Atypical Hemolytic-Uremic Syndrome
Conditions
Keywords
Atypical Hemolytic-Uremic Syndrome
Brief summary
The record Primary purpose is to assess the efficacy of eculizumab in adult patients with Atypical Hemolytic- Uremic Syndrome (aHUS) to control Thrombotic Microangiopathy (TMA) as characterized by thrombocytopenia, hemolysis and renal impairment.
Interventions
DRUGEculizumab
All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion: 1. Patient must be willing and able to give written informed consent. 2. Patient's age \> 18 years. 3. Patients exhibit thrombocytopenia, hemolysis and elevated Serum Creatinine. 4. Patients with diagnosis of aHUS with or without an identified complement regulatory protein genetic abnormality or anti-complement factor antibody and for whom etiologies of hemolytic uremic syndrome have been ruled out as confirmed in the
Exclusion criteria
5. Female patients of childbearing potential must be practicing an effective, reliable and medically approved contraceptive regimen during the entire duration of the study, including the follow-up period. At the time of the last follow-up visit, patients must agree to continue to use adequate contraception methods for up to 5 months following discontinuation of eculizumab treatment. 6. Able and willing to comply with study procedures Exclusion: 1. Chronic dialysis. 2. Prior eculizumab use or hypersensitivity to eculizumab, to murine proteins or to one of the excipients. 3. Known familial a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) deficiency (ADAMTS-13 \<5%). 4. Typical Hemolytic-Uremic Syndrome (HUS) (known Shiga toxin +). 5. History of malignancy within 5 years of screening. 6. Known human immunodeficiency virus (HIV) infection. 7. Identified drug exposure-related hemolytic-uremic syndrome (HUS). 8. Infection-related HUS. 9. HUS related to bone marrow transplant (BMT). 10. HUS related to vitamin B12 deficiency. 11. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome. 12. Patients with a confirmed diagnosis of sepsis defined as positive blood cultures within 7 days of the screening visit and not treated with antibiotics to which the organism is sensitive. 13. Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator confounds an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease. 14. Pregnancy or lactation. 15. Unresolved systemic meningococcal disease. 16. Any medical or psychological condition that, in the opinion of the investigator, could increase the patient's risk by participating in the study or confound the outcome of the study. 17. Patients receiving chronic intravenous immunoglobulin (IVIg) within 8 weeks or chronic Rituximab therapy within 12 weeks of screening visit. 18. Patients receiving other immunosuppressive therapies such as steroids, mechanist target of rapamycin (mTOR) inhibitors, calcineurin inhibitors (e.g., cyclosporine or tacrolimus) are excluded unless: \[1\] part of an established post-transplant anti-rejection regime, or \[2\] patient has confirmed anti-Complement Factor Antibodies requiring immunosuppressive therapy, or \[3\] steroids are being used for a condition other than aHUS (example asthma). 19. Participation in any other investigational drug trial or device trial, or procedures beginning 4 weeks prior to screening and throughout the entire trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Complete TMA Response | Through 26 weeks | Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and preservation of renal function (defined as \< 25% increase in serum creatinine from baseline) which were sustained for at least two consecutive measurements obtained at least four weeks apart. |
| Percentage of Patients With Modified Complete TMA Response | Through 26 weeks | Proportion of Patients with Modified Complete TMA response through 26 weeks of treatment was determined and defined by normalization of hematological parameters (platelet count and LDH) and improvement in renal function (defined as ≥ 25% reduction from the baseline value in serum creatinine, which were sustained for at least two consecutive measurements obtained at least four weeks apart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement | Through 26 weeks | Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m\^2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart. |
| Platelet Count Change From Baseline to 26 Weeks | Through 26 weeks | — |
| Percentage of Patients With Complete Hematologic Response | Through 26 weeks | Proportion of Patients with Complete Hematologic response through end of study was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart. |
| Percentage of Patients With Modified Complete TMA Response | Through End of Study, Median Exposure 52 Weeks | Proportion of Patients with Modified Complete TMA response through end of study was determined and defined by normalization of hematological parameters (platelet count and LDH) and improvement in renal function (defined as ≥ 25% reduction from the baseline value in serum creatinine, which were sustained for at least two consecutive measurements obtained at least four weeks apart. |
| Platelet Count Change From Baseline to 52 Weeks | Through 52 Weeks | — |
| Percentage of Patients With Complete TMA Response | Through End of Study, Median Exposure 52 Weeks | Proportion of Patients with Complete TMA response through end of study was determined and defined by normalization of hematological parameters (platelet count and LDH) and preservation of renal function (defined as \< 25% increase in serum creatinine from baseline) which were sustained for at least two consecutive measurements obtained at least four weeks apart. |
| Percentage of Patients With Platelet Count Normalization | Through 26 weeks | Proportion of Patients with Platelet Count Normalization through 26 weeks of treatment was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks |
Countries
Belgium, France, Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 44 patients diagnosed with aHUS signed the informed consent and of these, 41 patients were treated. Three patients were excluded from the study due to failed screening procedure and did not receive eculizumab.
