Title: Prokinetics For the Treatment of Functional Dyspepsia: An Updated Systematic Review
and Network Meta-analysis
Version: 0 Date: 01 Sep 2023
Reviewer:  Zipan Lyu
Reviewer's report:
Authors:
Yanqing Li, Qingqing Qi, Nana Wang, Han Liu
Title:
"Prokinetics For the Treatment of Functional Dyspepsia: An Updated Systematic Review and
Network Meta-analysis"
Brief Summary of the Manuscript:
The manuscript presents an updated systematic review and network meta-analysis focused on
prokinetic agents' efficacy and safety for treating functional dyspepsia (FD). The study includes
28 randomized controlled trials involving 5,790 participants and evaluates six prokinetic agents
along with a placebo. The primary outcomes examined are total efficacy rates and adverse events
associated with these treatments. The results suggest that both metoclopramide and cinitapride
demonstrate the potential for higher total efficacy rates compared to other prokinetics, with
cinitapride showing a lower risk of total adverse events. However, caution is advised due to data
limitations and variability in the definition of total efficacy rate among studies.
Overall Impression of the Work:
Strengths:
1. The manuscript addresses an important clinical topic ”FD treatment” and provides an updated
and comprehensive analysis.
2. The study employs a network meta-analysis approach, enhancing the comparison of multiple
treatments simultaneously.
3. The study highlights the significance of cinitapride, a relatively new prokinetic agent, which
enhances its relevance for current clinical practice.
Weaknesses:
1. Limited data and variability in the definition of total efficacy rate hinder the generalizability
of the findings.
2. The network meta-analysis faces challenges due to the small number of studies and
participants for certain interventions.
3. The manuscript acknowledges potential bias from pharmaceutical industry funding in some
studies, but the impact of this bias is not fully explored.
4. The network inconsistency observed in some comparisons raises questions about the
reliability of certain results.
Overall, the study offers valuable insights into the comparative efficacy and safety of prokinetic
agents for FD treatment. However, the limitations stemming from data scarcity and variability
underscore the need for further well-designed trials to confirm the observed trends. The work's
emphasis on cinitapride's potential benefits provides a valuable contribution to the field, but the
challenges posed by the network meta-analysis's limitations must be taken into account when
interpreting the conclusions. Therefore, the manuscript can be considered for publication after
major revision in BMC Gastroenterology.
Some challenge comments:
1. While this updated manuscript presents valuable insights into the field of functional dyspepsia,
it is crucial to address the issue of protocol registration for the network meta-analysis. The
protocol for this analysis has not been registered, which raises concerns regarding transparency
and potential bias. I kindly request that the authors provide the protocol for this meta-analysis and
explicitly outline any discrepancies between the planned methodology and the actual execution.
Providing a clear rationale for any deviations from the initial plan is essential for the robustness
and credibility of the study.
2. While this network meta-analysis provides valuable insights into the relative efficacy of
different prokinetic agents, there seem to be inconsistencies in the results' interpretation. Please
provide more detailed explanations regarding how the statistical methods were applied and how
the reported odds ratios translate into clinically meaningful differences in efficacy.
3. This manuscript acknowledges the variability in the definitions of the total efficacy rate across
studies, which can influence the network meta-analysis results. How might this variability in
outcome definitions affect the reliability and comparability of the included studies, and how
does it potentially limit the robustness of the network meta-analysis findings?
4. This study selection process includes trials with varying sample sizes, methodologies,
and study populations. How does the potential heterogeneity in study designs and patient
characteristics impact the validity and generalizability of the observed treatment effects and
adverse event profiles?
5. Network meta-analyses are susceptible to publication bias, where positive results are more
likely to be published. Have you considered the potential impact of unpublished or gray literature
studies that could contribute to a more comprehensive understanding of the true effects of the
prokinetic agents under investigation? Please provide the excluded studies’ list.
Some comments for improving the academic writing quality of the manuscript are as follows:
1. Original: This updated net-work meta-analysis included four more RCTs[3, 4, 11, 12]
compared with the previously published meta-analysis[2].
Suggestion: This updated network meta-analysis included an additional four randomized
controlled trials (RCTs)[3, 4, 11, 12] in comparison to the previously published meta-
analysis[2].
2. Original: The results of this network meta-analysis showed the total efficacy rate of
six prokinetic agents—metoclopramide, cinitapride, mosapride, domperidone, itropride, and
acotiamide—were higher than that of placebo.
