The IBV Valve trial: a multicenter, randomized, double-blind trial of endobronchial therapy for severe emphysema.

ORIGINAL INVESTIGATION

The IBV Valve Trial A Multicenter, Randomized, Double-Blind Trial of Endobronchial Therapy for Severe Emphysema Douglas E. Wood, MD,* Daniel A. Nader, DO,w Steven C. Springmeyer, MD,z Mark R. Elstad, MD,y Harvey O. Coxson, PhD,8 Andrew Chan, MD,z Navdeep S. Rai, MD,# Richard A. Mularski, MD,** Christopher B. Cooper, MD,ww Robert A. Wise, MD,zz Paul W. Jones, MD,yy Atul C. Mehta, MD,88 Xavier Gonzalez, MD,z and Daniel H. Sterman, MD,zz for the IBV Valve Trial Research Team

Background: Lung volume reduction surgery improves

quality of life, exercise capacity, and survival in selected patients but is accompanied by significant morbidity. Bronchoscopic approaches may provide similar benefits with less morbidity. Methods: In a randomized, sham procedure controlled,

double-blind trial, 277 subjects were enrolled at 36 centers. Patients had emphysema, airflow obstruction, hyperinflation, and severe dyspnea. The primary effectiveness measure was a significant improvement in disease-related quality of life (St. George’s Respiratory Questionnaire) and changes in lobar lung volumes. The primary safety measure was a comparison of serious adverse events.

Received for publication April 11, 2014; accepted August 1, 2014. From the *Department of Cardiothoracic Surgery, University of Washington, Seattle; zSpiration Inc., Redmond; #St. Joseph Medical Center, Tacoma, WA; wCancer Treatment Centers of America at Southwestern Regional Medical Center, Oklahoma State University, Tulsa, OK; yGeorge E. Whalen DVA Medical Center, Salt Lake City, UT; 8Department of Radiology, Vancouver General Hospital, Vancouver, BC, Canada; zDepartment of Medicine at UC Davis, University of California at Davis, Davis; wwDepartment of Medicine at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; **The Center for Health Research, Kaiser Permanente Northwest, Portland, OR; zzJohns Hopkins University, Baltimore, MD; yySt. George’s Hospital Medical School, London, UK; 88Cleveland Clinic Main Campus, Cleveland, OH; and zzUniversity of Pennsylvania Medical Center, Philadelphia, PA. Supported by Spiration Inc. Presented at the American Thoracic Society, May 2012, San Francisco, CA as abstract. S.C.S. and X.G. are employees of Spiration. D.E.W., D.A.N., M.R.E., H.O.C., A.C., N.S.R., R.A.M., C.B.C., and A.C.M. received support for conducting research. D.E.W., C.C., R.A.W., P.W.J., A.C.M., and D.H.S. received reimbursement for expenses and time as steering committee members. Reprints: Douglas E. Wood, MD, Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, 1959 N.E. Pacific, AA-115, P.O. Box 356310, Seattle, WA 98195-6310 (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.bronchology.com. Copyright r 2014 by Lippincott Williams & Wilkins

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Results: There were 6/121 (5.0%) responders in the

treatment group at 6 months, significantly >1/134 (0.7%) in the control group [Bayesian credible intervals (BCI), 0.05%, 9.21%]. Lobar volume changes were significantly different with an average decrease in the treated lobes of 224 mL compared with 17 mL for the control group (BCI, 272, 143). The proportion of responders in St. George’s Respiratory Questionnaire was not greater in the treatment group. There were significantly more subjects with a serious adverse event in the treatment group (n = 20 or 14.1%) compared with the control group (n = 5 or 3.7%) (BCI, 4.0, 17.1), but most were neither procedure nor device related. Conclusions: This trial had technical and statistical

success but partial-bilateral endobronchial valve occlusion did not obtain clinically meaningful results. Safety results were acceptable and compare favorably to lung volume reduction surgery and other bronchial valve studies. Further studies need to focus on improved patient selection and a different treatment algorithm. Trial Registry: ClinicalTrials.gov NCT00475007. Key Words: emphysema, bronchial valves, endobronchial therapy (J Bronchol Intervent Pulmonol 2014;21:288–297)

C

hronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States, is a disease characterized by progressive airflow limitation that is only partially reversible.1 The airflow obstruction derives from a combination of airway inflammation (chronic bronchitis) and lung parenchymal destruction (emphysema). Emphysema affects an estimated 1.8% of the world population.2 The pathophysiological effects of emphysema are loss of lung elastic recoil, air trapping, and lung hyperinflation. Hyperinflation is directly associated with patient-centered outcomes such as

J Bronchol Intervent Pulmonol

Volume 21, Number 4, October 2014



dyspnea and exercise limitation, both of which have a negative impact on health-related quality of life.3 In the 1990s, improved techniques for lung volume reduction surgery (LVRS) were introduced.4 LVRS benefits patients by removing the predominantly nonfunctioning lung parenchyma resulting in improved survival, maximal exercise, and quality of life in selected patients.5–7 In the National Emphysema Treatment Trial (NETT), the operative mortality, after exclusion of a high-risk group, in the first 90 days was 5.2%, but 30-day major pulmonary morbidity occurred in 29.8% of patients, and cardiovascular morbidity occurred in 20.0% of patients.5,8 Bronchial valve therapy offers potential benefit similar to LVRS, but with a lower complication rate, and also eligibility for a larger group of patients. Bronchial valves were developed to block inspired air from entering the most diseased areas of emphysema. Blocking inspired air can reduce ventilation,9,10 dynamic hyperinflation,11 target-lobe volume,9 and produce visible atelectasis.9,12,13 Intrabronchial valve (IBV Valve) studies began with a bilateral treatment and showed safety and improved quality of life with target-lobe volume reduction.9,14 The studies also showed that complete lobe occlusion was associated with pneumothorax, particularly when the left upper lobe (UL) was completely occluded.10,13 In contrast, partial treatment of a lobe achieved moderate effectiveness with a lesser likelihood of pneumothorax.13 Therefore, the objective of this trial was to improve quality of life, effect changes in lobar volumes, and to minimize the complication of pneumothorax.

