Advancements in airway stents: a comprehensive update.

PURPOSE OF REVIEW: This review provides an overview of the evolving field of airway stenting (AS), highlighting its relevance in the management of central airway obstruction (CAO). It discusses recent advancements, including 3D-printed silicone stents (3DPSS), metallic stents, biodegradable stents (BS), and drug-eluting stents (DES), which are transforming clinical practice. The review underscores the ongoing challenges in patient selection, stent choice, and long-term management in the context of an evolving landscape. RECENT FINDINGS: Innovations, particularly 3DPSS, have shown promise in providing patient-specific solutions. These stents offer improved symptom relief, enhanced quality of life, and lower complication rates, especially for complex airway diseases. The use of BS and DES is explored, raising prospects for future applications. SUMMARY: The evolution of AS reflects a deepening understanding of airway obstructions. Recent innovations, such as 3DPSS, BS, and DES, show considerable promise in addressing the limitations of conventional stents. However, challenges related to complications, patient selection, and long-term management persist, demanding further research. Wide practice variations in the management of AS highlight the need for more clinical data and standardized guidelines. The search for the ideal stent continues, driven by the pursuit of better outcomes for patients with CAO.

Malignant Central Airway Obstruction: What's New?

Malignant central airway obstruction (MCAO) is a debilitating and life-limiting complication that occurs in an unfortunately large number of individuals with advanced intrathoracic cancer. Although the management of MCAO is multimodal and interdisciplinary, the task of providing patients with prompt palliation falls increasingly on the shoulders of interventional pulmonologists. While a variety of tools and techniques are available for the management of malignant obstructive lesions, advancements and evolution in this therapeutic venue have been somewhat sluggish and limited when compared with other branches of interventional pulmonary medicine (e.g., the early diagnosis of peripheral lung nodules). Indeed, one pragmatic, albeit somewhat uncharitable, reading of this article's title might suggest a wry smile and shug of the shoulders as to imply that relatively little has changed in recent years. That said, the spectrum of interventions for MCAO continues to expand, even if at a less impressive clip. Herein, we present on MCAO and its endoscopic and nonendoscopic management-that which is old, that which is new, and that which is still on the horizon.

Prospective cohort of cryobiopsy in interstitial lung diseases: a single center experience.

RATIONALE: Transbronchial cryobiopsy has been increasingly used to diagnose interstitial lung diseases. However, there is uncertainty regarding its accuracy and risks, mainly due to a paucity of prospective or randomized trials comparing cryobiopsy to surgical biopsy. OBJECTIVES: To evaluate the diagnostic yield and complications of cryobiopsy in patients selected by multidisciplinary discussion. METHODS: This was a prospective cohort from 2017 to 2019. We included consecutive patients with suspected interstitial lung diseases being considered for lung biopsy presented at our multidisciplinary meeting. MEASUREMENTS AND MAIN RESULTS: Of 112 patients, we recommended no biopsy in 31, transbronchial forceps biopsy in 16, cryobiopsy in 54 and surgical biopsy in 11. By the end of the study, 34 patients had had cryobiopsy and 24 patients, surgical biopsy. Overall pathologic and multidisciplinary diagnostic yield of cryobiopsy was 47.1% and 61.8%, respectively. The yield increased over time for both pathologic (year 1: 28.6%, year 2: 54.5%, year 3: 66.7%, p = 0.161) and multidisciplinary (year 1: 50%, year 2: 63.6%, year 3: 77.8%, p = 0.412) diagnosis. Overall rate of grade 4 bleeding after cryobiopsy was 11.8%. Cryobiopsy required less chest tube placement (11.8% vs 100%, p < 0.001) and less hospitalizations compared to surgical biopsy (26.5% vs 95.7%, p < 0.001), but hospitalized patients had a longer median hospital stay (2 days vs 1 day, p = 0.004). CONCLUSIONS: Diagnostic yield of cryobiopsy increased over time but the overall grade 4 bleeding rate was 11.8%.

Accuracy of a Robotic Endoscopic System in Cadaver Models with Simulated Tumor Targets: ACCESS Study.

