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Ganaxolone Treatment For Refractory Epilepsy

Ganaxolone Treatment For Refractory Epilepsy


In a meta-analysis conducted to evaluate the use of ganaxolone for refractory epilepsy, researchers collected data from four randomized controlled trials involving a total of 659 patients. The analysis revealed that ganaxolone significantly improved the reduction in mean seizure frequency by ≥50% when compared to a placebo. This positive effect was supported by trial sequential analysis (TSA). However, there was no statistically significant difference in the percentage of seizure-free days between ganaxolone and placebo. 

In terms of safety, the study found that adverse events (AEs), serious adverse events, and AEs leading to the discontinuation of the study drug were not significantly different between ganaxolone and placebo. 

The findings suggest that ganaxolone may be a safe and potentially effective treatment option for refractory epilepsy, but further research is needed to confirm these results.


Epilepsy is a prevalent neurological disorder affecting millions globally, with varying prevalence across age groups. It is primarily treated with antiseizure medications, which are effective for many but not all patients. A significant portion of individuals still experience seizures despite medication use, leading to refractory epilepsy. Refractory epilepsy is defined as the failure of two well-tolerated and appropriately selected antiseizure medications to control seizures.

Research has shown that refractory epilepsy affects a substantial percentage of epilepsy patients and is associated with reduced quality of life and increased healthcare costs. There is a growing need for effective treatments for refractory epilepsy.

Ganaxolone, a synthetic analogue of allopregnanolone, has shown promise as a potential treatment for epilepsy. It acts on GABAA receptors and GABAA receptors containing d-subunits, making it a candidate for seizure control. Animal studies demonstrated its effectiveness in controlling induced seizures, leading to further research.

Initial clinical trials of ganaxolone showed mixed results, with limited efficacy in some patients. However, alterations to the drug’s formulation improved its bioavailability, leading to reduced seizure frequency in drug-resistant focal-onset seizures in adults. Multicenter studies suggested that ganaxolone might be effective in the most drug-refractory patient populations.

Notably, ganaxolone received approval from the US Food and Drug Administration (FDA) for the treatment of CDKL5 deficiency disorder associated with refractory epilepsy. This success has led to further research and an application for approval in the European Union.

Given the variability in previous studies, a systematic review and meta-analysis of available randomized controlled trials (RCTs) were conducted to assess the safety and efficacy of ganaxolone in treating refractory epilepsy.

Notable Key Points:

  • Ganaxolone shows promise as an effective antiseizure medication for individuals with refractory epilepsy.
  • Ganaxolone has demonstrated the ability to reduce seizure frequency by at least 50%.
  • Safety assessments indicate that ganaxolone has a safety profile similar to that of a placebo, and patients generally tolerate it well.



In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this systematic review and meta-analysis were meticulously conducted. Furthermore, the research is registered in PROSPERO (CRD42022334522) to ensure a rigorous review process.

The study involved a comprehensive search of various databases, including EMBASE, Medline, Scopus, the Cochrane Library, and, from their inception up to June 20, 2022. The search utilized specific keywords related to epilepsy and ganaxolone. 

Following the removal of duplicate studies using Endnote X9, two investigators manually reviewed titles, keywords, and abstracts to identify studies that met the predetermined eligibility criteria. In cases of disagreement, a discussion with a third author was undertaken to reach a consensus. 

Key findings from the study indicate that ganaxolone may hold promise as an effective antiseizure medication for patients dealing with refractory epilepsy. It has shown the potential to reduce seizure frequency by at least 50%, while maintaining a safety profile similar to that of a placebo, and patients generally tolerate it well.

The study focused on specific efficacy and safety outcomes:


  1. Primary Efficacy Outcome: This outcome centered on the proportion of patients who experienced a reduction in seizure frequency of at least 50% from their baseline during the double-blind phase, referred to as the “50% response rate.”


  1. Secondary Efficacy Outcome: Additionally, the study considered the percentage of seizure-free days throughout the trial process as a secondary measure of effectiveness.


For safety evaluation, the research encompassed various aspects:


  • Total Number of Adverse Events (AEs): The study analyzed the overall count of adverse events associated with ganaxolone.
  • Serious Adverse Events (SAEs): It also examined serious adverse events that occurred during the course of the study.
  • AEs Leading to Study Drug Discontinuation: The analysis included adverse events that led to the discontinuation of the study drug.


To ensure data accuracy, two investigators (ZYY and JHM) meticulously selected and assessed the relevant information.

Inclusion Criteria 

The study adhered to the Population, Intervention, Comparison, Outcome, and Study type (PICOS) question format for defining its inclusion criteria:


(a) Population: The study included participants who had received a diagnosis of refractory epilepsy.

(b) Intervention: The research focused on interventions involving the administration of ganaxolone.

(c) Comparison: The study compared the effects of ganaxolone with those of a placebo.

(d) Outcome: Objective indicators were utilized to assess the effectiveness of the treatment for refractory epilepsy.

(e) Study type: The study primarily considered Randomized Controlled Trials (RCTs) in its analysis. 

Exclusion Criteria

The study’s exclusion criteria were applied as follows:


  1. Unavailability of Essential Data: Studies lacking crucial data necessary for the analysis were excluded from consideration.


  1. Inappropriate Study Types: Research falling under specific categories such as reviews, protocols, comments, retrospective studies, and case reports were not included in this meta-analysis.