Bronchial Valve Treatment for Severe COPD With Emphysema

before a 6-week run-in period. Subjects eligible for LVRS or lung transplant received surgical counseling before participation. Computed tomography (CT) scans were obtained using multidetector row scanners at full suspended inspiration with standardized parameters (e-Appendix). CT and lung perfusion scans were visually assessed for UL predominant emphysema for patient selection.5,9,10 Quantitative analysis of lung volumes was performed using Pulmonary Workstation software version 2.0 (VIDA Diagnostics, Iowa City, IA).15 Patient Treatment

Random assignment (1:1) with allocation concealment took place after anesthesia for bronchoscopy and a script was used for the control subjects but no valves were placed. In all patients, airways were examined and sized for valve placement at the segmental or subsegmental level, depending on airway size. Once valve size was determined for all target airways, the patient was then randomized to treatment or control. If the patient was randomized to control, a catheter was passed into the target airways and a script read out loud indicating (sham) valve deployment. The study device (IBV Valve; Spiration Inc., Redmond, WA) was compressed into a delivery catheter for placement in segmental or subsegmental airways (Fig. 1). Details about valve loading, airway sizing, and valve placement have been published.10,14 The lingular segments on the left and 1 segment or subsegment airway in the right UL were not treated, to achieve bilateralpartial lobe occlusion. Patient Follow-up

PATIENTS AND METHODS Study Design

A separate team without knowledge of the group assignment provided follow-up evaluations

This was a prospective, adaptive, randomized, controlled, double-blind, multicenter trial. This study was conducted in accordance with the amended Declaration of Helsinki. Patient Selection

The complete inclusion and exclusion criteria are in the e-Appendix (see Supplemental Digital Content, http://links.lww.com/LBR/A114) and were similar to prior studies.10,14 Subjects were patients with emphysema between 40 and 74 years of age, had severe dyspnea, and could not have had >2 hospitalizations for COPD exacerbation or respiratory infection in the prior year. Optimization of medical management occurred r

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FIGURE 1. The Spiration(r) IBV Valve(r). www.bronchology.com |

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to maintain blinding. Follow-up intervals were the same for both groups and occurred at 1, 3, and 6 months. Outcome Measures

The primary effectiveness objective was to compare treatment and control groups in disease-related quality of life as measured by the St. George’s Respiratory Questionnaire (SGRQ) and changes in lobar lung volumes as measured by quantitative CT. The threshold for SGRQ improvement was a reduction in total score Z4 points from baseline and the CT threshold was Z10% increase in non–upper lobe (NUL) volume and any decrease in UL volume. The primary safety measure was a difference between treatment and control groups in the number of subjects with a predefined serious adverse event (SAE) [e-Appendix, see Supplemental Digital Content, http://links.lww.com/LBR/A114]. Statistics

This study was adaptive and prospectively designed using Bayesian statistical methods. Possible sample sizes ranged from 200 to 500, with subject accrual designed to stop if


prespecified criteria involving Bayesian predictive probabilities were met (details in eAppendix). Consistent with the design, objectives, and demographic comparisons were analyzed using Bayesian statistical methods. “Statistical significance” is not a Bayesian concept but can be inferred if a 95% Bayesian credible interval (BCI) for a difference (of means or proportions) excludes 0. Device or procedure relatedness was considered present if the clinical events committee adjudicated the event as definitely or probably related. Isolated post hoc comparisons were made using traditional hypothesis tests, with t tests being used for continuous variables and w2 or Fisher exact test being used for proportions. RESULTS

The trial stopped accruing subjects after the second interim analysis because the trial had reached the prespecified criteria; 6 months later, at the conclusion of follow-up, the primary objective met its criterion for success. A total of 277 subjects were enrolled at 36 investigative sites with 43% female subjects. The 2 groups

TABLE 1. Demographic and Baseline Characteristics With Bayesian Credible Intervals (BCI) for the Differences Between Treatment and Control Groups Treatment Group (N = 142)

Age Weight (kg) FEV1 (L) FEV1% Predicted FVC (L) FVC % predicted TLC (L) TLC % predicted RV (L) RV % predicted DLCO DLCO % predicted Prescribed O2 (L/min) PO2 (mm Hg) PCO2 (mm Hg) 6-minute walk test (m) MMRC SF-36 PF SF-36 PCS SGRQ total UL volume (mL) NUL volume (mL)

Control Group (N = 135)

Difference (Treatment Control)

Mean

SD

Mean

SD

95% BCI

64.67 76.09 0.87 29.79 2.71 71.47 7.57 128.06 4.64 216.01 9.56 36.43 1.24 67.82 39.85 314.12 2.68 27.28 33.02 54.79 3392.13 3413.90

6.25 17.02 0.27 7.48 0.80 15.12 1.39 15.98 1.07 50.10 4.01 12.69 1.31 11.29 5.28 88.60 0.66 19.30 7.80 15.47 902.39 900.52

64.79 75.78 0.85 29.74 2.65 70.82 7.50 128.17 4.64 215.79 9.34 35.00 1.32 66.99 40.80 308.64 2.65 24.21 31.34 57.06 3273.95 3338.94

6.13 18.01 0.29 7.90 0.86 17.39 1.74 19.83 1.32 55.94 4.50 13.11 1.24 10.71 4.79 81.56 0.72 19.07 7.83 15.17 876.95 812.28

1.60, 1.35 3.89, 4.48 0.05, 0.08 1.78, 1.88 0.14, 0.25 3.23, 4.52 0.31, 0.44 4.41, 4.18 0.29, 0.29 12.45, 12.86 0.79, 1.24 1.66, 4.50 0.38, 0.22 1.83, 3.49 2.15, 0.25 14.76, 25.72 0.14, 0.19 1.49, 7.64 0.18, 3.54 5.91, 1.38 93.39, 329.44 128.77, 278.33

BCI indicates Bayesian credible interval; DLCO, carbon monoxide diffusing capacity; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; MMRC, Modified Medical Research Council Dyspnea Scale; NUL, non–upper lobe; RV, residual volume; SGRQ, St. George’s Respiratory Questionnaire; TLC, total lung volume; UL, upper lobe.


