Timothy Shipley, PhD
In-house Editor
BMC Gastroenterology
22 November 2011
Dear Dr Shipley,
Re: Manuscript reference number 1652596493527337
Please find attached our revised manuscript entitled “Efficacy of omeprazole, famotidine, mosapride
and teprenone in patients with upper gastrointestinal symptoms: an omeprazole-controlled
randomized study (J-FOCUS),” in which we have taken into account the additional comments
provided by the reviewers.
We wish to thank you and the reviewers for taking the time to re-review our manuscript. The
comments were particularly insightful and have helped us to improve our manuscript. Our responses
to individual comments are summarized below. The revisions to the text are indicated with yellow
highlighting in the manuscript and by page and line numbers in our point-by-point responses below.
Please address all correspondence to:
Kouichi Sakurai, MD
Department of Gastroenterology and Hepatology,
Graduate School of Medical Sciences, Kumamoto University
1-1-1 Honjo, Kumamoto 860-8556, Japan
Tel: +81-96-373-5149
Fax: +81-96-371-0582
E-mail: sakurai@s3.kcn-tv.ne.jp
We hope that the revised manuscript is now acceptable for publication in BMC Gastroenterology. We
look forward to hearing from you in due course.
Yours sincerely,
Kouichi Sakurai, MD
Responses to the peer reviewers’ comments
Reviewer: Grigorios Leontiadis
Point # 5. (Urine antibody testing is not a valid method to test for H. pylori infection. Were all
patients tested for H. pylori or only a proportion of them?)
Response to authors’ response: Urine antibody testing is FDA approved, but if the authors cannot
identify national or international guidelines that recommend this test as a diagnostic test in clinical
practice, they should add the choice of test in the list of study limitations.
Response: Although we have not yet found any national/international guidelines recommending this
test, this is not overly surprising, considering that the test was only approved in 2006 and further
evidence is clearly needed to overcome the reluctance to new assays to simplify clinical testing. It is
possible that some patients with H. pylori infection were included in the study. However, we believe
that this would be true with any test. We chose the urine antibody test as it provides relatively quick
results, is much more convenient for use in an office setting, and causes no discomfort, unlike some
alternative procedures. In accordance with this comment, we have added the following paragraph:
“First, we used a urine antibody test to screen patients for evidence of H. pylori infection. Although
this test shows high sensitivity and accuracy, it is possible that some patients with H. pylori infection
were included in this study. Although the use of endoscopic biopsy may have avoided this possibility,
this procedure is uncomfortable for the patient, time consuming and costly. Urea breath testing, rapid
urease tests or serology are well established alternatives but, considering their reported accuracies and
specificities [34], they are unlikely to improve the true detection rate, over that achieved with the
urine antibody test in this study.” (Page 19, Lines 442–450).
Point #6. (One of the exclusion criteria was when a patient was “judged to be ineligible for study
entry by the investigator”. This is vague and subjective and does not allow comparison of the results
of the current study with previous or future studies. It also undermines the generaliseablity of the
results in clinical practice. How can the clinicians be sure that their patients are similar to the study
population if one exclusion criterion is not defined?)
Response to authors’ response: I do not agree that this is a common criterion in clinical trials, at
least not in high quality trials. The purpose of having pre-defined and well-defined inclusion criteria
is to minimize subjectivity during eligibility assessment; this purpose is defeated when an additional
exclusion criterion named “judged to be ineligible for study entry by the investigator” is used. The
authors should elaborate on this in the discussion of study limitations.
Response: Although we understand the reviewer’s concern, we believe that many investigators will
consider whether a specific patient could be included in a clinical trial even before applying the
clinical trial criteria. This may be based on their knowledge of the patient’s cooperativity, prior
treatment adherence or likelihood of returning for follow-up visits. The investigator, with access to
the patient’s history, may also identify other grounds for excluding that patient that we did not
consider when designing the trial. Nevertheless, we have included the following paragraph as a
potential limitation of the study:
“Second, it is possible that the opportunity for the investigators to exclude patients based on their
judgment of eligibility could have introduced some bias into the study, as the investigators may have
preferentially included patients likely to respond favorably to treatment. However, we deemed this to
be important and useful, as our exclusion criteria could not cover every eventuality.” (Page 19, Lines
450–454).
Point # 8. (What measures were taken to maintain concealment of allocation prior to study entry?)
Response to authors’ response: The authors’ response is not relevant to the question. The authors are
advised to read the article: Schulz, K.F., Grimes, D.A. (2002). Allocation concealment in randomised
trials: Defending against deciphering. The Lancet, 359(9306), 614-618. This explains what allocation
concealment is and what is meant by measures taken to maintain it. The revised response to point #8
should be included in the article.
Response: Study drug allocation tables were prepared by the study organizer and managed by a
clinical research coordinator at each institute. During screening/enrollment, the physician recorded the
subject’s characteristics and provided this information to the clinical research coordinator, who then
allocated the subject an ID and study drug based on the allocation tables prepared by the organizer.
There were no deviations in the allocation of subjects based on their background characteristics. This
information has been added to the manuscript on Page 8, Lines 169–173 and 181–182.