Pre-assignment details
At screening, patients had to have signs or symptoms of hemolysis; serum creatinine level ≥ ULN and platelet count \< LLN
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab Eculizumab: All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 26 Week Treatment Period | Adverse Event | 1 |
| 26 Week Treatment Period | Lack of Efficacy | 1 |
| 26 Week Treatment Period | Pregnancy | 1 |
| Screening Period | Screen Failure | 3 |
Baseline characteristics
| Characteristic | Eculizumab |
|---|---|
| Age, Continuous | 40.3 Years STANDARD_DEVIATION 15.33 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 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 | 38 Participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 41 |
| serious Total, serious adverse events | 19 / 41 |
Outcome results
Primary
Percentage of Patients With Complete TMA Response
Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and preservation of renal function (defined as \< 25% increase in serum creatinine from baseline) which were sustained for at least two consecutive measurements obtained at least four weeks apart.
Time frame: Through 26 weeks
Population: The tabulations of the proportions of patients with Complete TMA Response through 26 weeks were performed for the ITT population. Exact binomial two-sided 95% CI using the Clopper-Pearson method for the responder rate was presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Complete TMA Response | 73.2 Percentage of Participants |
Primary
Percentage of Patients With Modified Complete TMA Response
Proportion of Patients with Modified Complete TMA response through 26 weeks of treatment was determined and defined by normalization of hematological parameters (platelet count and LDH) and improvement in renal function (defined as ≥ 25% reduction from the baseline value in serum creatinine, which were sustained for at least two consecutive measurements obtained at least four weeks apart.
Time frame: Through 26 weeks
Population: The tabulations of the proportions of patients with Modified Complete TMA Response through 26 weeks were performed for the ITT population. Exact binomial two-sided 95% CI using the Clopper-Pearson method for the responder rate was presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Modified Complete TMA Response | 56.1 Percentage of Participants |
Secondary
Percentage of Patients With Complete Hematologic Response
Proportion of Patients with Complete Hematologic response through end of study was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart.
Time frame: Through 26 weeks
Population: The tabulations of the proportions of patients with Complete Hematologic Response through 26 weeks were performed for the ITT population. The number of patients with response and responder rate, along with an exact two-sided 95% CI were summarized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Complete Hematologic Response | 87.8 Percentage of Participants |
Secondary
Percentage of Patients With Complete Hematologic Response
Proportion of Patients with Complete Hematologic response through end of study of treatment was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart.
Time frame: Through End of Study, Median Exposure 52 Weeks
Population: The tabulations of the proportions of patients with Complete Hematologic Response through end of study were performed for the ITT population. The number of patients with response and responder rate, along with an exact two-sided 95% CI were summarized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Complete Hematologic Response | 97.6 Percentage of Participants |
Secondary
Percentage of Patients With Complete TMA Response
Proportion of Patients with Complete TMA response through end of study was determined and defined by normalization of hematological parameters (platelet count and LDH) and preservation of renal function (defined as \< 25% increase in serum creatinine from baseline) which were sustained for at least two consecutive measurements obtained at least four weeks apart.
