Thrombotic Microangiopathy
Conditions
Keywords
Complement, Trigger, Secondary thrombotic microangiopathy, Acute kidney injury
Brief summary
This study will investigate the efficacy and safety of ravulizumab compared to placebo in adult participants with thrombotic microangiopathy (TMA) associated with a trigger. Participants will be randomized to receive either ravulizumab plus best supportive care or placebo plus best supportive care. The treatment period is 26 weeks followed by a 26-week off-treatment follow-up period.
Interventions
BIOLOGICALRavulizumab
Body weight-based doses of ravulizumab will be administered intravenously as loading dose regimen followed by maintenance dosing every 8 weeks.
OTHERPlacebo
Matching placebo
OTHERBest Supportive Care
Participants will receive medications, therapies, and interventions per standard hospital treatment protocols (unless specifically prohibited by the protocol).
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 18 years of age or older 2. Body weight ≥ 30 kilograms 3. Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab 4. TMA associated with a trigger (autoimmune disease, infection, solid organ transplant, drugs, and malignant hypertension) 5. Vaccinated against meningococcal infection (Neisseria meningitidis), within 3 years prior to, or at the time of, randomization. Participants who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics for at least 2 weeks after the vaccination. If participant cannot receive the meningococcal vaccine, then participant must be willing to receive antibiotic prophylaxis coverage against N. meningitidis during the entire Treatment Period and for 8 months following the final dose of study drug. Additional vaccination (Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae) may be considered based on individual patient condition.
Exclusion criteria
1. Any known gene mutation that causes atypical hemolytic uremic syndrome (aHUS) 2. Postpartum aHUS 3. Known chronic kidney disease 4. TMA due to hematopoietic stem cell transplantation ≤ 12 months of Screening 5. Primary and secondary glomerular diseases other than lupus 6. Diagnosis of primary antiphospholipid antibody syndrome 7. Shiga toxin-producing Escherichia coli infections including but not limited to Shiga toxin-related hemolytic uremic syndrome 8. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13' (ADAMTS13) deficiency (activity \< 5%) 9. Positive direct Coombs test which in the judgement of the Investigator is indicative of a clinically significant immune-mediated hemolysis not due to TMA 10. Clinical diagnosis of disseminated intravascular coagulation (DIC) in the judgement of the Investigator 11. Presence of sepsis requiring vasopressors within 7 days prior to or during Screening 12. Presence of monoclonal gammopathy including but not limited to multiple myeloma 13. Known bone marrow insufficiency or failure evidenced by cytopenias 14. Unresolved N. meningitidis infection 15. History of malignancy within 5 years of Screening with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence 16. Use of any complement inhibitors within the past 3 years 17. Respiratory failure requiring mechanical ventilation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26 | Week 26 | TMA response required the following: 1) Normalization of platelet count without transfusion support during the prior 7 days. 2) Normalization of LDH. 3) Improvement in glomerular filtration rate (eGFR) of \>= 30% compared to baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Complete TMA Response | Baseline through Week 26 | The Kaplan-Meier estimate of time to event of complete TMA response is reported. TMA response required the following: 1) Normalization of platelet count without transfusion support during the prior 7 days. 2) Normalization of LDH. 3) Improvement in eGFR of \>= 30% compared to baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. Participants who did not have a response were censored at the date of last visit or study discontinuation at the time when the analysis was performed. |
| Number of Participants With Hematologic Response at Week 26 | Week 26 | Hematologic response required the following: (1) Normalization of platelet count without transfusion support during the prior 7 days, and (2) normalization of LDH. |
| Number of Participants With Renal Response at Week 26 | Week 26 | Renal response is improvement in eGFR of \>= 30% compared to baseline. If a participant is on dialysis ≤5 days prior to the date of eGFR assessment, the eGFR will be set to 10 milliliter/minute/1.73 meter square (mL/min/1.73 m\^2) for that assessment. If a participant is on dialysis during the entire 26 week randomized Treatment Period, or through early discontinuation of study drug, then the change in eGFR was not calculated. |
| Number of Participants On Dialysis at Week 26 | Week 26 | — |
| Change From Baseline in eGFR at Week 26 | Baseline, Week 26 | If a participant is on dialysis during the entire 26 week randomized Treatment Period, or through early discontinuation of study drug, then the change in eGFR was not calculated. |
Countries
Belgium, Brazil, Canada, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ravulizumab Participants received weight-based dosages of ravulizumab for 26 weeks during the Initial Treatment Period. Participants received a loading dose of ravulizumab intravenously on Day 1, followed by maintenance dosing on Day 15 and once every 8 weeks thereafter. | 9 |
| Placebo Participants received weight-based dosages of placebo matched to ravulizumab for 26 weeks during the Initial Treatment Period. Participants received a loading dose of placebo matched to ravulizumab intravenously on Day 1, followed by maintenance dosing on Day 15 and once every 8 weeks thereafter. | 7 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 0 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 1 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Ravulizumab |
|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 17.7 | 52.4 years STANDARD_DEVIATION 16.77 | 48.2 years STANDARD_DEVIATION 15.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 9 | 0 / 7 |
| other Total, other adverse events | 9 / 9 | 7 / 7 |
| serious Total, serious adverse events | 6 / 9 | 3 / 7 |
Outcome results
Primary
Number of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26
TMA response required the following: 1) Normalization of platelet count without transfusion support during the prior 7 days. 2) Normalization of LDH. 3) Improvement in glomerular filtration rate (eGFR) of \>= 30% compared to baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, and any measurement in between.