BACKGROUND: Bronchoscopy for the diagnosis of peripheral pulmonary lesions continues to present clinical challenges, despite increasing experience using newer guided techniques. Robotic bronchoscopic platforms have been developed to potentially improve diagnostic yields. Previous studies in cadaver models have demonstrated increased reach into the lung periphery using robotic systems compared to similarly sized conventional bronchoscopes, although the clinical impact of additional reach is unclear. OBJECTIVES: This study was performed to evaluate the performance of a robotic bronchoscopic system's ability to reach and access artificial tumor targets simulating peripheral nodules in human cadaveric lungs. METHODS: Artificial tumor targets sized 10-30 mm in axial diameter were implanted into 8 human cadavers. CT scans were performed prior to procedures and all cadavers were intubated and mechanically ventilated. Electromagnetic navigation, radial probe endobronchial ultrasound, and fluoroscopy were used for all procedures. Robotic-assisted bronchoscopy was performed on each cadaver by an individual bronchoscopist to localize and biopsy peripheral lesions. RESULTS: Sixty-seven nodules were evaluated in 8 cadavers. The mean nodule size was 20.4 mm. The overall diagnostic yield was 65/67 (97%) and there was no statistical difference in diagnostic yield for lesions <20 mm compared with lesions measuring 21-30 mm, the presence of a concentric or eccentric radial ultrasound image, or relative distance from the pleura. CONCLUSIONS: The robotic bronchoscopic system was successful at biopsying 97% of peripheral pulmonary lesions 10-30 mm in size in human cadavers. These findings support further exploration of this technology in prospective clinical trials in live human subjects.

Application of 3D Printing for Patient-Specific Silicone Stents: 1-Year Follow-Up on 2 Patients.

Managing complex benign airway disease is a major challenge in interventional pulmonology. Airway stent placement can result in complications due to a variety of factors, including poor fit of the stent in the airway. We report the 1-year outcome of 2 patients with airway disease caused by granulomatosis with polyangiitis (Wegener's) affecting the left main bronchus and secondary carina. These patients had not responded to systemic therapy or standard bronchoscopic techniques and had complications with commercially available airway stents. We describe a first-in-human, clinical experience to address these issues. Using computed tomography (CT) imaging and 3D printing technology, we generated and implanted patient-specific silicone airway stents to address airway disease. 3D patient-specific stent prescription was created using a CT scan of the patient's chest and a proprietary software package originally developed for orthopedic surgical planning. Silicone stents were manufactured and implanted. Observation for > 1 year after implantation compared to the 6 months prior to patient-specific stent implant were compared for the number, clinically required stent changes, procedure time, and general clinical improvement per usual standard of care after airway stenting. Patients showed improved durability, a shorter procedure time, and improvement of patient-reported symptoms leading to a reduced need for stent changes and modifications. The use of 3D printing technology to make patient-specific silicone stents is feasible with early clinical proof of concept noting a durable improvement over 1 year of follow-up.

Electromagnetic navigation bronchoscopy to access lung lesions in 1,000 subjects: first results of the prospective, multicenter NAVIGATE study.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) is an image-guided, minimally invasive approach that uses a flexible catheter to access pulmonary lesions. METHODS: NAVIGATE is a prospective, multicenter study of the superDimension™ navigation system. A prespecified 1-month interim analysis of the first 1,000 primary cohort subjects enrolled at 29 sites in the United States and Europe is described. Enrollment and 24-month follow-up are ongoing. RESULTS: ENB index procedures were conducted for lung lesion biopsy (n = 964), fiducial marker placement (n = 210), pleural dye marking (n = 17), and/or lymph node biopsy (n = 334; primarily endobronchial ultrasound-guided). Lesions were in the peripheral/middle lung thirds in 92.7%, 49.7% were <20 mm, and 48.4% had a bronchus sign. Radial EBUS was used in 54.3% (543/1,000 subjects) and general anesthesia in 79.7% (797/1,000). Among the 964 subjects (1,129 lesions) undergoing lung lesion biopsy, navigation was completed and tissue was obtained in 94.4% (910/964). Based on final pathology results, ENB-aided samples were read as malignant in 417/910 (45.8%) subjects and non-malignant in 372/910 (40.9%) subjects. An additional 121/910 (13.3%) were read as inconclusive. One-month follow-up in this interim analysis is not sufficient to calculate the true negative rate or diagnostic yield. Tissue adequacy for genetic testing was 80.0% (56 of 70 lesions sent for testing). The ENB-related pneumothorax rate was 4.9% (49/1,000) overall and 3.2% (32/1,000) CTCAE Grade ≥2 (primary endpoint). The ENB-related Grade ≥2 bronchopulmonary hemorrhage and Grade ≥4 respiratory failure rates were 1.0 and 0.6%, respectively. CONCLUSIONS: One-month results of the first 1,000 subjects enrolled demonstrate low adverse event rates in a generalizable population across diverse practice settings. Continued enrollment and follow-up are required to calculate the true negative rate and delineate the patient, lesion, and procedural factors contributing to diagnostic yield. TRIAL REGISTRATION: ClinicalTrials.gov NCT02410837 . Registered 31 March 2015.

