Study setting {9}
The trial will be conducted in the Central Denmark Region, which has approx. 1.3 m residents. The prehospital emergency medical services (EMS) in the region consist of one regional emergency medical dispatch centre and 70 ambulances manned by 600–700 EMS providers. The prehospital emergency medical services of the Central Denmark Region dispatch 2,000–3,000 ambulances to patients suspected of AECOPD annually. Based on Danish data from 2020, the 30-day mortality was 13% (95% confidence interval (CI): 11–14) in the Central Denmark Region (18). The region has six hospitals capable of receiving and treating prehospital patients with AECOPD.
The EMS providers (emergency medical technicians and paramedics) will participate in the trial by identifying, including and treating eligible patients. Depending on the observed inclusion rate, the trial may be expanded to include two other regions of Denmark (the Region of Southern Denmark and the North Denmark Region).
Eligibility criteria {10}
The eligibility criteria for inclusion in the trial are age above 40 years and suspicion of AECOPD by the attending EMS providers where underlying COPD must be confirmed. The COPD confirmation may be obtained from one of the following sources: verbal confirmation of COPD (from the patient, relatives or caretakers present at the scene) or written confirmation of COPD with ID identifying the patient (from discharge letters, medical record text or lists of medication).
Table 2
Inclusion and exclusion criteria
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Inclusion criteria:
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1. Patients over the age of 40 years
2. The treating emergency medical service (EMS) provider (emergency medical technician (EMT) or paramedic) suspects acute exacerbation of chronic obstructive pulmonary disease (AECOPD)
3. Confirmation of the EMS provider’s suspicion of chronic obstructive pulmonary disease (COPD)
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Exclusion criteria:
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1. Non-chronic obstructive pulmonary disease (COPD) bronchospasm
2. Known or suspected pregnancy
3. Prehospital non-invasive ventilation (NIV), invasive ventilation or bag-mask-assisted ventilation
4. Allergy to inhalation drug (Salbutamol)
5. Transfer between hospitals
6. Acute treatment by EMS providers with more than two doses (5 mg salbutamol) of inhalation drug before randomisation
7. Readmission within 30 days from a previous randomisation
8. Suspicion of acute coronary syndrome (ACS)*
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Legend: *In concordance with the local standard operating procedure and based on: symptoms, electrocardiogramme, trinitrotoluene (TnT) and medical consult.
Who will take informed consent? {26a}
AECOPD is associated with severe dyspnoea, anxiety, desperation and decreased consciousness, especially in the prehospital phase of treatment. Hence, patients are often in a state in which they cannot receive and understand information, making informed consent to study participation impossible. Therefore, the STOP-COPD trial is approved as an acute trial by the Danish Medical Research Ethical Committee. Consent prior to inclusion and treatment is waived, and consent must therefore be obtained as soon as possible after hospital admission. Consent will be obtained by members of the research staff or associated physicians. Information about the trial will be provided in writing and verbally. Declining to give consent will in no way influence the subsequent treatment given to the patient. If a patient declines to give consent, data collection for the patient in question will be discontinued.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
N/A. No biological data or specimens are collected or stored in this trial.
Interventions
Explanation for the choice of comparators {6b}
In this trial, titrated oxygen delivery aiming at a blood oxygen saturation (SpO2) of 88–92% is tested against standard high dose oxygen. Hence, the comparator is standard high dose oxygen where blood saturation is allowed to reach high levels (exceeding 92%).
Intervention description {11a}
Standard treatment
Patients included in the standard (control) group will be treated with inhaled bronchodilators nebulised with 100% oxygen at a flow rate of 6–8 l/min. A bi-nasal end-tidal carbon dioxide (EtCO2) meter will be placed in the patient’s nose during nebulisation for EtCO2 measurement during treatment and transport, which also masks the patient for group allocation. The need of additional treatment will be assessed at the discretion of the treating EMS provider, according to local standard operating procedures (SOP). When nebulised bronchodilators are not being delivered, the patient will receive supplemental oxygen according to local SOP. At hospital arrival, the patient will have an arterial blood gas drawn and analysed within 30 min.
