Reviewer's report 
 Fluvoxamine for fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a Title: 
randomised controlled trial. 
 1  24 May 2004 Version: Date: 
 Martin I Prince Reviewer: 
Reviewer's report: 
General 
The authors describe a double blind placebo controlled randomised trial of the use of Fluvoxamine in 
cholestatic liver disease. The importance of the problem of fatigue is well accounted for in the 
introduction. A rationale for using the trial drug (i.e. fatigue may be a manifestation of sub clinical 
depression or share a common aetiological pathway) is outlined. Consort statement reporting principles have been adhered to. Results are presented on an intention to treat basis. There was an 
initial difference in fatigue scores between the two groups due to random variation. It is unclear if this 
affected the negative outcome of the trial 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
1. The main weakness of the trial is that it is severely underpowered. The power calculation is based 
upon very optimistic estimates of benefit with active drug and similarly optimistic estimates of 
difference between placebo and active arms. This point should be made more strongly in the 
discussion- the authors state that a small beneficial effect may have been missed. In a study of this size a substantial beneficial effect may have been missed although it would unlikely from the data presented. The methods for performing the power calculation are not stated, I presume that a 
non-parametric method has been used. It is important to state this, as it is necessary for the reader 
to see that a non-parametric method has been used in the power calculation as these statistics were 
then used in the analysis. 
2. The authors state that subgroup analysis was performed analysing the data for patients with PBC 
and PSC separately. As there are no space constraints in this electronic journal, this data should be 
published. An important role for this paper is to inform future systematic reviews and meta analyses. 
These reviews are usually specific to individual diagnoses. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
1. Figure 2 adds little additional data not contained in table 3 and may be removed. The text states 
that figure 3 contains both intention to treat and per protocol analysis. Only one set of data appears 
to be actually represented. 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
1. It is probably worth noting that the Beck inventory was developed on patients without chronic 
non-psychiatric illness and may therefore not be specific in some patients with liver disease, for 
example four questions ask about fatigue, low energy, decrease appetite and decreased libido all of 
which may be features of liver disease per se. 
2. There are no records of whether blinding was successful. If this data is available it should be 
included. 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
None 
Reviewer's report 
 Fluvoxamine for fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a Title: 
randomised controlled trial. 
 1  24 May 2004 Version: Date: 
 Martin I Prince Reviewer: 
Reviewer's report: 
General 
The authors describe a double blind placebo controlled randomised trial of the use of Fluvoxamine in 
cholestatic liver disease. The importance of the problem of fatigue is well accounted for in the 
introduction. A rationale for using the trial drug (i.e. fatigue may be a manifestation of sub clinical 
depression or share a common aetiological pathway) is outlined. Consort statement reporting principles have been adhered to. Results are presented on an intention to treat basis. There was an 
initial difference in fatigue scores between the two groups due to random variation. It is unclear if this 
affected the negative outcome of the trial 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
1. The main weakness of the trial is that it is severely underpowered. The power calculation is based 
upon very optimistic estimates of benefit with active drug and similarly optimistic estimates of 
difference between placebo and active arms. This point should be made more strongly in the 
discussion- the authors state that a small beneficial effect may have been missed. In a study of this size a substantial beneficial effect may have been missed although it would unlikely from the data presented. The methods for performing the power calculation are not stated, I presume that a 
non-parametric method has been used. It is important to state this, as it is necessary for the reader 
to see that a non-parametric method has been used in the power calculation as these statistics were 
then used in the analysis. 
2. The authors state that subgroup analysis was performed analysing the data for patients with PBC 
and PSC separately. As there are no space constraints in this electronic journal, this data should be 
published. An important role for this paper is to inform future systematic reviews and meta analyses. 
These reviews are usually specific to individual diagnoses. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
1. Figure 2 adds little additional data not contained in table 3 and may be removed. The text states 
that figure 3 contains both intention to treat and per protocol analysis. Only one set of data appears 
to be actually represented. 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
1. It is probably worth noting that the Beck inventory was developed on patients without chronic 
non-psychiatric illness and may therefore not be specific in some patients with liver disease, for 
example four questions ask about fatigue, low energy, decrease appetite and decreased libido all of 
which may be features of liver disease per se. 
2. There are no records of whether blinding was successful. If this data is available it should be 
included. 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
None 
Please review this paper.
user
Reviewer's report 
 Fluvoxamine for fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a Title: 
randomised controlled trial. 
 1  24 May 2004 Version: Date: 
 Martin I Prince Reviewer: 
Reviewer's report: 
General 
The authors describe a double blind placebo controlled randomised trial of the use of Fluvoxamine in 
cholestatic liver disease. The importance of the problem of fatigue is well accounted for in the 
introduction. A rationale for using the trial drug (i.e. fatigue may be a manifestation of sub clinical 
depression or share a common aetiological pathway) is outlined. Consort statement reporting principles have been adhered to. Results are presented on an intention to treat basis. There was an 
initial difference in fatigue scores between the two groups due to random variation. It is unclear if this 
affected the negative outcome of the trial 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
1. The main weakness of the trial is that it is severely underpowered. The power calculation is based 
upon very optimistic estimates of benefit with active drug and similarly optimistic estimates of 
difference between placebo and active arms. This point should be made more strongly in the 
discussion- the authors state that a small beneficial effect may have been missed. In a study of this size a substantial beneficial effect may have been missed although it would unlikely from the data presented. The methods for performing the power calculation are not stated, I presume that a 
non-parametric method has been used. It is important to state this, as it is necessary for the reader 
to see that a non-parametric method has been used in the power calculation as these statistics were 
then used in the analysis. 
2. The authors state that subgroup analysis was performed analysing the data for patients with PBC 
and PSC separately. As there are no space constraints in this electronic journal, this data should be 
published. An important role for this paper is to inform future systematic reviews and meta analyses. 
These reviews are usually specific to individual diagnoses. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
1. Figure 2 adds little additional data not contained in table 3 and may be removed. The text states 
that figure 3 contains both intention to treat and per protocol analysis. Only one set of data appears 
to be actually represented. 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
1. It is probably worth noting that the Beck inventory was developed on patients without chronic 
non-psychiatric illness and may therefore not be specific in some patients with liver disease, for 
example four questions ask about fatigue, low energy, decrease appetite and decreased libido all of 
which may be features of liver disease per se. 
2. There are no records of whether blinding was successful. If this data is available it should be 
included. 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
None 
assistant