility visit.This surveillance will end 25 months after vaccination and mark the trial’s end. | PMC10399005 |
Laboratory methods | acute febrile illness | ENTERIC FEVER | All healthcare facilities partnered with the study will be encouraged to conduct a blood culture in case a patient has an acute febrile illness that lasts more than 2 days, has a temperature of ≥ 38 °C documented at the facility, or if the physician intends to begin antimicrobial therapy. The physician may defer the blood culture in case no antimicrobials are being initiated, if there is a confirmed alternate aetiology that excludes enteric fever, or if the patient has a documented negative blood culture report within the past 7 days.All blood cultures will be collected under aseptic conditions and as per study SOPs. The blood volumes to be collected and inoculated into blood culture bottles (BacT/Alert) will be 5 mL for children between 1 and 15 years of age, and 8–10 mL for those ≥ 15 years. In case the study physician requires additional blood for investigations, it will be drawn during the same phlebotomy procedure. The weights of culture bottles before and after sample collection will be documented, along with the dates/times of loading into the BacT/Alert machine and of positivity. Any blood or bone-marrow cultures that are positive for Any additional serum samples collected from participants will also be stored at − 80 °C and tested for IgA HLyE antibodies, and other assays as indicated during their routine diagnosis. | PMC10399005 |
Vaccination | allergic, ®, fever, febrile illness, typhoid | ADVERSE EVENTS, RECRUITMENT, FEBRILE ILLNESS, TYPHOID | Once the fever surveillance is operational, eligible participants from selected vaccine clusters will be invited to designated vaccination clinics over a period of 2 months and have a unique vaccination code sent to their phones. This process will be repeated after the mop-up recruitment drive. In case of vaccination with any other vaccine within 30 days of the TyphiBEV® vaccination date, or a febrile illness in the week prior, the date will be rescheduled. Participants will be excluded if they decline consent, have received a typhoid vaccine in the past 3 years, are allergic to any component of TyphiBEV®, are nursing mothers, are pregnant, or are planning pregnancy around the vaccination date. If a participant is absent on their scheduled vaccination date, or subsequent rescheduled date, and does not respond to two reminders sent 7 days apart, they will be considered as having refused the vaccine. Participants that are ineligible or refuse the vaccine will continue to be part of the fever surveillance.At the clinic, a trained vaccinator will check each participant’s unique code and government-issued identity card against the study database to verify their assignment to the intervention arm, and then dispense a single 0.5-mL, intramuscular dose of TyphiBEV® to eligible participants. Vaccinators, a doctor, and a nurse will make up the vaccination team at each clinic, which will also observe the patient for 30 min after vaccination in case of any immediate adverse events. The first 3600 vaccinated participants will be asked to maintain an adverse events diary for 7 days. Participants will also be contacted every month to check for any illnesses in that period.Serious adverse events (SAEs) will be monitored by a study investigator who will inform the study’s Principal Investigator (PI) of them. Any that are unexpected and related to the vaccination in the PI’s opinion will be reported to the CMC IRB within 24 h of the PI being aware of them, using the SAE reporting form. Trial-related adverse events will be treated as per CMC Vellore’s institutional guidelines. | PMC10399005 |
Blinding | fever | The study participants will not be blinded to their vaccination statuses as there is no control vaccine. Only the teams conducting fever surveillance and monthly contacts will be blinded to this and be trained to not seek out vaccination details. The coding for the primary analysis will be first conducted in a dataset with ‘dummy’ cluster and trial arm identifiers, and only then applied to the full dataset. This will be replicated by an independent analyst, who has not viewed the original results. | PMC10399005 | |
Sample size calculation | infectious disease, typhoid fever, typhoid | INFECTIOUS DISEASE, CNS INFECTIONS, TYPHOID FEVER, TYPHOID | The sample size was calculated using a simulation approach as outcome is an infectious disease that affects the probability of further infections in that cluster. The required number of participants was sampled from the VDSS 2021 dataset so that the simulation used the empirical distributions of age and household size in the study area (to explore potential sample sizes larger than the VDSS dataset, we replicated it before sampling). The ‘households’ were subsequently set within clusters of the required size, these clusters were randomised, and the discrete-time (one-month blocks) simulation began. We made conservative assumptions about the population proportion under 30 (47% assumed), typhoid incidence rate in the control arm (190 per 100,000 per year across all age groups combined), vaccine uptake (as low as 75%), and 70% reduction in risk due to vaccination. Further details of the simulations are provided in Additional file The simulation model reflected several important features of the trial but considered cluster membership to be constant throughout the 2 years of the trial and so did not represent the anticipated in- and out-migration.Through this trial, we will test the null hypothesis of no vaccine effect on the incidence rate of blood culture-confirmed typhoid fever among participants. The sample size required to achieve this was determined to be 60 clusters of approximately 2800 individuals each. This will provide our trial with > 90% power for both total and overall vaccine effects. It will also provide some power to demonstrate the vaccine’s effectiveness above specific margins. | PMC10399005 |
