Review for 10.1186/1471-230X-12-42 (2012)

Reviewer's report
Title:Efficacy of omeprazole, famotidine, mosapride and teprenone in patients
with upper gastrointestinal symptoms: an omeprazole-controlled randomized
study (J-FOCUS)
Version: 2Date:25 August 2011
Reviewer: Grigorios Leontiadis
Reviewer's report:
This is the report of a non-blinded randomized controlled trial that assessed four
medications for H. pylori-negative, endoscopically uninvestigated patients with
dyspepsia in Japan. This is a clinically important question with limited data
available for Japanese patients with dyspepsia. Overall the reported is well
written. The limitations of the study are clearly stated appropriately discussed in
the Discussion section page 17. The instigators were fully justified not to use a
placebo arm. However there are several methodological and reporting
deficiencies. See below.
Major compulsory suggested revisions:
1. The study was registered in April 2011, almost 3 years after the end of the
study (June 2008). Isn’t prospective registration (i.e. prior to study conduction,
not just prior to submission) a requirement for BMC Gastroenterology?
2. The initial size of the study groups (142:132:125:72) does not reflect the
randomization ratio of 2:2:2:1. The three first groups should have almost equal
number of patients. This reflects a flawed randomization method or inadequate
concealment of allocation prior to study entry allowing the investigators to choose
which patient gets which drug. Alternatively, this may mean that there were a
large number of post-randomization exclusions which are not mentioned in the
manuscript.
3. There are several problems with the safety outcomes. In the register protocol,
safety is listed as one of the outcomes. However the is no mention about safety
of in the manuscript neither in the Outcome section nor in the Results. There is
only a mention in the abstract that there were no treatment related adverse
effects and a statement in page 10 (statistical analysis) that “safety variables
were analyzed using all randomized patients (i.e., intention to-treat population).
First of all the methods for assessing safety should be reported in detail (passive
reporting or active questioning, open or closed questions). The results should
also be reported in the main text. It should be explained how can the proportion
of patients adverse effects be zero, when the analysis was ITT and there were
patients missing from this analysis.
4. Page 10. Statistical Analysis: It reads “The effect of teprenone on dyspeptic or
GERD symptoms was assumed to be lower than that of the other agents.
Considering the symptom severity of included patients, it was planned for ethical
reasons to keep the group allocated to teprenone as small as possible. It was
estimated that the effect of teprenone could be confirmed with half the number of
individuals allocated to the other agents.” They authors should provide evidence
(with references) for their belief that teprenone is inferior to the other treatments.
If so, it was unethical to have such an arm in the study.
5. Urine antibody testing is not a valid method to test for H. pylori infection.
Where all patients tested for H. pylori or only a proportion of them?
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?
7. “Anticholinergics and antidepressants were discontinued at least 1 week
before study entry and were not allowed during the study period”. Abruptly
stopping these drugs can lead to discontinuation syndromes which include upper
GI symptoms. The effect of the (discontinued) prior medication on the study
outcome should be assessed.
8. What measures were taken to maintain concealment of allocation prior to
study entry?
9. The primary analysis should be the ITT analysis and should be reported in the
abstract.
10. Please explain if rescue medication was offered or allowed.
11. Please stated whether compliance was assessed? If so, please report the
findings.
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I have acted as a consultant for AstraZeneca and Axcan Pharma and have
received speaking honoraria from AstraZeneca, Sanofi-Aventis, Janssen-Cilag,
and GlaxoSmithKline