Atypical Hemolytic Uremic Syndrome
Conditions
Keywords
aHUS
Brief summary
The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of adult patients with plasma therapy-sensitive Atypical Hemolytic-Uremic Syndrome (aHUS).
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
NON_RANDOMIZED
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 Critera: 1. Male or female patients' ≥18 years of age who have been diagnosed with Atypical Hemolytic-Uremic Syndrome (aHUS). 2. Patients must be receiving PT for aHUS and must be observed to receive ≥ 1 PT treatment every two weeks and no more than 3 PT treatments/week (at an unchanged frequency) for at least 8 weeks before first dose of IP. 3. Platelet Count Pre-PT Baseline Set-Point (collected in the hours before the Qualifying PT Episode) is within 75% of the average of the Pre-PT platelet counts collected at Screening and during the Observation Period. 4. Known complement regulatory protein genetic abnormality. 5. Lactate dehydrogenase (LDH) level at screening or at the onset of the current aHUS episode was ≥ ULN. If LDH is normal at screening, other markers indicative of ongoing hemolysis such as haptoglobin, schistocytes should be evaluated and discussed with Sponsor. 6. Creatinine level ≥ ULN for age. 7. 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 and for up to 5 months following eculizumab treatment discontinuation. 8. Able to give written informed consent. 9. Able and willing to comply with study procedures.
Exclusion criteria
1. TTP, (defined as ADAMTS-13 activity \<5%) from an historical observation (prior to initiation of plasma therapy) or as tested at the screening visit by the central laboratory. 2. Malignancy within 5 years of screening. 3. Typical HUS (Shiga toxin +). 4. Known HIV infection. 5. Identified drug exposure-related HUS. 6. Infection-related HUS. 7. HUS related to bone marrow transplant. 8. HUS related to vitamin B12 deficiency. 9. Patients with a confirmed diagnosis of sepsis. 10. 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. 11. Pregnancy or lactation. 12. Unresolved meningococcal disease. 13. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome. 14. 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. 15. Patients who have received previous treatment with eculizumab. 16. Patients receiving IVIg within 8 weeks or Rituximab therapy within 12 weeks of the screening visit. 17. Patients receiving other immunosuppressive therapies such as steroids, mTOR inhibitors or tacrolimus are excluded unless: \[1\] part of an established post-transplant anti-rejection regime, \[2\] patient has confirmed anti-CFH antibody requiring immunosuppressive therapy, and \[3\] dose of such medications have been unchanged for at least 4 weeks prior to the screening period and throughout the Observation Period or \[4\] patient is experiencing an acute aHUS relapse immediately after transplant. 18. Patients receiving Erythrocyte Stimulating Agents (ESAs) unless already on a stable dose for at least 4 weeks prior to the screening period, or a washout period of at least 2 weeks from the last dose of ESA therapy. 19. Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedures beginning 4 weeks prior to screening and throughout the entire trial. 20. Hypersensitivity to eculizumab, to murine proteins or to one of the excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With TMA Event-free Status | Through 26 weeks | TMA Event-free status is defined as the absence for at least 12 weeks of \[1\] decrease in platelet count of \> 25% from the Platelet Count Pre-PT Baseline Set Point; \[2\] PT while the patient is receiving eculizumab, and \[3\] new dialysis. |
| Percentage of Patients With Hematologic Normalization | Through 26 weeks | Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks. |
| Percentage of Patients With Complete TMA Response | Through 26 weeks | The proportion of patients who achieved a Complete TMA Response from baseline through 26 weeks of treatment with eculizumab was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as (≥25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With TMA Event-free Status | Through End of Study, Median Exposure 156 Weeks | TMA Event-free status is defined as the absence for at least 12 weeks of \[1\] decrease in platelet count of \> 25% from the Platelet Count Pre-PT Baseline Set Point; \[2\] PT while the patient is receiving eculizumab, and \[3\] new dialysis. |
| Percentage of Patients With Hematologic Normalization | Through End of Study, Median Exposure 156 Weeks | Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks. |
| TMA Intervention Rate | Through 26 weeks | TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through 26 weeks) for PE/PI and (from the fifteenth day following the first eculizumab dose through 26 weeks) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period. |
| Platelet Count Change From Baseline to 156 Weeks | From Baseline to 156 Weeks | — |
| Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration | Induction Phase for 4 weeks followed by Maintenance Phase starting on Week 5 through 26 weeks or longer. | — |
| Percentage of Patients With Complete TMA Response | Through End of Study, Median Exposure 156 Weeks | The proportion of patients who achieved a Complete TMA Response from baseline through end of study with eculizumab was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as (≥25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks. |