Intervention treatment
Patients included in the intervention group will be treated with inhaled bronchodilator nebulised with compressed atmospheric air (21% oxygen) at a flow rate of 6–8 l/min. A bi-nasal EtCO2 meter will be placed in the patient’s nose during nebulisation for EtCO2 measuring during treatment and while delivering supplemental oxygen, as needed. During nebulisation, oxygen will be titrated to achieve a SpO2 of 88–92%. The need for additional bronchodilator treatment will be assessed at the discretion of the treating EMS provider according to local SOP. When nebulised bronchodilators are not being delivered, the patient will receive supplemental oxygen to achieve a SpO2 of 88–92%. At hospital arrival, the patient will have an arterial blood gas drawn and analysed within 30 min.
Table 3
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Intervention treatment
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Standard treatment
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SpO2 < 88%
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Supplemental oxygen via the EtCO2 meter up to 6 l/min. If higher oxygen levels are needed, oxygen will be used as driver for the nebuliser. If the SpO2 remains under 88%, additional oxygen may be added via the EtCO2 meter.
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Supplemental oxygen via the EtCO2 meter, if needed.
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SpO2 88–92%
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No intervention
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No intervention
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SpO2 > 92%
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No intervention
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No intervention
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Criteria for discontinuing or modifying allocated interventions {11b}
In the intervention and control group alike, the SOP for requesting support from a physician-manned response unit is unchanged. In case of treatment failure with worsened clinical presentation, a prehospital physician may be requested according to the SOP. The prehospital physician then makes the decision on whether to discontinue the allocated treatment. Termination and reason for termination of treatment will be registered and used in the data analysis.
Strategies to improve adherence to interventions {11c}
Twice weekly, members of the research staff will do real time audits on data base registrations with feedback to individual EMS providers in case of irregularities. The audits will focus on; firstly, the screening of all eligible patients and, secondly, EMS providers protocol adherence.
If suitable patients are not screened for participation, the EMS providers will be contacted by the research staff as a reminder and to establish if any unforeseen inclusion problems have been encountered. Based on frequent audits and experience from previous studies, we expect a high recruitment rate. Protocol violations will be registered and reported in the final manuscript. The data monitoring committee (DMC) will conduct interim analyses, including protocol violations, on predefined milestones. If the DMC recommends measures to reduce the number of protocol violations, the Trial Steering Committee will act accordingly.
Relevant concomitant care permitted or prohibited during the trial {11d}
Enrolment will occur when the patient is physically present in the ambulance care area. Before the EMS provider and patient are present in the ambulance, acute treatment is allowed with up to 5 mg of Salbutamol nebulised with oxygen. The EMS providers will be thoroughly trained to reduce this period to a minimum. Besides receiving the allocated trial treatment with different compositions of gases for nebulisation and target SpO2, the patients will receive the usual prehospital and in-hospital care at the full discretion of the treating EMS providers and in-hospital clinicians. However, patients are excluded when treated with non-invasive ventilation (NIV) or invasive ventilation by the physician-manned response unit prior to randomisation.
Provisions for post-trial care {30}
N/A. Trial participants will not be compensated for their participation. Trial participants are insured through the national Danish patient insurance scheme.
Outcomes {12}
Primary and secondary outcomes are presented in Table 4. All outcome assessments will be completed on day 30 after randomisation. Patients who are readmitted will be registered as such and their 30-day mortality will be determined from the first admission.
Table 4
Primary and secondary outcomes
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Primary outcome:
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• 30-day mortality presented as risk difference (RD) and risk ratio (RR) measured from randomisation. The outcome will be assessed using the electronic patient journal.
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Secondary outcomes:
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• 24-hour mortality and 7-day mortality presented as RD and RR measured from randomisation.
• Length of hospitalisation presented as days from randomisation to discharge.
• Intensive care unit (ICU) admission rate presented as RD and RR of enrolled patients admitted to ICU from randomisation to hospital discharge.
• Length of ICU stay as total number of days in ICU from randomisation to discharge presented as mean differences.
