The STARLINER study (ClinicalTrials.gov NCT03261037) is a multicentre, ongoing study that plans to enrol approximately 180 patients across approximately 40 community and tertiary clinical centres in Canada, France, Ireland, Italy, the Netherlands and Russia (for further details, visit https://clinicaltrials.gov/ct2/show/study/NCT03261037). To reflect clinical practice, where many patients may not be treated at ILD tertiary centres (i.e. specialist centres), this study will aim for approximately two-thirds of sites to be community centres.
This study will assess disease behaviour in patients with suspected ILD, including IPF, during the peri-diagnostic period, which will consist of the pre-diagnostic period (from inclusion to diagnosis; up to a maximum of 12 months) and the post-diagnostic period (from diagnosis to treatment initiation; or up to 6 months after diagnosis) (Fig. 1). Disease behaviour will be assessed in terms of pulmonary function and physical functional capacity, which will be measured at home using daily spirometry and accelerometry, respectively, and at site visits using site spirometry and the 6-min walk test (6MWT), respectively.
Patients will leave the study if they do not receive a diagnosis within 12 months of inclusion or if they receive a non-ILD diagnosis (Fig. 1). Patients diagnosed with ILD within 12 months of inclusion will remain in the study for a maximum of 6 months after the patient receives a diagnosis from the investigator, or until the date treatment commences. Therefore, the total length of the study will vary for each patient (up to a maximum of 18 months) depending on their individual patient journey and local clinical practice.
The study design will be facilitated by a digital ecosystem consisting of two pillars (Fig. 2). Pillar 1 will comprise the spirometers and accelerometers that will be used for home-based assessments, which will have a real-time connection to a tablet computer, allowing patients to view their results in real time. Pillar 2 will include the digital collaboration platform, which will enable virtual MDT discussions between community and tertiary sites (Fig. 2). Additionally, the tablet computer will act as a bridge between the two pillars, linking the patient data to the collaboration platform, where investigators will be able to access their patients’ data in real time (Fig. 2).
Symptomatic patients (unexplained dyspnoea on exertion and/or cough) with suspected ILD/IPF aged 50 years or more with radiological evidence (on chest radiograph or computed tomography scan) of ILD/IPF will be eligible for inclusion. In accordance with the investigators’ judgement, patients must be able to comply with the study protocol and must provide signed informed consent to the investigators. Patients will be excluded if they participate in any investigational study within 28 days prior to inclusion, have a history of clinically significant cardiac disease that could explain their symptomatology in the opinion of the investigators, or have a known history of any connective tissue disease, including, but not limited to, rheumatoid arthritis, scleroderma, systemic lupus erythematosus or mixed connective tissue disease.
No investigational medicinal product will be assessed in this study, and patients will be managed according to the standard of care at the discretion of the treating clinician. All medications taken for comorbid conditions will be continued as necessary and will be recorded throughout the study. Three mandatory site visits will be conducted at baseline, diagnosis and end of study for each individual patient, and additional site visits will be scheduled at the discretion of the investigator. This study will be conducted under real-life conditions, and therefore the timing of all mandatory and additional site visits will not be pre-determined, although additional site visits should include at least one visit during each study period (pre- and post-diagnosis). Mandatory assessments will consist of pulmonary function, physical functional capacity and patient-reported outcome (PRO) measures (see Table S1 in the Electronic Supplementary Material). Any other assessments will be performed at the discretion of investigators, according to local clinical practice.
For home-based assessments, daily measurement of forced vital capacity (FVC; in millilitres) will be performed using a portable handheld spirometer (Spirobank® Smart; Medical International Research, Rome, Italy) (Table 1). Patients will receive training on how to perform spirometry at enrolment and will perform “test blows” until they can demonstrate a reliable manoeuvre. Patients will also be provided with a manual and will have access to a digital avatar to help them complete the spirometry assessments successfully. Physical functional capacity will be assessed using continuous daily measurement of steps per day and calorie expenditure with an accelerometer resembling a watch (Steel HR; Withings, Issy-les-Moulineaux, France) (Table 1), which will be worn around the wrist. Patients will receive training on how to use the accelerometer at enrolment and will be provided with an instruction manual for the device.
At site visits, pulmonary function and physical functional capacity will be assessed, according to the instructions provided to investigators in the study procedure manual, using site spirometry and the 6MWT, respectively (Table 1; see also Table S1 in the Electronic Supplementary Material). The 6MWT will only be performed at sites where a formalised process is available and the test can be performed under safe conditions. Patients will complete the PRO assessments at baseline and at the request of the investigator just prior to, or during, site visits, and they will always be completed in the same order. PROs will include the King’s Brief Interstitial Lung Disease questionnaire, the modified Medical Research Council Dyspnoea Scale, the 5-Level EuroQol 5-Dimension questionnaire, the Fatigue Assessment Scale, a Cough-Visual Analogue Scale (VAS), an Urge-to-Cough VAS and a Fatigue-VAS (Table 1).
