Atypical Hemolytic Uremic Syndrome, Thrombotic Microangiopathies
Conditions
Keywords
TMA, aHUS
Brief summary
The purpose of this study is to evaluate the platelet count change from baseline and safety of OMS721 (narsoplimab) in adults and adolescents with atypical hemolytic uremic syndrome (aHUS). The study will also evaluate pharmacokinetics (PK), pharmacodynamics (PD), and anti-drug antibody response (ADA).
Detailed description
This is a Phase 3, uncontrolled, open-label study to evaluate the effect of OMS721 in subjects with aHUS. The primary outcome to be measured is platelet count change from baseline. The secondary outcomes to be measured are other efficacy measures, safety, PK, PD, and immunogenicity (i.e., presence of anti-drug antibody \[ADA\] response. Subjects with plasma therapy-resistant aHUS and plasma therapy-responsive aHUS will be eligible. The efficacy endpoints, including the primary efficacy endpoint, may not be relevant for plasma therapy-responsive subjects because these subjects may enter the study with normal markers of aHUS activity due to successful treatment with plasma therapy. Therefore, efficacy analyses will be performed separately in the plasma therapy-resistant and plasma therapy responsive subjects. The principal efficacy analyses will be the analyses in the plasma therapy resistant cohort and efficacy analyses of the plasma therapy-responsive cohort will be supportive. Safety analyses will be conducted in all subjects.
Interventions
BIOLOGICALOMS721 (narsoplimab)
Intravenous loading dose followed by daily subcutaneous injections
Sponsors
Omeros Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Are age \>= 12 years old at screening (Visit 1). 2. Have a primary aHUS, diagnosed clinically, and have ADAMTS13 activity \> 5% in plasma. Participants are eligible with or without a documented complement mutation or anti-CFH antibody. Participants are categorized according to their response to plasma therapy (plasma exchange or plasma infusion): * Plasma therapy-resistant aHUS participants must have all of the following: * Screening platelet count \< 150,000/μL despite at least four plasma therapy treatments in a 7-day period prior to screening * Evidence of microangiopathic hemolysis (at least one of: 1. presence of schistocytes, 2. serum LDH \> 1.5 times upper limit of normal (ULN), and 3. haptoglobin \< LLN) * Serum creatinine \> ULN * Plasma therapy-responsive aHUS participants must have all of the following: * Have a documented history of requiring plasma therapy to prevent aHUS exacerbation defined as all of the following: * decrease in platelet count \> 25% when plasma therapy frequency has been decreased (including discontinuation of plasma therapy) * LDH \> 1.5 times ULN when plasma therapy frequency has been decreased (including discontinuation of plasma therapy) * Have received plasma therapy at least once every 2 weeks at an unchanged frequency for at least 8 weeks before first dose of OMS721 3. If sexually active and of childbearing potential, must agree to practice a highly effective method of birth control until the end of the study, defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner. 4. Do not have access to eculizumab treatment, have not derived therapeutic benefit from eculizumab treatment, or have not been able to tolerate eculizumab treatment.
Exclusion criteria
1. Have STEC-HUS. 2. Have a positive direct Coombs test. 3. Have a history of hematopoietic stem cell transplant. 4. Have HUS from an identified drug. 5. History of vitamin B12 deficiency-related HUS. 6. History of Systemic Lupus Erythematosus. 7. History of antiphospholipid syndrome. 8. Active cancer or history of cancer (except non-melanoma skin cancers) within 5 years of screening. 9. Have been on hemodialysis or peritoneal dialysis for ≥ 12 weeks. 10. Have an active systemic bacterial or fungal infection requiring systemic antimicrobial therapy (prophylactic antimicrobial therapy administered as standard of care is allowed). 11. Baseline resting heart rate \< 45 beats per minute or \> 115 beats per minute. 12. Baseline QTcF \> 470 milliseconds. 13. Have malignant hypertension (diastolic blood pressure \[BP\] \> 120 mm Hg with bilateral hemorrhages or cotton-wool exudates on funduscopic examination). 14. Have a poor prognosis with a life expectancy of less than three months in the opinion of the Investigator. 15. Are pregnant or lactating. 16. Have received treatment with an investigational drug or device within four weeks of the screening visit. 17. Have abnormal liver function tests defined as ALT or AST \> five times ULN. 18. Have HIV infection. 19. History of cirrhosis of the liver. 20. Are an employee of Omeros, an Investigator, a study staff member, or their immediate family member. 21. Have a known hypersensitivity to any constituent of the product. 22. Presence of any condition that the Investigator believes would put the subject at risk or confound the interpretation of the data. 23. Have previously completed treatment in an OMS721study. 