The following are objectives 1 to 6: to evaluate the effectiveness of POC PCR availability in general practice on (1) the number of recontacts to the GP for patients with symptoms of ARIs (primary outcome); (2) the number of redeemed antibiotic prescriptions, (3) health-related quality of life, and (4) GP and patient satisfaction. In addition, (5) the number of hospital admissions and (6) deaths are included as safety measures.

The following are objectives 7 and 8: to evaluate (7) the costs and (8) the cost-effectiveness of POC PCR availability in general practice compared with usual care.

The following is objective 9: to identify and analyze contextual facilitators and barriers as well as behavioral factors that influence potential uptake of the implementation process tied to the POC PCR equipment.

This study uses recontacts as a primary outcome of evaluating the effectiveness of the test, as this is a less-explored phenomenon associated with ARIs. Denmark is already one of the countries with the lowest consumption of antibiotics, which is why this measurement is also included in the study (as a secondary outcome in the analyses). While investigating patterns tied to antibiotic prescriptions are important, the scope of this study is to explore the wider operations of a general practice setting, which a primary but not isolated focus on recontacts allows.

The study will be conducted over a period of 25 weeks (Figure 1).

In the month leading up to the intervention period, the POC PCR device will be installed in the intervention clinics by staff from Roche Diagnostics A/S, and assays and equipment necessary for the testing will be sent to the clinics free of charge. Just before entering the trial period, each clinic will be trained by staff from the clinical trial unit from SDU. During the training session, the clinic will receive further information about patient inclusion, registration of eligible patients in the reimbursement system, and whether the clinic is about to enter an intervention period, including training on how to perform the POC PCR tests. In addition, all clinics will receive an information poster for patients to display in the waiting area. All GP clinics will receive a fee of DKK 6000 (approximately €800 or US $840; 1DKK= US $0.14) for participating in the study. In addition, GPs will be remunerated for performing the test (DKK 71.48 [approximately €9.50 or US $10] per test equivalent to already established POC tests). The clinics participating in the process evaluation will receive another DKK 1000 per interview (approximately €134), and DKK 2000 (approximately €268 or US $280) per whole day during observation studies.

An overview of the pretrial activities is presented in Textbox 1.

All patients with ARI contacting the participating GP clinics during the intervention or control period will be included in the study. Before or after the consultation with the GP, the clinic staff will hand out information materials about the project, including a leaflet with a QR code and a link to a questionnaire.

In the control period, patients with ARI will receive usual care, usually comprising no or limited diagnostic tests at the clinic, or nasal or pharyngeal swap for testing at an external laboratory with an expected response time of 1 to 3 days. During the intervention period, the POC PCR equipment will be used when the GP deems it relevant.

Developed by Roche Diagnostics A/S, the POC PCR test system tested in this study comprises an analysis instrument and assay tubes for testing (1) StrepA, (2) Sars-Cov-2 and Influenza, and (3) Influenza or respiratory syncytial virus (RSV). The test is performed on oropharyngeal (StrepA), nasopharyngeal (SARS-Cov-2 or Influenza, and Influenza or RSV), or nasal (Influenza or RSV) swap samples. Running the test takes approximately 20 minutes per assay.

After the consultation, the GP registers the project specific reimbursement codes in the electronic patients record system. Three different reimbursement codes are used: the first code is for the registration of each individual patient with ARI contacting the clinic. This code is used in both control and intervention periods. The second code is for each time the POC PCR test is performed (allowed only once per patient per consultation even though it is possible to perform multiple tests within the same consultation), and the third code is for situations where the test result is conveyed by phone or email to the patient the day after the test is performed. The last two codes are for intervention periods only. GPs are only remunerated for performing the test.

