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2.17. Ethics and dissemination | Organic Law | The study protocol (Version 8 – March 2, 2023) was approved by the local Institutional Review Board of the Bellvitge University Hospital (Barcelona, Spain) (Ethics and Clinical Investigation Committee, code PR129/22, on March 9, 2023).This Trial will be conducted according to the criteria set by the Declaration of Helsinki (revised on WMA 64th General Assembly, Fortaleza, Brazil, October 2013), Good Clinical Practice standards and applicable regulations. Every patient that accepts to participate will be requested to sign a written informed consent prior to initiating any research activities.Furthermore, patients must be informed that their participation in this research is entirely voluntary, and that they can withdraw at any time, under no penalty risk whatsoever. Investigators’ participation in this study is free, voluntary, unpaid, and independent.The level of confidentiality protection, in terms of personal data protection, as required by Spanish Law (Organic Law on Data Protection 3/2018), was also ensured. Every patient that accepts to participate in the study will be assigned consecutive numbers as they are enrolled, and these numbers (or codes) will be used in the eCRF, instead of personal data. The data collected will be encoded, so that the patient to whom they correspond is not identified. | PMC10194650 | |
2.18. Plans for communicating important protocol amendments to relevant parties | MINOR | Major protocol changes will be submitted for IRB approval, and minor changes will be informed to the IRB. As per good clinical practice, trial participants will be informed of any significant changes during the trial. | PMC10194650 | |
2.19. Who will obtain informed consent? | Study team members from the Digestive and General Surgery Department and the Gastroenterology Department will inform the screened patients about the study and ask them to sign the written informed consent form at Time 2. If he/she is interested to participate, the investigator of the study team will double-check the eligibility criteria before obtaining the signed written informed consent. | PMC10194650 | ||
2.20. Confidentiality | The results from this clinical trial are confidential and may not be transferred to third parties in any form or manner without written permission from the Sponsor. All individuals involved in the clinical trial are bound to this confidentiality clause in line with the Regulation (EU) 2016/679 of the European Parliament and of the Council of April 27, 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, as well as all other valid and applicable laws and regulations, such as the “While obtaining a signature for the Written Informed Consent, the Investigator will request written permission from the patient to directly access his/her data. With this permission granted, the patient’s data may be examined, analyzed, verified, and reproduced for the evaluation of the clinical trial.Data will be anonymized, so that the corresponding patient cannot be identified. Patient data will also be dissociated. Patients will be assigned consecutive numbers as they are enrolled in the study, and these identification numbers (or codes) will be used in the eCRF; the full name of the patient will not be included in the eCRFs. The principal investigator of each center will keep an updated patient identification list containing the name, clinical history number and the patient’s identification number (or code) for the clinical trial.The study monitor may have access to the patient’s identity and data related to the study monitoring procedures. Any person with direct access to the data (Regulatory Authorities, Trial Monitors, and Auditors) will take all possible precautions to maintain the confidentiality of patient’s identities. It is the Investigator’s responsibility to obtain a written informed consent from the study patients. It is the Trial Monitor’s responsibility to make sure that each patient has given his/her written consent to allow this direct access.The Investigator shall ensure that the documents provided to the Sponsor do not contain the patient’s name or any identifiable data. | PMC10194650 | ||
2.21. Declaration of interests | The authors have no conflict of interests to disclose. | PMC10194650 | ||
2.22. Availability of data and materials | The database management and statistical analysis will be carried out by the Biostatistics Unit of the IDIBELL. Only the sponsor and the biostatisticians will have access to the final trial dataset. The datasets used and/or analyzed during the study will be available from the corresponding author upon reasonable request. | PMC10194650 | ||
2.23. Ancillary and post-trial care | A specific insurance has been hired | PMC10194650 | ||
2.24. Dissemination policy: trial results, authorship | The study findings will be submitted to a peer-reviewed journal for publication and presented at relevant national and international scientific meetings. The authorship is based on the criteria set by the International Committee of Medical Journal Editors. | PMC10194650 | ||
2.25. Plans to give access to the full protocol, participant level-data and statistical code | The study protocol is registered on clinicaltrials.gov (NCT05473260). The Sponsor may grant access to the full protocol (in Spanish) on a case-by-case basis and upon reasonable request by the interested party.No public access to the patient dataset is planned to be given at this moment. Professor Judit Peñafiel, the Head of the Biostatistics Unit, will oversee the dataset and granting access to this information will be evaluated on a case-by-case basis and upon reasonable request by the interested party. | PMC10194650 | ||
3. Discussion | acute pancreatitis | ACUTE PANCREATITIS, MINOR, DISEASE, ACUTE PANCREATITIS | Acute pancreatitis is a high-incidence disease and current guidelines support in-hospital care, despite the severity. This implies a high economic burden in healthcare systems worldwide. Nonetheless, recent evidence suggests that mild acute pancreatitis can be safely and effectively treated with home monitoring with regular visits by a nurse under the supervision of a physician.This study may have limitations due to the open-label design and patient-reported outcomes. A patient’s knowledge of the assigned treatment arm could influence their view and reporting of their symptoms, although we do not believe this will be the case since treatments will be very similar, except for the administration route (for analgesic medication) and for the type of oral feeding. Additionally, following the usual clinical practice when managing admitted patients could generate different approaches between the different participating medical centers; however, the acute pancreatitis approach is quite standardized among the participating hospitals, with minor differences in the medication brands used by each center (similar to what is found in the real world).We expect the RHINO trial results to show that home monitoring is effective, safe, and not inferior to hospitalization for managing mild acute pancreatitis. We also expect to show that the economic costs are lower when treating these patients with home monitoring. Altogether, this multicenter large sample-sized trial could change the standard clinical approach to mild acute pancreatitis in Spain, kickstart similar trials throughout the world, optimize the use of limited healthcare budgets, and improve patients’ overall quality of life. | PMC10194650 |
Acknowledgments | Taulí;•Dr | VIDAL | We would like to thank the Spanish Gastroenterology Association (AEG) for the grant awarded. We also would like to thank the We would like to thank all RHINO study group members:•Dr Marta Gil Barrionuevo, Hospital de Viladecans;•Dr Marta Arnau Vidal, Hospital de Viladecans;•Dr Francisco Garcia Borobia, Corporació Sanitaria Parc Taulí;•Dr Anna Muñoz Campaña, Corporació Sanitaria Parc Taulí;•Dr Sergio González Martínez, Hospital Sant Joan Despí Moisés Broggi - Consorci Sanitari Integral (CSI);•Dr Andrea Sanz Llorente, Hospital Sant Joan Despí Moisés Broggi - Consorci Sanitari Integral (CSI);•Dr Stephani Tasayco Huamán, Hospital Universitari Vall Hebrón;•Dr Elisabeth Pando Rau, Hospital Universitari Vall Hebrón;•Dr Andrea Álvarez Torrado, Hospital de Igualada - Consorci Sanitari de l’Anoia (CSA);•Dr Elisabet Baena Sanfeliu, Hospital de Igualada - Consorci Sanitari de l’Anoia (CSA);•Dr Catalina Uribe Galeano, Hospital Fundació Sant Joan de Déu de Martorell;•Dr Ione Fornaguera Marimon, Hospital Fundació Sant Joan de Déu de Martorell;•Dr Gian Pier Protti Ruíz, Hospital Germans Trias i Pujol de Badalona;•Dr Alba Zarate Pinedo, Hospital Germans Trias i Pujol de Badalona;•Dr Anna Arroyo Serrano, Hospital de Terrassa;•Dr Andrea Adroher Alfonso, Hospital de Terrassa;•Dr Santiago Sánchez Cabús, Hospital de la Santa Creu i Sant Pau;•Dr Rodrigo Medrano, Hospital de la Santa Creu i Sant Pau. | PMC10194650 |
Supplementary Material | PMC10194650 | |||