Suggestion: The findings from this network meta-analysis indicated that the total efficacy rates
of six prokinetic agents—metoclopramide, cinitapride, mosapride, domperidone, itopride, and
acotiamide—were superior to that of the placebo.
3. Original: The total efficacy rate of metoclopramide was not significantly different with
cinitapride but was significantly higher than that of the other four prokinetic treatments.
Suggestion: While there was no statistically significant difference in the total efficacy rate
between metoclopramide and cinitapride, metoclopramide exhibited a significantly higher
efficacy compared to the other four prokinetic treatments.
4. Original: Moreover, the total efficacy rate of cinitapride was higher than that of mosapride.
Suggestion: Furthermore, cinitapride demonstrated a higher total efficacy rate than mosapride.
5. Original: In addition, the treatment ranking probability result showed metoclopramide ranked
first and cinitapride second. However, the ranking probability result should be interpreted very
cautiously, as it was usually not stable and was very likely to be influenced by the number of
included studies, event number and total sample size.
Suggestion: Additionally, the ranking probability analysis indicated metoclopramide as the top-
ranking treatment, followed by cinitapride. However, the stability of these rankings should be
interpreted cautiously, as they can be influenced by factors such as the number of included
studies, the number of events, and the overall sample size.
6. Original: The exact pathogenesis of FD is still unclear.
Suggestion: The precise underlying pathogenesis of FD remains uncertain.
7. Original: It is believed that many factors, such as gastroduodenal motility abnormalities,
visceral hypersensitivity, gastric acid, Helicobacter pylori infection and psychosomatic factors,
are involved in the pathogenesis process.
Suggestion: Many contributing factors, including gastroduodenal motility abnormalities,
visceral hypersensitivity, gastric acid, Helicobacter pylori infection, and psychosomatic
influences, are believed to be implicated in the pathogenic process.
8. Original: A number of clinical studies and meta-analyses have investigated the efficacy of
therapies relevant to inhibition of visceral hypersensitivity, acid suppression, Helicobacter pylori
eradication, and antipsychotic stress in the treatment of FD, and compared the efficacy and
adverse events of different drugs[36-40].
Suggestion: Numerous clinical studies and meta-analyses have explored the effectiveness of
therapies targeting the inhibition of visceral hypersensitivity, acid suppression, Helicobacter
pylori eradication, and antipsychotic interventions for FD treatment. These studies have also
conducted comparisons of the efficacy and adverse event profiles of various drugs[36-40].
9. Original: Both the previously published meta-analysis[2] and our updated network meta-
analysis compared the therapeutic effects of different prokinetic agents on FD.
Suggestion: Both the prior meta-analysis[2] and our current updated network meta-analysis have
evaluated the therapeutic effects of distinct prokinetic agents for the treatment of FD.
10. Original: Both meta-analyses aim to provide more evidence for clinicians to select prokinetic
agents.
Suggestion: The objective of both of these meta-analyses is to offer clinicians additional
evidence to aid in their selection of appropriate prokinetic agents.
Title: Prokinetics For the Treatment of Functional Dyspepsia: An Updated Systematic Review
and Network Meta-analysis
Version: 0 Date: 01 Sep 2023
Reviewer:  Zipan Lyu
Reviewer's report:
Authors:
Yanqing Li, Qingqing Qi, Nana Wang, Han Liu
Title:
"Prokinetics For the Treatment of Functional Dyspepsia: An Updated Systematic Review and
Network Meta-analysis"
Brief Summary of the Manuscript:
The manuscript presents an updated systematic review and network meta-analysis focused on
prokinetic agents' efficacy and safety for treating functional dyspepsia (FD). The study includes
28 randomized controlled trials involving 5,790 participants and evaluates six prokinetic agents
along with a placebo. The primary outcomes examined are total efficacy rates and adverse events
associated with these treatments. The results suggest that both metoclopramide and cinitapride
demonstrate the potential for higher total efficacy rates compared to other prokinetics, with
cinitapride showing a lower risk of total adverse events. However, caution is advised due to data
limitations and variability in the definition of total efficacy rate among studies.
Overall Impression of the Work:
Strengths:
1. The manuscript addresses an important clinical topic ”FD treatment” and provides an updated
and comprehensive analysis.
2. The study employs a network meta-analysis approach, enhancing the comparison of multiple
treatments simultaneously.
3. The study highlights the significance of cinitapride, a relatively new prokinetic agent, which
enhances its relevance for current clinical practice.