Outcomes are on the individual patient level, and the clustering involves the entire GP clinic, not the individual GP. A balanced design with a common total cluster size and common period effect was adopted. As the study is a superiority trial, results from the feasibility study [16] and Danish national register data will inform the choice of parameters as inputs to the sample size formula derived by Li et al [19]. The intended effect size was fixed at a reduction from 0.32 to 0.28 based on the register results, which approximately corresponds to the distance between the median or mean to the 25th percentile. With a significance level of 0.05, power at 0.8, within-period within-cluster correlation of 0.02, and across-period within-cluster correlation as 0.01 to detect a difference between a prevalence of 0.32 recontacts in the control group and 0.28 in the intervention group, the sample size was calculated as 108 clinics, contributing 50 contacts each in the trial period. Pragmatically, the inclusion of 100 clinics was chosen.

Due to the intervention procedure (an oropharyngeal, nasopharyngeal, or nasal swab) and the use of project specific reimbursement codes, it is not possible to blind the patients and GPs.

The primary outcome is modeled as group difference in number of patients with ARI recontacting the GP from the date of the initial contact (day 0) and the following 7 days in the intervention and control periods [19]. Secondary outcomes include safety outcomes such as group difference in the total number of redeemed antibiotic prescriptions (day 0 and following 7 days), the total number of hospital admissions, and deaths (from the date of the initial contact [day 0] and following 14 days) and total treatment costs, productivity costs, quality-adjusted life years, and incremental cost-effectiveness or utility ratio (from day 0-28) [14]. In addition, patient (day 0) and GP satisfaction (after the end of trial) is evaluated along with patients’ health-related quality of life (day 7, 14, and 28). Furthermore, the study elucidates several aspects and factors based on the process evaluations’ qualitative design, which allows us to assess the quantitative outcomes. Where the quantitative outcomes emphasize measured effects, the qualitative design allows insight into, for instance, the participants’ perceptions of diagnostic practices in the clinic, the emergence and coordination of behavior, experiences, and interactions with the device, and thus explains how people use and perceive the device the way they do [16]. Multimedia Appendix 1 describes the different outcomes and points of interest including information on the specific measure, metric, applied instrument, time period, data source, and target population in a table overview.

The evaluation is based on both quantitative and qualitative methods. Quantitative data will be collected from national administrative registries and via web-based questionnaires; qualitative data will be collected via interviews and observations, including video observation (see details in subsequent sections).

The GPs or staff will distribute a leaflet with a QR code (and a link) to a web-based survey to all patients with ARI aged ≥15 years. For patients aged <15 years, the caregiver will be asked to answer the questionnaire. In the first questionnaire, the personal identification number and contact information will be collected, and the subsequent questionnaires will be distributed via a link in email and SMS text message at day 7, 14, and 28. In case of nonresponse, reminders will be sent within 2 days. Participants who complete all 4 questionnaires will be entered into a lottery for 1 gift card of Dkr 1000 for completing the first questionnaire and 1 gift card of Dkr 2500 for completing all 4 questionnaires. Questionnaires will be managed via a secure electronic questionnaire system (SurveyXact). Each questionnaire will take approximately 5 to 10 minutes to complete. Furthermore, a questionnaire will be sent to all participating GP clinics at the end of the trial followed by a reminder after 2 weeks in case of no response. The questionnaire will take approximately 5 minutes to complete. In it, the GPs will be asked about their overall experience of the equipment associated with (1) support for performing precise diagnostics, (2) support for clinical judgment, (3) the influence of the test results related to clinical management of patients, (4) the influence of the test results in patient communication concerning their condition, (5) disruption of consultation, (6) disruption in overall workflow, and (7) whether the equipment belongs in general practice. In addition, there is space for the GPs to write comments.

Comprehensive public register data on contacts and services provided in primary care, prescription of antibiotics, and hospital contacts and various characteristics of the GP clinics will be retrieved from the Danish Health Data Authority [20]. Furthermore, information on morbidity, socioeconomic status, and various demographic characteristics on each patient will be obtained from Statistics Denmark [21]. Data from the different registers are linked by the patients’ personal identification number. No data will be retrieved from the registers until the protocol paper is accepted for publication.