Abbreviations: | ACUTE PANCREATITIS | acute pancreatitisBedside Index for Severity in Acute PancreatitisData Safety Monitoring Committeeemergency roomhealth-related quality of lifequality of lifeVisual Analogue ScaleThe present study protocol (Version 8.0 – March 2, 2023) was approved by the Bellvitge University Hospital Institutional Review Board (Barcelona, Spain) – code PR129/22, on March 9, 2023). The study findings will be submitted to peer-reviewed journals and presented at relevant national and international scientific meetings.This research was awarded a grant by the Spanish Gastroenterology Society (AEG), which will be used to cover study-related costs. These include the costs of open access publication. The costs of the surgical procedures and the complementary tests will be paid by the Catalan Institute of Health and will not incur on any additional costs. The investigators will receive no economic compensation for carrying out the study.The written informed consent and the patient information sheet are available as supplementary materials (see Material 1, Supplemental Digital Content, Currently, we do not intend to carry out any ancillary studies. If any future studies are planned to be carried out later using the anonymized stored data, a new protocol should be made, and a new IRB approval should be sought.The authors have no conflicts of interest to disclose.The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.Supplemental Digital Content is available for this article.How to cite this article: Sorribas M, Carnaval T, Peláez N, Secanella L, Salord S, Sarret S, Videla S, Busquets J. Home monitoring vs hospitalization for mild acute pancreatitis. A pilot randomized controlled clinical trials. Medicine 2023;102:20(e33853).ClinicalTrials.gov Identifier: NCT05473260. | PMC10194650 | |
References | PMC10194650 | |||
Background | DISEASES | Smoking continues to be a leading risk factor for several diseases globally. We hypothesised that an intervention delivered via text messages could help individuals who were looking to quit. | PMC10552416 | |
Methods | A two-arm, parallel-groups, randomised controlled trial was employed. Both groups received treatment as usual, with the intervention group also receiving a 12-week text messaging intervention. Participants were adult, weekly or more frequent smokers, recruited online and in primary health care centres. Research personnel were blinded, while participants were not. Primary outcomes were prolonged abstinence and point prevalence of abstinence, 3 and 6 months post-randomisation. All randomised participants were included in analyses. | PMC10552416 | ||
Results | Between 18 September 2020 and 16 June 2022, we randomised 1012 participants (intervention: 505, control: 507). Outcome data was available for 67% ( | PMC10552416 | ||
Conclusions | Amongst general population help-seekers—who on average had smoked for 25 years—access to a 12-week text messaging intervention produced higher rates of self-reported smoking abstinence in comparison to treatment as usual only. The intervention could be part of the societal response to the burden which smoking causes; however, findings are limited by risk of bias due to attrition, self-reported outcomes, and lack of blinding. | PMC10552416 | ||
Trial registration | The trial was preregistered in the ISRCTN registry on 27/07/2020 (ISRCTN13455271). | PMC10552416 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12916-023-03073-5. | PMC10552416 | ||
Keywords | Open access funding provided by Linköping University. | PMC10552416 | ||
Background | There are 1.14 billion tobacco smokers globally, with 7.41 trillion cigarette-equivalents being consumed annually [Data from the Public Health Agency in Sweden showed that in 2021 [Digital interventions may contribute to the societal response to reduce the prevalence of smoking. These interventions are characterised by delivering cessation support materials using text messages, e-mail, mobile phone apps, etc. Text messaging-based interventions are particularly important since they rely on standard technology, which is increasingly prevalent globally, and can be delivered at relatively low cost. This means that they may be able to reach further into the community than face-to-face interventions. Early trials of text messaging-based interventions showed promising results, notably the txt2stop trial (In Sweden, there have been two trials of text messaging interventions. Both have targeted younger individuals in well-defined settings: the first amongst college and university students [ | PMC10552416 | ||
Methods | We conducted a 2-arm RCT with parallel-groups (1:1), following a Bayesian sequential design. The trial was preregistered in the ISRCTN registry on 27/07/2020 (ISRCTN13455271) and received ethical approval from the Swedish Ethical Review Authority on 16/06/2020 (Dnr 2020–01427). A trial protocol was submitted prior to enrolment [ | PMC10552416 | ||
Participants | RECRUITMENT | Recruitment took place in two different settings. First, online advertisement (Google, Bing, and Facebook) was used to recruit individuals seeking help to quit smoking. Individuals clicking on the advert were taken to the study website which contained study information and instructions on how to sign up. Second, health care professionals at 54 participating primary health care units in the south of Sweden advertised the trial to patients through printed media (e.g. flyers, leaflets, business cards, posters). Like the website, the printed media contained study information and instructions on how to sign up. Regardless of setting, individuals were instructed sign up for the trial by sending a text message to a dedicated telephone number. Within 5 min, they received a text message in response, with a hyperlink to study information and an informed consent form.Participants consenting to take part in the trial were immediately redirected to a baseline questionnaire, after which eligible participants were randomised. Individuals aged 18 years or older who smoked at least 1 cigarette per week were eligible for the trial. Most of the study information, and all questionnaires, were delivered to participants through their mobile phone and was in Swedish; thus, participants without access to a mobile phone and who did not comprehend Swedish well enough to sign up for the trial were excluded. | PMC10552416 | |
Interventions | weight gain | AIDS, COMPLICATIONS | Both intervention and control groups were given treatment as usual, and neither were restricted from using other available smoking cessation aids. The intervention group were in addition given access to a text messaging intervention. Treatment as usual was in this trial defined as follows. For participants recruited through online advertisements, it was defined as referral to a nationally available smoking cessation helpline and a nationally organised website with general information about smoking and health. For participants recruited through primary health care units, it was defined as the same type of referral as participants recruited online, with additional referral from the primary health care units to have a conversation with a nurse or smoking cessation specialist about smoking cessation and health.Two versions of the intervention were available: one general version and one that was tailored specifically for individuals undergoing elective surgery. Both versions were based on findings from our previous research [Over the first few weeks, participants received 2–4 messages per day, which was reduced to 2 messages per day during the middle part of the intervention, and further reduced to 1 message per day during the latter part of the intervention. The content of the messages was primarily informational and encouraging, and some messages asked participants to do specific tasks, such as throw away ashtrays. None of the messages asked participants to respond, but participants could request extra supportive messages by sending a text message with one of three keywords: weight, relapse, or craving. A message was then sent back to participants with specific information about potential weight gain, what to do if one relapses, or help if they were experiencing nicotine cravings. Unique for the elective surgery version was that additional messages about complications and recovery from surgery were included, and some of the messages included hyperlinks to web-based modules which contained materials specifically designed for the surgery context. Please see the study protocol for more details [ | PMC10552416 |
Baseline measures | At baseline, participants were asked to complete an electronic questionnaire on their mobile phones. The questionnaire asked about the following: gender, age, the number of years smoking, monthly/weekly/daily smokers and the number of cigarettes typically smoked in this interval, lifetime number of quit attempts, cessation counselling experience, use of quit smoking helpline, and use of snus (which is a moist oral tobacco product which is common in Sweden, sometimes translated as | PMC10552416 | ||
