CHEST COMMENTARY| VOLUME 165, ISSUE 1, P16-18, JANUARY 2024Download Full Issue
Upcoming Clinical Trials in Critical Care, Diffuse Lung Disease, Pulmonary Vascular Disease, and Thoracic Oncology in 2024
Adam Edward Lang, Michael N. Kammer, Aravind Menon, et al
Chest 2024; 165: 16-18
DOI:https://doi.org/10.1016/j.chest.2023.07.029
Abbreviations:
CTEPH (chronic thromboembolic pulmonary hypertension), IPF(idiopathic pulmonary fibrosis), PAH (pulmonary arterial hypertension)
The future of pulmonary health looks bright, with many exciting trials querying interesting clinical dilemmas and novel drug mechanisms being assessed to treat challenging diseases. Highlighted in this paper are the clinical trials that may drastically change the trajectory of how we practice medicine in the areas of critical care, diffuse parenchymal lung disease, pulmonary vascular disease, and thoracic oncology.
Critical Care
Providing oxygen to critically ill patients has become ubiquitous. However, evaluating oxygenation targets, and the impact of hyperoxia, is a growing area with discrepant findings from clinical trials. The currently enrolling Mega Randomised Registry Trial Comparing Conservative vs. Liberal Oxygenation Targets (Mega-ROX) plans to address the impact of conservative oxygenation targets on 90-day in-hospital mortality in patients on mechanical ventilation.1 This international, parallel-group registry trial aims to randomize 40,000 adult patients to either conservative oxygen therapy (minimum Fio2 21%; oxygen saturation target range 91%-94%) or liberal oxygen therapy (minimum Fio2 30%; oxygen saturation target ≥ 91%). This study will help shape how patients who are mechanically ventilated are managed.
A second ubiquitous intervention in critically ill patients on mechanical ventilation is stress ulcer prophylaxis. Trials have focused on comparing specific agents and classes of medications used for stress ulcer prophylaxis, but none have revisited its necessity after advancements in the general management of critically ill patients. The Re-EValuating the Inhibition of Stress Erosion (REVISE) trial, an international placebo-controlled parallel-group trial, will randomize 4,800 adult patients on mechanical ventilation to either IV pantoprazole or matching placebo, with a primary efficacy outcome of upper GI bleeding.2 Safety outcomes include mortality, ventilator-associated pneumonia, and Clostridium difficile infection. Results of this study will provide up-to-date guidance on whether this intervention is efficacious in the time where bleeding rates are lower than historic trials, and when early enteral nutrition is a mainstay of therapy.
Diffuse Parenchymal Lung Disease
Treprostinil, a prostacyclin analog, widely used as a pulmonary vasodilator, has antifibrotic effects by decreasing fibroblast proliferation through multiple mechanisms.3 Exploratory analyses from a previous trial of inhaled treprostinil in patients with pulmonary hypertension from interstitial lung disease showed a modest increase in FVC.4 The Study of Efficacy and Safety of Inhaled Treprostinil in Subjects With Idiopathic Pulmonary Fibrosis (TETON) now seeks to formally determine if inhaled treprostinil can improve FVC in patients with idiopathic pulmonary fibrosis (IPF). This double-anonymized placebo-controlled trial hopes to enroll 396 patients, assessing the primary end point of absolute change in FVC at 52 weeks. If positive, this would be a valuable addition to the treatment armamentarium because enrollment is allowed while on background antifibrotic therapy.
The use of a genomic marker-directed screening process for intervention represents a paradigm shift in interstitial lung disease research, and is a unique aspect of the Prospective Treatment Efficacy in IPF Using Genotype for Nac Selection (PRECISIONS) trial. Based on promising pharmacogenetic data from a subgroup analysis of a prior negative trial which included N-acetylcysteine in the intervention arm, this study looks at the effect of N-acetylcysteine on patients with IPF harboring a TOLLIP genotype.5 Additionally, there is a substudy within this trial comparing home spirometry measurements to correlate with the in-center spirometry, which could become a potential outcome measurement in future trials. The study plans to prescreen 1,000 patients with IPF, and enroll 200 patients with the specific TOLLIP genotype to a randomized double-anonymized trial of N-acetylcysteine or placebo. The primary end point is a composite of 10% relative FVC decline, first respiratory hospitalization, lung transplantation, and all-cause mortality.