Digital Collaboration Platform
At study enrolment, each patient will receive a handheld spirometer, an accelerometer, a tablet computer and user manuals. Patients will be able to view their spirometry and accelerometry data on their tablet computers, which will also act as a conduit for real-time data transmission to the collaboration platform, where investigators will be able to access their patients’ data (Fig. 2). In the event that patients do not wish to have access to their clinical data, or become distressed as a result of viewing it, investigators will have the option to block the patient’s data access on the tablet. Investigators will be notified via email and text message if a patient has not measured their pulmonary function for 3–4 consecutive days or if more than 10% relative decline from baseline in FVC (in millilitres) is recorded for three consecutive days. Patients will also be able to request for their site investigators to contact them via a “call back” feature on their tablet computer. Investigators from community sites will be able to share data (such as high-resolution computed tomography images and home assessment results) with other centres via the collaboration platform, allowing virtual MDT discussions to take place between community and tertiary sites (Fig. 2). Discussions between centres can take place at any time during the study, with all diagnoses at the discretion of the investigators. Participation in the virtual MDT is optional, and the clinical experts included will depend on the requirements of the individual sites. The study sponsor will not have access to the digital collaboration platform. Patient data from the tablet computers will be anonymised and transferred to the study database for analysis.
The primary endpoint of this study is the time-adjusted semi-annual change in FVC (in millilitres) in patients with IPF, measured using daily home spirometry, during the peri-diagnostic period. A full list of study endpoints is presented in Table S2 in the Electronic Supplementary Material.
Secondary endpoints include changes in FVC in patients with ILD, excluding patients with IPF, measured using daily home spirometry; changes in FVC in patients with ILD and IPF, measured using site spirometry; changes in physical functional capacity in patients with ILD and IPF, measured using daily home accelerometry and site 6MWT; and the correlation between home and site measurements for pulmonary function and physical functional capacity. Changes in health status and quality of life, measured using PROs, and the incidence of non-elective hospitalisations, investigator-reported acute exacerbations and mortality will also be recorded (see Table S2 in the Electronic Supplementary Material).
A number of exploratory endpoints will also be assessed, including an analysis of baseline characteristics and changes in FVC by ILD subgroup. At the end of the study, patients and investigators will complete structured surveys that will collect data on the usefulness and practicality of the collaboration platform and the digital ecosystem; for example, their general experiences with the technology and whether investigators collaborated with a tertiary site. Any non-compliance to home assessments (for seven or more consecutive days) will be counted objectively throughout the study period.
This study has no investigational medicinal product and patients will leave the study prior to initiating pharmacological treatment for ILD; therefore, there will be no safety objectives. Any events thought to be related to a medicinal product used during the course of a patient’s standard medical treatment will be reported to the market authorisation holder or local health authority, according to local regulatory requirements.
The planned sample size of 180 patients is based on an assumption that approximately 40% of enrolled patients will be diagnosed with IPF, 50% will be diagnosed with non-IPF ILD and 10% will receive a non-ILD diagnosis or will remain undiagnosed 12 months post-enrolment.
The primary endpoint of time-adjusted semi-annual change in FVC (in millilitres) in patients with IPF will be presented descriptively, with two-sided 95% confidence intervals. FVC change for individual patients will be estimated by applying a linear regression model to all data points. The estimated FVC change for each individual patient will then be used to calculate the mean FVC change in the overall cohort of patients with IPF. A repeated-measures mixed model will be applied to estimate the FVC change over 6 months as a sensitivity analysis.
The secondary endpoint of time-adjusted semi-annual change in FVC (in millilitres) in patients with ILD, excluding patients with IPF, measured using home spirometry, will be analysed using the same method as for the primary endpoint. Changes in physical functional capacity and PROs will be summarised descriptively over time. The correlation between home and site measurements of FVC and physical functional capacity will be analysed using Pearson’s correlation coefficient, taking the individual mean FVC changes and accelerometry values for each patient into account.
Data Monitoring Committee and Interim Analyses
The study will be conducted under the leadership of a steering committee. In the absence of the use of any investigational medicinal product, an independent review committee or a data safety monitoring board/data monitoring committee will not be needed. Interim analyses will be performed at least once per year. The first interim analysis is planned for when 20 enrolled patients are diagnosed with IPF and can be fully evaluated with regard to the pre-diagnostic period.
Ethics and Dissemination
This study will be conducted in full conformance with the International Conference on Harmonisation (ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country where the research is conducted, whichever affords the greater protection to the individual. The study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).