Outcomes | AIDS | The primary outcomes were prolonged abstinence and point prevalence of smoking abstinence, measured at 3 and 6 months post-randomisation. Prolonged abstinence was defined following the Russell standard [Secondary outcomes were 7-day point prevalence of smoking abstinence, number of cigarettes smoked weekly (if still smoking), number of quit attempts since baseline, and number of uses of other smoking-cessation aids since baseline.Three potential mediating factors were assessed: importance, confidence, and knowledge of how to quit (know-how). To reduce participant burden across the entire trial period, we decided against using multi-item questionnaires to measure these factors, instead relying on face valid single-item measures based on importance and confidence rulers [Items used to assess three potential mediatorsThere were three follow-up intervals: 1, 3, and 6 months post-randomisation. At the 1-month follow-up, the three hypothesised mediators were assessed only. All follow-ups were initiated by sending text messages to participants with hyperlinks to questionnaires. In all cases, the following additional attempts were made to collect data:A total of 2 reminders were sent 2 days apart.If no response was given to (1), then questions were sent directly in a text message, asking participants to respond directly with a text (no hyperlink). We only asked for primary outcome measures at this stage.If there was no response given to (2) at 3 and 6 months, we attempted to call participants to collect primary outcomes. A maximum of 5 call attempts were made. | PMC10552416 | |
Randomisation and blinding | Allocation was done according to a computer-generated random sequence. Participants were stratified according to which of the two versions of the intervention was appropriate (general or surgery). Block randomisation was used to ensure equal number of participants in each group within stratum, using random block sizes of 2 and 4. Randomisation was done immediately after participants responded to the baseline questionnaire using their mobile phone. Once a response was received by the backend server, allocation took place automatically, and participants were told about group allocation via a text message. Research personnel were not able to affect the allocation and all study procedures were automated, preventing subversion of allocation concealment.Participants were aware of their group allocation; however, research personnel were blinded. All questionnaires were completed by participants on their own mobile phones, without supervision by research personnel. Non-responders were called, and during the call, it was possible that participants revealed their allocation to assessors. This means that there was a risk of detection bias (see Limitations). | PMC10552416 | ||
Statistical analysis | The statistical methods applied were pre-specified in the trial protocol [All models were estimated using Bayesian inference [ | PMC10552416 | ||
Primary and secondary outcomes | REGRESSION, SECONDARY | For the primary and secondary outcome measures, differences between the two groups at the follow-up intervals with respect to prolonged abstinence and 4-week and 7-day point prevalence of abstinence were analysed using logistic regression. Negative binomial regression was used to analyse the number of quit attempts, use of other smoking cessation services, and cigarettes smoked weekly (amongst those who still smoked). Models were adjusted for baseline characteristics (gender, age, nicotine dependence, importance, confidence, and know-how) as well as the stratifying variable in the randomisation procedure (general or surgery eligibility).Effect modification analyses were performed for the primary outcomes, exploring interactions between group allocation and baseline variables. We also estimated effect modification based on which setting participants were recruited from (online or primary health care) and which version of the intervention they were eligible for (general or surgery). | PMC10552416 | |
Attrition analyses | REGRESSION | Analyses comparing responders and non-responders with respect to baseline variables were conducted using logistic regression. We used Cauchy priors for covariates, with a standard normal hyperprior for the scale parameter to induce shrinkage. Models were estimated with and without interaction terms between baseline variables and group.Based on the assumptions of repeated attempt models [ | PMC10552416 | |
Sample size | RECRUITMENT | We used a Bayesian sequential design to monitor recruitment [Effect: Harm: Futility: For the effect and harm criteria, we used a standard normal prior for covariates (mean = 0, SD = 1) and a slightly wider prior was used for the futility criterion (mean = 0, SD = 2). The criteria are targets; thus, at each interim analysis, we evaluated each target for each covariate and decided to continue or stop recruitment. Note that this Bayesian approach allows us to look at the data an unlimited number of times without worrying about multiplicities and error rates, as would be necessary using a frequentist approach. Also, since no fixed sample size is prespecified, we reduced the risk of stopping both too early and too late [ | PMC10552416 | |
Ancillary analyses | PMC10552416 | |||
Interactions | POI | RECRUITMENT, INTERACTION | Interaction models revealed some attenuation of effects with respect to baseline variables. Most consistently, there was evidence that age was a moderator for both primary outcomes at the 3-month interval and for prolonged abstinence at the 6-month interval. These analyses suggests that older participants were more likely to benefit from the intervention, as the interaction term had an OR of 1.03 (95% CoI = 1.00; 1.05, probability of interaction [POI] = 98.9%) for prolonged abstinence at 3 months, 1.02 (95% CoI = 1.00; 1.04, POI = 96.6%) for point prevalence at 3 months, and 1.02 (95% CoI = 1.00; 1.05, POI = 97.1%) for prolonged abstinence at 6 months.There was also evidence that the intervention was more effective amongst those who scored higher on the confidence item at baseline (being more confident about being able to quit). However, this was less consistent with the moderation effect only marked in point prevalence at 3 months (OR = 1.17, 95% CoI = 1.02; 1.34; POI = 98.7%) and prolonged abstinence at 5 months (OR = 1.13, 95% CoI = 0.98; 1.30, POI = 94.7%). Finally, evidence that men were less likely to benefit from the intervention was found with respect to point prevalence at 3- and 6 months, with the evidence weaker for the latter. The OR was 0.45 (95% CoI = 0.20; 1.04, POI = 96.8%) at 3 months and 0.53 (95% CoI = 0.22; 1.24, POI = 92.9%) at 6 months.We found no evidence of interactions between group allocation and recruitment method nor with access to the general or the surgery version of the intervention. However, these analyses were limited by small sample sizes. | PMC10552416 |
Attrition | We found evidence that older participants in both groups were more likely to respond to follow-up at 6 months (se Fig. Response/No-response plotted against age at baseline and divided by group: (Associations between the number of attempts to collect data and primary outcomes are presented in Fig. Primary outcomes plotted against number of attempts to collect data: ( | PMC10552416 | ||
Discussion | We found evidence that access to a 12-week text messaging intervention produced higher self-reported smoking abstinence in comparison to treatment as usual only. Effects on abstinence were observed immediately after the intervention period and persisted 3 months later. In addition, amongst those who continued to smoke, those with access to the intervention reported a lower number of cigarettes smoked weekly. This is the first time the effectiveness of a text messaging smoking cessation intervention has been evaluated amongst the general population in Sweden, and while the point estimates of effect sizes were found to be larger than those of international studies, they are still comparatively similar. For instance, one meta-analysis of text messaging interventions reported an overall OR of 1.37 (95% CI = 1.25–1.51) for smoking abstinence [Participants were long-time smokers (mean 25.3 years), with a history of multiple quit attempts (mean 7.2 attempts), yet the intervention was effective and showed no evidence of being less effective amongst those having smoked for longer. This is encouraging, as its important to both find ways of preventing individuals from becoming long time smokers and help those who have smoked for a long time to quit. All participants were referred to existing resources for smoking cessation, yet access to the intervention still improved abstinence rates. About a quarter of intervention group participants decided to stop the program prematurely. We did not require participants to give any reason for doing so (in accordance with ethical procedures); however, we may speculate that this was due to the program not suiting their needs, that they decided to abandon their quit attempt, or that they felt that they no longer needed support as they had successfully quit. On the other hand, more than three quarters of participants used the program to completion, seemingly finding it a helpful tool. | PMC10552416 | ||