Cost effectiveness of bronchial thermoplasty in patients with severe uncontrolled asthma.

RATIONALE: Based on its clinical effectiveness, bronchial thermoplasty (BT) was approved by the Food and Drug Administration in 2010 for the treatment of severe persistent asthma in patients 18 years and older whose asthma is not well-controlled with inhaled corticosteroids and long-acting beta-agonist medicines. OBJECTIVE: Assess the 10 year cost-effectiveness of BT for individuals with severe uncontrolled asthma. METHODS: Using a Markov decision analytic model, the cost-effectiveness of BT was estimated. The patient population involved a hypothetical cohort of 41-year-old patients comparing BT to usual care over a 10-year time frame. The main outcome measure was cost in 2013 dollars per additional quality adjusted life year (QALY). RESULTS: Treatment with BT resulted in 6.40 QALYs and $7512 in cost compared to 6.21 QALYs and $2054 for usual care. The incremental cost-effectiveness ratio for BT at 10 years was $29,821/QALY. At a willingness to pay per QALY of $50,000, BT continues to be cost effective unless the probability of severe asthma exacerbation drops below 0.63 exacerbation per year or the cost of BT rises above $10,384 total for all three bronchoscopic procedures needed to perform thermoplasty and to cover the entire bronchial tree (baseline = $6690). CONCLUSIONS: BT is a cost-effective treatment for asthmatics at high risk of exacerbations. Continuing to follow asthmatics treated with BT beyond 5 years will help inform longer efficacy and support its cost-effectiveness.

Design of a prospective, multicenter, global, cohort study of electromagnetic navigation bronchoscopy.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) procedures allow physicians to access peripheral lung lesions beyond the reach of conventional bronchoscopy. However, published research is primarily limited to small, single-center studies using previous-generation ENB software. The impact of user experience, patient factors, and lesion/procedural characteristics remains largely unexplored in a large, multicenter study. METHODS/DESIGN: NAVIGATE (Clinical Evaluation of superDimension™ Navigation System for Electromagnetic Navigation Bronchoscopy) is a prospective, multicenter, global, cohort study. The study aims to enroll up to 2,500 consecutive subjects presenting for evaluation of lung lesions utilizing the ENB procedure at up to 75 clinical sites in the United States, Europe, and Asia. Subjects will be assessed at baseline, at the time of procedure, and at 1, 12, and 24 months post-procedure. The pre-test probability of malignancy will be determined for peripheral lung nodules. Endpoints include procedure-related adverse events, including pneumothorax, bronchopulmonary hemorrhage, and respiratory failure, as well as quality of life, and subject satisfaction. Diagnostic yield and accuracy, repeat biopsy rate, tissue adequacy for genetic testing, and stage at diagnosis will be reported for biopsy procedures. Complementary technologies, such as fluoroscopy and endobronchial ultrasound, will be explored. Success rates of fiducial marker placement, dye marking, and lymph node biopsies will be captured when applicable. Subgroup analyses based on geography, demographics, investigator experience, and lesion and procedure characteristics are planned. DISCUSSION: Study enrollment began in April 2015. As of February 19, 2016, 500 subjects had been enrolled at 23 clinical sites with enrollment ongoing. NAVIGATE will be the largest prospective, multicenter clinical study on ENB procedures to date and will provide real-world experience data on the utility of the ENB procedure in a broad range of clinical scenarios. TRIAL REGISTRATION: ClinicalTrials.gov NCT02410837 . Registered 31 March 2015.

