Major comments:
1. How many sites will be involved in this trial? The authors mention a multicenter
trial but should identify the sites and provide estimates of enrollment from each
site.
45 centres
2. What is the specific radiologic assessment? The authors mention both HRCT
and 10mm slice thicknesses. Are you proposing to perform lobar segmentation
using such thick slices? If densitometric measures of emphysema are to be
performed on thin slices, a HU threshold of -950 or -960 should be used. What
software will be used for this analysis? The authors should provide a table of CT
scanning algorithms by brand of CT scanner. While a phantom is likely not
needed for such investigation, how will study qualified CT scanners be
determined?
Each centres scanner was assessed by the core lab according to a specific protocol
with a phantom
Both thick and thin slices were obtained at full inspiration and at residual volume
All analysis done by single core lab (MeddQIA)
Software used was a novel standardised CAD software for quantitative image
analysis
3. The authors mention that bronchoscopy is “performed under general
anesthesia or deep sedation with amnestic properties.” Is there a standard
protocol that will be followed for medication administration? How will general
anaesthesia or deep sedation be determined?
General anaesthesia and deep sedation was according to local practice in fact all
centres used general anaesthesia according to local practice
4. At the bottom of Page 7, the authors report that “stent placements are targeted
to segmental airways leading to regions with the highest RV”. How will this be
determined? Will it be done using both inspiratory and expiratory CT scans to
look for regions of gas trapping? Physiologic measures of hyperinflation will not
provide regional discrimination of lung function/dysfunction, and simple measures
of emphysema on the inspiratory scan may be an imperfect assessment of gas
trapping.
These were identified by the radiology core lab analysing the inspiratory and
expiratory scans
5. The authors mention on page 9 that “Only those subjects with complete
6-month data will be include in this analysis.” How will the investigators deal with
subject death/missing data? Will this also be addressed in a manner similar to
NETT where subjects unable to provide data/missing data will be considered as
“non-responders”?
6. At the bottom of page 10, the authors mention that “Irrespective of the final
efficacy results, the EASE Trial will significantly advance our knowledge of
patients with severe emphysema on optimal medical management.” How will
these be accomplished with a smaller sample size than NETT and less
phenotypic data? Further, the medication use is not standardized. This comment
and the comments pertaining to the natural history of emphysema should be
removed.
Removed as requested
Discretionary comments:
1. The investigators are including subjects 35 years old or older. Most studies
typically start at age 50. Why such a young inclusion age? These younger
subjects likely have more severe or more rapidly progressive disease and may
respond differently to therapy than their older counterparts.
Most standard guidelines GOLD etc define COPD by age over 35 years in fact for
the study 65.9±7.9
2. The authors mention using cardiac echo to assess heart function and
pulmonary vascular disease in subjects with severe emphysema. Prior
investigation in NETT suggests that such tests are of marginal utility and that
right heart catheterization is suggested in this population. While echo will likely
provide evidence of RV dysfunction, it may not be optimal for screening subjects
for hemodynamically significant pulmonary vascular disease.
Where echo was not satisfactory or borderline results were obtained right heart
catheterisation was performed> Performing right heart catherisation in such a large
study in all patients would not be ethical as it would have introduced further
unwarranted risks.
Minor comments:
1. The authors mention on page 3 that “even a mild exacerbation can cause the
patient’s condition”. Exacerbation should be defined/clarified for the reader. While
it may be obvious to the subspecialist, it will not be to general readership.
2. On page 10, the authors mention a placebo effect. Will subjects undergoing
the stenting tend to have more blood tinged sputum? If so, that may bias both the
subject and second blinded team.
Possible but no way of addressing this without subjecting patients in the sham group
to additional risks without potential benefits
3. Table 1: Inclusion Criteria “subject agrees to consult with a cardiologist prior to
randomization if findings determine the need for such consultation.” What are
these criteria?
Intentionally vague as patients may have chest pain or possible markers of cardiac
ischaemia that require cardiac assessment prior to anaesthesia. Anyone that the
investigator considers at risk may be sent for a cardiac assessment.