Generalisability and limitations | BLIND, ATTRITION | Participants were recruited online and through primary health care centres, mimicking closely how the intervention could be disseminated in the real-world. Inclusion criteria were allowing, and few participants who showed interest in the trial were excluded. This pragmatic trial design leads us to interpret findings as estimates of effectiveness rather than efficacy, which strengthens the external validity of the trial. The design did however also limit our ability to blind participants, as they were naturally aware if they received the intervention or not. Although one could imagine some form of sham intervention with text messages containing non-smoking related information, it is unlikely that this would convince those seeking help that they had received cessation support.Attrition rates were high in this trial, as is often the case with online trials with low thresholds of participation [Outcome measures were self-reported in this trial, which may be susceptible to recall bias and exacerbate the risk of social desirability bias. The Society for Research on Nicotine and Tobacco does however recommend that, in studies with limited face-to-face contact, it is neither required nor desirable to use biochemical verification [All study procedures were automated, ensuring that the concealment of the allocation sequence could not be subverted nor that research personnel could become aware of allocation. However, to reduce attrition bias, we called participants who did not respond to our initial attempts to collect data. This induces a risk of detection bias, which has been shown to affect outcome reporting [ | PMC10552416 | |
Conclusions | Access to a 12-week text messaging intervention produced higher self-reported smoking abstinence at 3 and 6 months post-randomisation amongst help-seekers in the general population. A pragmatic design allows for estimates to be interpreted as effectiveness, with risk of bias due to attrition, self-reported outcomes, and lack of blinding. | PMC10552416 | ||
Acknowledgements | Not applicable. | PMC10552416 | ||
Authors’ contributions | MB and PB conceptualised the study and designed the trial. MB prepared the statistical analysis plan. KUG and JB were responsible for the data collection. MB and JB did the statistical analysis, accessed and verified the underlying data, and wrote the first draft of the report. PB and KUG revised the manuscript, and all authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors read and approved the final manuscript. | PMC10552416 | ||
Funding | Open access funding provided by Linköping University. The trial was funded by Region Östergötland (Forsknings-ALF, Dnr: LIO-896081). The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. | PMC10552416 | ||
Availability of data and materials | A study protocol, including a statistical analysis plan, is available open-access [ | PMC10552416 | ||
Declarations | PMC10552416 | |||
Ethics approval and consent to participate | The study received ethical approval from the Swedish Ethical Review Authority on 16/06/2020 (Dnr 2020–01427). All participants gave consent to participate after having been given full information about study procedures. | PMC10552416 | ||
Consent for publication | Not applicable. | PMC10552416 | ||
Competing interests | MB and PB owns a private company (Alexit AB) that maintains and distributes evidence-based lifestyle interventions to be used by the public and in health care settings. Alexit AB played no role in developing the intervention, study design, data analysis, data interpretation, or writing of this report. Services developed and maintained by Alexit AB were used for sending text messages and data collection. KUG and JB declare no conflicts of interest. | PMC10552416 | ||
References | PMC10552416 | |||
Background | DENTAL PLAQUE | The effect of cymenol mouthwashes on levels of dental plaque has not been evaluated thus far. | PMC10422750 | |
Objective | PLAQUE | To analyse the short-term, in situ, anti-plaque effect of a 0.1% cymenol mouthwash using the DenTiUS Deep Plaque software. | PMC10422750 | |
Methods | PLAQUE, DENTAL PLAQUE, PLAQUE | Fifty orally healthy participants were distributed randomly into two groups: 24 received a cymenol mouthwash for eight days (test group A) and 26 a placebo mouthwash for four days and a cymenol mouthwash for a further four days thereafter (test group B). They were instructed not to perform other oral hygiene measures. On days 0, 4, and 8 of the experiment, a rinsing protocol for staining the dental plaque with sodium fluorescein was performed. Three intraoral photographs were taken per subject under ultraviolet light. The 504 images were analysed using the DenTiUS Deep Plaque software, and visible and total plaque indices were calculated (ClinicalTrials ID NCT05521230). | PMC10422750 | |
Results | PLAQUE | On day 4, the percentage area of visible plaque was significantly lower in test group A than in test group B (absolute = 35.31 ± 14.93% vs. 46.57 ± 18.92%, p = 0.023; relative = 29.80 ± 13.97% vs. 40.53 ± 18.48%, p = 0.024). In comparison with the placebo, the cymenol mouthwash was found to have reduced the growth rate of the area of visible plaque in the first four days by 26% (absolute) to 28% (relative). On day 8, the percentage areas of both the visible and total plaque were significantly lower in test group A than in test group B (visible absolute = 44.79 ± 15.77% vs. 65.12 ± 16.37%, p < 0.001; visible relative = 39.27 ± 14.33% vs. 59.24 ± 16.90%, p < 0.001; total = 65.17 ± 9.73% vs. 74.52 ± 13.55%, p = 0.007). Accounting for the growth rate with the placebo mouthwash on day 4, the above results imply that the cymenol mouthwash in the last four days of the trial reduced the growth rate of the area of visible plaque (absolute and relative) by 53% (test group A) and 29% (test group B), and of the area of total plaque by 48% (test group A) and 41% (test group B). | PMC10422750 | |
Conclusions | DENTAL PLAQUE, PLAQUE | The 0.1% cymenol mouthwash has a short-term anti-plaque effect in situ, strongly conditioning the rate of plaque growth, even in clinical situations with high levels of dental plaque accumulation. | PMC10422750 | |
Keywords | PMC10422750 | |||
Introduction | periodontitis, gingivitis, tooth | DENTAL CARIES, PERIODONTITIS, PERIODONTAL DISEASES, GINGIVITIS, DENTAL PLAQUE, PLAQUE, DENTAL CARIES | Dental caries and periodontal diseases are among the most prevalent conditions globally, producing severe health and economic burdens that significantly reduce the quality of life of those affected [There is consensus in the literature regarding the roles of professional tooth cleaning, oral hygiene instructions, and, especially, the self-performed mechanical removal of dental biofilm for the prevention and management of dental caries and periodontal diseases like gingivitis and periodontitis [Essential oils (EOs) are among the most-investigated active anti-plaque agents [Within the family of EOs, o-cymen-5-ol (cymenol) is a natural phenolic compound derived from isopropyl cresol, whose mechanism of action is believed to be due to the alteration of the cell wall and cell membrane permeability [Similar to the traditional approach employed in studies of other chemical adjuvants, the effects of cymenol on dental plaque levels have been evaluated via the Turesky clinical index [Accordingly, the present investigation aimed to evaluate the short-term in situ anti-plaque effect of 0.10% cymenol mouthwashes using our DenTiUS Deep Plaque image analysis software. | PMC10422750 |
Materials and methods | This was a balanced, randomised, triple-blind, parallel study on the short-term anti-plaque effects of a commercialised cymenol-based mouthwash. The Ethics Committee of Clinical Investigation of Galicia (CEIC, Spain) approved the project and registered 2021/301. The protocol for this trial and the supporting CONSORT checklist are available as Supporting Material S1 and S2, respectively. The study was registered on ClinicalTrials.gov with the ID NCT05521230 (date of registration 30/08/2022). The authors can confirm that all ongoing and related trials for this intervention are recorded and can be accessed via the following URL: | PMC10422750 | ||
Selection of the study group: inclusion and exclusion criteria | periodontitis, bleeding, gingivitis | PERIODONTITIS, BLEEDING, GINGIVITIS | Participants were sought for voluntary enrolment in the setting of the Faculty of Medicine and Dentistry of Santiago de Compostela (Universidade de Santiago de Compostela -USC-, Spain) from October 2021 to April 2022. Two clinicians adopting a previously standardised approach evaluated all the volunteers who verified compliance with the established inclusion and exclusion criteria. The subjects chosen were systemically healthy adults aged between 20 and 45 years with a good oral health status, i.e., a minimum of 24 permanent teeth, no evidence of gingivitis or periodontitis (bleeding on probing < 10%) [ | PMC10422750 |
Study phases and mouthwash protocols | GingiLacer | Adopting the above criteria, 60 participants were selected and randomly distributed into two groups. Two phases of mouthwash application were established (Fig.