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showed no differences in demographics or baseline characteristics as shown in Table 1. All subjects underwent bronchoscopy and all subjects received treatment as assigned. Followup of all expected, nonwithdrawn subjects at 6 months was completed in 253 of 255 nonwithdrawn subjects (99.2%). Objective blinding was maintained in 97% of subjects. The subject flow diagram is shown in Figure 2. Procedural Results

The bronchoscopy procedure time for the treatment group was 57 (± 25) minutes compared with 29 (± 11) minutes for the sham control group (P < 0.0001). The median hospital stay was 1 day for both groups and the mean was 2.2 (± 6) for the treatment group and 1.0 (± 0) for the control group. The number of valves was 931 in 142 treatment subjects or an average of 6.6 valves per subject. Effectiveness Measures

The primary composite measure showed that 6 of 121 (5.0%) of the subjects in the treatment

group and 1 of 134 (0.7%) in the control group were responders by SGRQ and CT with a 2-sided 95% BCI of (0.048%, 9.212%) for the difference between percentages of responders. The posterior probability superiority in the treatment group was 97.0%, which exceeded the prespecified success threshold of 95%. These results are shown in Table 2, along with individual results of the components of SGRQ and CT lobar volume changes. The SGRQ did not show improvement in the treatment group at 6 months and the proportion of responders was not different between treatment and control groups. The lobar volume changes were significantly different with the treated UL demonstrating an average decrease of 224 mL at 6 months compared with 17 mL for the control group (BCI, 272, 143). The proportion of subjects with a decrease in UL volume was 82%. The average increase in volume of the NUL was 214 mL in the treatment group compared with 27 mL in the control group (BCI, 155, 326). The proportion of responders by both

983 assessed for Study Eligibility

706 Not Enrolled: Did not meet Inclusion Criteria: 557 Died: 4 Withdrew Consent: 77 Other Reason: 25 No Response: 7 Withdrawn due to Closed Enrollment: 36

277 were Randomized into the Study (1:1 Randomization)

142 Randomized into the Treatment Group

135 Randomized into the Control Group

At 6 Months 121 Treatment Subject Visits

At 6 Months 134 Control Subject Visits

13 withdrew prior to 6 months 1 withdrew at 6 month visit 6 died 2 missed visit

1 withdrew at 6 month visit 1 died

FIGURE 2. Consort diagram showing disposition of subjects throughout the trial. r


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TABLE 2. Primary Composite Effectiveness Measure and Individual Components of Quantitative CT Volumes and SGRQ (Baseline to 6 mo) Treatment Group (N = 142)


Difference (Treatment Control) 95% BCI

6/121 (5.0%)

1/134 (0.7%)

0.048%, 9.212%*

224 ± 299 (98/120, 82) 214 ± 384 (34/120, 28)

17 ± 204 (71/133, 53) 27 ± 292 (12/133, 9)

272, 14* 155, 326*

+ 2.15 ± 16.36 39/121 (32.2)

1.41 ± 11.26 53/133 (39.8)

0.04, 7.07* 19.0%, 4.2%

Responders

Composite measure SGRQ and NUL and UL CT volume (mL) UL (# < 0, %) NUL (#Z10%, %) SGRQ Mean change Responders Z 4, (%)

*Statistically significant. BCI indicates Bayesian credible interval; CT, computed tomography; NUL, non–upper lobe; SGRQ, St. George’s Respiratory Questionnaire; UL, upper lobe.

UL and NUL was significantly greater, 19.2%, in the treatment group compared with 2.3% in the control group (BCI, 9.4%, 24.6%). Table 3 shows a comparison of mean change between baseline and 6 months for the treatment and control groups. Overall, the treatment group declined in FEV1, FVC, RV, PCO2, and 6-minute walk test. The significant changes in some parameters in the treatment group are associated with procedure adverse events (e-Appendix) and safety results. Safety Results

There were no occurrences of migration, erosion, expectoration, or serious device-related pneumonia in the study subjects. There were no unanticipated, serious, device-related adverse

events. The primary safety measure was the difference between the treatment and control groups in the defined SAE per subject. There were significantly more subjects with an SAE in the treatment group (n = 20 or 14.1%) compared with the control group (n = 5 or 3.7%) (BCI, 4.0, 17.1). Analysis of the SAEs shows that no one type of event was primarily responsible for the difference. The separate categories are shown in Table 4 and the most frequent event is COPD exacerbations (7 in the treatment group and 2 in the control group). There were 6 deaths in the treatment group and 1 in the control group. No death was considered device related. Three deaths were cardiovascular in origin (day 26 in the control group, and day 95, 165 in the treatment group). One death

TABLE 3. Mean Change (Baseline to 6 mo) for Tests and Questionnaires for Treatment and Control Groups Treatment Group (N = 142)

FEV1 (L) FEV1% predicted FVC (L) FVC % predicted TLC (L) TLC % predicted RV (L) RV % predicted Prescribed O2 (L/min) PO2 (mm Hg) PCO2 (mm Hg) 6-minute walk test (m) MMRC SF-36 PF SF-36 PCS