Randomisation | Randomisation will be stratified according to four broad areas in the city with different anticipated incidences of | PMC10399005 | ||
Outcomes | Febrile illness | ADVERSE EVENTS, INDURATION, SECONDARY, TYPHOID FEVER, FEBRILE ILLNESS | The primary outcome is blood culture-confirmed typhoid fever.The secondary effectiveness outcomes are:• Febrile illness episodes lasting at least 3 days where healthcare is sought• Hospitalised culture-confirmed The safety outcomes, defined only in vaccine recipients, are:o Local induration at site of vaccinationo Reported fevero Headacheo Fatigue/tirednesso Anorexiao Abdominal paino Serious adverse eventso Solicited and unsolicited adverse eventsThe key process outcome is the proportion of participants age 1–29 in intervention clusters that are vaccinated, and will be reported in a CONSORT flow chart. | PMC10399005 |
Estimands | To provide full clarity for our first two objectives, the corresponding estimands are described in Table Structured statement of estimands | PMC10399005 | ||
Statistical analysis | febrile illness | EVENT, RECRUITMENT, FEBRILE ILLNESS, REGRESSION, EVENTS, TYPHOID FEVER | Our primary summary measure of the effect is a rate ratio (RR), from which vaccine effectiveness can be expressed as (1 − RR) × 100%. This will be estimated using an individual-level analysis using Poisson regression that will account for time at risk with censoring at the last known follow-up time. This is expected to be less than 2 years when participants migrate out of the study area. We will present an adjusted RR from a regression model including, covariates, the randomisation strata, participant age, gender, and household size. We will also compute unadjusted RRs but the adjusted RR will be considered ‘primary’. A difference in rates will also be computed after fitting the regression model, by standardization [For measures of vaccine effectiveness which are described here as contrasts between vaccinated participants in vaccine clusters and unvaccinated participants in non-vaccine clusters, such as the total effect, we will use instrumental variable methods. Under this approach, while data from all participants are included in the analysis, we estimate the effect of vaccine only in those who would take it if available in their cluster (i.e. would ‘comply’). Although we do not observe this compliance in the non-vaccine arm, by randomisation we would expect the same proportion as in the vaccine arm, and this underlies the approach. The details of exactly how this will be done will be specified in subsequent versions of the statistical analysis plan.The time at risk for the overall effect will begin 28 days after vaccination is completed in all intervention clusters. For participants that move into a trial cluster from outside the trial area, time at risk for the overall effect will begin at recruitment. For the total effect, time at risk for non-vaccine clusters begins as for the overall effect. In vaccine clusters, this will begin 28 days after vaccination is completed across clusters or 28 days after an individual is vaccinated (whichever is later) and no risk-time is contributed by those unvaccinated. Time at risk ends at the study’s close, the time of an event (culture-confirmed typhoid fever), withdrawal from the study, or migration from the study area or within the area but between trial arms (whichever is earliest).The primary outcome might have missing data if a trial participant with a febrile illness visits a study-associated healthcare facility but refuses a blood culture. We will describe the frequency of such refusals by trial arm. We will multiply impute the blood culture results for these participants under the missing at random assumption and conduct sensitivity analyses to explore the impact on the total and overall vaccine effect estimates of making alternative assumptions.We do not have any plans for interim analyses of vaccine effectiveness, or subgroup analyses except that we will estimate the total effect in participants aged 1–14 years. We will conduct simple descriptive analyses of safety events in vaccinated participants, and of vaccine uptake in eligible vaccine arm participants.A first draft of a detailed statistical analysis plan has been created and will be finalised before analysis. | PMC10399005 |
Data management, confidentiality, and quality assurance (QA) | CRF | RECRUITMENT, CRF | Operational management of the trial will be aided by an externally validated, custom-built database management software. It will link with the VDSS and be used for recruitment, scheduling, and tracking of participant contacts and outcomes. Primary clinical data will be recorded on validated instances of Redcap (Research Electronic Data Capture) [We will consider any document where demographic, clinical, or laboratory data is first recorded prior to entry into our digital Case Record Forms (CRFs) as source data. This includes hospital records, clinical charts, office charts, pharmacy, and laboratory records. If hospital data is unavailable in electronic format, the study team will maintain scanned copies until the CRFs are verified. If a CRF is the first place where data is entered, it will be considered source data. Hardcopy study documents will be stored securely in a confidential location. To maintain the anonymity of participants, they will only be referred to by their participant ID on study documents, except in informed consent sheets. All data collected during the trial will be stored at the site for at least 3 years after its completion. The PI will have complete access to the final dataset.A dedicated QA team will regularly validate a proportion of the data entered into CRFs and ensure that all trial processes follow the protocol and Good Clinical Practices. The microbiology labs that process blood samples will participate in an external QA programme. The study processes will be reviewed by an external monitoring team at the end of one year. | PMC10399005 |