Time frame: Through End of Study, Median Exposure 52 Weeks
Population: The tabulations of the proportions of patients with Complete TMA Response through end of study were performed for the ITT population. Exact binomial two-sided 95% CI using the Clopper-Pearson method for the responder rate was presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Complete TMA Response | 80.5 Percentage of Participants |
Secondary
Percentage of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement
Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m\^2 from baseline sustained for at least two consecutive measurements obtained at least four weeks apart
Time frame: Through End of Study, Median Exposure 52 Weeks
Population: The tabulations of the proportions of patients with Estimated Glomerular Filtration Rate (eGFR) Improvement through end of study were performed for the ITT population. The number of patients with response and responder rate, along with an exact two-sided 95% CI were summarized for each parameter.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement | 61.0 Percentage of Participants |
Secondary
Percentage of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement
Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m\^2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart.
Time frame: Through 26 weeks
Population: The tabulations of the proportions of patients with Estimated Glomerular Filtration Rate (eGFR) Improvement through 26 weeks were performed for the ITT population. The number of patients with response and responder rate, along with an exact two-sided 95% CI were summarized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement | 53.7 Percentage of Participants |
Secondary
Percentage of Patients With Modified Complete TMA Response
Proportion of Patients with Modified Complete TMA response through end of study was determined and defined by normalization of hematological parameters (platelet count and LDH) and improvement in renal function (defined as ≥ 25% reduction from the baseline value in serum creatinine, which were sustained for at least two consecutive measurements obtained at least four weeks apart.
Time frame: Through End of Study, Median Exposure 52 Weeks
Population: The tabulations of the proportions of patients with Modified Complete TMA Response through end of study were performed for the ITT population. Exact binomial two-sided 95% CI using the Clopper-Pearson method for the responder rate was presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Modified Complete TMA Response | 63.4 Percentage of Participants |
Secondary
Percentage of Patients With Platelet Count Normalization
Proportion of Patients with Platelet Count Normalization through 26 weeks of treatment was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks
Time frame: Through 26 weeks
Population: The tabulations of the proportions of patients with Platelet Count Normalization through 26 weeks were performed for the ITT population. The number of patients with response and responder rate, along with an exact two-sided 95% CI were summarized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Platelet Count Normalization | 97.6 Percentage of Participants |
Secondary
Percentage of Patients With Platelet Count Normalization
Proportion of Patients with Platelet Count Normalization through end of study of treatment was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks
Time frame: Through End of Study, Median Exposure 52 Weeks
Population: The tabulations of the proportions of patients with Platelet Count Normalization through end of study were performed for the ITT population. The number of patients with response and responder rate, along with an exact two-sided 95% CI were summarized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Platelet Count Normalization | 100.0 Percentage of Participants |
Secondary
Platelet Count Change From Baseline to 26 Weeks
Time frame: Through 26 weeks
Population: Change from baseline platelet counts were analyzed for the ITT population using a repeated measures Analysis of variance (ANOVA) model. The estimated LS means of change from baseline at each post-baseline visit alongside with 95% CIs and P-values were calculated, as were the parameter estimates for the covariates and their associated P-values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Eculizumab | Platelet Count Change From Baseline to 26 Weeks | 117.68 10^9 cells/L |
p-value: <0.000195% CI: [92.77, 142.59]ANOVA
Secondary
Platelet Count Change From Baseline to 52 Weeks
Time frame: Through 52 Weeks
Population: Change from baseline platelet counts were analyzed for the ITT population using a repeated measures ANOVA model. The estimated LS means of change from baseline at each post-baseline visit alongside with 95% CIs and P-values were calculated, as were the parameter estimates for the covariates and their associated P-values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Eculizumab | Platelet Count Change From Baseline to 52 Weeks | 102.49 10^9 cells/L |
p-value: <0.000195% CI: [68.15, 136.82]ANOVA