• In-hospital need for non-invasive ventilation (NIV) (at 24 hours, 7 days and 30 days) presented as RD and RR measured from randomisation.
• In-hospital need for invasive ventilation (at 24 hours, 7 days and 30 days) presented as RD and RR measured from randomisation.
• Time to in-hospital NIV presented as Aalen-Johansen curves and hazard ratio (HR) measured in days from randomisation.
• Time to in-hospital invasive ventilation presented as Aalen-Johansen curves and hazard ratio measured in days from randomisation.
• Proportion of patients with acidosis on arrival to hospital presented as RD and RR measured on in-hospital arterial blood gas (ABG) drawn < 30 min. from hospital arrival.
• Degree of acidosis on ABG (pH) presented as mean or median differences.
• Patient-experienced dyspnoea score (verbal rating scale 0–10) measured before intervention treatment and at hospital arrival presented as median differences.
• Readmission rate from day 2 to day 30 after discharge presented as RD and RR.
• Time to readmission from discharge to day 30 presented as Arlen-Johnson curves and HR.
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Participant timeline {13}
Sample size {14}
The sample size estimate for the STOP-COPD trial is based on results from the CRT by Austin et al. (5). An absolute risk reduction of 5% for in-hospital mortality was found in the intention-to-treat analysis in favour of a restricted titrated oxygen treatment to patients with suspected AECOPD.
However, the STOP-COPD trial differs from the CRT by Austin et al. with respect to study setup. In the CRT, not all included patients were treated with inhaled bronchodilators, and the control group received higher oxygen concentrations than prescribed in current standard practice. Furthermore, a larger uncertainty is associated with a CRT setup as a result of reduced power. In addition, a limited number of clusters increases the risk of cluster-specific confounding, considering administrative differences between sites, etc. To accommodate for these differences, we translated the findings in the CRT by Austin et al. to our study by using a conservative estimate of a 3% reduced (risk difference) 30-day mortality in favour of titrated oxygen treatment. At a power of 80%, an expected drop out of max. 4% and a significance level of 5%, the total required sample size will be 1,888 patients − 944 in each treatment arm. Due to the uncertainty of the estimated risk reduction, a sample size re-estimation is planned. When data have been collected for the first 500 patients, a re-estimation of the sample size will be made based on the observed risk difference seen in this interim analysis. A new sample size from the re-estimation will be considered in terms of its clinical relevance and feasibility and forwarded as a recommendation from the DMC.
Recruitment {15}
All patients treated with nebulised salbutamol in the ambulances will be screened for study participation using a randomisation smartphone app (see section 16a).
Assignment of interventions: allocation
Sequence generation {16a}
Patients will be randomised in a 1:1 ratio. A randomised block design will be utilised, using receiving hospital, sex and age group (above/below 70 years of age) as block factors. Each block will be of random size comprising four, six or eight patients. The patients will be randomised by trained EMS providers using a smartphone app supported by The Clinical Trial Unit, Aarhus University, Denmark. This app will be accessible from smartphones or tablets and requires no login information besides the receiving hospital’s ID. In the app, the following items of information are requested: receiving hospital, patients Civil Registration Number and inclusion/exclusion criteria. The randomisation sequence incorporating the block design will be generated by an independent data manager and will not be accessible to the clinicians responsible for patient enrolment.
Concealment mechanism {16b}
N/A. This is an open label trial.
Implementation {16c}
N/A. See section 16a
Assignment of interventions: Blinding
Who will be blinded {17a}
The trial will be single blinded with patients blinded to treatment allocation. The EMS providers will be instructed to keep the patients blinded, but they will not themselves be blinded. A protocol for emergency unblinding is unnecessary.
Procedure for unblinding if needed {17b}
N/A. See section 17a.
Data collection and management
Plans for assessment and collection of outcomes {18a}
The first data will be collected by the EMS providers during randomisation, including the Civil Registration Number and data on admission hospital and inclusion/exclusion criteria. After obtaining informed consent and 30 days after randomisation, all other data will be collected from the electronic patient record and registered in the electronic case report form by trained research staff. One hundred days after randomisation, a safety follow-up will be made searching the electronic patient record for late registration of death.