Obs

Mean

SD

Obs

Mean

SD

95% BCI

118 118 118 118 118 118 118 118 121 110 114 120 119 109 108

0.07 2.11 0.28 7.26 0.04 0.54 0.31 12.57 0.13 1.76 2.10 24.02 0.24 0.90 0.11

0.17 5.49 0.46 11.37 0.82 14.67 1.00 51.11 0.83 8.91 4.47 69.81 1.02 20.81 7.94

132 132 132 132 131 131 131 131 134 125 128 133 133 132 130

0.00 0.04 0.00 0.30 0.09 0.89 0.07 4.24 0.15 1.28 0.62 3.40 0.14 2.53 0.73

0.16 5.74 0.43 12.80 1.27 24.97 1.29 64.70 0.66 8.46 4.20 76.63 1.00 17.38 7.53

(0.11, 0.02)* (3.56, 0.74)* (0.39, 0.17)* (10.60, 4.54)* (0.13, 0.40) (3.65, 6.50) (0.09, 0.67)* (2.26, 31.34)* (0.21, 0.17) (2.73, 1.77) (0.38, 2.59)* (38.84, 2.44)* (0.35, 0.16) (6.58, 3.31) (2.63, 1.37)

*Statistically significant. BCI indicates Bayesian credible interval.


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TABLE 4. Serious Adverse Events Defined for the Primary Safety Measure Listed by Category for the Treatment and Control Groups IBV Treatment Group (N = 142) Events

Bronchospasm COPD flare Death Pneumonia Pneumothorax Respiratory failure Total

1 7 6 1 3 4 22

n (%)

1 7 6 1 3 4 20

IBV Control Group (N = 135) Events

(0.7) (4.9) (4.2) (0.7) (2.1) (2.8) (14.1)

1 2 1 2 0 0 6


n (%)*

1 2 1 2 0 0 5

(0.7) (1.5) (0.7) (1.5) (0.0) (0.0) (3.7)

Estimate

95% BCIw

0.0 3.4 3.5 0.8 2.1 2.8 10.4

2.3, 2.2 0.5, 7.9 0.2, 7.5 3.6, 1.7 0.3, 5.1 0.7, 6.1 4.0, 17.1

*Percentage is number of patients experiencing event/number of patients in treatment group ( 100). wSubjects could have >1 type of AE or >1 instance of the same type of AE. BCI indicates Bayesian credible interval; COPD, chronic obstructive pulmonary disease; IBV, intrabronchial valve.

(day 82) was related to a COPD exacerbation that progressed to respiratory failure, 1 death (day 59) started with gastrointestinal bleeding on day 5, and another was from liver cirrhosis and multiorgan failure (day 190). One death (day 14) was probably procedure related as discussed below. Device-related or Procedure-related SAEs

8 10 12

COPD Exacerbation

There were more COPD exacerbations after bronchoscopy, in the period of 0 to 4 weeks, in the treatment group (44 episodes) compared with the control group (10 episodes). During weeks 5 to 24, the COPD exacerbations were not different between treatment and control groups with 51 in the treatment and 41 in the control group (P = 0.45). Pneumonia

There were only 3 (2.1%) instances of pneumonia in a valve treated location and none were serious. There were 26 episodes in a nonvalve treated location and 6 or 23% occurred in the first 4 weeks. There were 3 episodes of serious pneumonia and 2 of these were in control group patients. DISCUSSION

The goal of this trial was to demonstrate acceptable clinical efficacy and a low incidence of

2

4

6

IBV Control

0

Number of Events

The number of SAEs was 28 for 20 treatment and 5 control subjects and 19 were neither procedure nor device related. Six were procedure related, and 3 were considered device related. The 3 device-related events were pneumothoraces related to complete occlusion treatment (e-Appendix). The 6 procedure-related SAEs that occurred in 5 treatment subjects included 2 COPD exacerbations on day 2, 2 respiratory failures on days 6, 7 with 1 progressing to death, and 1 bronchospasm on day 5. The subject that died on day 14 developed apnea during the procedure, was hospitalized for 4 days, and readmitted on day 7 with systemic inflammatory response syndrome and respiratory failure. Figure 3 shows the timing of all 36 SAEs and highlights that the largest number of events occurred within 1 week of the procedure. Of all

adverse events, including moderate and mild events, 57% of the treatment group and 48% of the control adverse events occurred within the first 4 weeks after the procedure (data not shown).

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25+ Time of Onset (Weeks from Randomization)

FIGURE 3. All 36 serious adverse events for treatment and control groups over time after the procedure and randomization (some of the 28 subjects had >1 SAE). IBV indicates intrabronchial valve; SAE, serious adverse event. r



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adverse events, specifically pneumothorax. The incidence of pneumothorax with bilateral-partial treatment was very low with only 1 episode (0.7%) which resolved after 2 days. The effectiveness, although statistically significant for the treatment responders compared with control, was not clinically meaningful with a 5% responder rate. The partial bronchial valve occlusion of both ULs had, as expected, a significant effect on the lobar volumes at end-inspiration with >200 mL volume shift to the untreated lobes. This pattern confirms prior work9,16,17 showing redistribution of air to the nontreated lobes. We previously found that a 350 mL shift was associated with significant improvement in the SGRQ and others have confirmed a targetlobe volume reduction of >350 mL as clinically significant.13,18 This trial achieved, on average, a volume shift of only 200 mL and this is likely responsible for the lack of improvement in quality of life for the treatment group. The inclusion of a patient-reported outcome, the SGRQ, as a coprimary measure, necessitated a double-blind study design. Others have questioned this study design16,19 as a chest x-ray shows the device and the risk of serious complications for the control group. Blinding was successfully maintained in 97% of the subjects and there were no serious complications from the procedure for the control patients. The sham procedure and blinding did allow measurement of the combined placebo and study effects for the control group. These effects were notable because as shown in Table 2, at 6 months the SGRQ was improved in the control group by 1.4 points, and was improved >3 points at 1 and 3 months after treatment [e-Appendix, see Supplemental Digital Content, http://links.lww.com/ LBR/A114]. Complications associated with the IBV Valve device itself were minimal with only 2% incidence of pneumonia in the valve location and no significant increase in COPD exacerbations compared with control during weeks 5 to 25. There was 1 instance of hemoptysis (0.7%) requiring bronchoscopic evaluation in the treatment group. These results compared favorably to the results from the Endobronchial Valve for Emphysema Palliation Trial (VENT trial) and the Zephyr valve16 where there were 13 episodes (6.1%) of hemoptysis including 1 fatality and significantly more episodes of COPD exacerbations in the treatment group compared with the control group.