Flowchart of the development of this experimentIn phase 1, each group was randomly subjected to the application of mouthwash for four days: a cymenol mouthwash (test group A; n = 30), which corresponded to the product GingiLacer Encías Delicadas (active ingredients: 0.10% cymenol, 0.10% zinc chloride, potassium glycyrrhizate, and fluoride salts); or a placebo mouthwash (test group B; n = 30), which contained no active ingredients but was organoleptically similar or identical to the cymenol version. The participants used a rinse of 10 millilitres (ml) for 60 s, three times a day, with an interval of seven to nine hours between them. Then, in phase 2, all the participants used the cymenol mouthwash for four days following the exact dosing and schedule as in phase 1.The volunteers performed no other oral hygiene measures during the eight days of mouthwash application. To evaluate their compliance, the antiseptic bottles were weighed at the beginning and end of the two application phases. Each mouthwash (cymenol and placebo) was provided to a participant in an opaque bottle with instructions about the necessary volume and an extra amount for possible losses. The R free distribution software [ | PMC10422750 | |
Staining of dental plaque and intraoral photography | rigidity | DENTAL PLAQUE | The participants attended the Faculty of Dentistry on two occasions during the development of phase 1 and once in phase 2. In the first appointment for phase 1 (day 0), we performed ultrasound scaling and polishing with a brush/cup and polishing pastes. Dental floss or interproximal brushes were used where appropriate for the interproximal areas. In this way, all the participants had an initial level of dental plaque close to zero at the start of the experiment. A series of rinses was then employed to stain the dental plaque, with sodium fluorescein as the developer:
One rinse for 10 s with 20 ml of phosphate buffer.One rinse for one minute with 15 ml of 1240 parts per million (ppm) fluorescein in a phosphate buffer.Three rinses for 10 s with 25 ml of phosphate buffer.At both the second appointment in phase 1 (day 4) and the only one in phase 2 (day 8), the same rinsing protocol as that described above was performed to stain the dental plaque with sodium fluorescein.On days 0, 4, and 8, the participants in each mouthwash test group (i.e., test group A or B) performed the sodium fluorescein rinse protocol before intraoral photographs were taken under ultraviolet light using our self-designed intraoral image replication device (number of patent registration: 2572333). This has been designed based on the following requirements that guarantee the positional standardisation of all its elements: the rigidity and stability of the device as a whole; the option to adjust and spatially fix the attachments to enable it to be adapted to any individual; the capacity to register its position numerically; and the ease of handling and transport.Three intraoral photographs were taken of each subject at each appointment: one frontal (from canine to canine) and two lateral (from the premolar to the first molar, including the upper and lower sectors) (Fig.
Photographs were taken under ultraviolet light on days 0, 4, and 8 in one patient of test group A (left) and one patient of test group B (right) | PMC10422750 |
Analysis of the intraoral photographs using the DenTiUS Deep Plaque software | tooth | PLAQUE, DENTAL PLAQUE, PLAQUE | The digital quantification of the bacterial plaque in the photographic images was carried out using an image processing program of our design named DenTiUS Deep Plaque [DenTiUS Deep Plaque is an application based on digitally processing photographic images of dentition to quantify the bacterial plaque on tooth surfaces. Its use is indicated for analysing dental plaque evolution patterns and evaluating the effectiveness of different oral hygiene measures. The software allows the automatic determination of the levels of visible, non-visible, and total dental plaque (Fig.
Determination of dental plaque levels by DenTiUS Deep Plaque software: graphical representation of plaque-free teeth, visible plaque, and non-visible plaqueA series of clinical indices can be calculated for each type of plaque, and the following are those that were evaluated in the present trial:
Plaque area: Percentage of the tooth surface with dental plaque.Plaque growth area: The growth rate of the dental plaque area per unit of time in hours (percentage area/hour).These indices were calculated absolutely on the analysed image without using a previous reference and relatively on the analysed image utilising the moment of professional dental cleaning as a reference (Figs.