All EMS providers involved in the treatment of enrolled patients will be trained to optimise data quality and validity. All data will be entered into the electronic case report form according to a data dictionary created prior to patient enrolment. The electronic case report form will be tested and validated before the trial is initiated.
Plans to promote participant retention and complete follow-up {18b}
If a patient is discharged before consent is obtained, the patient will be contacted by telephone to arrange a physical meeting or a video call where full information on study participation will be given. Furthermore, the patient is given the opportunity to raise questions and signed written informed consent may be agreed upon.
Data management {19}
All baseline and follow-up data will be collected from the electronic prehospital patient record and electronic patient record by trained research staff and entered into the electronic case report form in Research Electronic Data Capture (REDCap). The electronic case report form will comprise safety ranges and data entry validation rules ensuring correct data entry.
Confidentiality {27}
All confidential data on the included patients will be stored in REDCap – both the electronic case report forms and the signed electronic consents. In REDCap, the data will be stored during the full inclusion period and will be exported only for analysis. Data analysis will be performed on the data exported from REDCap and stored in a secure electronic data base (MidtX) hosted by the Central Denmark Region according to European Union regulations (19). Data will be handled according to all relevant Danish and European Union provisions, including the General Data Protection Regulation and the Data Protection Act (20, 21). The project will be registered with the internal register of research projects of the Central Denmark Region, with permission from the Danish Data Protection Agency. Each patient will receive a unique trial identification number. During the trial, the sponsor, investigator, research staff and coordinator will have access to the entire databases (REDCap and MidtX). The Good Clinical Practice unit, regulatory agencies and other relevant entities will have direct access to patient records and to all relevant trial data including the electronic case report form, as applicable. The DMC does not have direct access to data; instead, specified analysed data will be shared according to the charter for the DMC; additional data may be shared on request.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
N/A. No trial-related biological specimens will be collected.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Differences in mortality are calculated as RD and RR, performed using linear regression and Poisson regression, respectively, with robust variance estimation (22–24). For the primary analysis, the estimation is a crude analysis. All results will be presented with 95% CI. All binary secondary outcomes will be analysed in the same way as the primary outcome. Time-to-event outcomes will be analysed using Cox proportional-hazards regression and Tobit regression. Continuous outcomes will be analysed using linear regression. The patient-experienced dyspnoea score will be analysed using linear mixed effects models.
Interim analyses {21b}
Interim analyses will be made on predefined milestones (i.e., after 200, 500, 1,000 and 1,500 enrolled patients) once follow-up data have been collected. The results from the interim analyses will be presented only to the DMC who can recommend immediate trial discontinuation for reasons of futility or harm based on the following criteria; 1) patients have a statistically significantly higher risk of death in one treatment arm than in the other (1% significance level), 2) patients have a significantly higher risk of safety issues (untreated hypoxia defined as repeated measures of SpO2 lower than 88% for a duration of ≥ 5 minutes after allocation – the significance level will be set at the discretion of the DMC).
Methods for additional analyses (e.g., subgroup analyses) {20b}
The following subgroup analyses will be made; 1) primary and secondary outcome for groups defined by pulse-oximetry-measured blood saturation (< 88%, 88–92% and > 92%) determined prior to the first administration of inhaled bronchodilators; 2) primary and secondary outcomes using prehospital transport time as a regression variable; 3) primary and secondary outcomes analysed on patient groups defined by a final diagnosis of AECOPD (yes/no); and 4) primary and secondary outcomes analysed by patient groups defined by in-hospital NIV and invasive ventilation.
If statistical analysis and methods that are not described in the protocol are deemed useful and
important in the reporting of results, this will be stated clearly in the main article.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
All analyses will be made on an intention-to-treat basis. Patients with missing data on the primary outcome will be excluded. Sensitivity analyses will be made using multiple-imputation-chained equations with 100 imputation sets and including relevant first- and second-order variables in the imputation model (25). Possible differences in patient characteristics and exposure between complete cases and dropouts are addressed by sensitivity analyses adjusted by appropriate patient characteristics using inverse probability of treatment weights (IPTW). Balanced diagnostics are conducted using the threshold criteria given by Zhang et al. (26).