Trial oversight | EVENTS, EVENT, RECRUITMENT | A Trial Steering Group (TSG), comprised of the lead investigators, the data manager, internal quality manager, and the trial statisticians, will meet at least once a month to discuss trial operations. Interim reports will be prepared for the independent Data Safety and Monitoring Board (DSMB), comprised of an epidemiologist, statistician, paediatrician, physician, and a clinical pharmacologist, to address the recruitment of participants, vaccine uptake, and event rates in both arms of the trial. The DSMB will review these data to decide whether any additional sample size calculations are required, and whether to recommend an extension of the trial to allow more outcome events to accumulate. The board will advise the TSG on changes that may be required in the trial’s operations to achieve its objectives.A Scientific Advisory Group, comprised of the lead investigators, independent experts in clinical trials and community interventions, representatives from the Directorate of Public Health, and policy experts, will also review the processes and progress of the trial once every 6 months and provide feedback. | PMC10399005 | |
Discussion | ®, typhoid | TYPHOID | TCVs are highly efficacious interventions against typhoid that are cost-effective and can be used to protect children from the age of 6 months [Efficacy studies of TCVs in various settings, regions, and age groups are necessary to help with their effective programmatic use. Our trial’s results will also inform the Indian Government on the effectiveness of TyphiBEV® among children and young adults in urban settings, which they may use for a country-wide rollout of TCVs. | PMC10399005 |
Trial status | TYPHOID | This manuscript is based on protocol version 1.1, dated 26/04/2023 and titled ‘Vellore Typhoid Vaccine Impact Trial’. A timeline of the study can be found in Fig. Timeline of study procedures (SPIRIT figure) | PMC10399005 | |
Acknowledgements | We would like to acknowledge the support provided by Peter Smith from the London School of Hygiene and Tropical Medicine, Nicholas Grassly from the Imperial College London, Jason Andrews from Stanford University, Andrew Pollard and Xinxue Liu from the University of Oxford, Supriya Kumar and Thea Norman from the Bill and Melinda Gates Foundation, and Jayaprakash Muliyil from the Christian Medical College Vellore, with the design of this project. | PMC10399005 | ||
Publication policy | A manuscript detailing the results of this study will form the primary publication and be published in a peer-reviewed journal. Authorship will be determined as per ICMJE guidelines and all other contributors will be acknowledged. The authors will also acknowledge that this trial was funded by the Bill and Melinda Gates Foundation, with vaccines donated by BiologicalE. The Directorate of Public Health, Government of Tamil Nadu, will review all publications prior to their submission. | PMC10399005 | ||
Authors’ contributions | JJ, DKA | The study was conceptualised by JJ and GK. JJ, AC, TM, VA, WR, VB, PS, VRM, JAS, PK, DKA, and NS formulated the study design. TM, PS, AC, and JJ developed the analysis plan. The protocol was drafted by NS and DKA, with subsequent edits by JJ, TM, and AC. All authors have approved the submitted protocol manuscript. All authors have agreed both to be personally responsible for their contributions to the protocol and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. | PMC10399005 | |
Funding | typhoid | TYPHOID | This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation (grant number INV-036437). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. BiologicalE will donate typhoid conjugate vaccine TyphiBEV®. TM is funded by the UK Medical Research Council (grant numbers MC_UU_00004/07 and MC_UU_00004/09). AC is funded by the UK Medical Research Council (grant number MC_UU_00004/09). The funders and vaccine donors played no role in the design of this study, nor will they play any role in the collection, analysis, or interpretation of data. | PMC10399005 |
Availability of data and materials | De-identified, participant-level data will be made available via a public archive within 3 months of the primary publication, along with the statistical analysis plan and analysis code. Genome sequences obtained will be uploaded to a sequence library. Supplementary analyses may be conducted on this data with attribution to the source. The template consent and participant information sheets and data collection forms can be obtained from the corresponding author on request. | PMC10399005 | ||
Declarations | PMC10399005 | |||
Ethics approval and consent to participate | The study proposal was reviewed and approved by India’s Health Ministry Screening Committee (proposal ID 2022–16229, dated 16 March 2022). The protocol was approved by the IRB of CMC Vellore (IRB minutes number 14247, dated 29/09/2021). Any changes or amendments made to the protocol will be submitted to the IRB for approval.Written informed consent will be taken from all adult participants and from the parents of child participants with assent being sought wherever applicable. This will include consent for study staff to review participants’ medical and diagnostic records and store any additional serum samples for future research. | PMC10399005 | ||
Consent for publication | Not applicable—no identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. | PMC10399005 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10399005 | ||