Complications associated with the procedure in this trial were greater in the treatment group. However, comparing 30-day mortality with the NETT, this IBV trial had a 30-day mortality of 0.7% in the treatment group compared with 2.2% in the NETT surgery group and 0.2% in the NETT control group.5 Importantly, the 30-day mortality in IBV-treated subjects in this trial was not significantly different from the control group in NETT (P = 0.37). Using the NETT definitions for major pulmonary and cardiovascular morbidity,8 this trial treatment group had 30-day instances of 4.2% and 1.5% compared with 28.1% and 20.0%, respectively, in the NETT. Nonetheless, the procedure-related complications in this trial were increased in the treatment group compared with control, probably because of the longer procedure duration. In the Multicenter European study with IBV Valves,17 which had a similar design as the present study, the type of adverse events reported are similar to the ones reported in the current study. The European study had a blinding duration of only 3 months and the total number of enrolled subjects was 73 patients (37 treatments and 36 controls). In the European study there were 7 patients with SAEs in the treatment group (18.9%) and 4 in the control group (11.11%) compared with the 14.1% and 3.7% reported in the study being reported. While this trial was ongoing, the VENT trial was published in 2 parts.16,18 Those investigators performed single-lobe complete occlusion with the Zephyr valve but did not achieve clinically meaningful results. Despite technical problems resulting in only 56% and 48% complete lobar occlusion at 6 months, the investigators identified a subgroup with higher heterogeneity and complete interlobar fissures that had a greater response. A recent randomized study using the IBV Valve confirmed single-lobe complete treatment was superior to bilateral-partial occlusion treatment.20 Using imaging biomarkers for patient selection with excellent technical results, they showed that single-lobe complete occlusion significantly improved pulmonary function, exercise, and quality of life. CONCLUSIONS

Bilateral-partial bronchial valve occlusion of both ULs of in patients with severe emphysema shifted lung volume from the treated lobes to the untreated lobes to a significant degree. However, the lobar volume shift of 200 mL was not r




accompanied by an improvement in the healthrelated quality of life measure as seen previously. This trial was a technical and statistical success, but it did not achieve clinically meaningful results. Device safety was confirmed and pneumothorax was reduced by partial lobar treatment. This and concurrent studies add to the accumulating knowledge that bronchial valve treatment, especially when using imaging biomarkers for low collateral ventilation paired with complete occlusion of a single lobe, remains a promising treatment for selected patients with severe emphysema. ACKNOWLEDGMENTS The authors would like to thank Andrew Mugglin PhD for statistical support and guidance. IBV Valve Trial Research Team (alphabetical by institution): Akron General Medical Center, Akron. OH. Sanjiv Tewari, MD (Principal Investigator); Debra Hudock, RN, MSN, CNS (Principal Clinic Coordinator); Diane Fultz, RRT; Christine Fygetakes, RRT; Lee Ann Williams, CNP; Akhil Bindra, MD; Harish Kakarala, MD; Kar-Ming Lo, MD; Michael Passero, MD. Alexian Brothers Hospital Network, Elk Grove Village, IL. Edward J. Diamond, MD (Principal Investigator); Kevin Kovitz, MD (Coprincipal Investigator); Mary Vance (Principal Clinic Coordinator); Judy Goodman, CCRC; Leah Gooch; Mary Joseph, PhD; Rebecca Meredith, BA; John E. Pantano, MD; Marilyn Borkgren, RN; Sadia Benzaquen, MD; Sara Greenhill, MD. Cleveland Clinic Foundation, Cleveland, OH. Michael Machuzak, MD (Principal Investigator); Thomas Gildea, MD (Coprincipal Investigator); Yvonne Meli, RN, BC, CCRP (Principal Clinic Coordinator); Diane Faile, BS, RRT; Richard Rice; Atul Mehta, MBBS; Brian Mann, MD; David Mason, MD; Joseph G. Parambil, MD; Omar A. Minai, MD. Columbia University Medical Center, New York, NY. Roger Maxfield, MD (Principal Investigator); Patricia Jellen, MSN RN (Principal Clinic Coordinator); Fran Brogan, MSN; Angela Di Mango, MD; Byron Thomahow, MD; Chip Yip, MD; David Lederer, MD; Mathew Bachetta, MD; William Bulman, MD; Joshua Sonett, MD; Mark Ginsburg, MD. Emory University Hospital, Atlanta, GA. Seth D. Force, MD (Principal Investigator); (Jennifer) Noel, Walker, RN (Principal Clinic Coordinator); Alexis, Neill, RN; Ellen Lyons, RRT; Jayne Thompson, RN; Maryse Van Dyke; Shannon Smith, RN; David Shaz, MD; Alvaro Velasquez, MD. HealthPartners Research Foundation/Regions Hospital, St. Paul, MN. Charlene E. McEvoy, MD (Principal Investigator); Avi Nahum, MD (Coprincipal Investigator); Alain Broccard, MD; (Coprincipal Investigator); Natalie K. Woodruff (Principal Clinic Coordinator); Alex Adams, RRT; Pamela J. Neuenfeldt; Eric Korbach, MD; Kealy Ham, MD; Krista Graven, MD. Kaiser Permanente Medical Center Los Angeles, Los Angeles, CA. Luis M. Moreta-Sainz, MD (Principal

