Table 3.

Proposed Clinical Trial Design for new therapy to prevent chronic renal allograft injury

Aim: To demonstrate that bortezomib prevents progression of chronic antibody mediated damage

1. Patient Selection. Identify patients at high risk for graft lost

• 12–60 months after kidney transplantation

• Serum donor-specific alloantibody with mean fluorescence index (MFI) >2000 (on 2 sequential measurements within 1–3 months of each other). No DSA at the time of transplant (i.e., de novo DSA)

• Renal allograft biopsy at the time of enrollment to demonstrate the absence of moderate-to-severe transplant glomerulopathy (cg score <1) and an absence of acute cellular rejection grade Ia or higher (Banff).

• Randomize to receive bortezomib monotherapy vs placebo (blinded)

2. Surrogate Endpoint for InitialTrial.

Primary endpoint:

• Reduction in MFI level 1 year after treatment (paired t test with each patient serving as their own control).

Secondary endpoints:

• Lack of progression of cg score on 1 year follow-up biopsy

• Lack of progression of peritubular capillaritis score on 1 year follow-up biopsy

• Lack of decline in renal function 1 year after treatment

3. Initial approval based on surrogate endpoint.

• If primary endpoint is reached (i.e., drug actually reduces DSA), then the drug will be given approval by regulatory agencies for the treatment of chronic antibody mediated injury.

4. Final Approval.

• Long-term follow-up to demonstrate that the therapy improves long-term graft survival in the study cohort. Likely, this would be 5 years or more after initial approval.

The following is an example of the type of protocol that meets the criteria that we describe in the text: 1) identify a patient population with a specific risk factor for late graft loss (de novo DSA); 2) utilize a surrogate endpoint for initial regulatory approval; and 3) long-term follow-up to demonstrate that the therapy improves graft survival.