References | PMC10399005 | |||
Objective: | To establish whether the use of a WaterPik | PMC10693741 | ||
Design: | A single-centre, two-arm, parallel-group, single-blind, randomised controlled clinical trial with a 1:1 allocation ratio. | PMC10693741 | ||
Setting: | Orthodontic department at York Hospital, York Teaching Hospitals NHS Foundation Trust, UK. | PMC10693741 | ||
Participants: | A total of 40 fit and well participants, aged 10–20 years, being treated with upper and lower fixed orthodontic appliances. | PMC10693741 | ||
Methods: | Participants were randomly allocated, using stratified block randomisation, to the control group (MTB) or intervention group ‘(Waterpik | PMC10693741 | ||
Results: | PLAQUE | An interim analysis of results was performed with 40 patients recruited and 85% of data collected. The overall mean differences between the groups were as follows: plaque index = 0.199 ( | PMC10693741 | |
Conclusions: | In terms of oral hygiene, our study did not find evidence to support the claim of benefit of using a Waterpik | PMC10693741 | ||
Introduction | orthodontic | PLAQUE, DECALCIFICATION, PLAQUE | It is widely accepted that it is more difficult to maintain good oral hygiene when wearing orthodontic appliances (As well as the effect on the periodontium, stagnating plaque around orthodontic appliances predisposes to decalcification. This can leave permanent, unsightly white or brown marks on the teeth that can progress to cavitation. The incidence of decalcification varies depending on the diagnostic techniques and criteria used, and a meta-analysis reported an incidence of 68.4% (Plaque removal using a toothbrush is widely recommended for oral hygiene when wearing fixed orthodontic appliances (The WaterPik | PMC10693741 |
Specific objectives and null hypotheses | The aim of the present study was to establish whether the use of a WaterPikNull hypotheses: the use of a WaterPik | PMC10693741 | ||
Methods | PMC10693741 | |||
Trial design and any changes after trial commencement | bleeding, coin toss | BLEEDING, RECRUITMENT | This study was a single-centre, single-operator, two-arm, parallel-group, stratified, single-blind RCT trial with a 1:1 allocation ratio, conducted in the Department of Orthodontics at York Hospital, UK.Changes after the commencement of the trial were as follows:Due to the COVID-19 pandemic, there was a reduced pool of potential participants. For the first 33 participants, stratified block randomisation was carried out based on age, gender and baseline interdental bleeding index. It is standard practice using stratified block randomisation that once enough participants in an individual block have been recruited, recruitment to this block would cease. However, the decision was made to continue recruiting patients who met the inclusion criteria, even if their block was full, and randomise them by a single coin toss, to ensure that the sample size was achieved (see ‘Sample size calculation’ below).An interim analysis of results was carried out due to issues with recruitment during the COVID-19 pandemic, and the ethical challenges associated with carrying out research in the already overstretched NHS. Following the analysis, the decision was made to stop the trial as there had been fewer dropouts than expected and the sample size had been reached. The decision was discussed with the trial sponsor and ethics committee. Any data collected between the initial interim analysis and the decision being made to stop the trial were included in this final analysis. | PMC10693741 |
Participants, eligibility criteria and setting | Potential participants for the trial were consecutive patients treated by a single Specialty Registrar in Orthodontics at York Hospital, UK. Patients treated were non–fee-paying patients who were treated under the UK National Health Service (NHS). The eligibility criteria are shown in Eligibility criteria for participants. | PMC10693741 | ||
Interventions | The interventions provided for each group are shown in The interventions provided to both groups.DN, dental nurse; OHE, oral health education. | PMC10693741 | ||
Outcomes | trauma | PLAQUE, PLAQUE | Participants were seen at baseline (T0), 8 weeks (T1), 32 weeks (T2) and 56 weeks (T3). At these time points, clinical indices to assess oral hygiene and gingival health were completed. The trial indices were performed by the same clinician.The primary outcome was plaque level, measured using the Orthodontic Modification of Plaque Index (OMPI) (Secondary outcome measures were gingival health, incidence of oral hygiene-related trauma, adherence with an oral hygiene regime and satisfaction with an oral hygiene regime. Gingival health was measured using the Gingival Index (GI) (The outcomes and the outcome measures used are shown in detail in The outcomes and the outcome measures used in the trial. | PMC10693741 |
Sample size calculation | To establish sample size, a power calculation was performed by the trial statistician (JK) based on the primary outcome OMPI. The significance level of the study was set at 5% (α = 0.05). The clinically significant effect size was set as 0.5 based on previous studies (The Power Analysis and Sample Size software (PASS, | PMC10693741 | ||
Randomisation: Sequence generation, allocation concealment and implementation | PMC10693741 | |||