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Investigator); Nancy Elbaum, RN (Principal Clinic Coordinator); Cecilia Pineda, RN; Mercedes Cardona; Arash Kharestan, MD; Mihran Garabedian, MD. Kaiser Permanente Northwest, Portland, OR. Richard A. Mularski, MD,MSHS, MCR (Principal Investigator); Thomas P. Yan, MD, (Coprincipal Investigator); Kathleen Arnold, RN, BSN (Principal Clinic Coordinator); Carol Young; Elease Rumbaugh, RN, NP; Heather Houston, RN; Helen Walsh, RN, MPH; Roger Macdonald, RN, MEd, ND; Alistair Scriven, MD; David Schmidt, MD, PhD; Jonathan Rettmann, MD; Joshua Filner, MD, MPH; Noel Wardell, MD; Susan Mikkelsen, MD; Thomas Stibolt, MD. Lehigh Valley Medical, Allentown, PA. Robert (Robb) Kruklitis, MD, PhD (Principal Investigator); Gerard Petersen, MD (Coprincipal Investigator); Jennifer Rovella, MD (Coprincipal Investigator); Madeline Sharkey, RN (Principal Clinic Coordinator); Marika Vermeersch, RN; Terry Kloiber; Dorothea Direso, MD; Jeff Marsh, MD; Jonathon Hertz, MD; Joseph Paprota, MD. Medical College of Wisconsin, Milwaukee, WI. Mario Gasparri, MD (Principal Investigator); Christopher Plambeck, MD (Coprincipal I); Barb Alivo, RN (Principal Clinic Coordinator); Trisha Wilcox, NP; Joanne Scherwinski; Daryl Pearlstein, MD; Randolph Lipchik, MD; William Tisol, MD. Mission Internal Medicine Group, Mission Viejo, CA. George Schiffman, MD, FCCP (Principal Investigator); Rudy Marquez, MD, FCCP (Coprincipal Investigator); Gladys Andreas (Principal Clinic Coordinator); Bruce Tammelin, MD; Edmond Vartany, MD; Richard Bell; Margaret Amaya. Mount Sinai School of Medicine, New York, NY. Timothy Harkins, MD (Principal Investigator); E. Neil Schachter, MD, (Coprincipal Investigator); Olivera Calukovic (Principal Clinic Coordinator); E. Neil Schachter, MD; Scott J. Swanson, MD; Ireen Khan; Ketan Patil; Nancy Davis, RN; Oleg Epelbaum, MD; Paul Barrette; Savil Erickson-Torres, MD; Susan Comninel, RN; Virginia Litle, MD. National Jewish Hospital, Denver, CO. Russell Bowler, MD (Principal Investigator); Ali Musani, MD (Coprincipal Investigator); Holly Currier (Principal Clinic Coordinator); Kim McPeak; Adam Friedlander, MD; Kurt Jensen, MD; Scott Van daWalker, NP; Katherine Ross Garces, RN. Oklahoma State University, Tulsa, OK. Daniel Nader, DO (Principal Investigator); Johnny Stephens, PharmD (Coprincipal Investigator); Faye Biggs (Principal Clinic Coordinator); Diana Tameny (Principal Clinic Coordinator); Jeffrey Stroup, PharmD., BCPS; Mary Donovan, RN; Damon Baker, DO; Montgomery Roberts, DO; Mousumi Som, MD; Nicole A. Farrar, DO; Randall Reust, DO; Scott Hendrickson, DO. Overlook Hospital, Summit, NJ. Robert A. Restifo, DO (Principal Investigator); Robert Sussman, MD;Vincent Donnabella, MD (Coprincipal Investigator); Federico Cerrone, MD; Mark Zimmerman, MD; Virginia Hala, RN, CCRC (Principal Clinic Coordinator); Marissa Rienton Lim, CCRC; Kathy Izzo, CCRC. Pulmonary & Critical Care Associates of Baltimore, Baltimore, MD. William Krimsky, MD (Principal Investigator); Ajay Behari, MD (Coprincipal Investigator); Sy Sarkar, MD (Coprincipal Investigator); Stuart King (Principal Clinic Coordinator); Eileen Opdyke, RN; Joel Atwood; Sherry Crawshaw, PA; Stuart Willes, MD.