24. Have received intravenous immunoglobulin (IVIG) treatment within 8 weeks of screening visit. 25. Have received rituximab within 24 weeks of screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Count (10^9 Platelets/L) Change From Baseline at Week 26 | Week 26 | The primary outcome to be measured is platelet count change from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Thrombotic Microangiopathies (TMA) Response | 26 weeks | Complete TMA response defined as normalization of platelet count, normalization of serum lactate dehydrogenase (LDH), and \> 25% decrease in serum creatinine by at least 2 consecutive measures over at least 4 consecutive weeks, within the initial 26-week period |
| TMA Event-free Status | 26 weeks | No decrease in platelet count of \> 25% from baseline, no plasma exchange or plasma infusion, and no initiation of new dialysis over at least 12 consecutive weeks, within the initial 26-week period |
| Increase in Estimated Glomerular Filtration Rate (eGFR) | 26 weeks | Increase of greater than 15 ml/min/1.73 m2 in eGFR calculated by the modification of diet in renal disease (MDRD) Equation |
| Hematological Normalization | 26 weeks | Normalization of platelet count and normalization of serum LDH by 2 consecutive measurements over at least 4 weeks, within the initial 26-week period |
| TMA Remission | 26 weeks | Platelet count greater than or equal to 150,000/μL on at least 2 consecutive measures over at least 2 consecutive weeks, within the initial 26-week period |
| Incidence of Antidrug Antibodies (ADA) | 771 days post-dose | Incidences of ADA in participants with aHUS, administered OMS721 (narsoplimab) |
| Change From Baseline in Serum Creatinine (mg/dL) | 26 weeks | Assessment of subject's change from baseline in serum creatinine. |
| Safety as Measured by Incidences of Adverse Events, Vital Signs, ECG, and Clinical Laboratory Tests | Pre-dose and up to 771 days post-dose | Assessment of safety of OMS721 (narsoplimab) in participants with aHUS by incidence of Adverse Events, clinically significant vital sign abnormalities, ECG abnormalities, and clinical laboratory test abnormalities |
| Change From Baseline in Haptoglobin (mg/dL) | 26 weeks | Assessment of subject's change from baseline in haptoglobin |
| Pharmacokinetics (PK): Trough Plasma Concentration, Lower Limit of Quantification (LLOQ) | Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (RT) (if occurs): RT Days 1-4; Follow-Up at Day 771 | Pharmacokinetics (PK): Trough plasma concentration, lower limit of quantification (LLOQ) |
| Pharmacokinetics (PK): Maximum Plasma Concentrations (Cmax) | Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771 | Pharmacokinetics (PK): Maximum plasma concentrations (Cmax) |
| Pharmacokinetics (PK): Area Under Time-concentration Curve (AUC) | Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771 | Pharmacokinetics (PK): Area under time-concentration curve (AUC) |
| Pharmacodynamics (PD): Inhibition of C3 Activity (%) | Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771 | Pharmacodynamics (PD): Inhibition of C3 activity |
| Pharmacodynamics (PD): Inhibition of C4 Activity (%) | Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771 | Pharmacodynamics (PD): Inhibition of C4 activity |
| Change From Baseline in Serum LDH (U/L) | 26 weeks | Assessment of subject's change from baseline in serum LDH |
Countries
Lithuania, Poland, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OMS721 (Narsoplimab) Administration of OMS721 (narsoplimab)
OMS721 (narsoplimab): Intravenous loading dose followed by daily subcutaneous injections | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Protocol Violation | 2 |
Baseline characteristics
| Characteristic | OMS721 (Narsoplimab) | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 6 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Lithuania | 3 participants | — |
| Region of Enrollment Poland | 3 participants | — |
| Sex: Female, Male Female | 5 Participants | — |
| Sex: Female, Male Male | 1 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 5 / 6 |
Outcome results
Primary
Platelet Count (10^9 Platelets/L) Change From Baseline at Week 26
The primary outcome to be measured is platelet count change from baseline.
Time frame: Week 26
Population: Any patent who received drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OMS721 (Narsoplimab) | Platelet Count (10^9 Platelets/L) Change From Baseline at Week 26 | 42 10^9 platelets/L |
Secondary
Change From Baseline in Haptoglobin (mg/dL)
Assessment of subject's change from baseline in haptoglobin
Time frame: 26 weeks
Population: Any patient who received drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OMS721 (Narsoplimab) | Change From Baseline in Haptoglobin (mg/dL) | 30 mg/dL |
Secondary
Change From Baseline in Serum Creatinine (mg/dL)
Assessment of subject's change from baseline in serum creatinine.