Weaknesses:
1. Limited data and variability in the definition of total efficacy rate hinder the generalizability
of the findings.
2. The network meta-analysis faces challenges due to the small number of studies and
participants for certain interventions.
3. The manuscript acknowledges potential bias from pharmaceutical industry funding in some
studies, but the impact of this bias is not fully explored.
4. The network inconsistency observed in some comparisons raises questions about the
reliability of certain results.
Overall, the study offers valuable insights into the comparative efficacy and safety of prokinetic
agents for FD treatment. However, the limitations stemming from data scarcity and variability
underscore the need for further well-designed trials to confirm the observed trends. The work's
emphasis on cinitapride's potential benefits provides a valuable contribution to the field, but the
challenges posed by the network meta-analysis's limitations must be taken into account when
interpreting the conclusions. Therefore, the manuscript can be considered for publication after
major revision in BMC Gastroenterology.
Some challenge comments:
1. While this updated manuscript presents valuable insights into the field of functional dyspepsia,
it is crucial to address the issue of protocol registration for the network meta-analysis. The
protocol for this analysis has not been registered, which raises concerns regarding transparency
and potential bias. I kindly request that the authors provide the protocol for this meta-analysis and
explicitly outline any discrepancies between the planned methodology and the actual execution.
Providing a clear rationale for any deviations from the initial plan is essential for the robustness
and credibility of the study.
2. While this network meta-analysis provides valuable insights into the relative efficacy of
different prokinetic agents, there seem to be inconsistencies in the results' interpretation. Please
provide more detailed explanations regarding how the statistical methods were applied and how
the reported odds ratios translate into clinically meaningful differences in efficacy.
3. This manuscript acknowledges the variability in the definitions of the total efficacy rate across
studies, which can influence the network meta-analysis results. How might this variability in
outcome definitions affect the reliability and comparability of the included studies, and how
does it potentially limit the robustness of the network meta-analysis findings?
4. This study selection process includes trials with varying sample sizes, methodologies,
and study populations. How does the potential heterogeneity in study designs and patient
characteristics impact the validity and generalizability of the observed treatment effects and
adverse event profiles?
5. Network meta-analyses are susceptible to publication bias, where positive results are more
likely to be published. Have you considered the potential impact of unpublished or gray literature
studies that could contribute to a more comprehensive understanding of the true effects of the
prokinetic agents under investigation? Please provide the excluded studies’ list.
Some comments for improving the academic writing quality of the manuscript are as follows:
1. Original: This updated net-work meta-analysis included four more RCTs[3, 4, 11, 12]
compared with the previously published meta-analysis[2].
Suggestion: This updated network meta-analysis included an additional four randomized
controlled trials (RCTs)[3, 4, 11, 12] in comparison to the previously published meta-
analysis[2].
2. Original: The results of this network meta-analysis showed the total efficacy rate of
six prokinetic agents—metoclopramide, cinitapride, mosapride, domperidone, itropride, and
acotiamide—were higher than that of placebo.
Suggestion: The findings from this network meta-analysis indicated that the total efficacy rates
of six prokinetic agents—metoclopramide, cinitapride, mosapride, domperidone, itopride, and
acotiamide—were superior to that of the placebo.
3. Original: The total efficacy rate of metoclopramide was not significantly different with
cinitapride but was significantly higher than that of the other four prokinetic treatments.
Suggestion: While there was no statistically significant difference in the total efficacy rate
between metoclopramide and cinitapride, metoclopramide exhibited a significantly higher
efficacy compared to the other four prokinetic treatments.
4. Original: Moreover, the total efficacy rate of cinitapride was higher than that of mosapride.
Suggestion: Furthermore, cinitapride demonstrated a higher total efficacy rate than mosapride.
5. Original: In addition, the treatment ranking probability result showed metoclopramide ranked
first and cinitapride second. However, the ranking probability result should be interpreted very
cautiously, as it was usually not stable and was very likely to be influenced by the number of
included studies, event number and total sample size.
Suggestion: Additionally, the ranking probability analysis indicated metoclopramide as the top-
ranking treatment, followed by cinitapride. However, the stability of these rankings should be
interpreted cautiously, as they can be influenced by factors such as the number of included
studies, the number of events, and the overall sample size.
6. Original: The exact pathogenesis of FD is still unclear.
Suggestion: The precise underlying pathogenesis of FD remains uncertain.
7. Original: It is believed that many factors, such as gastroduodenal motility abnormalities,
visceral hypersensitivity, gastric acid, Helicobacter pylori infection and psychosomatic factors,
are involved in the pathogenesis process.