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Pulmonary Associates of Mobile, P.C., Mobile, AL. Allan Seibert, MD (Principal Investigator); Michele Hemphill, RN (Principal Clinic Coordinator); Letoya Craig; Nicole Saizan, RN; Tony Cowan, RT; Caesar Agagan, MD; Peter Lutz, MD. Rhode Island Hospital, Providence, RI. Douglas Martin, MD (Principal Investigator); Sidney Braman, MD (Principal Investigator); Muhanned Abu-Hijleh (Principal Investigator); Amy Palmisciano RN, BSN (Principal Clinic Coordinator); Avery Couture; Christine Newman, RN; Erin E. Johnson; Gina Ruggiera; Melissa Skoutas; Kevin Dushay, MD; Yaser Abu-El-Sameed, MD. Sarasota Memorial Hospital, Sarasota, FL. Kirk Voelker, MD (Principal Investigator); Kathy Pope-Nix, RN (Principal Clinic Coordinator); Nancy Clapp, RN, BA, CCRC; Gregory Ferreira, MD; Kisha Morgan, MD; Todd Horiuchi, MD; Mary Bradley, RN; Gail Wagoner, RN. Scott & White Memorial Hospital, Temple, TX. Juan Sanchez, MD (Principal Investigator); Dominic deKeratry, MD (Principal Investigator); Craig Cernosek, DC, CRC III (Principal Clinic Coordinator); Chris Herrick; Heather Smith; Melisa Carney; Rhoda Wardlow; Ryan Whittle; Ester-Fields, DO; Marilynn-Prince-Fiocco, MD; ShirleyFong-Jones, MD. Southern Illinois University School of Medicine, Springfield, IL. Stephen R. Hazelrigg, MD (Principal Investigator); Cathy Leslie, RN (Principal Clinic Coordinator); Cathy Leslie, RN; Cheryl Ogden, RN; Diane Drew; Theresa Boley, RN. St. Joseph Medical Center, FHS, Tacoma, WA Richard A. Kahlstrom, MD (Principal Investigator); Navdeep Rai, MD (Coprincipal Investigator); Chris Biljan, RN (Principal Clinic Coordinator); Laura Crews, RN, BSN, CCRC; Trina Wesner; Ann Lee, MD; Clifton Ty Baylor, MD; David Shaw, MD; Manuel Iregui, MD; Stacie Krabill, ARNP; Stephen Ryan, MD; Lydia Clipper, RNC, CCRP; Wendy White; Alejandro Arroliga, MD. University of Alabama at Birmingham, Birmingham, AL. Robert Cerfolio, MD (Principal Investigator); Keith M. Wille, MD; Sandra Calloway (Principal Clinic Coordinator); Hilary Moran, RN; Jeana Alexander, RN, BSN; Valerie Maldonado. University of California Davis Medical Center, Sacramento, CA. Andrew Chan, MD (Principal Investigator); Roblee Allen, MD (Coprincipal Investigator); Maya Juarez (Principal Clinic Coordinator); Tina Tham; Timothy Albertson, MD; Brian Morrissey, MD; Mark Avdalovic, MD; Richart Harper, MD; Samuel Louie, MD; Nicholas Stollenwerk, MD; Macey Sockolov; Ricio Mendoza; Jimmy Yu, Krysta Chaldekas; Sandy Algaze; Tina Tran. University of California Medical Center at Los Angeles, Los Angeles, CA. Christopher Cooper, MD (Principal Investigator); Irawan Susanto, MD; Patricia Eshaghian, MD; Robert Cameron, MD; Eric Kleerup, MD; Donald Tashkin, MD; Milan Patel (Principal Clinic Coordinator); John Dermand (Principal Clinic Coordinator); Marlon Abrazado (Technical Support). University of California San Diego Health System, San Diego, CA. Gordon Yung, MD (Principal Investigator); Smita A. Desai, DO (Coprincipal Investigator); Christopher Whitehead (Principal Clinic Coordinator); Bobbie Munden, RN (Principal Clinic Coordinator); Laura Gabel (Koenig) CCRC; Colleen Channick, MD; Samir Makani, MD; Victor Test, MD.



University of Chicago Medicine, Chicago, IL. D. Kyle Hogarth, MD (Principal Investigator); Imre Noth, MD (Coprincipal Investigator); Spring Holland, CCRC (Principal Clinic Coordinator); Cathy Brown, RN; Latriese Sardin; Irena Garic; Edward Naurekas, MD; Mary Strek, MD; Pamela McShane, MD; Steven White, MD. University of Florida, Gainesville, FL. Michael A. Jantz, MD, FCCP (Principal Investigator); Sebastian FernandezBussy, MD (Coprincipal Investigator); Robin Carrie, ARNP (Principle Clinic Coordinator); Edward Hensel, RN; Jessica Sanders, CVT, CPFT; Hassan Alnuaimat, MD; Carolyn Graisbery, RN. University of Iowa Hospitals and Clinics, Iowa City, IA. Geoffrey McLennan, MB, BS, FRACP, PhD (Principal Investigator); Kimberly Baker, MD (Principal Investigator); Tom Recker, MD (Coprincipal Investigator); Kim Sprenger, RN (Principal Clinic Coordinator); Andrea Chapman; Angela Delsing; Janet Keating; Kaylene Crawford; Phyllis Pirotte, RN; Sara Kraus; Dawn Flaherty, MD; Dwight Look, MD; Karl Thomas, MD; Sherif El-Mahdy, MD. University of Louisville, Louisville, KY. Jinesh Mehta, MD (Principal Investigator); Maria del Mar Cirino-Marcano, MD (Principal Investigator); Rodney Folz, MD (Principal Investigator); Fidaa Shaib, MD (Coprincipal Investigator); Brian Beattie (Principal Clinic Coordinator); Anna Rich; Brian Mattingly; Heidi Wilson; Mohamed Saad, MD. University of Pennsylvania Health System, Philadelphia, PA. Andrew R. Haas, MD, PhD (Principal Investigator); Colin T. Gillespie, MD; Daniel H. Sterman, MD; Barbara Finkel, MSN, RN, CCRC (Principal Clinic Coordinator); Susan Metzger, MSN, RN (Current Clinic Coordinator); Kayla MyThao Le; Victoria Fleck; Hans Lee, MD; Michael W. Sims, MD; Steven L. Leh, MD. University of Texas Health Science Center at San Antonio, San Antonio, TX. Luis F. Angel, MD (Principal Investigator); Regina T. Whitener (Principal Clinic Coordinator); Deborah J. Levine, MD; Stephanie Levine, MD; Adam Cline. University of Utah Health Sciences Division, Salt Lake City, UT. Mark Elstad, MD (Principal Investigator); Barbara Cahill, MD (Coprincipal Investigator); Chakravarthy Reddy, MD (Coprincipal Investigator); Wayne Samuelson, MD (Coprincipal Investigator); Sanjeev Murthi Raman, MD (Coprincipal Investigator); Tauni Maughan, BSN (Principal Clinic Coordinator); Judy Jensen, MS, CCRC (Principal Clinic Coordinator); Kelly Peterson-Short, RN (Coprincipal Coordinator); Leonie Morrison-de Boer, MD (Coprincipal Coordinator). University of Virginia Medical Center, Charlottesville, VA. Jonathon D. Truwit, MD, MBA (Principal Investigator); Y. Michael Shim, MD (Coprincipal Investigator); Margaret E. Donowitz, MSN, RN, APN2 (Principal Clinic Coordinator); A. Renee Campbell, RRT, RPFT; Ajeet G. Vinayak, MD; Kyle B. Enfield, MD. University of Washington Medical Center, Seattle, WA. Douglas E. Wood, MD (Principal Investigator); Michael Mulligan, MD (Coprincipal Investigator); Linda Harrison, CCRC (Principal Clinic Coordinator); Catherine Pagoaga; Connie J. Wallum; Mehakpreet, Romana, MD; Skye Steptoe. VA Palo Alto Health Care System, Palo Alto, CA. Ware Kuschner, MD (Principal Investigator); Ganesh Krishna, MD (Principal Investigator); Harmon Paintal, MD (Coprincipal