Sequence generation | orthodontic | Participants were allocated using stratified block randomisation. The participants were stratified based on three prognostic characteristics: gender, age and IBI at baseline. It has been shown that female orthodontic patients report cleaning their teeth more often than male patients (Using three prognostic characteristics resulted in eight blocks into which patients could be placed. These eight blocks are shown in For each block, six sealed opaque envelopes were produced by the author DT. Inside each envelope was a paper slip which read either ‘Intervention’ or ‘Control’. There were three intervention and three control envelopes produced for each block. A folder was produced for each block and labelled with the block number and description. The six envelopes were placed inside each of the eight block folders. These were kept separately and thus concealed the allocation sequence from DT. | PMC10693741 | |
Concealment | For allocation of the participants, sealed envelopes containing either intervention or control were used. | PMC10693741 | ||
Implementation | Patients were enrolled into the trial at the start of their visit by DT. At the end of the appointment to place the fixed appliances, DT then allocated the participant into one of the eight blocks and informed the dental nurse of which block they were in. DT then left the clinic and the dental nurse took out the relevant block folder. The patient was then asked to choose an envelope from the folder, and this was opened by the nurse, allocating them into intervention or control. | PMC10693741 | ||
Blinding | BLIND | This was a single blind trial. The operator carrying out the indices (DT) was blinded to the patient allocation. The participants could not be blinded to their allocation. The participants were told that they must not tell DT whether they had a WaterPik | PMC10693741 | |
Statistical analysis | gingiva, trauma, bleed | SECONDARY, BLEED | Statistical analysis was performed using IBM SPSS version 27 software (IBM Corp., Armonk, NY, USA). Summary descriptive statistics were produced to report demographic features and for each oral health variable.A generalised linear mixed model was used to assess whether there was a difference between the intervention and control groups in terms of all outcomes (OMPI, GI and IBI), over time. A generalised linear mixed model is the ideal statistical model as it allows comparison of groups over time with non-normally distributed data and missing data (An intraclass correlation coefficient (ICC) was generated, using a ‘two-way mixed’ model to assess intra-rater reliability in the measurement of the OMPI. The comparison was made between the clinical score and a repeated measurement calculated from the clinical photographs at a separate time. Reliability testing was not carried out on the GI or IBI because reliability studies for invasive gingival indices have shown that there is a trend for scores to worsen, possibly because the first examination increases the tendency for the gingiva to bleed the second time around (The incidence of trauma secondary to oral hygiene practice, adherence with an oral hygiene regime and satisfaction with an oral hygiene regime were analysed by a comparison of frequency between the two groups. | PMC10693741 |
Ethical considerations | Ethical approval was sought for the trial through the Integrated Research Application System (IRAS). This was approved by the Health Research Authority and Health and Care Research Wales (HRA & HCRW) on 23 August 2019. The IRAS project ID was 266235. The trial was registered with York Teaching Hospital NHS Foundation Trust who acted as the sponsor. The trial was registered with ClinicalTrials.gov Protocol Registration and Results system. The Protocol ID is NCT04604262. | PMC10693741 | ||
Results | PMC10693741 | |||
Participant flow | RECRUITMENT | A flow chart of participants through the trial is shown in CONSORT participant flow chart.Adapted from A single patient in the intervention group withdrew from the study after the 32-week indices, as he wished to start using an electric toothbrush.Recruitment for the trial began on 15 November 2019. The first patient to be recruited started the trial on 6 January 2020. The trial was stopped early after the interim analysis of results on 2 November 2021. At the point of stopping the trial, 85% of data had been collected. A total of 40 participants had been recruited; all 40 participants had indices at 8 weeks (n = 20 intervention, n = 20 control); 32 participants had indices at 32 weeks (n = 17 intervention, n = 15 control); and 19 participants had indices at 56 weeks (n = 9 intervention, n = 10 control).Fewer dropouts occurred than expected. At the interim analysis of results, the power calculation had been met for both groups at 56 weeks. Due to the constraints caused by the COVID-19 pandemic and extra pressure on the NHS, it was unethical to continue with the trial. | PMC10693741 | |
Baseline data | Baseline data are shown in Baseline data.The groups were similar at baseline in terms of age. There were more female patients in the control group. The PI and GI were very similar at baseline between the two groups. The mean IBI was slightly higher in the control group. | PMC10693741 | ||
Numbers analysed for each outcome | Bleeding, trauma | BLEEDING, PLAQUE | The analysis was performed on an intention-to-treat basis. This means that all patients who were randomised to receive an intervention were included in the analysis, regardless of whether they completed the trial (The results for PI, GI and IBI are shown in Difference of each outcome between control and treatment group using generalised linear mixed model.CI, confidence interval; GI, Gingival Index; IBI, Interdental Bleeding Index; OMPI, Orthodontic Modification of Plaque Index.The mean OMPI at each interval with 95% confidence interval (CI) error bars is shown in Mean OMPI at each time interval with 95% CI error bars. Baseline OMPI is not shown, as baseline indices were recorded before fitting appliances. The OMPI requires appliances to be in situ to be recorded.CI, confidence interval; OMPI, Orthodontic Modification of Plaque Index.The mean GI at each interval with 95% CI error bars is shown in Mean GI at each time interval with 95% CI error bars.CI, confidence interval; GI, Gingival Index.The mean IBI at each interval with 95% error bars is shown in Mean IBI at each time interval with 95% CI error bars.The ICC for OMPI was 0.911 (95% CI 0.700–0.977), demonstrating good evidence for the repeatability of measurements of OMPI.No participant had trauma detected at any visit in either group. | PMC10693741 |