Quantification of visible plaque and non-visible plaque levels on day 4 (left) and day 8 (right) in an example patient in test group A
Quantification of visible plaque and non-visible plaque levels on day 4 (left) and day 8 (right) in an example patient in test group B | PMC10422750 |
Statistical analysis | PLAQUE | Given that the present study had a parallel design of independent groups, and accounting for the possibility of using a two-tailed test of mean differences between two independent groups, an effect size of 0.80, an alpha error of 0.05, and a statistical power of 0.80, a minimum sample size of 26 subjects were required in each group. Due to the possible loss of patients for various reasons, each study group initially consisted of 30 participants. The sample size calculation was performed with the program G*Power version 3.1.9.4 [The statistical analysis was conducted using the freely distributed R software [
Inter-mouthwash analysis between independent groups: test group A vs. test group B in phase 1 (cymenol and placebo mouthwashes, respectively); test group A vs. test group B in phase 2 (cymenol mouthwashes in both groups). After using the Shapiro-Wilk test to determine the normal distribution of the data, either the Student’s t-test for independent samples (normal distribution) or the Mann-Whitney U (non-normal distribution) test was employed to compare the means obtained in both groups with the DenTiUS Deep Plaque clinical indices at baseline (day 0) and after using the mouthwash (days 4 and 8). In all cases, statistical significance was set as Inter-mouthwash analysis in a paired group: test group A in phase 1 (cymenol mouthwash) vs. phase 2 (cymenol mouthwash), and test group B in phase 1 (placebo mouthwash) vs. phase 2 (cymenol mouthwash). After testing for the normal distribution of the data using the Shapiro-Wilk test, either the repeated measures ANOVA (normal distribution) or the Wilcoxon test (non-normal distribution) and post hoc tests were applied with the Bonferroni correction to obtain a pairwise comparison of the DenTiUS Deep Plaque (DDP) clinical indices for a particular study group at the different timepoints (days 0, 4, and 8). In all cases, statistical significance was set as a | PMC10422750 | |
Results | PMC10422750 | |||
Clinical characteristics of the study groups | GINGIVAL BLEEDING, PLAQUE | Ten volunteers were excluded from the initial sample of 60 participants, leaving 50 subjects separated into two study groups: test group A (n = 24) and test group B (n = 26). The mean ages of the volunteers were 21.87 ± 1.51 and 22.00 ± 3.07, respectively, with a predominance of females in both groups (58.33% and 76.92%, respectively). In the whole-mouth assessment, all the participants had very low levels of bacterial plaque (mean = 6%) and periodontal parameters indicative of health (mean gingival bleeding = 3%, probing depth = 1.75 mm, and absence of clinical attachment loss). No significant differences were detected between the two study groups in any of the clinical parameters recorded (Table
Clinical characteristics of the study groupsValues indicate means (± standard deviations) and the number of subjects. After applying the Shapiro-Wilk test and determining the non-normal distribution of almost all the clinical variables, the Mann-Whitney U test was used to compare the quantitative clinical variables between the two study groups; the exception was the variable “probing pocket depth” (where the Student’s t-test was applied for independent groups). Fisher´s exact test was used to assess the association of the qualitative variables between the two study groups. A significance level of p < 0.05 was establishedmm, millimetres; SD, standard deviation | PMC10422750 | |
Inter-mouthwash analysis between independent groups: test group A | PLAQUE, PLAQUE | Table
DenTiUS Deep Plaque clinical indices were obtained in test groups A and B in phase 1 (after using the cymenol and placebo mouthwashes, respectively) and phase 2 (after using the cymenol mouthwash in both groups)Total plaque: visible plaque + non-visible plaqueSD, standard deviation*Due to the non-normal distribution of some of the contrasted variables, the Mann-Whitney U test was applied to compare the two groupsIn phase 1 on day 0 (after professional dental cleaning), the percentages of the visible plaque areas were similar between the groups (5.57 ± 3.57% vs. 5.68 ± 3.53%, p = 0.906).On day 4 of the same phase, the percentage of the visible plaque area was significantly lower in the cymenol subjects than in the placebo subjects, both in absolute (35.31 ± 14.93% vs. 46.57 ± 18.92%, p = 0.023) and relative (29.80 ± 13.97% vs. 40.53 ± 18.48%, p = 0.024) terms. The subjects who used the cymenol mouthwashes also had a lower total plaque area value (57.49 ± 13.26% vs. 62.75 ± 16.85% in the placebo subjects, p = 0.225), although these results did not achieve statistical significance. During the first four days of the experiment, the visible plaque area growth rate was significantly lower in the cymenol participants than in those in the placebo participants, both in absolute (0.36 ± 0.15% vs. 0.49 ± 0.20%, p = 0.016) and relative (0.31 ± 0.14% vs. 0.43 ± 0.19%, p = 0.017) terms. Concerning the placebo, these results mean that the cymenol mouthwash reduced the growth rate of the visible plaque area in the first four days by 26% (absolute) to 28% (relative).Again, in phase 2 on day 8, the percentage of the visible plaque area was significantly lower in test group A than in test group B (absolute = 44.79 ± 15.77% vs. 65.12 ± 16.37%, p < 0.001; relative = 39.27 ± 14.33% vs. 59.24 ± 16.90%, p < 0.001), as was the percentage of the total plaque area (65.17 ± 9.73% vs. 74.52 ± 13.55%, p = 0.007). Despite both groups using the cymenol mouthwash in the last four days of the trial, the visible plaque area growth rate was significantly lower in the cymenol volunteers than those given the placebo (absolute = 0.23 ± 0.08 vs. 0.34 ± 0.08, p < 0.001; relative = 0.20 ± 0.07 vs. 0.31 ± 0.08, p < 0.001); this was also the case for the total plaque area growth rate (0.34 ± 0.05 vs. 0.39 ± 0.07, p = 0.005). However, given the growth that occurred with the placebo mouthwash on day 4, the results above imply that the use of the cymenol mouthwash in the last four days of the trial reduced the growth rate of both the visible plaque area (absolute and relative) in these four days by 53% (test group A) and 29% (test group B), and the total plaque area by 48% (test group A) and 41% (test group B). | PMC10422750 | |
Inter-mouthwash analysis in a paired group: test group A, phase 1 (cymenol mouthwash) | PLAQUE, PLAQUE | In test group A, which received the cymenol mouthwash in both phase 1 and phase 2, there were statistically significant differences in the percentages of the visible plaque area between day 0 (5.57 ± 3.57%) vs. day 4 (35.31 ± 14.93%, p < 0.001) and day 8 (44.79 ± 15.77%, p < 0.001).Table
DenTiUS Deep Plaque clinical indices were obtained for test group A on day 4 (phase 1: receiving the cymenol mouthwash) and day 8 (phase 2: receiving the cymenol mouthwash)Total plaque: visible plaque + non-visible plaqueSD, standard deviation*Due to the non-normal distribution of some of the contrasted variables, the Wilcoxon test was applied to compare the two groups | PMC10422750 | |
Inter-mouthwash analysis in a paired group: test group B, phase 1 (placebo mouthwash) | PLAQUE, PLAQUE | In test group B, which received the cymenol mouthwash in phase 2, there were statistically significant differences in the percentages of the visible plaque area between day 0 (5.68 ± 3.53%) vs. day 4 (i.e., after the placebo mouthwash: 46.57 ± 18.92%, p < 0.001) and day 8 (i.e., after the cymenol mouthwash; 65.12 ± 16.37%, p < 0.001).Table
DenTiUS Deep Plaque clinical indices were obtained for test group B on day 4 (phase 1: receiving the placebo mouthwash) and day 8 (phase 2: receiving the cymenol mouthwash)Total plaque: visible plaque + non-visible plaqueSD, standard deviation | PMC10422750 | |
Discussion | PMC10422750 | |||