Plans to give access to the full protocol, participant-level data and statistical code {31c}
All trial-related documents, including the protocol, will be publicly available at the trial website. De-identified participant-level data will be made available upon reasonable request. Anonymised data will be stored for 25 years.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The coordinating centre is placed at the research unit at the Prehospital Emergency Medical Services in the Central Denmark Region. The day-to-day management of the trial will be handled by the Trial Coordinator and the Principal Investigator in collaboration. The Trial Steering Committee consists of the Principal Investigator, the Trial Coordinator and clinical experts in prehospital emergency medicine and pulmonary medicine. The Steering Committee will oversee the trial by reviewing and approving any study protocol modifications and by reviewing trial progress. The Steering Committee will gather after the DMC have held their scheduled meetings and discuss DMC recommendations. In case of unexpected events, the Steering Committee will gather at short notice.
Composition of the data-monitoring committee, its role and reporting structure {21a}
The DMC will be responsible for safeguarding the interests of the trial participants and for assessing the
safety and efficacy of the interventions during the trial. Also, the DMC is responsible for monitoring the overall conduct of the trial. The DMC consists of three specialists with expertise in anaesthesiology, intensive care and clinical research, and thus holds clinical and statistical expertise as recommended (27). The DMC is independent of the sponsor and other members of the research staff. The DMC will review de-identified data for safety at five predetermined milestones (200, 500, 1,000 and 1,500 enrolled patients), but can, at any time, require extra reviews. Unless group differences are observed that require unblinding (as determined by the DMC), the DMC will be blinded to treatment groups. The trial will continue while the DMC reviews data. After a review, the DMC will prepare a short report for the Steering Committee with recommendations for continuation, modifications or termination of the trial. The final decision on potential modifications or termination will rest with the Steering Committee and the Sponsor-investigator. A detailed charter for the DMC will be available on the STOP-COPD trail website after patient inclusion starts.
Adverse event reporting and harms {22}
During data entry into the electronic case reports forms (performed twice weekly), the electronic prehospital patient record will be screened for adverse events by research staff and any findings will be registered. Adverse events reported to by EMS providers, prehospital physicians, in-hospital clinicians, patients or relatives will be registered by the Sponsor-investigator. The Sponsor-investigator will classify the events as one of the following; adverse events, adverse reactions, serious adverse events, serious adverse reactions or suspected unexpected adverse reactions according to the list of adverse reactions in the summary of product characteristics. Suspected unexpected serious adverse events will be reported to the Good Clinical Practise unit, which will report to the EudraVigilance database. Due to the short half-life of the intervention and control drug, adverse events will be registered only if occurring in the prehospital phase. The reporting will be according to legislation and guidelines (19, 28).
Frequency and plans for auditing trial conduct {23}
The Good Clinical Practice unit from Aarhus University will monitor and audit the trial. Before patient enrolment, a detailed monitoring plan will be prepared in collaboration between the Good Clinical Practice unit and the Sponsor-investigator. The Good Clinical Practice unit will audit the following on all enrolled patients; primary outcome; consent; in/exclusion criteria and adverse events. Additionally, 10% of all enrolled patients will have a complete audit comprising all collected data points.
Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}
Changes to the protocol will be decided on Steering Committee meetings and reported to the European Union clinical trials unit according to current legislation (19, 28). Changes affecting the in- and exclusion criteria, interventions and randomisation will be conveyed thoroughly to the prehospital clinicians (EMS providers and prehospital physicians).
Dissemination plans {31a}
Following the CONSORT guidelines, the trial results will be published regardless of any negative, inconclusive or positive results (29, 30). The results will be published in an international peer-reviewed journal with open access and disseminated as conference presentations. If the results from the trial have public interest, they will also be presented to mainstream media. The trial results will be shared with the participating EMS providers, patients and others at the trial website. Within one year after the trial concludes, the results will be uploaded to the European Union Clinical Trials database (19, 31). Authorship will follow the International Committee of Medical Journal Editors guidelines (32).