Suggestion: Many contributing factors, including gastroduodenal motility abnormalities,
visceral hypersensitivity, gastric acid, Helicobacter pylori infection, and psychosomatic
influences, are believed to be implicated in the pathogenic process.
8. Original: A number of clinical studies and meta-analyses have investigated the efficacy of
therapies relevant to inhibition of visceral hypersensitivity, acid suppression, Helicobacter pylori
eradication, and antipsychotic stress in the treatment of FD, and compared the efficacy and
adverse events of different drugs[36-40].
Suggestion: Numerous clinical studies and meta-analyses have explored the effectiveness of
therapies targeting the inhibition of visceral hypersensitivity, acid suppression, Helicobacter
pylori eradication, and antipsychotic interventions for FD treatment. These studies have also
conducted comparisons of the efficacy and adverse event profiles of various drugs[36-40].
9. Original: Both the previously published meta-analysis[2] and our updated network meta-
analysis compared the therapeutic effects of different prokinetic agents on FD.
Suggestion: Both the prior meta-analysis[2] and our current updated network meta-analysis have
evaluated the therapeutic effects of distinct prokinetic agents for the treatment of FD.
10. Original: Both meta-analyses aim to provide more evidence for clinicians to select prokinetic
agents.
Suggestion: The objective of both of these meta-analyses is to offer clinicians additional
evidence to aid in their selection of appropriate prokinetic agents.
Please review this paper.
user
Title: Prokinetics For the Treatment of Functional Dyspepsia: An Updated Systematic Review
and Network Meta-analysis
Version: 0 Date: 01 Sep 2023
Reviewer:  Zipan Lyu
Reviewer's report:
Authors:
Yanqing Li, Qingqing Qi, Nana Wang, Han Liu
Title:
"Prokinetics For the Treatment of Functional Dyspepsia: An Updated Systematic Review and
Network Meta-analysis"
Brief Summary of the Manuscript:
The manuscript presents an updated systematic review and network meta-analysis focused on
prokinetic agents' efficacy and safety for treating functional dyspepsia (FD). The study includes
28 randomized controlled trials involving 5,790 participants and evaluates six prokinetic agents
along with a placebo. The primary outcomes examined are total efficacy rates and adverse events
associated with these treatments. The results suggest that both metoclopramide and cinitapride
demonstrate the potential for higher total efficacy rates compared to other prokinetics, with
cinitapride showing a lower risk of total adverse events. However, caution is advised due to data
limitations and variability in the definition of total efficacy rate among studies.
Overall Impression of the Work:
Strengths:
1. The manuscript addresses an important clinical topic ”FD treatment” and provides an updated
and comprehensive analysis.
2. The study employs a network meta-analysis approach, enhancing the comparison of multiple
treatments simultaneously.
3. The study highlights the significance of cinitapride, a relatively new prokinetic agent, which
enhances its relevance for current clinical practice.
Weaknesses:
1. Limited data and variability in the definition of total efficacy rate hinder the generalizability
of the findings.
2. The network meta-analysis faces challenges due to the small number of studies and
participants for certain interventions.
3. The manuscript acknowledges potential bias from pharmaceutical industry funding in some
studies, but the impact of this bias is not fully explored.
4. The network inconsistency observed in some comparisons raises questions about the
reliability of certain results.
Overall, the study offers valuable insights into the comparative efficacy and safety of prokinetic
agents for FD treatment. However, the limitations stemming from data scarcity and variability
underscore the need for further well-designed trials to confirm the observed trends. The work's
emphasis on cinitapride's potential benefits provides a valuable contribution to the field, but the
challenges posed by the network meta-analysis's limitations must be taken into account when
interpreting the conclusions. Therefore, the manuscript can be considered for publication after
major revision in BMC Gastroenterology.
Some challenge comments:
1. While this updated manuscript presents valuable insights into the field of functional dyspepsia,
it is crucial to address the issue of protocol registration for the network meta-analysis. The
protocol for this analysis has not been registered, which raises concerns regarding transparency
and potential bias. I kindly request that the authors provide the protocol for this meta-analysis and
explicitly outline any discrepancies between the planned methodology and the actual execution.
Providing a clear rationale for any deviations from the initial plan is essential for the robustness
and credibility of the study.
2. While this network meta-analysis provides valuable insights into the relative efficacy of
different prokinetic agents, there seem to be inconsistencies in the results' interpretation. Please
provide more detailed explanations regarding how the statistical methods were applied and how
the reported odds ratios translate into clinically meaningful differences in efficacy.