Tracheobronchial smooth muscle atrophy and separation.

We report a case series involving 4 patients with chronic obstructive pulmonary disease who were on an appropriate medical regimen including a high dose of inhaled corticosteroids (ICS). During bronchoscopy, patients were found to have an excessive dynamic collapse of the posterior wall and its separation from the ends of the adjacent cartilaginous rings. This was causing a near-total occlusion of the tracheal and bronchial lumen during exhalation, thereby presenting with an obstructive pattern on the pulmonary functions. We suspect that this was caused by the atrophy of the smooth muscles of the tracheobronchial wall. We reviewed the literature to explore the mechanisms causing atrophy of the bronchial smooth muscle, focusing on the potential role of long-term ICS use.

Patient-specific airway stent using three-dimensional printing: a review.

The primary function of an airway stent is to reestablish patency, impeding restenosis, supporting the tracheobronchial wall, or occluding fistulas. But stent-related complications are prevalent and can have devastating consequences. For this reason, stents are considered a last resort when there are no alternatives in treatment. Additionally, commercially available airway stents often poorly fit patients with complex airways, and they can cause various complications. At the end of the 20th century, three-dimensional (3D) printing technology was created. It has been transformative in healthcare and has been used in several applications. One of its first utilizations was the anatomical modeling of body structures that helps preoperative planning. In respiratory medicine, this technology has been essentially used in central airway diseases to produce 3D airway models and to create airway splints and prostheses. In the last decade, it has led to a transformation and allowed progress in personalized medicine, making patient-specific stents for individuals with complex airway problems. A patient-specific stent using 3D printing may minimize complications, improve quality of life, and reduce the need for repeated procedures. This review describes the recent advances in 3D printing technology, its use for developing airway prostheses to treat complex airway diseases, and the current evidence that supports its use.

Determination of patient-specific airway stent fit using novel 3D reconstruction measurement techniques: a 4-year follow-up of a patient.

Managing complex benign airway disease is a major challenge in interventional pulmonology. With the introduction of additive manufacturing in the medical field, patient-specific (PS) implants are an innovate prospect for airway management. Historically, stents were oversized to resist migration. However, the optimal degree and impact of stent oversizing remains unclear. The ability to design stents based on computed tomography (CT) invites opportunity to understand sizing. Here, we report a novel three-dimensional (3D) image reconstruction tool to quantify fit repeatedly over time. Analysis of CT imaging before and after successive stent implants in a single patient with different areas of stenosis and malacia was done. Nine PS airway stents over 4 years (five left mainstem and four right mainstem) were studied. The distance between the airway model and stent was calculated. The CT images were correlated to stent designs in CloudCompare software (v2.10-alpha) for novel analysis. Heat map was exported depicting the distances between the airway and the stent to the clinician's prescribed stent model. Corresponding histograms containing distances, mean, and standard deviation were reported. It is possible to measure stent fit based on heat map quantification on patient imaging. Observation of the airway over time and stent change suggests that the airway became more open over time requiring increased stent diameters. The ability to design and measure stent fit over time can help quantify the utility and impact of PS silicone airway stent. The airway appears to display plasticity such that there is notable change in stent prescription over time.

Ergonomics of bronchoscopy: good advice or a pain in the neck?

Interventional pulmonologists require a unique set of skills including precise motor abilities and physical endurance, but surprisingly the application of ergonomic principles in the field of bronchoscopy remains limited. This is particularly intriguing when considering the significant impact that poor ergonomics can have on diagnostic aptitude, income potential and overall health. It is therefore imperative to provide comprehensive education to physicians regarding the significance of ergonomics in their work, especially considering the introduction of advanced diagnostic and therapeutic procedures. By implementing simple yet effective measures (e.g. maintaining neutral positions of the wrist, neck and shoulder; adjusting the height of tables and monitors; incorporating scheduled breaks; and engaging in regular exercises), the risk of injuries can be substantially reduced. Moreover, objective tools are readily available to assess ergonomic postures and estimate the likelihood of work-related musculoskeletal injuries. This review aims to evaluate the current literature on the impact of procedure-related musculoskeletal pain on practising pulmonologists and identify modifiable factors for future research.

Innovation in rigid bronchoscopy-past, present, and future.

