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• W2322227250 abstract "A review of recently published literature in the area of bronchoscopically delivered interventions has unveiled a noteworthy changing trend in the conduct and design of these clinical trials. There are several aspects that deserve further discussion, including the ethics of the use of a sham bronchoscopy arm, disease-specific considerations in the use of sham bronchoscopy, and the questionable validity of using composite primary and safety endpoints in clinical trials. One of the challenges in therapeutic bronchoscopy interventional trials is the identification of the appropriate control or comparison group. In clinical trials methodology, a number of approaches can be considered, including delayed therapy, subtherapeutic therapy, best alternative therapy, and inert oral placebo or sham procedures. All of these approaches have respective attributes and drawbacks. There has been a recent trend to not utilize sham bronchoscopy as the control arm in therapeutic bronchoscopy trials (clinical trails.gov-NCT01812447, NCT01608490, NCT01822795, NCT01796392). This represents a clear departure from the use of sham bronchoscopy in less recent trials in response to the raised bar of FDA approval, particularly as it pertains to severe lung disease.1,2 In the new realm of therapeutic bronchoscopy, as a primary therapeutic modality for benign conditions as opposed to palliative management of inoperable malignancies, we have become accustomed to this new standard. A key incentive for individuals to participate in trials incorporating sham procedures is the notion of delayed therapy, which offers the ability of those participants randomized to sham to also receive potentially beneficial treatment; however, there are potential drawbacks with this approach as well. For example, anecdotally, we encountered interim cessation of a trial by a Data Safety Monitoring Board due to reaching prespecified stopping rules that precluded in-phase participants randomized to the sham-first arm to undergo the treatment phase. A challenge with the approach was discussing how the cessation of the trial would affect those randomized to sham. We were not informed about the reason for stopping. We could not ethically ask the participant to wait for the intervention if the trial was positive or on the contrary seek another therapy if findings were negative. It should be the responsibility of the study sponsor to disclose this information as soon as possible by recognizing the potential conflict that sponsors face when trying to manage the upshot of a negative clinical trial. Furthermore, researchers involved in developing the design and in overseeing the conduct of clinical trials need to contend with the scientific and ethical aspects in which a failure to treat could deny participants of potential benefits or possibly result in adverse consequences. Along these lines, the principle of clinical equipoise coined by Freedman3 represents a central axiom in clinical trials and particularly one that is at the forefront of the minds of investigators designing trials involving patients with significant comorbidity who could benefit from a potentially life-saving or life-prolonging intervention (eg, lung transplantation or lung volume reduction surgery). The concept involves starting with an honest null hypothesis and genuine medical uncertainty concerning the relative merits of the various treatment arms included in the design of the trial. Unique to procedurally based or surgical clinical trials is the concept of the “mega-placebo effect”—that is, enhanced perception of benefit beyond the true therapeutic benefit of the intervention alone will be greater in procedure-based trials given the intrinsic technical complexity.4 Specifically, the overall response to a procedure would likely be accompanied by a greater placebo component than to a placebo pill to which it is compared. In such a scenario, a difference between 2 treatments may result from differences in their placebo effects rather than from differences in the therapies themselves. This “mega-effect” provides the crux of the basis for the use of sham procedures in procedurally based clinical trials. The era of interventional bronchoscopy has involved trials with sham bronchoscopy in disease-focused entities such as asthma and emphysema.1,2 Both groups present challenges to long-held beliefs that these patients are at high risk for complications in the context of even simple bronchoscopy let alone complex interventional procedures, the latter of which are often under general anesthesia. In some texts, it is considered a relative contraindication to perform bronchoscopy in these patients. However, we have demonstrated that even complex bronchoscopy has acceptable safety profiles in such patients, particularly as plans are to diagnose entities that carry a more immediate adverse prognosis, such as cancer or severe infection, or that offer palliation of malignant airway obstruction when bronchoscopy is performed. Now with the advent of elective therapeutic bronchoscopy, in addition to consideration of sham procedures involving exposures to potential risks with general anesthesia, we needed to reevaluate these patients and bronchoscopy in a new context. Perhaps the best recent example of the use of a sham bronchoscopy arm was the Asthma Intervention Research (AIR2) trial.1 The AIR2 trial was a randomized (2:1) double-blinded, sham bronchoscopy controlled clinical trial conducted across 30 centers in 6 countries