Atypical Hemolytic Uremic Syndrome, Multiple Organ Dysfunction Syndrome, Thrombotic Microangiopathies
Conditions
Keywords
Hematopoietic Stem Cell Transplant
Brief summary
Hematopoietic stem cell transplantation (HCT)-associated thrombotic microangiopathy (TMA) is an understudied complication of HCT that significantly affects transplant related morbidity and mortality. The investigators hypothesize that early intervention with complement blocker eculizumab will double survival in HCT recipients with high risk TMA, as compared to historical untreated controls. An optimal eculizumab dosing schedule can be determined for this population through eculizumab pharmacokinetic/pharmacodynamic (PK/PD) testing.
Detailed description
This clinical trial is a prospective single arm multi-institution study in children and young adults undergoing allogeneic or autologous hematopoietic stem cell transplantation who will receive early therapy with eculizumab to prevent TMA-associated MODS after transplantation. The purpose of this research study is to examine efficacy of complement blocker eculizumab in HCT recipients with high risk TMA and to determine optimal eculizumab dosing regimen for HCT recipients with TMA using PK/PD studies. All patients will receive therapy based on their weight for 24 weeks. Survival will be assessed at 6 months from TMA diagnosis.
Interventions
DRUGEculizumab
Eculizumab will be administered as intravenous infusion (IV) over 60 minutes. The dosage form will be 300 mg single-use vials each containing 30 mL of 10 mg/mL sterile, preservative-free solution.
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Patients of any age undergoing allogeneic or autologous HCT * Histologic TMA diagnosis OR clinical TMA diagnosis and presenting with high risk disease features including elevated plasma sC5b-9 above laboratory normal value (≥244ng/ml) and proteinuria measured as ≥30mg/dL of protein on random urinalysis x2 or protein/creatinine ratio ≥1mg/mg or patient receiving renal replacement therapy. * Minimum weight of ≥ 5kg.
Exclusion criteria
* Known hypersensitivity to any constituent of the study medication. * Subjects with unresolved serious Neisseria meningitides infection or progressive severe infection. * Patients with diagnosis of TTP as defined by ADAMST13 activity test \<10%. * Patients previously treated with eculizumab or other complement blocker for TMA within the 60 days prior to first dose of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival | 6 months | Survival at 6 months after the date of TMA diagnosis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Organ Dysfunction | 6 months | Number of participants with organ dysfunction at 6 months after TMA diagnosis. Organ dysfunction definitions are listed in the protocol Appendix II that is uploaded to ClinicalTrials.gov site. |
| Non-relapse Mortality | 1 year | Non-relapse mortality descriptively compared with historical controls at 1 year |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab All patients will receive eculizumab based on their weight for 24 weeks.
Eculizumab: Eculizumab will be administered as intravenous infusion (IV) over 60 minutes. The dosage form will be 300 mg single-use vials each containing 30 mL of 10 mg/mL sterile, preservative-free solution. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Relapsed with primary malignancy within 6 months of TMA diagnosis making participant unevaluable. | 1 |
| Overall Study | The participant died on study prior to receiving 4 doses and was not evaluable. | 1 |
Baseline characteristics
| Characteristic | Eculizumab |
|---|---|
| Age, Categorical <=18 years | 20 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 23 |
| other Total, other adverse events | 22 / 23 |
| serious Total, serious adverse events | 19 / 23 |
Outcome results
Primary
Survival
Survival at 6 months after the date of TMA diagnosis
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Survival | 15 Participants |
p-value: <0.0001binomial test
Secondary
Non-relapse Mortality
Non-relapse mortality descriptively compared with historical controls at 1 year
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Non-relapse Mortality | 8 Participants |
Secondary
Number of Participants With Organ Dysfunction
Number of participants with organ dysfunction at 6 months after TMA diagnosis. Organ dysfunction definitions are listed in the protocol Appendix II that is uploaded to ClinicalTrials.gov site.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With Organ Dysfunction | 4 Participants |
Secondary
Number of Participants With Organ Dysfunction
Number of participants with organ dysfunction at 1 year after TMA diagnosis. Organ dysfunction definitions are listed in the protocol Appendix II that is uploaded to ClinicalTrials.gov site.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With Organ Dysfunction | 2 Participants |