Time frame: Week 26
Population: The Modified Intent-to-Treat Analysis Set included all randomized participants, excluding participants who enrolled prior to availability of ST-HUS and ADAMTS13 central laboratory results and were subsequently found to be ineligible after randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ravulizumab | Number of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26 | 2 Participants |
| Placebo | Number of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26 | 3 Participants |
Secondary
Change From Baseline in eGFR at Week 26
If a participant is on dialysis during the entire 26 week randomized Treatment Period, or through early discontinuation of study drug, then the change in eGFR was not calculated.
Time frame: Baseline, Week 26
Population: The Modified Intent-to-Treat Analysis Set included all randomized participants, excluding participants who enrolled prior to availability of ST-HUS and ADAMTS13 central laboratory results and were subsequently found to be ineligible after randomization. Here, Number of Participants analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline in eGFR at Week 26 | 25.8 milliliter/minute/1.73 meter^2 | Standard Deviation 19.9 |
| Placebo | Change From Baseline in eGFR at Week 26 | 17.5 milliliter/minute/1.73 meter^2 | Standard Deviation 7.59 |
Secondary
Number of Participants On Dialysis at Week 26
Time frame: Week 26
Population: The Modified Intent-to-Treat Analysis Set included all randomized participants, excluding participants who enrolled prior to availability of ST-HUS and ADAMTS13 central laboratory results and were subsequently found to be ineligible after randomization. Here, Number of Participants analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ravulizumab | Number of Participants On Dialysis at Week 26 | 1 Participants |
| Placebo | Number of Participants On Dialysis at Week 26 | 0 Participants |
Secondary
Number of Participants With Hematologic Response at Week 26
Hematologic response required the following: (1) Normalization of platelet count without transfusion support during the prior 7 days, and (2) normalization of LDH.
Time frame: Week 26
Population: The Modified Intent-to-Treat Analysis Set included all randomized participants, excluding participants who enrolled prior to availability of ST-HUS and ADAMTS13 central laboratory results and were subsequently found to be ineligible after randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ravulizumab | Number of Participants With Hematologic Response at Week 26 | 5 Participants |
| Placebo | Number of Participants With Hematologic Response at Week 26 | 6 Participants |
Secondary
Number of Participants With Renal Response at Week 26
Renal response is improvement in eGFR of \>= 30% compared to baseline. If a participant is on dialysis ≤5 days prior to the date of eGFR assessment, the eGFR will be set to 10 milliliter/minute/1.73 meter square (mL/min/1.73 m\^2) for that assessment. If a participant is on dialysis during the entire 26 week randomized Treatment Period, or through early discontinuation of study drug, then the change in eGFR was not calculated.
Time frame: Week 26
Population: The Modified Intent-to-Treat Analysis Set included all randomized participants, excluding participants who enrolled prior to availability of ST-HUS and ADAMTS13 central laboratory results and were subsequently found to be ineligible after randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ravulizumab | Number of Participants With Renal Response at Week 26 | 4 Participants |
| Placebo | Number of Participants With Renal Response at Week 26 | 4 Participants |
Secondary
Time to Complete TMA Response
The Kaplan-Meier estimate of time to event of complete TMA response is reported. TMA response required the following: 1) Normalization of platelet count without transfusion support during the prior 7 days. 2) Normalization of LDH. 3) Improvement in eGFR of \>= 30% compared to baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. Participants who did not have a response were censored at the date of last visit or study discontinuation at the time when the analysis was performed.
Time frame: Baseline through Week 26
Population: The Modified Intent-to-Treat Analysis Set included all randomized participants, excluding participants who enrolled prior to availability of ST-HUS and ADAMTS13 central laboratory results and were subsequently found to be ineligible after randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ravulizumab | Time to Complete TMA Response | NA days |
| Placebo | Time to Complete TMA Response | NA days |