Adherence with oral hygiene regime | In terms of adherence with an oral hygiene regime, <25% of the oral hygiene diaries were returned, so it was not appropriate to analyse the data and draw any conclusions on adherence with prescribed oral hygiene regime. As a research group, it was thought that the data from those participants who did return the diaries would be biased to such an extent, that to present the data would be misleading. | PMC10693741 | ||
Satisfaction with oral hygiene regime | Questionnaire responses regarding satisfaction with an oral hygiene regime are shown in | PMC10693741 | ||
Harms | No harms were reported or detected for any participant. | PMC10693741 | ||
Discussion | PMC10693741 | |||
Interpretation | orthodontic | PLAQUE | Based on the results of this trial, there is no benefit, in terms of plaque control or gingival health, in using a WaterPikThere is only one other published trial assessing orthodontic patients with a WaterPikPatients were recruited for the trial by | PMC10693741 |
Limitations | orthodontic | PLAQUE | There was a higher proportion of female participants in the control group (65%) compared to the intervention group (50%). As previously stated, female patients have been shown to have lower levels of plaque and have a greater level of knowledge of oral health (In terms of outcome measures, although the descriptors for scoring OMPI aim to be as objective as possible; it can be challenging to determine the subtle differences between whether a surface should be scored between a 1 and a 2 or a 2 and a 3. If a systematic error did indeed exist in the recording of the OMPI, this will likely have been applied to participants in both the intervention and control group. Therefore, it is unlikely to have affected the trial outcome.Another issue with the OMPI is whether it is a valid surrogate measure for plaque control. It could be argued that the OMPI in this trial only represents the quality of plaque control before an orthodontic examination. The Hawthorne effect has also been shown to reduce tooth surface area covered with plaque in orthodontic patients (Like GI, photographs to assess the intra-rater reliability of the IBI were not feasible. However, the intra-rater reliability of this index has been found to be in the range of 91.3%–93.1% ( | PMC10693741 |
Generalisability | The trial was carried out in a single NHS district general hospital and treatment was carried out by a single clinician. Patients in this setting do not pay for their treatment because it is funded by the NHS. It has been demonstrated that patients who self-fund orthodontic treatment have higher levels of compliance than those who receive state supported treatment ( | PMC10693741 | ||
Conclusions | In the population studied, there was no benefit in terms of oral hygiene in the use of a WaterPik | PMC10693741 | ||
Supplemental Material | PMC10693741 | |||
References | PMC10693741 | |||
Background | extensive-stage small-cell lung cancer | Anlotinib plus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC) achieves good efficacy, but there is still room for improvement. This clinical study examined the effectiveness of anlotinib plus etoposide for maintenance therapy in ES-SCLC. | PMC10663256 | |
Methods | Cancer | DISEASE PROGRESSION, ADVERSE EVENTS, DISEASE, REMISSION, CANCER | The current single-arm, prospective phase II study was performed at Jiangsu Cancer Hospital (March 2019 to March 2022). After successful primary etoposide-based therapy, anlotinib was administered at 12 mg/day on days 1 to 14 of 21-day cycles until disease progression or consent withdrawal. All patients also received etoposide at 50 mg/day on days 1 to 14 of 21-day cycles for a maximum of six cycles. Progression-free survival (PFS) constituted the primary study endpoint. Secondary endpoints were overall survival (OS), objective remission rate (ORR), disease control rate (DCR), and safety. In addition, adverse events (AEs) were assessed. | PMC10663256 |
Results | fatigue, proteinuria, hypertension, hemoptysis, all-grade, hand and foot syndrome | ORAL MUCOSITIS, DISEASE, GINGIVAL BLEEDING, LOSS OF APPETITE, HYPERTENSION | Twenty-eight patients were treated. Median PFS and OS were 8.02 (95%CI 5.36–10.67) and 11.04 (95%CI 10.37–11.68) months, respectively. Totally 9 and 18 participants showed a partial response and stable disease, respectively; ORR and DCR were 32.14% and 96.43%, respectively. The commonest all-grade AEs were fatigue (n = 11, 39.28%), hypertension (n = 11, 39.28%), loss of appetite (n = 9, 32.14%), oral mucositis (n = 7, 25.00%) and proteinuria (n = 6, 21.40%). Grade 3–4 AEs included fatigue (n = 4, 14.28%), hypertension (n = 2, 7.14%), hand and foot syndrome (n = 2, 7.14%), oral mucositis (n = 1, 3.57%), hemoptysis (n = 1, 3.57%), proteinuria (n = 1, 3.57%), gingival bleeding (n = 1, 3.57%), and serum creatinine elevation (n = 1, 3.57%). | PMC10663256 |
Conclusion | Maintenance anlotinib plus etoposide achieves promising PFS and OS in clinical ES-SCLC. | PMC10663256 | ||
Registration number | ChiCTR1800019421. | PMC10663256 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s10637-023-01398-9. | PMC10663256 | ||
Keywords | PMC10663256 | |||