  1. Handling Duplicate Research: In cases where duplicate studies had overlapping participant populations, only the most comprehensive report among them was selected for inclusion in the meta-analysis. 

Statistical Analysis 

The study employed Review Manager 5.4 software to analyze data gathered from the included studies. A random-effect model was utilized to calculate standard mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (95%CI). Statistical heterogeneity was assessed using the I² statistic, categorized as follows: ≥50% indicating “high heterogeneity,” 30%–50% indicating “moderate heterogeneity,” and ≤30% indicating “low heterogeneity.”

The GRADE Pro GDT application was used to compute anticipated absolute effects. Two-tailed tests were conducted, and a p-value of <0.05 was considered statistically significant. Trial sequential analysis (TSA) was performed to evaluate type I and II errors in the meta-analysis due to the limited number of samples, following the Copenhagen Trial Unit approach. TSA viewer software version beta was used for this analysis. The necessary information size was calculated to estimate the sample size, and the risk of type I and type II errors was set at 5% and 20%, respectively. The credibility of the conclusion was determined based on whether the cumulative Z-curve crossed the TSA boundary or RIS boundary, indicating the need for further studies.

The risk of bias in individual randomized controlled trials (RCTs) was assessed using the risk of bias plot generated by Review Manager 5.4 software.


The research conducted a meticulous and systematic review and meta-analysis in strict adherence to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline. Furthermore, the study demonstrated a commitment to transparency and rigor by registering the research protocol in PROSPERO under the registration number CRD42022334522. This meticulous approach is essential for ensuring the quality and reliability of the study’s findings.

The search for relevant studies was thorough, encompassing multiple comprehensive databases, including EMBASE, Medline, Scopus, the Cochrane Library, and The search strategy was thoughtfully designed using relevant keywords related to epilepsy and ganaxolone. The research team rigorously followed the predefined inclusion and exclusion criteria during the screening process.

After the initial search, a total of 641 studies were identified. Duplicate studies were efficiently removed through automated screening using Endnote X9, resulting in 363 exclusions. Subsequently, the research team manually reviewed the titles, keywords, and abstracts of the remaining studies to identify those that met the predefined eligibility criteria. Any discrepancies or disagreements among the reviewers were thoughtfully resolved through discussion with a third author, ensuring consensus.

The final selection process yielded four high-quality randomized controlled trials (RCTs) that met the inclusion criteria. These four trials involved a total of 659 patients, with 351 receiving ganaxolone and 308 receiving a placebo. The dosages of ganaxolone intervention ranged from 1500 to 1875mg/day, providing valuable insights into the drug’s efficacy and safety.


The study’s primary focus was to evaluate the clinical efficacy of ganaxolone in treating refractory epilepsy. The primary efficacy outcome, a reduction in seizure frequency of at least 50%, yielded significant and promising results, favoring the ganaxolone group over the placebo group. This finding is highly relevant and suggests that ganaxolone may indeed be an effective treatment option for patients with refractory epilepsy.

The research also considered secondary efficacy outcomes, such as the percentage of seizure-free days during the trial. Although this outcome did not show a significant difference between the two groups, the analysis provided important insights into the drug’s overall impact on seizure control.

Safety is a paramount concern in any medical intervention. Therefore, the study comprehensively analyzed adverse events (AEs) across all four RCTs. Encouragingly, the results demonstrated that ganaxolone exhibited a similar safety profile to the placebo, with no statistically significant differences in AEs, serious adverse events (SAEs), or AEs leading to study drug discontinuation between the two groups. This safety profile is a critical consideration for clinicians and patients when evaluating treatment options for refractory epilepsy.

Furthermore, the research employed advanced statistical techniques such as trial sequential analysis (TSA) to assess the robustness of its findings. The TSA for the 50% response rate reinforced the credibility of the conclusion, indicating that while more studies would be beneficial, the current evidence is compelling. Conversely, the analysis of AEs did not cross TSA boundaries, suggesting that the existing data are sufficiently reliable.

Lastly, the study meticulously assessed the risk of bias for each of the included trials, adhering to the standardized criteria established by the Cochrane Collaboration. While one study contributed to most of the observed bias, mainly in terms of reporting and incomplete outcome data, the remaining studies demonstrated low risk in other types of bias.

In summary, this systematic review and meta-analysis represents a comprehensive and methodologically sound investigation into the efficacy and safety of ganaxolone for refractory epilepsy. The study’s findings provide valuable insights into the potential benefits of ganaxolone as an antiseizure medication, with a particular focus on achieving a 50% reduction in seizure frequency. Moreover, the study underscores the importance of safety considerations in epilepsy treatment and highlights the favorable safety profile of ganaxolone.


In conclusion, our study’s findings strongly indicate that ganaxolone holds promise as an effective antiseizure medication for individuals grappling with refractory epilepsy. Notably, it is associated with a substantial reduction in seizure frequency, with at least a 50% improvement observed from baseline to the double-blind phase of treatment. Equally important, our analysis underscores that ganaxolone maintains a safety profile akin to that of the placebo, and patients generally tolerate it well.

However, it is crucial to acknowledge the limitations of our research. The dearth of relevant randomized controlled trials (RCTs) and the relatively small sample size warrant cautious interpretation of these results. To establish the full extent of ganaxolone’s efficacy and safety in the context of refractory epilepsy, further investigations with larger sample sizes and longer-term follow-ups are imperative. Such studies will contribute substantially to our understanding of ganaxolone’s potential as a treatment option for refractory epilepsy and help refine its clinical application.

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