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Investigator); Madhuri Agrawal (Principal Clinic Coordinator); Edmond Varney, MD; Rudy Marquez, MD.

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10. Sterman DH, Mehta AC, Wood DE, et al. A multicenter pilot study of a bronchial valve for the treatment of severe emphysema. Respiration. 2010;79:222–233. 11. Hopkinson NS, Toma TP, Hansell DM, et al. Effect of bronchoscopic lung volume reduction on dynamic hyperinflation and exercise in emphysema. Am J Respir Crit Care Med. 2005;171:453–460. 12. Toma TP, Hopkinson NS, Hillier J, et al. Bronchoscopic volume reduction with valve implants in patients with severe emphysema. Lancet. 2003;361:931–933. 13. Springmeyer SC, Bolliger CT, Waddell TK, et al. Treatment of heterogeneous emphysema using the Spiration IBV valves. Thorac Surg Clin. 2009;19: 247–253. 14. Wood DE, McKenna RJ Jr, Yusen RD, et al. A multicenter trial of an intrabronchial valve for treatment of severe emphysema. J Thorac Cardiovasc Surg. 2007;133:65–73. 15. Ukil S, Reinhardt JM. Smoothing lung segmentation surfaces in 3D x-ray CT images using anatomic guidance. Acad Radiol. 2005;12:1502–1511. 16. Sciurba FC, Ernst A, Herth FJF, et al. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010;363:1233–1244. 17. Ninane V, Geltner C, Bezzi M, et al. Multicentre European study for the treatment of advanced emphysema with bronchial valves. Eur Respir J. 2012;39: 1319–1325. 18. Herth FJF, Noppen M, Valipour A, et al. Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort. Eur Respir J. 2012;39: 1334–1342. 19. Strange C, Herth FJ, Kovitz KL, et al. Design of the Endobronchial Valve for Emphysema Palliation Trial (VENT): a non-surgical method of lung volume reduction. BMC Pulm Med. 2007;7:10, DOI: 10.1186/ 1471-2466-7-10. 20. Eberhardt R, Gompelmann D, Schuhmann M, et al. Complete unilateral versus partial bilateral endoscopic lung volume reduction in patients with bilateral lung emphysema. Chest. 2012;142:900–908.


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Endobronchial coils for the treatment of severe emphysema with hyperinflation (RESET): a randomised controlled trial.

Cost-effectiveness of endobronchial valve therapy for severe emphysema: a model-based projection based on the VENT study.

Pneumothorax following endobronchial valve therapy and its impact on clinical outcomes in severe emphysema.

Pieces to the puzzle of endobronchial valve insertion for emphysema.

Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial.

Lung perfusion and emphysema distribution affect the outcome of endobronchial valve therapy.

A randomized multicenter trial of minimally invasive rapid deployment versus conventional full sternotomy aortic valve replacement.

Electroacupuncture for Functional Constipation: A Multicenter, Randomized, Control Trial.

A European multicenter randomized controlled trial of single dose surfactant therapy for idiopathic respiratory distress syndrome.

Maintenance nifedipine therapy for preterm symptomatic placenta previa: A randomized, multicenter, double-blind, placebo-controlled trial.

Combined Bone Marrow-Derived Mesenchymal Stromal Cell Therapy and One-Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial.

Multicenter pilot treatment trial for psychogenic nonepileptic seizures: a randomized clinical trial.

A Randomized Clinical Trial of an Integrative Group Therapy for Children With Severe Mood Dysregulation.

A comparative study of sequential therapy and standard triple therapy for Helicobacter pylori infection: a randomized multicenter trial.

A protocol of a randomized controlled multicenter trial for surgical treatment of lumbar spondylolisthesis: the Lumbar Interbody Fusion Trial (LIFT).

Methods for a multicenter randomized trial for mixed urinary incontinence: rationale and patient-centeredness of the ESTEEM trial.

Inhaled nitric oxide as adjunctive therapy for severe malaria: a randomized controlled trial.

Intermittent Directly Observed Therapy for Abdominal Tuberculosis: A Multicenter Randomized Controlled Trial Comparing 6 Months Versus 9 Months of Therapy.

Rationale, methodology, and implementation of a nationwide multicenter randomized controlled trial of long-term mild hypothermia for severe traumatic brain injury (the LTH-1 trial).

The Tinnitus Retraining Therapy Trial (TRTT): study protocol for a randomized controlled trial.

Results of a multicenter randomized controlled trial of the clinical effectiveness of schema therapy for personality disorders.

High-fluoride toothpaste: a multicenter randomized controlled trial in adults.

Lung volume reduction coil treatment for patients with severe emphysema: a European multicentre trial.

Response to statin therapy in obstructive sleep apnea syndrome: a multicenter randomized controlled trial.