Introduction | SCLC, Small-cell lung cancer | PEARLY DISEASE, METASTASES, SCLC | Small-cell lung cancer (SCLC) SCLC features fast doubling time, elevated growth fraction, and extensive metastases in early disease phases, generally showing widespread hematogenous metastases [The best SCLC management is based on surgery, chemotherapy, targeted therapy, and radiotherapy [The vascular endothelial growth factor (VEGF) receptor (VEGFR) shows high expression in SCLC [Therefore, the current work aimed to explore the effectiveness of anlotinib plus etoposide for maintenance therapy in clinical ES-SCLC. | PMC10663256 |
Materials and methods | PMC10663256 | |||
Study design | Cancer | ONCOLOGY, CANCER | The current single-arm, prospective phase II trial was performed at the Oncology Department of Jiangsu Cancer Hospital between March 2019 and March 2022. The study followed the Declaration of Helsinki (2000), and had approval from the Ethics Committee of Jiangsu Cancer Hospital. Each patient provided signed informed consent. The current trial was registered at the Chinese clinical trial registry ( | PMC10663256 |
Participants | SCLC, tumor, pleural effusion, allergic, ascites, allergy, respiratory syndrome | PLEURAL EFFUSION, TUMOR, ASCITES, SCLC, ALLERGY, ONCOLOGY | Inclusion criteria were: (1) 18 to 75 years old; (2) proven with ES-SCLC by histopathological examination; (3) treatment with standard first-line Etoposide-platinum solely chemotherapy, without progression; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; (5) one or more computed tomography (CT) measurable lesions; (6) expected survival of at least 3 months; (7) major organ function indicators meeting the following criteria 7 days before the start of treatment: (a) hemoglobin (Hb) ≥ 90 g/L, (b) absolute neutrophil count (ANC) ≥ 1.5 × 10Exclusion criteria were: (1) presence of tumor types other than SCLC and mixed-SCLC; (2) a history of severe allergy or allergic constitution; (3) pregnant or breastfeeding women; (4) participation in other clinical trials; (5) pleural effusion or ascites that induced respiratory syndrome (CTCAE grade | PMC10663256 |
Intervention | toxicity, PD, death, SD | DISEASE PROGRESSION, DISEASE, REMISSION, ADVERSE EFFECTS | All patients underwent baseline imaging assessment after enrollment. The participants started treatment within 3 weeks (21 calendar days) from screening. All participants were administered anlotinib plus etoposide. Specifically, all participants were treated with oral anlotinib 12 mg q.d. on days 1–14 of 21-day cycles. Three weeks (21 d) were considered as one cycle. Anlotinib was continually administered until disease progression, consent withdrawal, or intolerable toxicity. The participants were also treated with oral etoposide 50 mg on days 1 to 14 of 21-day cycles. Etoposide treatment lasted for six cycles maximum.During treatment, imaging examinations were performed every 2 cycles to assess clinical efficacy according to RECIST 1.1 criteria, including complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). Safety were evaluated every 3 weeks (21 ± 7 days) until disease progression, consent withdrawal, loss to follow-up, or intolerable toxicity. In case of disease progression, the participants were included in the survival follow-up phase, in which follow-up was performed every 56 ± 7 days until death, loss to follow-up, or consent withdrawal. Anti-tumor therapy after disease progression was decided by the investigators. Follow-up was recommended, and patient data were recorded.Medication was discontinued in case of disease progression. In case of grade 3 or 4 adverse effects, the oral dose of anlotinib was lowered to the next dose level. In patients using a starting dose of 12 mg/day, 10 mg/day and then 8 mg/day were subsequently used. If the initial dose was 10 mg/day, it was lowered to 8 mg/day. No dose lowering was allowed after 8 mg/d; in such cases requiring dose adjustment, treatment discontinuation was applied. When the initial dose was 8 mg/day, treatment discontinuation was directly applied if dose adjustment was necessary. | PMC10663256 |
Endpoints | PD, death | DISEASE PROGRESSION, ADVERSE EVENT, ADVERSE EVENTS, DISEASE, DISEASE | The primary endpoint was PFS, which was the time elapsed from the start of therapy to first disease progression as judged by the investigators or per imaging findings or death. Secondary endpoints encompassed OS, ORR, disease control rate (DCR), and safety. OS represented the time elapsed from the start of therapy to death. Objective Response Rate (ORR) was defined as (CR + PR) / (CR + PR + SD + PD) × 100%, and Disease Control Rate (DCR) was defined as (CR + PR + SD) / (CR + PR + SD + PD) × 100%. Treatment-emergent adverse events (TEAEs) were evaluated on the basis of the Common Terminology Criteria for Adverse Events (CTCAE) 4.0. | PMC10663256 |
Sample size | Previous data revealed a PFS of 2 months in ES-SCLC without maintenance therapy following standard first-line etoposide chemotherapy [ | PMC10663256 | ||
Statistical analysis | The intent-to-treat (ITT) set encompassed all participants administered the treatment. The per-protocol analysis (PP) set included all participants with high compliance with the study protocol and strictly completed the trial processes per the study protocol. All participants in the PP set completed the drug therapy throughout the study according to the protocol.Data were analyzed with SPSS 22.0 (SPSS, USA). Normally and skewedly distributed continuous variables were presented as mean ± standard deviation and median (range), respectively. Categorical variables were presented as n (%). Kaplan-Meier curve analysis was utilized to estimate PFS and OS. | PMC10663256 | ||
Results | PMC10663256 | |||
Characteristics of participants | SCLC | ONCOLOGY, SMALL CELL LUNG CANCER, SCLC | From March 2019 to March 2022, eligibility screening was conducted for 32 advanced SCLC cases with no progression through first-line therapy (Fig.