examining the effectiveness of bronchial thermoplasty in severe persistent asthma. Those individuals randomized to the control arm underwent 3 sham procedures during the follow-up period.1 The sham procedures involved performing the mechanics of the entire procedure, including the motions of catheter deployment but without the electrical energy delivered.1 Interestingly, the sham arm participants were observed to have improvement in subjective symptoms ascertained by the Asthma Quality of Life Questionnaire after 12 months, but the effect was lower in magnitude than that in the bronchial thermoplasty–treated group.1 Some degree of placebo response of bronchoscopy among asthma patients was expected as described in prior clinical trials and with other medical device trials.4 Consideration of the frequency of adverse events in trials utilizing sham bronchoscopy is important in order to inform clinical trial design decision-making. In therapeutic bronchoscopy asthma–based clinical trials, the comparability of adverse event rates across the sham and treatment arms revealed an increased percentage of adverse events even in those studies involving nonsham controls. In the AIR2 trial, there were 106 events (69% mild, 30% moderate, and 1% severe) among the 54 control subjects (1.9 adverse events/participant).1 This contrasts with 407 (69% mild, 28% moderate, and 3% severe) events in the 55 subjects in the bronchial thermoplasty group (7.4 adverse events/participant).1 In the Research in Severe Asthma trial, which did not use a sham bronchoscopy arm, but rather a control group exposed to standard of care therapy, there were 136 respiratory adverse events in 15 subjects in the bronchial thermoplasty group: 49% mild, 41% moderate, and 10% severe (9.1 adverse events/participant). The control group (n=17) had 57 respiratory adverse events: 49% were mild, 47% were moderate, and 4% were severe (3.4 adverse events/participant).5 This suggests that use of sham bronchoscopy compared with standard-of-care controls in asthma therapeutic bronchoscopy trials is associated with a similar 2- to 3-fold increase in adverse events in the intervention arm compared with the control arm. Asthma patients have been well studied, and the placebo effect in these patients is quite striking, thereby posing challenges for investigators, particularly when examining subjective outcomes. In fact, a randomized controlled trial investigating the effect of albuterol, sham albuterol, and sham acupuncture showed all of them to be equally effective in controlling asthma symptoms, as judged by patient self-reported improvement, in contrast to objective improvement of forced expiratory volume in 1 second (FEV1), which was observed only in the active albuterol group.6 Placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma.6 This then raises challenges when conducting clinical trials research in asthma, particularly in bronchial thermoplasty trials, involving primary composite outcomes that are those most susceptible to subjective placebo effect in the context of few reliable objective/physiological outcomes for a disease that carries an intrinsic proneness to wide-ranging variability of lung function, measures of airway dynamic change, and inflammation. However, an assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes. Other “hard” health care utilization outcomes are valuable, but generally not as acceptable to the skeptical scientific community.7,8 Conduct of clinical research involving emphysema patients poses a different set of challenges. Patients with asthma are typically seeking quality of life improvement and less disruption due to an episodic disease. However, patients with severe emphysema tend to be much older, reaching the end stage of their diseases, may already be permanently disabled, and may perhaps be considering hospice or palliation. Perhaps the fortunate ones are looking to avoid the risks of lung volume reduction surgery or lung transplantation for what many believe is a self-inflicted disease in most cases. The bronchoscopic trials for emphysema taught us that we really do not fully understand the pathophysiology of emphysema. Subtle changes in the terminology can be noted in the literature, transitioning from initially referring to the procedure as bronchoscopic lung volume reduction and then to bronchoscopic treatment of emphysema as informed by lack of substantive effect on lung volumes in most individuals (ie, residual volume, total lung capacity, FEV1, or even impact on 6 min walk test). In contrast, participants have shown some notable improvements in dyspnea scores as assessed using instruments such as the St Georges Respiratory Questionnaire (SGRQ). Although certain subgroups were identified to have objective improvement in post hoc analysis, data generated from these trials have not yet led to FDA approval of this procedure. There have been 3 trials of bronchoscopic treatment of emphysema using a sham arm. The Exhale Airway Stents for Emphysema (EASE) trial was a 2:1 (treatment to sham) randomized, double-blinded (investigator teams divided into those who completed assessments vs. those who performed procedures with no further interaction with participants) trial of airway bypass2 and also 2 trials for the Spiration valve: one in the United States and the other in Europe.9 The EASE trial was performed with participants in both arms undergoing general anesthesia and involved a composite safety endpoint. However, the randomized patients were not similarly treated across the 2 arms. The procedure times