Qualitative data will be collected through an ethnographic fieldwork, which includes several key components. First, 10 pre- and postintervention interviews will be conducted with GPs and staff across 11 clinics. In addition, participant observations will take place in 5 clinics both before and during the intervention along with video observations in 3 out of the 5 clinics. Furthermore, 14 patient interviews will be held after the intervention.

Interviews with health professionals will focus on value assessments and sense-making processes tied to their experience with diagnostic technologies in general and the POC PCR equipment specifically. Participant observation will be conducted (with and without video-recorded participation) to obtain in-depth knowledge about everyday working life; organizational and communicative behavior; and interactions between health professionals, staff, and patients with (and without) the POC PCR equipment in the GP clinic. Finally, patient interviews will focus on their experience with use of the POC PCR equipment, feelings of diagnostic certainty, and reflections concerning the perceived impact of the POC PCR test on relational and communicative processes.

Questionnaire data will be collected by SurveyXact and stored on secure servers at University of Southern Denmark. After data cleaning, questionnaire data will be transferred to secure scientific servers at Statistics Denmark and linked to register data via the personal identification number, after which all data will be pseudonymized.

Qualitative data will be collected by means of digital recorders during interviews, by field notes during observations, and using a GoPro video camera (handheld by the researcher) during video observation. After collecting data, they will be stored on secure servers provided by SDU. NVivo software (QSR International) will be used for transcriptions and analytical purposes.

After publication of the study, the data manager will ensure that all study data are deleted.

Demographic characteristics of the included patients and GP clinics will be presented. Analysis of the binary primary outcome uses a standard logistic regression model on the individual (contact) level, accounting for clustering of patients in clinics by generalized estimating equations. Primary analysis will follow an intention-to-treat approach, and we want to show superiority. A corresponding analysis strategy will be applied for hospital admissions, deaths, and redeemed antibiotic prescriptions. A level of 5% will be set as statistically significant. Analyses will be performed with the most recent version of Stata (StataCorp).

The cost-effectiveness analyses will take both a national health care perspective and, separately for the purpose of sensitivity analysis, a limited restricted societal perspective, including health care costs, patient costs (travel cost), and productivity costs for patients or their caregiver (in case the patient is a child aged <15 y). Cost-effectiveness will be reported in terms of the incremental cost-effectiveness ratio (ICER) expressed as the difference in costs divided by the difference in outcome, between patients in the intervention and control groups. Costs will be estimated from the time of initial contact (day 0) and over a follow-up period of 28 days and calculated by category. Due to the short duration of the study, costs and outcomes will not be discounted. Costs will be expressed in Euros, in 2024 conversion rates. Effect will be measured as the total number of recontacts within 7 days and quality-adjusted life years within 28 days. Quality-adjusted life years are calculated as the area under the utility curve for each patient based on patients’ health-related quality of life measured by EQ-5D-5L for patients aged >15 years (in Denmark, individuals become responsible for managing their own health care at the age of 15, therefore not a requiring parental intermediary or proxy completion of the EuroQoL 5-Dimension) and valued using Danish value sets [22,23]. Missing costs or quality-of-life data will be handled by multiple imputations. Differences in mean costs and effect will be estimated using separate generalized linear regression models, with appropriate distribution and link functions for costs and outcomes. The models will control for treatment, time point, treatment-by-period interaction as fixed effects, and cluster at the GP level as a random effect. Furthermore, the models will adjust for baseline health care cost (6 months before the initial contact) and baseline utility [24]. Nonparametric confidence intervals for costs, effect, and ICER will be computed using a 2-stage bootstrapping technique with 1000 replications [25] and the 2.5th and the 97.5th percentile of the 1000 bootstrap replications. Conventional methods for estimating uncertainty around the ICER, such as cost-effectiveness acceptability curves, will be applied as well. Sensitivity analyses will be conducted to test assumptions, uncertainty around variable estimates, and the robustness of results.