Study flowchart
Baseline characteristics of the participantsITT: intent-to-treat; PP: per-protocol; ECOG PS: Eastern Cooperative Oncology Group Performance Status; ES-SCLC: extensive-stage small cell lung cancer | PMC10663256 |
Efficacy | DISEASE | Median PFS was 8.02 (95%CI 5.36–10.67) months (Table
Clinical outcomesITT: intent-to-treat; PP: per-protocol; mPFS: median progression-free survival; mOS: median overall survival; CR: complete response; PR: partial response; SD: stable disease; ORR: objective response rate; DCR: disease control rate
(
( | PMC10663256 | |
Safety | any-grade, TEAEs, TRAEs | Almost all participants (96.43%) experienced any-grade TEAEs. Any-grade TEAEs leading to anlotinib dose modification were observed in 35.71% of patients. TEAEs leading to anlotinib dose interruption were observed in 14.29% of cases. TEAEs leading to etoposide dose modification were observed in 7.14% of participants (Table
Summary of TEAEs in the ITT set (n = 28)ITT: intent-to-treat; TEAE: treatment emergent adverse eventsGrade 3–4 TRAEs were observed in 42.85% of participants. Grade 3–4 TEAEs leading to anlotinib dose modification were observed in 28.57% of cases. TEAEs leading to anlotinib dose interruption were observed in 7.14% of patients. TEAEs leading to etoposide dose modification were observed in 7.14% of participants (Table | PMC10663256 | |
Discussion | any-grade, SCLC, TEAEs | BRAIN METASTASIS, SCLC | This work examined the effectiveness of anlotinib combined with etoposide for maintenance treatment of ES-SCLC cases. The above findings suggest that maintenance treatment with anlotinib and etoposide after primary treatment with etoposide + platinum was effective and safe in clinical ES-SCLC.Patient survival in ES-SCLC after treatment with etoposide and platinum is poor. Indeed, in a study by Paz-Ares et al. [Although VEGF is expressed in SCLC, the anti-VEGF antibody bevacizumab yielded conflicting or disappointing results, with ORRs of 58.0-91.9 and median PFS of 4.7–7.8 months [Third-line anlotinib monotherapy showed promising efficacy in ES-SCLC cases with/without brain metastasis in the ALTER1202 trial [In this work, 96.43% of the examined participants experienced any-grade TEAEs, with grade 3–4 TEAEs in 42.85% of cases. Those numbers are lower than reported for ES-SCLC cases administered other TKIs as maintenance treatment in phase II trials. Indeed, maintenance treatment with sorafenib resulted in 23% treatment discontinuation due to AEs [This study had multiple limitations. First, this was a phase II trial without a control group. In addition, a single center design was used with small sample size. The recent advent of immunotherapy with platinum and etoposide as primary therapy [In conclusion, anlotinib and etoposide is promising and safe in ES-SCLC after primary therapy with etoposide + platinum. | PMC10663256 |
Acknowledgements | We are grateful to all participants involved in the present trial as well as to the clinicians who supported this research. | PMC10663256 | ||
Authors’ contributions | Conceptualization: BS and YW. Data curation: YW, XFZ, WQZ, QW, ZXH, LFW, and WJZ. Formal analysis: YW, TZ, HZS, KHY, LS, BZP, and RHG. Funding acquisition: BS and YW. Investigation: YW, XFZ, and BS. Methodology: YW, XFZ, FJF, and BS. Project administration: GRZ, FJF, and BS. Resources: all authors. Software: BS. Supervision: FJ, FJF, and BS. Validation: YW, XFZ, WQZ, QW, ZXH, FJF, and BS. Visualization: YW, XFZ, FJF, and BS. Writing-original draft: YW, XFZ, and BS. Writing-review & editing: all authors. | PMC10663256 | ||
Funding | Cancer | CANCER | The current project was funded by the National Natural Science Foundation of China (Grant No. 82272863), the Beijing Medical and Health Foundation Project (Grant No. YWJKJJHKYJJ-F2030E), and the Huilan Public Interest Project (Grant No. HL-HS-2020102) (to Bo Shen) and the China International Medical Foundation Project (Grant NO. Z-2014-06-2103) and the Project of Jiangsu Cancer Hospital (Grant No. ZJ202110) (to Yuan Wu). | PMC10663256 |
Data Availability | The data generated or analyzed during this study are included in this published article. | PMC10663256 | ||
Declarations | PMC10663256 | |||
Competing interests | The authors declare no competing interests. | PMC10663256 | ||
Ethics approval | Cancer | CANCER | This trial complied with the Declaration of Helsinki (2000) of the World Medical Association. It had approval from the Ethics Committee of the Jiangsu Cancer Hospital. Signed informed consent was provided by each patient. The study was registered at the Chinese clinical trial registry ( | PMC10663256 |
Consent to participate | Signed informed consent was provided by each patient. | PMC10663256 | ||
Consent to publish | N/A. | PMC10663256 | ||
Animal Studies | N/A. | PMC10663256 | ||
References | PMC10663256 | |||
Background | lung injury | Inhaling aerosolized nicotine and cannabis (colloquially called “vaping”) is prevalent among young adults. Instagram influencers often promote both nicotine and cannabis vaporizer products. However, Instagram posts discouraging the use of both products received national media attention during the 2019 outbreak of e-cigarette or vaping-associated lung injury (EVALI). | PMC10540020 | |
Objective | This experiment tested the impact of viewing Instagram posts about EVALI, varying in image and text valence, on young adults’ perceived harmfulness of nicotine and cannabis products, perceived risk of nicotine and cannabis vaporizer use, and intentions to use nicotine and cannabis vaporizers in the future. | PMC10540020 | ||
Methods | REGRESSION, POSITIVE | Participants (N=1229) aged 18-25 (mean 21.40, SD 2.22) years were recruited through Qualtrics Research Services, oversampling for ever-use of nicotine or cannabis vaporizers (618/1229, 50.3%). Participants were randomly assigned to view Instagram posts from young people portraying their experiences of EVALI in a 2 (image valence: positive or negative) × 2 (text valence: positive or negative) between-subjects experiment. Positive images were attractive and aesthetically pleasing selfies. The positive text was supportive and uplifting regarding quitting the use of vaporized products. Negative images and text were graphic and fear inducing. After viewing 3 posts, participants reported the perceived harmfulness of nicotine and cannabis products, the perceived risk of nicotine and cannabis vaporizer use, and intentions to use nicotine and cannabis vaporizers in the future. Ordinal logistic regression models assessed the main effects and interactions of image and text valence on perceived harmfulness and risk. Binary logistic regression models assessed the main effects and interactions of image and text valence on intentions to use nicotine and cannabis vaporizers. Analyses were adjusted for product use history. | PMC10540020 |
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