were longer in the treatment group, and a larger proportion was lost to follow-up because of death or lung transplantation in the sham versus airway bypass arms (7% vs. 3%). Adverse events were fairly balanced across the intervention and sham arms (14.4% airway bypass vs. 11.2% sham). The authors actually utilized a run-in phase noting a baseline adverse event rate of 8% in the sham group. The trial did not demonstrate significant improvement in the prespecified coprimary endpoint of FEV1 and dyspnea score and no sustained benefits despite early improvements in the physiological measures.2 The Spiration bronchial bypass valves have been the focus of several clinical trials, but the Pivotal European trial9 was designed specifically to look for known outcomes and for responders based on several previous trials. The coprimary endpoint was the SGRQ (subjective) and lung volume reduction based on CT scan interpretation (objective).9 Again the sham arm had shorter procedure times compared with the treatment group.9 Both the sham and treatment arms did show an improvement in the “subjective” SGRQ, supporting the notion of a placebo effect or perhaps Hawthorne effect, but the treatment group met the minimally clinically significant threshold of a −4-point change.9 A 20% versus 10% rate of complications and 8% versus 4% rate of serious adverse events was observed in the treatment versus sham arms, respectively.9 There were no clear benefits on the hard physiological measures.7 Prior trials did demonstrate improvements in the responders who had developed atelectasis, but this was in the face of a much higher rate of complications, specifically pneumothorax. The US-based Spiration trial published only in abstract form10,11 was essentially negative with a low responder rate even when there was a positive significant signal. This was a randomized 1:1 treatment to sham bronchoscopy trial. There was a notable placebo effect on SGRQ (or treatment effect of bronchoscopy) that diminished over time. This study also used a composite safety endpoint and the number of adverse events was increased in the treatment arm compared with the sham control arm; however, these were disproportionately noted with the use of sedation rather than anesthesia. The overall complication safety endpoint was noted to be 27% in the treatment group compared with 13% in the control group.11 The authors contended that this may be attributable to longer procedure times in the treatment group. The use of sham control arms in procedure-based trials has been subject to criticism and laud. Clearly this is an attempt to account for the placebo effect of procedure-based interventions; however, it is often even more difficult to account for “procedure-related” unknown effects when subjective outcomes are utilized, as illustrated by the examples provided. Furthermore, there has been a recent fairly consistent use of composite outcomes and composite safety outcomes in the therapeutic bronchoscopy clinical trials literature. This is an attempt to leverage a higher event rate from limited sample sizes in the setting of consideration of different outcomes or adverse events potentially directly attributable to the intervention. This has led to a lively discussion regarding the validity of the use of the composite outcome. In these trials, there is a role for “AND” composite outcomes and “OR” safety outcomes. The “AND” composite provides the best conservative ascertainment of an outcome using both subjective and objective measures, noting that the subject requires both outcomes to define clinical success. Importantly, readers should be able to parse out the composite components to gain a sense of whether the effect of an intervention is primarily being driven by a specific measure of the composite and in the setting of composite safety endpoints to ensure that any imbalance of the severity of the adverse events across the arms of a trial is not being masked by the composite nature of the endpoint. In summary, we have learned a great deal about the value and challenges of sham-controlled procedure-based bronchoscopy trials and the not-inconsequential risks these pose to patients with severe lung disease (∼10%). We also have some insight into the large placebo or “procedural effect” of bronchoscopy, which seems to be particularly pronounced among patients with asthma. In an era in which the FDA now seems to be reversing prior recommendations for the use of sham controls, serious areas of focus that remain include weighing the pros and cons of using sham bronchoscopy that vary across disease state, our pursuit of the identification of new outcome measures adequately capturing the response to bronchoscopically delivered interventions, and grappling with the consideration of the “AND” as well as the “OR” composite outcomes. Consider this only a starting point for a pragmatic discussion of these issues in the interventional pulmonary community to develop standard recommendations regarding the approach to therapeutic bronchoscopy clinical trials as we continue to move forward to identify potential clinically meaningful and significant interventions for our patients. Thomas R. Gildea, MD, MS, FACP, FCCP Reena Mehra, MD, MS [Black Square][Black Square][Black Square]" @default.
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• W2322227250 modified "2023-10-16" @default.
• W2322227250 title "Changing Landscape and Disease-specific Considerations of Therapeutic Bronchoscopy in Clinical Trials" @default.
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