Review for 10.1186/s12876-014-0197-7 (2014)

Reviewer's report
Title:Randomised, Double-blind, Placebo-controlled Trial of Oral Budesonide for
Prophylaxis of Acute Intestinal Graft-versus-Host Disease after Allogeneic Stem
Cell Transplantation ( PROGAST)
Version:2Date:26 June 2014
Reviewer: Amin Alousi
Reviewer's report:
1. Abstract: 3X3mg is not a standard abbreviation; would state 3mg capsule
three times daily.
2. Abstract, methods, results: The paper states grade>2 GI GVHD by day 100 as
the primary outcome. The methods section cites the Gluckberg's Grading System
as the reference. It is unclear if the author is confusing the term grade and
actually means stage or if they are referring to actually grade. Lower GI STAGE
means stool 500-1,000 is STAGE 1, >1,000 <1,5000 is STAGE 2, etc. GRADE 2
means – Stage 1 to 3 skin involvement; Grade 1 liver or gut involvement; ECOG
PS 1. As such, I do not know what the authors means by clinical grade 3-4 acute
intestinal GVHD? I suspect they mean STAGE but are mistakenly writing
GRADE.
3. The sentence of the abstract stating: "According to the premature termination
of the study (insert comma) the statistical power of this data did not culminate in
the original calculated value of 80%". This is non-factual statement. This
statement implies that premature closure of the study did not allow statistical
power to detect . . . What is correct is the following, The trial closed after X
patients were enrolled because of poor (or slow) accrual. Within the limits of the
the final sample size, we were unable to show any benefit for the addition of
budesonide to standard GVHD prophylaxis when compared to placebo in the
prevention of lower GI GVHD. The original statement implies that it is the
premature closure of the trial which limited the ability to find a difference which
may or may not (much more likely) be true.
Abstract Conclusion: last phrase of last sentence is not true and has nothing to
do with your study. It was not the aim of the study to show that budesonide could
or should be applied "therapeutically" (which I assume the author means for
treatment). Your study does not support the use of this drug as prophylaxis from
lower GI GVHD (period). Whether this drug has role as treatment is also of great
debate with a recent randomized trial closing early for lack of improvement when
used for the treatment of upper and lower GI GVHD (stool <1000ml).
Background: Please provide a reference stating that acute GVHD of the skin/liver
rarely becomes life threatening. I am unaware of such a paper. One should
simply state that lower GI GVHD is associated with lower response to standard
therapies (McMillian et al) and is associated with high NRM.
Background: Is steroid spelled correctly (steroide?)
Background: Does not really discuss why they think giving a topical steroid would
provide effective prophylaxis from GVHD? Is there animal models? Are they
hoping to mitigate chemotherapy induced inflammation/ cytotoxicity which may
result in local inflammatory environment for antigen presentation? Do the
hyopethsize that local steroids would prevent donor lymphocytes to migrate to
lymphoid tissues in the gut? What is their hypothesis?
Methods: Not precise- one would usually state patients were required to have
matched related or unrelated donor defined as X by X level typing. Single-antigen
mismatches were allowed.
Methods: Again, please clarify if they mean STAGE or GRADE for primary and
secondary endpoints.
Methods: Statistical analysis, do they have a reference or a reason for choosing
a rate of 30% GI Grade (likely mean stage) 2 as their baseline rate? I am
unaware of any studies where the rate of lower GI GVHD have been this high
especially when including matched sibling transplants (in 35% of patients).
Top of page 9: There are statistical tools for testing whether if the trial would
have continued to enroll and results continued on current trajectory- what the
likelihood (chance) that a statistical significance would have been detected
between the two arms. Was this test performed. Stating what the power of the
current sample size is completely irrelevant especially when considering the trial
results were completely overlapping.
Top of Page 9: I am unaware of any accepted histologic grading for chronic
GVHD, in fact, most patients with true chronic GI GVHD (with fibrosis) have a
normal biopsy. Perhaps they mean biopsy findings of late acute?
Discussion: Poorly written and deviates from the focus of the research study. the
conclusion should focus on why or why not they were able to show benefit of this
approach (their hypothesis).
Stating (repeating) what power their current sample size has in not only repetitive
but irrelevant. Regardless of what the actual sample size could have shown a
difference of- this is not germane to the actual findings.
First sentence on top of page 11 has nothing to do with the research trial and I
am not sure evidence/ current literature would support (one randomized study of
oral time released beclomethasone did not reach primary outcome and second
randomized- follow-up study closed early b/c of lack of efficacy). Would remove
this sentence.
Mid page 11: what is meant by the verum group. Not sure what point is being
made.
Conclusion: Would remove sentence about the power and simply state, this trial
closed prematurely because of slow accrual. Within the limitations of the sample
size, no significance difference in outcomes were able to be detected in primary
or secondary outcomes. Would remove the sentence that further studies with
larger patient populations are warranted- your results would certainly deter most
from embarking on such a trial. If one really believes that statement, would state
as the baseline rate in the control group was 15%- targeting (or enriching) a
group whom are at higher risk for lower GI GVHD (antigen mismatch, mud,
ablative conditioning, etc) should be considered in designing future trials.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Not suitable for publication unless extensively edited
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
No