Pulmonary Vascular Disease
For decades, there were no new pathways in the treatment of pulmonary arterial hypertension (PAH); however, that has recently changed, with multiple pathways under active investigation. The phase 3 results investigating sotatercept, a fusion protein intended to trap activins and growth differentiation factors, were recently released, demonstrating a 34.4-m improvement in 6-min walk distance, in addition to meeting eight of nine secondary end points.6 Although impressive, it remains unclear where this novel drug will fall into the treatment algorithm, and multiple phase 3 trials are enrolling to clarify its utility. The Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants (HYPERION) aims to enroll 662 participants to determine the impact of sotatercept as first-line therapy, with a primary outcome of time to clinical worsening. Furthermore, the A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (ZENITH) will investigate its impact in end-stage PAH, and aims to enroll 200 participants with a primary end point of time to all-cause death, lung transplantation, or PAH worsening-related hospitalization for > 24 h.
Other unique pathways are also under investigation. Seralutinib is a novel inhaled therapy which acts to inhibit platelet-derived growth factor receptor alpha/beta, colony stimulating factor 1, and stem cell factor receptor, all of which have been implicated in vascular remodeling. The phase 2 trial of seralutinib in PAH was reported in abstract form, and demonstrated an improvement in placebo-controlled pulmonary vascular resistance by 96.1 dynes, in addition to an improved 6-min walk distance and N-terminal prohormone of brain natriuretic peptide.7 The comprehensive results and phase 3 trial give hope that yet another pathway can target PAH.
Although multiple drugs across various pathways are effective in the treatment of PAH, riociguat remains the only effective medical therapy for patients with chronic thromboembolic pulmonary hypertension (CTEPH). A 10-mg dose of the endothelin receptor antagonist macitentan was shown to improve the pulmonary vascular resistance in a phase 2 trial of patients with inoperable CTEPH.8 Macitentan was recently studied at higher doses in the phase 3 trial, A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension (MACiTEPH). The trial aimed to enroll 230 participants with the primary end point of change in 6-min walk distance, with the hopes of adding a new pathway to the medical treatment of CTEPH. Unfortunately, in September 2023 it was reported that MACiTEPH was ended early due to futility. Although the trial was ended early, the pulmonary hypertension community is anticipating the results of this trial to be published, to have better insight into the patient population enrolled, and to better inform future trials in CTEPH.
Thoracic Oncology
Tobacco plays a major role in the landscape of thoracic oncology and mostly all areas of chest medicine. With only seven US Food and Drug Administration-approved pharmacotherapies for treating nicotine dependence, and five of those being forms of nicotine replacement therapy, there is a need for additional approved treatments. There are two randomized placebo-controlled trials investigating the efficacy and safety of cytisinicline at 6 and 12 weeks, which may change that.9 Topline results of A Study of Cytisinicline for Smoking Cessation in Adult Smokers (ORCA-2) provided positive phase 3 data, and A Second Study of Cytisinicline for Smoking Cessation in Adult Smokers (ORCA-3) recently completed enrollment. Both trials combined will total 1,602 participants, with a primary end point of smoking abstinence up to 12 weeks. Although cytisinicline may not take varenicline’s spot as the most effective pharmacotherapy, it could prove to be more affordable and improve access to treatment.
Additionally, of the eight trials from the National Cancer Institute’s Smoking Cessation at Lung Examination (SCALE) collaboration, results from three have been published while the other five are expected to be published prior to 2025.10 These look at interventions that can be incorporated into lung cancer screening, which across the trials include utilization of nicotine replacement therapy, varenicline, bupropion, Quitline, behavioral treatment, referral to community resources, and intensive telephone counseling. Results from the trials will be crucial to determine the best methods to treat individuals who use combustible tobacco in this high-risk population.
Early detection of lung cancer continues to improve survival, and noninvasive biomarkers have been sought to aide physicians in decision-making when patients have suspicious pulmonary nodules. A novel proteomic biomarker, Nodify XL2, has been developed to help physicians delineate risk of malignancy in patients with solid lung nodules. The Nodify XL2 Classifier Clinical Utility Study in Low to Moderate Risk Lung Nodules (ALTITUDE) is currently enrolling. This prospective observational study aims to enroll 2,000 patients to determine if the Nodigy XL2 classifier can reduce the number of invasive procedures performed on patients with benign lung nodules.11
In interventional pulmonology, there are multiple challenges to performing randomized clinical trials of novel medical devices because of the impracticability of patient consent and randomization within this setting. The Robotic Versus Electromagnetic Bronchoscopy for Pulmonary Lesion Assessment (RELIANT) trial changes this paradigm by embedding randomization within the pragmatic workflow based on its cluster-randomized waived-consent design.12 This study will enroll 500 participants to compare diagnostic yield between procedures performed by robotic vs electromagnetic bronchoscopy systems. The results of this study will be important for choice of diagnostic technique, but more broadly, will pave the way to future pragmatic trial designs within thoracic oncology.
