The Future of Clinical Trials on C3G: Lessons From the VALIANT and APPEAR Trials

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Clinical Trials in C3G: Future Directions and Considerations for Physicians

As treatment strategies for C3G evolve, future clinical trials are expected to incorporate new complement-targeting therapies, while also adapting to the challenges of studying a rare and heterogeneous disease.

Trial Design Evolution

• Inclusivity Is Key: Future trials aim to be more inclusive, enrolling both pediatric and adult populations, as well as transplant and non-transplant patients. Historically, pediatric inclusion has been limited, but this is now a priority to generate more comprehensive data.
• Learning From Existing Data: Leveraging rich genetic and molecular datasets will be critical. Trials will increasingly incorporate biomarkers and genetic phenotyping to identify patients more likely to benefit, relapse, or safely discontinue treatment.
• Precision Medicine Approach: Integrating molecular and genetic data into trial design could enable more tailored therapies and improve our understanding of treatment responses and disease progression.
• Collaboration and Data Sharing: Drawing on models like the chronic kidney disease clinical trials consortium, collaborative efforts and data pooling can help define robust clinical end points and advance biomarker research.

Inclusion and Exclusion Criteria

• Complement Inhibitor Washout: A 6-month washout period for patients previously on complement inhibitors is likely to remain standard to prevent residual drug effects from confounding trial results.
• Proteinuria Thresholds:
  • Current trials (e.g., APPEAR) typically require ≥1 g/day proteinuria to ensure measurable treatment effects and to study more aggressive disease phenotypes.
  • While this helps demonstrate efficacy, it may limit recruitment. Lower thresholds (e.g., 500 mg/day) might be considered if accompanied by robust biomarkers.
  • The NOBLE trial in transplant recipients pivoted from a proteinuria-based inclusion to histologic criteria, enabling successful recruitment and demonstrating histologic response despite minimal proteinuria.

The Role of Biomarkers

• Biomarkers hold promise for enabling less invasive end points in the future, akin to how PLA2R antibodies guide membranous nephropathy trials. However, validated biomarkers in C3G are not yet available for routine clinical or trial use.

Takeaway for Physicians: As therapies for C3G expand, trial designs must evolve to reflect real-world complexities. A personalized approach—guided by molecular insights and supported by collaborative research—will be essential to improve patient outcomes and ensure trial feasibility.