German laryngologist Gustav Killian performed the first "Direkte Bronchoskopie" using a rigid bronchoscope to extract a foreign airway body from the right main bronchus over a hundred years ago, transforming the practice of respiratory medicine. The procedure instantaneously became popular throughout the world. Chevalier Jackson Sr from the United States further advanced the instrument, technique, safety, and application. In the 1960s, Professors Harold H. Hopkins and N.S. Kapany introduced optical rods as well as fiberoptics that led Karl Storz to develop the cold light system improving endoluminal illumination, achievements that ushered in the modern era of flexible endoscopy. Several diagnostic and therapeutic procedures became possible such as transbronchial needle biopsy, transbronchial lung biopsy, airway electrosurgery, or cryotherapy. Dr. Jean-François Dumon from France advanced the use of Nd-YAG laser in the endobronchial tree and created the dedicated Dumon silicone stent introducing the whole new field of interventional pulmonology (IP). This major milestone revitalized interest in rigid bronchoscopy (RB). Now, advancements are being made in stenting, instrumentation, and education. RB robotic technology advancements are currently anticipated and can potentially revolutionize the practice of pulmonary medicine. In this review, we describe some of the most substantial advances related to RB from its beginning to the modern era.

Short-term Endoscopic Outcomes of Balloon and Rigid Bronchoplasty in the Management of Benign Subglottic and Tracheal Stenosis.

BACKGROUND: Endoscopic therapies are firmly established in the management algorithm of benign subglottic and tracheal stenosis (SGTS). The optimal dilation strategy, however, has yet to be elucidated. The objective of this study was to compare the efficacy and safety of balloon versus rigid bronchoplasty in the treatment of benign SGTS. METHODS: De novo cases of benign SGTS at our institution over a 9-year period were retrospectively identified. Patients were divided into 2 groups based on the initial dilation strategy of balloon or rigid bronchoplasty. Demographics, clinical findings, concurrent interventions, lesion characteristics, and complications were analyzed. Two reviewers independently assigned an index and follow-up endoscopic stenosis grade for each case. The mean stenosis grade at follow-up in both groups was then calculated and compared. RESULTS: Sixty-three patients with benign SGTS were included. Most stenoses in the rigid (80%) and balloon (63%) bronchoplasty groups were complex ( P =0.174). In addition, 94% (59/63) of index stenoses were classified as Cotton Myer Grade 3. At follow-up, no significant difference was found in the mean stenosis grade between dilation strategies (1.97 vs. 2.2, P =0.287). Furthermore, no procedural-related complications were observed in either group. CONCLUSION: Balloon and rigid bronchoplasty are safe and effective endoscopic tools in the early management of benign SGTS. A multimodality approach centered around mucosal sparing techniques remains vitally important to the overall and likely long-term success of treating this challenging disease entity.

A Blueprint for Success: A Multidisciplinary Approach to Clinical Operations Within a Bronchoscopy Suite.

Building an efficient facility for advanced bronchoscopic procedures involves many considerations. This review places particular emphasis on anesthesiology services, based on experience at a tertiary/quaternary care referral academic medical center. Topics include equipment requirements, applicable clinical standards, and multidisciplinary collaboration. Patient flow arrangements for both outpatients and inpatients, from preoperative care to discharge/disposition, are highlighted. The importance of effective business planning, personnel training, leadership, communication, team building, quality of care, and patient safety are also discussed.