| Platelet Count Change From Baseline to 26 Weeks | From Baseline to 26 Weeks | — |
| Percentage of Patients With Platelet Count Normalization | Through 26 Weeks | Platelet count normalization was defined as the platelet count observed to be ≥150 x 10\^9/L on at least two consecutive measurements which span a period of at least four weeks |
Countries
Canada, France, Germany, Italy, Netherlands, Sweden, United Kingdom
Participant flow
Recruitment details
C08-003A/B combined 2 studies: one for adults (C08-003A, N=15) and one for adolescents (C08-003B, N=5) Please refer to NCT00844428 for combined studies with enrollment number corresponding to each individual study
Pre-assignment details
Patients receiving PT for aHUS and observed to receive ≥ 1 PT every two weeks, and no more than 3 PT treatments/week for at least 8 weeks before the first dose of eculizumab. Patients who met the eligibility criteria during the Observation Period were enrolled into the Treatment Period which commenced with the first eculizumab dose.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Extension Treatment Period | Death | 1 |
| Post Treatment Period (Patients Who Disc | Death | 1 |
| Screening Period | Screen Failure | 3 |
Baseline characteristics
| Characteristic | Eculizumab |
|---|---|
| Age, Continuous | 32.3 Years STANDARD_DEVIATION 14.92 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 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 | 18 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 13 / 20 |
Outcome results
Primary
Percentage of Patients With Complete TMA Response
The proportion of patients who achieved a Complete TMA Response from baseline through 26 weeks of treatment with eculizumab was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as (≥25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks.
Time frame: Through 26 weeks
Population: Tabulations of the proportion of patients who achieved a complete TMA response from baseline through 26 weeks were performed. For this endpoint, for any relevant proportions, exact binomial 95% confidence intervals were produced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Complete TMA Response | 25 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.95% CI: [9, 49]
Primary
Percentage of Patients With Hematologic Normalization
Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks.
Time frame: Through 26 weeks
Population: Tabulations of the proportion of patients who achieved a hematologic normalization through 26 weeks were performed for the ITT population. Exact binomial 95% confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Hematologic Normalization | 90 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.95% CI: [68, 99]
Primary
Percentage of Patients With TMA Event-free Status
TMA Event-free status is defined as the absence for at least 12 weeks of \[1\] decrease in platelet count of \> 25% from the Platelet Count Pre-PT Baseline Set Point; \[2\] PT while the patient is receiving eculizumab, and \[3\] new dialysis.
Time frame: Through 26 weeks
Population: The tabulations of the proportions of patients who achieved a TMA Event-Free status through 26 weeks were performed for the ITT population. Exact binomial 95% confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With TMA Event-free Status | 80 Percentage of Participants |
Comparison: With a total of 20 patients enrolled between both protocols and, assuming that the true expected probability of TMA Event-Free for eculizumab-treated patients is 40%, then the study had 93.5% power to detect a statistically significant difference. Up to approximately 30 patients were to be enrolled.~All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.95% CI: [56, 94]
Secondary
Percentage of Patients With Complete TMA Response
The proportion of patients who achieved a Complete TMA Response from baseline through end of study with eculizumab was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as (≥25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks.
Time frame: Through End of Study, Median Exposure 156 Weeks
Population: Tabulations of the proportion of patients who achieved a complete TMA response from baseline through end of study were performed. For this endpoint, for any relevant proportions, exact binomial 95% confidence intervals were produced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Complete TMA Response | 55 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.95% CI: [32, 77]
Secondary
Percentage of Patients With Hematologic Normalization
Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks.
Time frame: Through End of Study, Median Exposure 156 Weeks
Population: Tabulations of the proportion of patients who achieved a hematologic normalization through end of study were performed for the ITT population. Exact 95% binomial confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Hematologic Normalization | 90 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.95% CI: [68, 99]
Secondary
Percentage of Patients With Platelet Count Normalization
Platelet count normalization was defined as the platelet count observed to be ≥150 x 10\^9/L on at least two consecutive measurements which span a period of at least four weeks Not specified.
