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 adolescent patients with plasma therapy-resistant 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
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients from 12 and up to 18 years weighing ≥ 40 kg who have been diagnosed with Atypical Hemolytic-Uremic Syndrome (aHUS). 2. Decrease in platelet count despite at least 4 plasma therapy (PT) treatments in the 1 week immediately prior to screening. 1. Screening platelet count , \< 150 x10\^9/L and at least 25% lower than the average remission platelet count or 2. If remission counts not available, platelet count at onset of the current aHUS episode must be ≤75x10\^9/L and platelet count at screening must be ≤ 100 x 10\^9/L despite PT treatment administration of at least 4 PT treatments in the 1 week immediately prior to screening 3. Known complement regulatory protein genetic abnormality 4. Lactate dehydrogenase (LDH) level ≥ ULN unless the patient has been receiving plasma exchange and LDH at the onset of the current aHUS episode was at least the ULN. If LDH is normal at screening, other markers indicative of ongoing hemolysis such as haptoglobin, schistocytes should be evaluated and discussed with Sponsor 5. Creatinine level ≥ ULN for age 6. 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 of eculizumab treatment discontinuation. 7. Patient's parents/legal guardian must be willing and able to give written informed consent and patient must be willing to give written informed assent. 8. 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. Renal function status requiring chronic dialysis 10. Patients with a confirmed diagnosis of sepsis 11. 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. 12. Pregnancy or lactation. 13. Unresolved meningococcal disease. 14. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome. 15. 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. 16. Patients who have received previous treatment with eculizumab 17. Patients receiving IVIG within 8 weeks or Rituximab therapy within 12 weeks of screening. 18. 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 or \[4\] patient is experiencing an acute aHUS relapse immediately after transplant 19. 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. 20. 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. 21. Hypersensitivity to eculizumab, to murine proteins or to one of the excipients 22. Patients between ages from 12 and up to 18 years weighing \< 40 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Count Change From Baseline to 26 Weeks | From Baseline to 26 weeks | — |
| Percentage of Patients With Platelet Count Normalization | Through 26 weeks | The primary objective of the study (per protocol) was to assess the effect of eculizumab to reduce TMA as measured by platelet count change from baseline (BL) during the Treatment Period (26 weeks) in patients with plasma therapy (PT)-resistant aHUS (protocol defined), including assessment of the proportion of patients who achieved Platelet Count Normalization from baseline 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Platelet Count Normalization | Through End of Study, Median Exposure 100.29 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. |
| 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. |
| 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 Hematologic Normalization | Through End of Study, Median Exposure 100.29 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 | — |
Countries
Austria, France, Germany, United Kingdom, United States
Participant flow
Recruitment details
C08-002A/B combined 2 studies: one for adults (C08-002A, N=16) and one for adolescents (C08-002B, N=1) Please refer to NCT00844545 for combined studies with enrollment number corresponding to each individual study
Pre-assignment details
Patients had to exhibit a decrease in platelet count despite at least 4 Plasma Therapy (PT) treatments in the 1 week immediately prior to screening. Patients who met the eligibility criteria during screening 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. | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Extension Treatment Period | Adverse Event | 2 |
| Post Treatment Period | Withdrawal by Subject | 1 |
| Treatment Period (26 Weeks) | Adverse Event | 1 |
| Treatment Period (26 Weeks) | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Eculizumab |
|---|---|
| Age, Continuous | 31.8 Years STANDARD_DEVIATION 13.32 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 15 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 17 / 17 |
Outcome results
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 confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Hematologic Normalization | 76 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients with aHUS.95% CI: [50, 93]
Primary
Percentage of Patients With Platelet Count Normalization
The primary objective of the study (per protocol) was to assess the effect of eculizumab to reduce TMA as measured by platelet count change from baseline (BL) during the Treatment Period (26 weeks) in patients with plasma therapy (PT)-resistant aHUS (protocol defined), including assessment of the proportion of patients who achieved Platelet Count Normalization from baseline 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.
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 confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Platelet Count Normalization | 82 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients with aHUS.95% CI: [57, 96]
Primary
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 visit 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 | 65.18 10^9 cells/L |
Comparison: With at least 12 patients enrolled and assuming a null hypothesis of no post-dose change from baseline in mean platelet count, the study had approximately 88% power to detect as statistically significant an effect size (mean change from baseline/standard deviation) of at least 1 when using a one sample t-test with a two-sided α=0.05. All analyses were based on the pooled data from the two protocols:C08-002A (adult) and C08-002B (Adolescent), a similar protocol, for patients \<18 years with aHUS.p-value: <0.000195% CI: [37.01, 93.36]ANOVA
Secondary
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 confidence intervals were produced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Complete TMA Response | 65 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients with aHUS.95% CI: [38, 86]
Secondary
Percentage of Patients With Complete TMA Response
The proportion of patients who achieved a Complete TMA Response from baseline through end of the study 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 100.29 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 confidence intervals were produced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Complete TMA Response | 76 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients with aHUS.95% CI: [50, 93]
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 100.29 Weeks
Population: Tabulations of the proportion of patients who achieved a hematologic normalization through end of study were performed for the ITT population. Exact binomial confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Hematologic Normalization | 88 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients with aHUS.95% CI: [64, 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 End of Study, Median Exposure 100.29 Weeks
Population: The Tabulations of the proportion of patients who achieved platelet count normalization through end of the study were performed for the ITT population. Exact binomial confidence intervals were produced for the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Percentage of Patients With Platelet Count Normalization | 88 Percentage of Participants |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients with aHUS.95% CI: [64, 99]
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 | 145.16 micrograms/mil | Standard Deviation 26.56 |
| Eculizumab | Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration | min concentration during induction period | 93.66 micrograms/mil | Standard Deviation 22.1 |
| Eculizumab | Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration | max concentration during maintenace | 345.14 micrograms/mil | Standard Deviation 89.74 |
| Eculizumab | Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration | Min concentration during maintenance | 151.80 micrograms/mil | Standard Deviation 68.16 |
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 | 111.62 10^9 cells/L |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients with aHUS.p-value: <0.000195% CI: [98.12, 125.13]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 the study) for PE/PI and (from the fifteenth day following the first eculizumab dose through end of the 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 100.29 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 | 0.04 # events/patient/day | Standard Deviation 0.11 |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients 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 | 0.04 # events/patient/day | Standard Deviation 0.1 |
Comparison: All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients \< 18 years of age for adolescent patients with aHUS.p-value: <0.0001Wilcoxon (Mann-Whitney)