Evaluation of Clinical Outcomes and Simultaneous Digital Tracking of Daily Physical Activity, Heart Rate, and Inhalation Behavior in Patients With Pulmonary Arterial Hypertension Treated With Inhaled Iloprost: Protocol for the Observational VENTASTEP Study

Christian Mueller, Barbara Stollfuss, Alexander Roitenberg, Jonas Harder, Manuel J Richter, Christian Mueller, Barbara Stollfuss, Alexander Roitenberg, Jonas Harder, Manuel J Richter

Abstract

Background: Pulmonary arterial hypertension (PAH)-a progressive, ultimately fatal disease-patients often experience dyspnea, which can limit their daily physical activities. Iloprost is an inhaled therapy for PAH that has shown efficacy in clinical trials. However, clinical trials in PAH have provided only limited data on daily physical activity. Digital monitoring of daily physical activity in PAH is therefore attracting growing interest. To fully understand a patient's response to treatment, monitoring of treatment adherence is also required. The Breelib nebulizer for administration of iloprost saves inhalation data, thus allowing digital monitoring of adherence.

Objective: This study aims to perform parallel digital tracking of daily physical activity parameters, heart rate, and iloprost inhalation data in patients with PAH, before and after starting inhaled iloprost treatment. The primary objective is to investigate correlations between changes in digital measures of daily physical activity and traditional clinical measures. Secondary objectives are to assess iloprost inhalation behavior, the association between daily physical activity measures and time since last inhalation, changes in sleep quality and heart rate, the association of heart rate with daily physical activity measures and iloprost inhalation, and adverse events.

Methods: VENTASTEP is a digital, prospective, observational, multicenter, single-arm cohort study of adults with PAH in Germany, starting inhaled iloprost treatment via the Breelib nebulizer, in addition to existing PAH therapy. The study comprises a baseline period without iloprost treatment (≤2 weeks) and an observation period with iloprost treatment (3 months±2 weeks). The Apple Watch Series 2 and iPhone 6s are used with a dedicated study app to continuously measure digital daily physical activity parameters and heart rate during the baseline and observation periods; the watch is also used with a 6-min walk distance (6MWD) app to measure digital 6MWD at baseline and the end-of-observation visit. Inhalation frequency, completeness, and duration are monitored digitally via the nebulizer and the BreeConnect app. Sleep quality is assessed using the Pittsburgh Sleep Quality Index at baseline and the end-of-observation visit. Changes in traditional outcome measures (6MWD, Borg dyspnea scale, EuroQol 5-dimensions questionnaire, functional class, and brain natriuretic peptide [BNP] or N-terminal proBNP) between baseline and the end-of-observation visit will be correlated with changes in digital daily physical activity parameters and digital 6MWD as the primary analysis.

Results: The first participant was enrolled in February 2018 (estimated study completion by July 2019; planned sample size: 80 patients).

Conclusions: The VENTASTEP study will inform future research on the utility of digital parameters as outcome assessment tools for disease monitoring in PAH. The study will also provide insight into clinical outcomes, daily physical activity, and quality of life in patients adding inhaled iloprost, to existing PAH therapy.

Trial registration: ClinicalTrials.gov NCT03293407; https://ichgcp.net/clinical-trials-registry/NCT03293407 (Archived by WebCite at http://www.webcitation.org/6ywPGcn4I).

International registered report identifier (irrid): DERR1-10.2196/12144.

Keywords: Breelib; behavior; daily physical activity; digital monitoring; health-related quality of life; heart rate; iloprost; inhalation; pulmonary arterial hypertension; sleep.

Conflict of interest statement

Conflicts of Interest: JH is an employee of xbird GmbH (Berlin, Germany), which created the study app (for analysis of daily physical activity and heart rate) and the 6MWD app. Bayer selected xbird GmbH to join their accelerator program Grants4Apps in 2016. CM, AR, and BS are employees of Bayer Vital GmbH (Leverkusen, Germany), which is the local representative of the marketing authorization holder for inhaled iloprost in Europe (Bayer AG, Leverkusen, Germany). MJR has received support from United Therapeutics and Bayer Pharma AG and speaker fees from Actelion, Bayer Pharma AG, Mundipharma, Roche, and OMT.

©Christian Mueller, Barbara Stollfuss, Alexander Roitenberg, Jonas Harder, Manuel J Richter. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 15.04.2019.

Figures

Figure 1
Figure 1
Data sources and processing in the VENTASTEP study. Inhalation data from the nebulizer and motion sensor data, location changes ≥500 m, and heart rate data from the wearable are transferred to the smartphone via Bluetooth and stored there temporarily by the BreeConnect app and study app. Motion sensor and barometer data from the smartphone itself are also stored in the study app. The data are sent from the smartphone via encrypted transmission to a secure cloud server for storage and processing to generate the digital study variables, which are then transferred to the electronic data capture system of the clinical research organization for final analysis. Patient- and investigator-reported outcomes are also saved and analyzed in the electronic data capture system of the clinical research organization. 6MWD: 6-min walk distance; BNP: brain natriuretic peptide; CRO: clinical research organization; NT-proBNP: N-terminal pro–brain natriuretic peptide; HRQoL: health-related quality of life; WHO FC: World Health Organization functional class.
Figure 2
Figure 2
Study visits and data collection. 6MWD: 6-min walk distance; BNP: brain natriuretic peptide; NT-proBNP: N-terminal pro–brain natriuretic peptide; HRQoL: health-related quality of life; WHO FC: World Health Organization functional class.
Figure 3
Figure 3
Timeline of key studies of inhaled iloprost and studies of digitally monitored daily physical activity in pulmonary arterial hypertension. Studies of inhaled iloprost (with traditional or digital endpoints) are shown above the timeline, and other studies in pulmonary arterial hypertension with digital monitoring of daily physical activity are shown below the timeline. Blue shading indicates studies with digital monitoring of daily physical activity. Published studies are positioned on the timeline by year of publication; unpublished studies are shown with their ClinicalTrials.gov ID numbers and positioned on the timeline by year of (anticipated) study completion. CTEPH: chronic thromboembolic pulmonary hypertension; e-MOTION PH: electronic activity level monitoring pilot in pulmonary hypertension; ERA: endothelin receptor antagonist; LONGACT: correlation of long-term wrist actigraphy recorded physical performance and 6-min walk distance in patients with pulmonary arterial hypertension; mHealth: mobile health intervention in pulmonary arterial hypertension; MOTION: measuring outcomes in patients with pulmonary arterial hypertension not on active treatment; PAH: pulmonary arterial hypertension; PH: pulmonary hypertension; PHANTOM: pulmonary hypertension and anastrozole trial; TRACE: effect of selexipag on daily life physical activity of patients with pulmonary arterial hypertension; VENTASTEP: evaluation of inhaled iloprost effects using the Breelib nebulizer, on clinical outcomes and physical activity of patients with advanced pulmonary arterial hypertension; WHOLEi+12: whole muscle exercise training in pulmonary hypertension; ZHPHCohort: Zürich Pulmonary Hypertension Outcome Assessment Cohort.

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