Table 2 Primary and secondary endpoints

Primary endpoint

Time to all-cause graft loss defined as any of:

• Return to dialysis

• Graft nephrectomy

• Re-transplantation

• eGFR <15 mL/min/1.73m²

• Death from any cause

This event-driven endpoint will be analyzed when at least 221 all-cause graft loss events have occurred

Interim efficacy analysis

• Interim Analysis 1: sample size re-estimation when approximately 100 patients have completed 1 year of follow-up

• Interim Analysis 2: eGFR slope will be assessed when approximately 200 patients reach 1 year. The use of change in eGFR to assess risk of graft failure in chronic active AMR is based on prior modeling validation [4]

Secondary safety endpoints

1. TEAEs, serious TEAEs, and AESIs

 a. For clazakizumab, the following AESIs have been identified: LFT abnormalities, neutropenia, thrombocytopenia, hyperlipidemia, GI perforations, hypersensitivity and anaphylaxis, malignancy, and opportunistic infections

2. Viral infection monitoring for BKV, CMV, and EBV by PCR

3. Laboratory tests including LFTs, CBC, plasma lipids, hsCRP

4. Vital signs, ECGs, and physical examination

5. Incidence of antibodies to clazakizumab

Secondary efficacy endpoints

1. Incidence and time to death-censored graft loss (defined as return to dialysis, graft nephrectomy, re-transplantation, or eGFR <15 mL/min/1.73 m² but excluding death from any cause)

2. Change in mean eGFR from baseline to EOT

3. Change in spot UACR from baseline to EOT

4. Change in DSA titers and MFI scores from baseline to EOT

5. Incidence of acute rejection episodes (TCMR and AMR) from baseline to EOT

6. Change in Banff lesion grading score (2015 criteria of pre-treatment to post-treatment (Week 52) kidney biopsies) [31]

7. Overall patient survival

Secondary PK endpoints

The PK endpoints for a subset of subjects who consent to participate in the PK/PD sub-study will include the following:

1. Maximum concentrations (C_max, steady state C_max [C_{max ss}])

2. Trough concentrations (C_trough, steady state C_trough [C_{trough ss}])

3. Area under the concentration-time curve at steady state (AUC_{0-tau ss})

4. Time of maximum concentration (T_max, steady state T_max [T_{max ss}])