Time frame: Through End of Study, Median Exposure 156 Weeks
Population: The tabulations of the proportion of patients who achieved platelet count normalization through end of study were performed for the ITT population. Exact binomial 95% confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Platelet Count Normalization | 90 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years95% CI: [68, 99]
Secondary
Percentage of Patients With Platelet Count Normalization
Platelet count normalization was defined as the platelet count observed to be ≥150 x 10\^9/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 proportion of patients who achieved platelet count normalization through 26 weeks were performed for the ITT population. Exact binomial 95% confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Platelet Count Normalization | 90 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years95% CI: [68, 99]
Secondary
Percentage of Patients With TMA Event-free Status
TMA Event-free status is defined as the absence for at least 12 weeks of \[1\] decrease in platelet count of \> 25% from the Platelet Count Pre-PT Baseline Set Point; \[2\] PT while the patient is receiving eculizumab, and \[3\] new dialysis.
Time frame: Through End of Study, Median Exposure 156 Weeks
Population: The tabulations of the proportions of patients who achieved a TMA Event-Free status through 26 weeksend of study were performed for the ITT population. Exact binomial 95% confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With TMA Event-free Status | 95 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.95% CI: [75, 100]
Secondary
Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration
Time frame: Induction Phase for 4 weeks followed by Maintenance Phase starting on Week 5 through 26 weeks or longer.
Population: PK parameters Cmin and Cmax were estimated using a population PK model developed from the observed PK concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eculizumab | Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration | max concentration during induction period | 161.47 micrograms/mil | Standard Deviation 27.29 |
| Eculizumab | Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration | min concentration during induction period | 112.43 micrograms/mil | Standard Deviation 16.98 |
| Eculizumab | Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration | max concentration during maintenance | 427.48 micrograms/mil | Standard Deviation 67.54 |
| Eculizumab | Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration | min concentration during maintenance | 212.45 micrograms/mil | Standard Deviation 53.75 |
Secondary
Platelet Count Change From Baseline to 156 Weeks
Time frame: From Baseline to 156 Weeks
Population: Change from baseline platelet counts were analyzed for the ITT population using a repeated measurement ANOVA model. A least squares (LS) mean for the change from baseline was produced for each study day for which a measurement of platelet count was scheduled. Significance of change was assessed at the 5% level at each time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Eculizumab | Platelet Count Change From Baseline to 156 Weeks | -3.68 10^9 cells/L |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.p-value: 0.730795% CI: [-25.15, 17.79]ANOVA
Secondary
Platelet Count Change From Baseline to 26 Weeks
Time frame: From Baseline to 26 Weeks
Population: Change from baseline platelet counts were analyzed for the ITT population using a repeated measurement ANOVA model. A least squares (LS) mean for the change from baseline was produced for each study day for which a measurement of platelet count was scheduled. Significance of change was assessed at the 5% level at each time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Eculizumab | Platelet Count Change From Baseline to 26 Weeks | 6.75 10^9 cells/L |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 yearsp-value: 0.542395% CI: [-15.73, 29.23]ANOVA
Secondary
TMA Intervention Rate
TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through end of study) for PE/PI and (from the fifteenth day following the first eculizumab dose through end of study) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.
Time frame: Through End of Study, Median Exposure 156 Weeks
Population: A signed rank test assessed differences in magnitudes of change in TMA intervention rate between the pre-eculizumab treatment period and during eculizumab treatment period for ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | TMA Intervention Rate | 0.00 #events/patient/day | Standard Deviation 0.02 |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
TMA Intervention Rate
TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through 26 weeks) for PE/PI and (from the fifteenth day following the first eculizumab dose through 26 weeks) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.
Time frame: Through 26 weeks
Population: A signed rank test assessed differences in magnitudes of change in TMA intervention rate between the pre-eculizumab treatment period and during eculizumab treatment period for ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | TMA Intervention Rate | 0 #events/patient/day | Standard Deviation 0 |
Comparison: All analyses were based on the pooled data from the two protocols: C08-003A (adult) and C08-003B (adolescent), a similar protocol, for patients \<18 years with aHUS.p-value: <0.0001Wilcoxon (Mann-Whitney)