Safety and Efficacy of Eculizumab in High-risk TA-TMA

Keywords

• transplant-associated thrombotic microangiopathy (TA-TMA)
• allogeneic hematopoietic stem cell transplantation
• Eculizumab

Lead sponsor

First Affiliated Hospital of Zhejiang University is the lead sponsor of 255 studies on the registry; 139 are open to participants now.

Study arms

• Experimental
  Eculizumab group

  Eculizumab treatment for High-Risk TA-TMA

  Drug: Eculizumab

Interventions

• DrugEculizumab

  Dosing Regimen Weight-based induction therapy: Eculizumab 10-\<40 kg: 600 mg * 40 kg: 900 mg Dosing frequency: Loading phase (first 5 doses) First 5 doses: 1 dose every 48 hours × 2 doses, then 1 dose every 72 hours × 3 doses Induction phase (subsequent 4 doses) Subsequent 4 doses: once weekly for 4 weeks Maintenance phase Once every 2 weeks, continued up to 24 weeks Dose adjustment principles: Based on eculizumab trough concentration (target ≥100 μg/mL), CH50 level (\<10% of the lower limit of normal), and sC5b-9 target: \<244 ng/mL Monitoring frequency: Loading phase: daily monitoring Induction and maintenance phases: monitoring prior to each dose

Primary outcomes

1. 6-month overall survival rate after diagnosis of TA-TMA

   This endpoint is defined as the proportion of patients who survive for 6 months (180 days) from the date of TA-TMA diagnosis among all enrolled patients with confirmed TA-TMA in the study population.

   Time frame: 6 months after diagnosis of TA-TMA

Secondary outcomes

1. Complete TMA response (cTMA-R)

   Within the 26-week treatment period, the subject must meet all of the following criteria: 1) platelet count improvement of ≥50% from baseline; 2) urine protein-to-creatinine ratio (UPCR) reduction of ≥50% from baseline; 3) lactate dehydrogenase (LDH) returning to the normal range and no schistocytes on peripheral blood smear. All three criteria must be met in at least two consecutive assessments separated by ≥4 weeks, and must be maintained in all subsequent assessments from the first consecutive achievement through the end of Week 26. This is defined as a sustained cTMA-R.

   Time frame: 26-week treatment period

2. Cumulative incidence and recovery rate of MODS at 6 months after diagnosis of TA-TMA

   Over the 6-month (180-day) observation period following the diagnosis of TA-TMA, the proportion of patients with newly developed or worsened multiple organ dysfunction syndrome (MODS). This is calculated as a cumulative incidence under a competing risks model, considering death as a competing event (since patients who die cannot experience a new MODS event).

   Time frame: 6 months after diagnosis of TA-TMA

3. 1-year overall survival rate after HSCT

   The proportion of patients who are alive at 1 year (365 days) from the date of hematopoietic stem cell infusion, among all transplanted patients in the intention-to-treat population.

   Time frame: 1 year (365 days) from the date of hematopoietic stem cell infusion

4. 1-year non-relapse mortality (NRM) after HSCT

   The cumulative incidence of any death not attributable to disease relapse or progression within the 1-year (365-day) observation period after transplantation.

   Time frame: 1-year (365-day) after transplantation.

5. Organ-specific functional recovery (kidney, lung, cardiovascular, etc.)

   Following hematopoietic stem cell transplantation or a specific disease (e.g., TA-TMA), the recovery of one or more specific organ functions from a dysfunctional state during treatment or at the nadir of illness to a predefined, clinically meaningful normal or near-normal functional level, with the improvement sustained for a specified period to confirm stability.

   Time frame: 6 months after diagnosis of TA-TMA

6. Safety assessments (infection, infusion-related reactions, etc.

   Infection: Clinically significant disease caused by pathogenic microorganisms (e.g., bacteria, viruses, fungi, parasites) requiring medical intervention. Infusion-related reaction: Any adverse event occurring during the study drug infusion or within a specified time window (e.g., within 1 hour or 24 hours) after the infusion ends.

   Time frame: 6 months after diagnosis of TA-TMA

7. Maximum Plasma Concentration [Cmax] of eculizumab

   Quantitative characterization of the maximum plasma concentration \[Cmax\] of eculizumab. This describes the processes of absorption, distribution, metabolism, and excretion of eculizumab in the human body-i.e., the action of the body on the drug.

   Time frame: 6 months after diagnosis of TA-TMA

8. Safety assessments (CD3+ T cells, CD19+ B cells, CD56+ NK cells)

   Quantitative description of the effects of eculizumab treatment on the absolute counts and relative percentages of peripheral blood CD3+ T cells, CD19+ B cells, and CD56+ NK cells in patients.

   Time frame: 6 months after diagnosis of TA-TMA

9. Minimum Plasma Concentration [Cmin] of eculizumab

   Quantitative characterization of the minimum plasma concentration \[Cmin\] of eculizumab. This describes the processes of absorption, distribution, metabolism, and excretion of eculizumab in the human body-i.e., the action of the body on the drug.

   Time frame: 6 months after diagnosis of TA-TMA

Individual participant data

Plan to share: Yes — The IPD will be made available after the publication of the primary results, upon reasonable request, and subject to approval by the study steering committee and the relevant ethics committees. Data will be de-identified (anonymized) and will be shared under a formal data-use agreement that ensures confidentiality and restricts use to approved secondary analyses. The detailed sharing plan, including the timeline and criteria for access, will be described in the study protocol and will comply with applicable data protection regulations.

Supporting information: Study protocol, Sap, Icf, Csr