All qualitative analyses will be analyzed using the reflexive thematic analysis by Braun and Clarke [26]. Following this approach, the transcripts will be initially read and reread, with participants taking notes along the way using the annotations feature in CASDAQ software NVivo (version 14; QSR International). Afterward, still using NVivo, the data will be coded inductively. Codes are then grouped into themes and subthemes that capture, on a general level, the identified factors promoting and impeding potential users’ use of the POC PCR equipment.

Specifically, preintervention interviews with GPs and staff focus on the organization of the clinic and everyday experiences in the clinic as well as expectations regarding the upcoming intervention, diagnostic processes, and technology.

Postintervention interviews with GPs and staff focus on experiences of the usefulness, effect, and meaningfulness of the POC PCR test during the intervention.

Interviews with patients focus on the participants’ experience with their symptoms, diagnosis, treatment, and use of health technologies for diagnostic purposes and also on their reflections concerning the perceived impact of the POC PCR test on relational and communicative processes (eg, whether the test enhances feelings of trust, of being taken seriously, and of reassurance). Participants accompanying a child aged <15 years will be interviewed relative to their considerations and experiences associated with the experience of being in the consultation with the child.

Analysis of the preintervention video observation data will focus on the learning processes in connection with training sessions and characteristics of standard practices in the clinic relating to patients with ARI. Analysis of video observation data collected during intervention will focus on how usefulness and potential implementation barriers and facilitators play out during the everyday working life of GPs and staff.

As the project entails an evaluation study of an already CE-certified diagnostic tool, approval from the Danish Medicine Agency and the Scientific Committees of Medical Ethics (from Danish: De Videnskabsetiske Medicinske Komiteer) has been waived. The study has been assessed and approved by Local Ethics Committee at University of Southern Denmark (case number 23/1584) and University of Southern Denmark’s Research and Innovation Organization (SDU RIO; journal number: 11.907).

In addition, the project has been registered on ClinicalTrials.gov (NCT06120153).

Informed consent is not required for collection of questionnaires and register-based data according to the Danish Data Protection Act Section 10. For the interviews and observations, written and oral consent is obtained from the GP or staff before video observation in the clinic. When a patient arrives for consultation, oral and written information about the project is given and consent for observation is obtained. Only if the patient consents, the consultation is observed and recorded. After observation, the researcher asks the patient for permission to a follow-up interview. The patient is provided a copy of the consent form and written information about the project, General Data Protection Regulation, and contact information for the project team.

None of the questionnaires or planned interviews contain psychological trigger questions nor is the intervention expected to give rise to any unwanted effects, as the POC PCR equipment used applied is a CE-certified diagnostic tool already in clinical use in other settings. Whether the POC PCR test is used by the health professional is entirely up to the individual to decide. Whether the GPs or patients choose to participate in the project does not have any influence on their treatment, and it is completely voluntary to fill out questionnaires or participate in interview- and observation studies.

Data from interviews and observations will be stored at a secure server provided by SDU. Personal information (names, cities, and other locations) will be pseudonymized during the stages of transcribing the data and rewriting the field notes. For the purpose of scientific publications, screenshots from video recordings will be deidentified as sketches, as drawings, or with blurred features.

In line with the collaboration agreement signed between SDU and Roche Diagnostics A/S, only researchers and project team members from SDU have access to the data.

In accordance with the contractual agreement signed by SDU and Roche Diagnostics A/S, SDU can present and publish data and results from the project regardless of the outcome in concordance with Danish law. Full disclosure is given to Roche Diagnostics A/S related to the sponsor’s supporting role in the project in all written and oral presentations. Roche Diagnostics A/S has the right to review and offer comments for written or oral presentations as well as the right to intervene if any confidential information provided by Roche Diagnostics A/S is made public. Around 30 days before submission for publication, Roche Diagnostics A/S must receive the material intended for publication or public presentation for review. However, it is SDU’s right to decide whether any comments or inputs from Roche Diagnostics A/S will be included in the publications. Roche Diagnostics A/S is allowed to use publications or abstracts from the project when reference is made to the author or authors in accordance with applicable law, and only after such publications have been made publicly available.