Safety of Rifampicin at High Dose for Difficult-to-Treat Tuberculosis: Protocol for RIAlta Phase 2b/c Trial

Round 1

Reviewer 1 Report

Summary: The authors present the design of their up coming clinical trial to study high dose rifampicin in high risk populations to assess the safety and efficacy of this regimen. 

1. The investigators are enrolling patients with different risk factors and it appears they are not targeting a specific number of patients with each risk factor. Can the authors clarify whether this is true? If so, can the authors discuss the generalizability of these results? 

2. Can the authors clarify what the target enrollment for each trial site is? 

3. The audience for this paper will likely be TB researchers/clinicians. However, in the interest of making this communication informative to a boarder range of researchers/clinicians I recommend expanding the introduction to discuss the below topics briefly. 

·  As the authors discuss, they are conducting their trial in uncommon geographic regions for TB. It would be helpful to understand the TB incidence rates in these regions. It would also be helpful to know the incidence rates of the risk factors the trial is selection for (HIV, HCV/HBV, etc). 

· Can you provide a more quantitative measure of Cmax/drug exposure for the high risk populations instead of "barely reaching the threshold"?        

4. Under the secondary objective section, the paragraph for pharmacokinetics is included twice. Remove the second entry. 

5. Given the trial size this may not be possible, but have the investigators considered any subgroup analysis for the most common adverse event(s)? 

6. Can the authors clearly detail the factors they will control for when selecting the historical controls? 

7. Can the authors discuss how common genetic variants are in the European population for the genes they will study? 

8.  How do the authors plan to address bias that might arise from different doctors at different time periods assigning an AE to be likely caused by study drug? 

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

The study is carried out in a very systematic manner. The discussion part is written very well whilst there is a need to add the discussion part in order to summarize your study and its outcomes. However, there are certain other corrections and suggestions for the manuscript improvement that must be resolved; the comments are stated below:

However, several pharmacological, bacterial, and host factors may negatively affect treatment efficacy in daily practice. Some groups of people are more vulnerable to TB because of risk factors (e.g., advanced age, immunosuppression, diabetes, or liver disease) that increase their risk of active disease, poor treatment outcomes, and potentially more side effects or interactions related to TB treatment.

In the above paragraph, the authors need tp add further detail about the adverse events and side effects of the prior Rifampicin regimen under the introduction heading.

The secondary efficacy endpoint includes the proportion of participants and historical controls who have sputum culture conversion at 8 weeks after treatment onset or proportion of participants with clinical improvement according to the treating physician (if follow-up images are available for extra-pulmonary TB) but without a follow up sample at 8 weeks after treatment onset.

Ø  Since it is a research paper needs the human endpoint and the research endpoint in the above-mentioned lines. As a result, it must be revised under the heading aim and endpoint.

The trial will provide useful information on the efficacy and pharmacokinetics of 35 mg/kg rifampicin dosing and explore possible correlations between occurring adverse events and the rifampicin genetic polymorphisms involved in metabolism and hepatotoxicity.

 Background information between the previous regimen and the anti-TB drug particularly, rifampicin, in the preceding paragraphs under the heading discussion must be added.

 

 

Heading - Intervention

A legend to the study diagram as it is missing under the heading

 A section “Conclusion” must be added in the end to conclude the whole study and the results

 

 

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

Authors have presented a relevant strategy to treat Tuberculosis in a subset of patient highly vulnerable to TB. However, I am not sure whether this kind of strategy can be published as a research article. This appears to be a strategy for a drug regimen. I suggest authors to complete the trial and then publish the findings.  

Author Response

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Author Response File: Author Response.docx

Reviewer 4 Report

The authors summarized the protocol and its rationale of the RIAlta trial, and this paper would trigger well-design studies in the future. Therefore, this study is worth to publish in this journal. There are some revises to improve a quality of this study.

 

1.       In each section of Method, the authors should describe differences with previous studies.

2.       Moreover, for readers to understand the difference, a new table should be added.

3.       In each section of Method, if there is some limitations and issues, add the limitation.

4.       Finally, the strengthen and weakness of the RIAlta trial need to be described in a new section added at first or last of Method.

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

I still feel, the manuscript is just a roadmap for their future study. The manuscript cannot be judged until there are some findings. 

Reviewer 4 Report

The authors revised appropriately. No further correction is necessary.