Advancing Treatment for C3G; Targeting the Complement System for Personalized Kidney Care - Episode 12
APPEAR C3G Trial: Trial Design, Results, and the Importance of Patient-Led Treatment Progress
Panelists discuss how Jonathan Barratt, MBChB, PhD, FRCP, outlined the APPEAR-C3G study design, which featured a 6-month randomized period followed by an open-label extension, with primary end points including changes in proteinuria, glomerular filtration rate (GFR), and kidney biopsy features, emphasizing the study’s alignment with FDA guidance for ultrarare diseases.
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APPEAR-C3G Study Design and Key Insights
The APPEAR-C3G study was designed to evaluate a treatment for C3 glomerulopathy (C3G), an ultra-rare kidney disease, with strong alignment to regulatory expectations and significant patient input.
Study Design
- Structure:
- A 6-month randomized controlled phase followed by an open-label extension
- Patient Population:
- Included both native and recurrent disease cases, as well as immune complex-mediated membranoproliferative glomerulonephritis(MPGN)
- Sample Size:
- Small, reflecting the rarity of C3G; significantly smaller than trials for more common kidney diseases
Primary End Points
- Proteinuria reduction at 6 months (short-term efficacy marker)
- Change in estimated GFR (eGFR) over 12 months (longer-term renal function indicator)
- Kidney biopsy findings (histologic outcomes)
Regulatory and Clinical Significance
- The study mirrored the VALIANT trial in design, enabling comparison across trials and easing regulatory evaluation
- Use of surrogate markers—proteinuria, eGFR, and biopsy—was essential for drug approval:
- Supported by the Kidney Health Initiative
- FDA approval based on these end points marks a milestone for rare disease therapies
- Achieved in part due to the collaboration between researchers, regulators, and patients
Patient Involvement
- Patients played a crucial role in shaping study design:
- Advocated for a 6-month placebo phase (not longer)
- Accepted repeat biopsies in exchange for access to open-label treatment
- Their input helped align trial feasibility with ethical and practical concerns
Conclusion
The APPEAR-C3G study represents a collaborative success in rare disease research. It demonstrates that with well-defined surrogate end points and stakeholder engagement, regulatory pathways can be established even for ultrarare conditions. The outcomes pave the way for continued innovation and patient-centered drug development in glomerular diseases.