3. This manuscript acknowledges the variability in the definitions of the total efficacy rate across
studies, which can influence the network meta-analysis results. How might this variability in
outcome definitions affect the reliability and comparability of the included studies, and how
does it potentially limit the robustness of the network meta-analysis findings?
4. This study selection process includes trials with varying sample sizes, methodologies,
and study populations. How does the potential heterogeneity in study designs and patient
characteristics impact the validity and generalizability of the observed treatment effects and
adverse event profiles?
5. Network meta-analyses are susceptible to publication bias, where positive results are more
likely to be published. Have you considered the potential impact of unpublished or gray literature
studies that could contribute to a more comprehensive understanding of the true effects of the
prokinetic agents under investigation? Please provide the excluded studies’ list.
Some comments for improving the academic writing quality of the manuscript are as follows:
1. Original: This updated net-work meta-analysis included four more RCTs[3, 4, 11, 12]
compared with the previously published meta-analysis[2].
Suggestion: This updated network meta-analysis included an additional four randomized
controlled trials (RCTs)[3, 4, 11, 12] in comparison to the previously published meta-
analysis[2].
2. Original: The results of this network meta-analysis showed the total efficacy rate of
six prokinetic agents—metoclopramide, cinitapride, mosapride, domperidone, itropride, and
acotiamide—were higher than that of placebo.
Suggestion: The findings from this network meta-analysis indicated that the total efficacy rates
of six prokinetic agents—metoclopramide, cinitapride, mosapride, domperidone, itopride, and
acotiamide—were superior to that of the placebo.
3. Original: The total efficacy rate of metoclopramide was not significantly different with
cinitapride but was significantly higher than that of the other four prokinetic treatments.
Suggestion: While there was no statistically significant difference in the total efficacy rate
between metoclopramide and cinitapride, metoclopramide exhibited a significantly higher
efficacy compared to the other four prokinetic treatments.
4. Original: Moreover, the total efficacy rate of cinitapride was higher than that of mosapride.
Suggestion: Furthermore, cinitapride demonstrated a higher total efficacy rate than mosapride.
5. Original: In addition, the treatment ranking probability result showed metoclopramide ranked
first and cinitapride second. However, the ranking probability result should be interpreted very
cautiously, as it was usually not stable and was very likely to be influenced by the number of
included studies, event number and total sample size.
Suggestion: Additionally, the ranking probability analysis indicated metoclopramide as the top-
ranking treatment, followed by cinitapride. However, the stability of these rankings should be
interpreted cautiously, as they can be influenced by factors such as the number of included
studies, the number of events, and the overall sample size.
6. Original: The exact pathogenesis of FD is still unclear.
Suggestion: The precise underlying pathogenesis of FD remains uncertain.
7. Original: It is believed that many factors, such as gastroduodenal motility abnormalities,
visceral hypersensitivity, gastric acid, Helicobacter pylori infection and psychosomatic factors,
are involved in the pathogenesis process.
Suggestion: Many contributing factors, including gastroduodenal motility abnormalities,
visceral hypersensitivity, gastric acid, Helicobacter pylori infection, and psychosomatic
influences, are believed to be implicated in the pathogenic process.
8. Original: A number of clinical studies and meta-analyses have investigated the efficacy of
therapies relevant to inhibition of visceral hypersensitivity, acid suppression, Helicobacter pylori
eradication, and antipsychotic stress in the treatment of FD, and compared the efficacy and
adverse events of different drugs[36-40].
Suggestion: Numerous clinical studies and meta-analyses have explored the effectiveness of
therapies targeting the inhibition of visceral hypersensitivity, acid suppression, Helicobacter
pylori eradication, and antipsychotic interventions for FD treatment. These studies have also
conducted comparisons of the efficacy and adverse event profiles of various drugs[36-40].
9. Original: Both the previously published meta-analysis[2] and our updated network meta-
analysis compared the therapeutic effects of different prokinetic agents on FD.
Suggestion: Both the prior meta-analysis[2] and our current updated network meta-analysis have
evaluated the therapeutic effects of distinct prokinetic agents for the treatment of FD.
10. Original: Both meta-analyses aim to provide more evidence for clinicians to select prokinetic
agents.
Suggestion: The objective of both of these meta-analyses is to offer clinicians additional
evidence to aid in their selection of appropriate prokinetic agents.
assistant