Methodological approach | PLAQUE, DENTAL PLAQUE, PLAQUE | The efficacy of active chemical anti-plaque agents is usually assessed by quantifying dental plaque using conventional clinical indices. However, these measurements have several limitations that can produce inaccurate results and complicate agent comparisons [Our research team has recently developed DenTiUS Deep Plaque, a method that enables the assessment of the entire dentition. In particular, as well as discriminating between plaque and clean teeth, the software allows clinical indices to be obtained automatically [Although this is the first study in the literature to use our DenTiUS Deep Plaque image analysis software to evaluate the anti-plaque effect of a chemical agent, an internal validation conducted with an in situ 5-day bacterial plaque growth model found that the degree of correlation between the conventional (clinical) and the automated quantification indices was very high on days 1, 2, and 3 of plaque formation (Spearman rho ≥ 0.770) [ | PMC10422750 | |
Anti-plaque effect of cymenol | inflammation, xerostomia, gingivitis, demineralisation | XEROSTOMIA, INFLAMMATION, GINGIVITIS, DEMINERALISATION, DENTAL PLAQUE, PLAQUE | A meta-analysis and meta-regression study concluded that using EO-containing mouthwashes as adjuncts to mechanical plaque control is more effective at reducing plaque and gingival inflammation than brushing and flossing alone or combined with CPC rinses [A literature review found that only a few studies to date have assessed the performance of cymenol for various purposes using in vitro [About the in vitro studies, the majority have analysed aspects unrelated to the anti-plaque activity of cymenol, e.g., its capacity to reduce both the demineralisation of human enamel [Similarly, some in vivo investigations have evaluated aspects unrelated to the anti-plaque activity of cymenol, such as its ability to reduce xerostomia [As already discussed in the In comparison to sodium fluoride dentifrices, the use of cymenol-based toothpaste by orally healthy individuals has been found to significantly lower TQH scores by 13.20% after six weeks (i.e., 42 days) [On the other hand, compared to their baseline, gingivitis patients using both a cymenol-containing toothpaste and a cymenol-mouthwash have been found to experience significant reductions in their mean TQH values of 38% after seven and 14 days, and 41% after 42 days [One of this project’s main limitations was that the size of the study group samples probably conditioned the non-detection of significant differences in the total plaque area percentages between the two groups in the first four days of application. Although the total plaque levels of test group A were about 6% lower, the effect size established for the calculated sample size was 0.08 (equivalent to a difference of 8%). In addition, including a third study group who had received the placebo mouthwash without any active ingredients in both phase 1 and phase 2 would have enabled us to determine the pattern of the plaque growth rate in the last four days of the experiment. Regarding the limitations associated with the imaging methodology applied, it should be noted that digital images are two-dimensional photographs of a three-dimensional environment. On the other hand, digital images of the palatal and lingual surfaces were not taken. However, in this regard, several authors have demonstrated through clinical indices that plaque values on buccal surfaces are similar to those found on palatal/lingual surfaces, evidencing that dental plaque on the buccal surface is representative of plaque on the palatal/lingual surface [The future perspective of clinical studies on the efficacy of oral hygiene techniques or products requires automated methods to analyse dental plaque levels using imaging. This would enable more objective comparisons to be made between different chemical adjuvants. Consequently, further research with computerised tools based on artificial intelligence is necessary to determine the best active ingredients in the fight against dental plaque. | PMC10422750 |
Acknowledgements | Not applicable. | PMC10422750 | ||
Authors’ contributions | A. Regueira-Iglesias | DENTAL PLAQUE | C. Balsa-Castro and I. Tomás contributed to the conception and design of the study; B. Suárez-Rodríguez and T. Blanco-Pintos explored the patients, prepared the mouthwashes, and performed the experiments; N. Vila-Blanco and M.J. Carreira developed the software tool for the quantification of dental plaque levels; C. Balsa-Castro performed the statistical analysis, graphs, and tables; B. Suárez-Rodríguez, A. Regueira-Iglesias and I. Tomás drafted the manuscript; M.J. Carreira carried out a critical revision of the manuscript. All authors approved the final version of the manuscript. | PMC10422750 |
Funding | Grant 2021-CE112 funded this research by Lacer, S.A. The funders were not involved in collecting and analysing the data or interpreting the results. | PMC10422750 | ||
Data Availability | Data will be made available on a case-by-case basis, and additional information will be provided by contacting the corresponding author. | PMC10422750 | ||
Declarations | PMC10422750 | |||
Ethics approval and consent to participate | The research was conducted following the principles of the Declaration of Helsinki (revised in 2000) on studies involving human experimentation [ | PMC10422750 | ||
Consent for publication | In the present study, publication of participant-identifiable data is not required; therefore, obtaining specific consent to this is not applicable. | PMC10422750 | ||
Competing interests | The authors have no conflicts of interest to declare. | PMC10422750 | ||
References | PMC10422750 | |||
Methods | In October 2020, we conducted a prospective trial involving patients presenting at testing centres with symptoms of COVID-19. We compared detection rates and performance of RDT, saliva PCR and nasopharyngeal (NP) PCR, according to VL and symptoms duration. | PMC9955963 | ||
Results | SENSITIVITY | Out of 949 patients enrolled, 928 patients had all three tests performed. Detection rates were 35.2% (95%CI 32.2–38.4%) by RDT, 39.8% (36.6–43.0%) by saliva PCR, 40.1% (36.9–43.3%) by NP PCR, and 41.5% (38.3–44.7%) by any test. For those with viral loads (VL) ≥10Sensitivity of RDT compared to NP PCR was 87.4% (83.6–90.6%) for all positive patients, 94.5% (91.5–96.7%) for those with VL≥10Specificity of RDT was 100% (99.3–100%) compared to any PCR. RDT sensitivity was similar <4 days (87.8%, 83.5–91.3%) and ≥4 days (85.7%, 75.9–92.6%) after symptoms onset (p = 0.6). Sensitivity of saliva and NP PCR were 95.7% (93.1–97.5%) and 96.5% (94.1–98.1%), respectively, compared to the other PCR. | PMC9955963 | |
Conclusions | RDT results allow rapid identification of COVID cases with immediate isolation of most contagious individuals. RDT can thus be a game changer both in ambulatory care and community testing aimed at stopping transmission chains, and even more so in resource-constrained settings thanks to its very low price. When PCR is performed, saliva could replace NP swabbing. | PMC9955963 | ||
Trial registration | ClinicalTrial.gov Identifier: | PMC9955963 | ||
Data Availability | All relevant data are within the paper and its | PMC9955963 | ||