NAVIGATE 24-Month Results: Electromagnetic Navigation Bronchoscopy for Pulmonary Lesions at 37 Centers in Europe and the United States.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive, image-guided approach to access lung lesions for biopsy or localization for treatment. However, no studies have reported prospective 24-month follow-up from a large, multinational, generalizable cohort. This study evaluated ENB safety, diagnostic yield, and usage patterns in an unrestricted, real-world observational design. METHODS: The NAVIGATE single-arm, pragmatic cohort study (NCT02410837) enrolled subjects at 37 academic and community sites in seven countries with prospective 24-month follow-up. Subjects underwent ENB using the superDimension navigation system versions 6.3 to 7.1. The prespecified primary end point was procedure-related pneumothorax requiring intervention or hospitalization. RESULTS: A total of 1388 subjects were enrolled for lung lesion biopsy (1329; 95.7%), fiducial marker placement (272; 19.6%), dye marking (23; 1.7%), or lymph node biopsy (36; 2.6%). Concurrent endobronchial ultrasound-guided staging occurred in 456 subjects. General anesthesia (78.2% overall, 56.6% Europe, 81.4% United States), radial endobronchial ultrasound (50.6%, 4.0%, 57.4%), fluoroscopy (85.0%, 41.7%, 91.0%), and rapid on-site evaluation use (61.7%, 17.3%, 68.5%) differed between regions. Pneumothorax and bronchopulmonary hemorrhage occurred in 4.7% and 2.7% of subjects, respectively (3.2% [primary end point] and 1.7% requiring intervention or hospitalization). Respiratory failure occurred in 0.6%. The diagnostic yield was 67.8% (range: 61.9%-70.7%; 55.2% Europe, 69.8% United States). Sensitivity for malignancy was 62.6%. Lung cancer clinical stage was I to II in 64.7% (55.3% Europe, 65.8% United States). CONCLUSIONS: Despite a heterogeneous cohort and regional differences in procedural techniques, ENB demonstrates low complications and a 67.8% diagnostic yield while allowing biopsy, staging, fiducial placement, and dye marking in a single procedure.

Advanced Diagnostic and Therapeutic Bronchoscopy: Technology and Reimbursement.

Advanced interventional pulmonary procedures of the airways, pleural space, and mediastinum continue to evolve and be refined. Health care, finance, and clinical professionals are challenged by both the indications and related coding complexities. As the scope of interventional pulmonary procedures expands with advanced technique and medical innovation, program planning and ongoing collaboration among clinicians, finance executives, and reimbursement experts are key elements for success. We describe advanced bronchoscopic procedures, appropriate Current Procedural Terminology coding, valuations, and necessary modifiers to fill the knowledge gap between basic and advanced procedural coding. Our approach is to balance the description of procedures with the associated coding in a way that is of use to the proceduralist, the coding specialist, and other nonclinical professionals.

Robotic Bronchoscopy for Peripheral Pulmonary Lesions: A Multicenter Pilot and Feasibility Study (BENEFIT).

BACKGROUND: The diagnosis of peripheral pulmonary lesions (PPL) continues to present clinical challenges. Despite extensive experience with guided bronchoscopy, the diagnostic yield has not improved significantly. Robotic-assisted bronchoscopic platforms have been developed potentially to improve the diagnostic yield for PPL. Presently, limited data exist that evaluate the performance of robotic systems in live human subjects. RESEARCH QUESTION: What is the safety and feasibility of robotic-assisted bronchoscopy in patients with PPLs? STUDY DESIGN AND METHODS: This was a prospective, multicenter pilot and feasibility study that used a robotic bronchoscopic system with a mother-daughter configuration in patients with PPL 1 to 5 cm in size. The primary end points were successful lesion localization with the use of radial probe endobronchial ultrasound (R-EBUS) imaging and incidence of procedure related adverse events. Robotic bronchoscopy was performed in patients with the use of direct visualization, electromagnetic navigation, and fluoroscopy. After the use of R-EBUS imaging, transbronchial needle aspiration was performed. Rapid on-site evaluation (ROSE) was used on all cases. Transbronchial needle aspiration alone was sufficient when ROSE was diagnostic; when ROSE was not diagnostic, transbronchial biopsy was performed with the use of the robotic platform, followed by conventional guided bronchoscopic approaches at the discretion of the investigator. RESULTS: Fifty-five patients were enrolled at five centers. One patient withdrew consent, which left 54 patients for data analysis. Median lesion size was 23 mm (interquartile range, 15 to 29 mm). R-EBUS images were available in 53 of 54 cases. Lesion localization was successful in 51 of 53 patients (96.2%). Pneumothorax was reported in two of 54 of the cases (3.7%); tube thoracostomy was required in one of the cases (1.9 %). No additional adverse events occurred. INTERPRETATION: This is the first, prospective, multicenter study of robotic bronchoscopy in patients with PPLs. Successful lesion localization was achieved in 96.2% of cases, with an adverse event rate comparable with conventional bronchoscopic procedures. Additional large prospective studies are warranted to evaluate procedure characteristics, such as diagnostic yield. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03727425; URL: www.clinicaltrials.gov.