Introduction | SARS, MERS | VIRUS | COVID-19 is responsible for a dramatic health and social situation around the globe. Rapid and accurate detection of SARS-CoV-2 virus in symptomatic individuals is essential for taking immediate measures such as patient isolation and quarantine. Testing is the cornerstone of pandemic management [Because of these limitations of PCR, there is definitely a need to investigate alternative testing methods that better reflect transmissibility, to break transmission chains more rapidly and efficiently, release the pressure on the health system and ease the way for patients.To address the issues of laboratory infrastructure and procedures, as well as turnaround time, several companies have developed point of care antigen rapid diagnostic tests (RDT) to detect SARS-CoV-2. These tests are performed on NP swabs for the time being. Manufacturers report analytical sensitivity above 95% for all of these tests, while independent laboratory based studies report variable performances [To address the swabbing issue, there has been several attempts to use saliva for the detection of SARS-CoV-2, as it has been done for different viruses, including coronaviruses responsible for SARS and MERS [To simultaneously investigate analytical (PCR and RDTs) and sampling procedures (saliva and NP swab), we conducted a prospective clinical trial in symptomatic patients, in order to compare the detection rate of SARS-CoV-2 and sensitivity of i) RDT on NP swab, ii) PCR on NP swab and iii) PCR on saliva. Secondary objectives were to compare detection rates and sensitivity stratified by VL categories and symptoms duration. | PMC9955963 |
Methods | PMC9955963 | |||
Ethic statement | The study protocol and related documents were approved by the ethical review committee of Canton Vaud (CER-VD 2020–02269). The trial was registered in ClinicalTrial.gov (Identifier: NCT04613310). The authors confirm that all ongoing and related trials for this drug/intervention are registered. All subjects gave a written informed consent in accordance with the Declaration of Helsinki. | PMC9955963 | ||
Study design and participants | This was an observational prospective comparative clinical trial. From September 25 | PMC9955963 | ||
Study procedures | palate, drooling | Patients collected themselves the saliva for PCR analysis under supervision and according to a video sequence explained step by step by the health professional. Briefly they swabbed their upper and lower gingival space, plus cheeks on both sides, plus under the tongue to end with the hard and soft palate, and this for at least 20 seconds. They finished by drooling twice liquid saliva in the provided 3 ml tube containing universal transport medium, putting the swab in the tube and closing its cap. No coughing or sniffing prior to sample collection was required. Water was avoided 10 minutes prior to collection. Other drinks, food, and nasal sprays were avoided 20 minutes before sample collection. The saliva sampling procedure was chosen after multiple attempts in a pilot study in known negative and positive in- and outpatients.Then, the health professional collected two nasopharyngeal swabs, one for PCR and one for RDT analyses. Test and control lines were read by the person having collected the swab after 15 to 20 minutes and judged as positive intense, positive weak, or negative. Results were immediately entered into REDCap database. Remaining samples (saliva and the other NP swab) were sent to the molecular diagnostics laboratory for RT-PCR analysis. The patient was considered as positive for SARS-CoV-2 if any of the PCR results or the RDT result on nasopharynx was positive. Due to the nature of the intervention, blinding (to each-other PCR and RDT results) was limited to the molecular diagnosis laboratory. Once identifying information was no longer required for the basic functioning of the trial (i.e. the requirement to identify patient for result return), all eCRFs were strictly anonymised. | PMC9955963 | |
Brand of rapid diagnostic tests evaluated | Three antigen-based RDTs were assessed: 1) STANDARD Q | PMC9955963 | ||
SARS-CoV-2 RT-PCR, cycle thresholds and viral load quantification | SARS-CoV-2 RT-PCR were performed the same day or the next morning using an in-house RT-PCR on the automated molecular diagnostic platform targeting the E gene [ | PMC9955963 | ||
Outcomes | SECONDARY | The primary outcomes were the detection rates of SARS-CoV-2 positive patients by PCR on saliva, PCR on NP swab, and RDTs on NP swab, as well as the diagnostic performance (sensitivity and specificity) of i) RDT against NP PCR, ii) saliva PCR against NP PCR, and iii) any test against the other two tests. The secondary outcomes were the viral load of SARS-CoV-2 measured by NP PCR according to RDT results, the viral load by NP PCR and saliva PCR, as well as the diagnostic performance of RDT according to duration and intensity of symptoms. | PMC9955963 | |
Sample size | We based our sample size of 250 positive among 1250 cases tested to have a precision of ±2% on the NP PCR detection rate if the latter was 20% and the power 80%, based on a confidence interval of 95%. | PMC9955963 | ||
Statistical analysis | All patients having a result available for the 3 tests were included in the study analysis population. Statistical analyses were conducted using Stata IC 15 (Stata Corp., College Station, Texas, USA) and R statistical software v.4.0.2 (Vienna Austria). Detection rate, sensitivity, and specificity of each test with 95% confidence intervals (CIs) were estimated using standard descriptive methods and subsequently compared using Pearson proportion test for unpaired data, and pairwise proportion tests for paired data. The McNemar test was used to compare PCR and RDT test status (saliva PCR vs NP PCR test status, RDT vs NP PCR test status; paired comparisons). Analyses were stratified by viral load categories. The thresholds chosen for binary stratified analyses by VL were 10 | PMC9955963 | ||
Results | cough, sore throat, fever | SORE THROAT, MINOR | 949 patients presumed SARS-CoV-2 providing consent were enrolled. Median age was 31 years (IQR 25–42; range 18–87) with 49% being female. On the day of testing, 96% of participants had at least one major symptom (41% fever, 64% cough, 62% sore throat, 32% anosmia/ageusia) and 4% at least one minor and a close contact with a documented COVID-19 case. Median duration of symptoms at the time of swab collection/testing was 2 days (IQR = 2, range 0–30).Among the 928 who had all three tests done, 333 (36%) were tested using STANDARD Q | PMC9955963 |
Study patients’ flow. | PMC9955963 | |||
Detection rates of RDT, NP PCR and saliva PCR | Of the 928 patients analysed, 327 (35.2%; 95%CI 32.2–38.4%) tested positive by RDT, 369 (39.8%; 36.6–43.0%) by saliva PCR, 372 (40.1%; 36.9–43.3%) by NP PCR, and 385 (41.5%; 38.3–44.7%) by any of the 3 tests ( | PMC9955963 | ||
Detection rates of COVID patients by RDT, nasopharyngeal PCR and saliva PCR. | A) all positive patients; B) positive patients with viral loads ≥10When considering the 293 (31.6%) patients with a VL ≥10 | PMC9955963 | ||
Diagnostic test performance (sensitivity, specificity) of RDTs, NP PCR and saliva PCR | The sensitivity of RDT compared to NP PCR was 87.4% (83.6–90.6). When considering those with a VL ≥10 | PMC9955963 | ||
Sensitivity of three brands of antigen RDT compared to nasopharyngeal PCR. | A) all positive patients; B) positive patients with viral loads ≥10The sensitivity of RDT according to viral load categories remained higher than 95% up to 10 | PMC9955963 | ||
Number of patients positive by RDT (in red) and nasopharyngeal PCR (in blue) and sensitivity of RDT according to viral load categories. | SENSITIVITY | Sensitivity of the three RDT brands compared to NP PCR was 92.9% (86.4–96.9%) for STANDARD Q | PMC9955963 | |
Log viral loads by NP PCR according to the RDT brand used. | The diagnostic performance of NP PCR and saliva PCR were equivalent: sensitivity was 95.7% (93.1–97.5%) for saliva compared to NP PCR and 96.5% (94.1–98.1%) for NP compared to saliva PCR, with an intraclass correlation coefficient (ICC) of 0.935 (95%CI [0.926–0.943]) between these tests.When using patients with any test positive as reference, sensitivity was 84.9% (81.0–88.3%) for RDT, 95.8% (93.3–97.6%) for saliva PCR, and 96.6% (94.3–98.2%) for NP PCR. The difference was not significant between NP PCR and saliva PCR test status (p = 0.71), but was so between RDT and NP PCR or saliva PCR (p<0.001). Specificity of RDT was 100% (99.3–100%), which means that there was no false positive RDT. In two instances, RDT was positive, and NP PCR was negative, but the saliva PCR was positive with viral loads of 4.0x10 | PMC9955963 |
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