Time frame: 26 weeks
Population: Any patient who received drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OMS721 (Narsoplimab) | Change From Baseline in Serum Creatinine (mg/dL) | 1.53 mg/dL |
Secondary
Change From Baseline in Serum LDH (U/L)
Assessment of subject's change from baseline in serum LDH
Time frame: 26 weeks
Population: Any patient who received drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OMS721 (Narsoplimab) | Change From Baseline in Serum LDH (U/L) | -12 U/L |
Secondary
Hematological Normalization
Normalization of platelet count and normalization of serum LDH by 2 consecutive measurements over at least 4 weeks, within the initial 26-week period
Time frame: 26 weeks
Population: Any patient who received drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OMS721 (Narsoplimab) | Hematological Normalization | 1 Participants |
Secondary
Incidence of Antidrug Antibodies (ADA)
Incidences of ADA in participants with aHUS, administered OMS721 (narsoplimab)
Time frame: 771 days post-dose
Population: Any patient who received drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OMS721 (Narsoplimab) | Incidence of Antidrug Antibodies (ADA) | 1 Participants |
Secondary
Increase in Estimated Glomerular Filtration Rate (eGFR)
Increase of greater than 15 ml/min/1.73 m2 in eGFR calculated by the modification of diet in renal disease (MDRD) Equation
Time frame: 26 weeks
Population: Any patient who received drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OMS721 (Narsoplimab) | Increase in Estimated Glomerular Filtration Rate (eGFR) | 0 Participants |
Secondary
Pharmacodynamics (PD): Inhibition of C3 Activity (%)
Pharmacodynamics (PD): Inhibition of C3 activity
Time frame: Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771
Population: Any patient who received drug and measurable C3 activity.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OMS721 (Narsoplimab) | Pharmacodynamics (PD): Inhibition of C3 Activity (%) | 84.4 Inhibition of C3 activity (%) |
Secondary
Pharmacodynamics (PD): Inhibition of C4 Activity (%)
Pharmacodynamics (PD): Inhibition of C4 activity
Time frame: Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771
Population: Any patient who received drug and measurable C4 activity.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OMS721 (Narsoplimab) | Pharmacodynamics (PD): Inhibition of C4 Activity (%) | 91.9 Inhibition of C4 activity (%) |
Secondary
Pharmacokinetics (PK): Area Under Time-concentration Curve (AUC)
Pharmacokinetics (PK): Area under time-concentration curve (AUC)
Time frame: Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771
Population: PK modeling for calculating the AUC was not performed because the study was not completed.
Secondary
Pharmacokinetics (PK): Maximum Plasma Concentrations (Cmax)
Pharmacokinetics (PK): Maximum plasma concentrations (Cmax)
Time frame: Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771
Population: The observed Cmax values on the 6 patients have been provided.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OMS721 (Narsoplimab) | Pharmacokinetics (PK): Maximum Plasma Concentrations (Cmax) | 48350 ng/mL |
Secondary
Pharmacokinetics (PK): Trough Plasma Concentration, Lower Limit of Quantification (LLOQ)
Pharmacokinetics (PK): Trough plasma concentration, lower limit of quantification (LLOQ)
Time frame: Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (RT) (if occurs): RT Days 1-4; Follow-Up at Day 771
Population: Pharmacokinetics trough plasma concentrations are provided on the pre-dose levels for the six patients enrolled.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OMS721 (Narsoplimab) | Pharmacokinetics (PK): Trough Plasma Concentration, Lower Limit of Quantification (LLOQ) | 15477.2 ng/mL | Standard Deviation 6471.62 |
Secondary
Safety as Measured by Incidences of Adverse Events, Vital Signs, ECG, and Clinical Laboratory Tests
Assessment of safety of OMS721 (narsoplimab) in participants with aHUS by incidence of Adverse Events, clinically significant vital sign abnormalities, ECG abnormalities, and clinical laboratory test abnormalities
Time frame: Pre-dose and up to 771 days post-dose
Population: The safety population includes all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OMS721 (Narsoplimab) | Safety as Measured by Incidences of Adverse Events, Vital Signs, ECG, and Clinical Laboratory Tests | 6 Participants |
Secondary
Thrombotic Microangiopathies (TMA) Response
Complete TMA response defined as normalization of platelet count, normalization of serum lactate dehydrogenase (LDH), and \> 25% decrease in serum creatinine by at least 2 consecutive measures over at least 4 consecutive weeks, within the initial 26-week period
Time frame: 26 weeks
Population: Any patient who received drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OMS721 (Narsoplimab) | Thrombotic Microangiopathies (TMA) Response | 0 Participants |
Secondary
TMA Event-free Status
No decrease in platelet count of \> 25% from baseline, no plasma exchange or plasma infusion, and no initiation of new dialysis over at least 12 consecutive weeks, within the initial 26-week period
Time frame: 26 weeks
Population: Any patient who received drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OMS721 (Narsoplimab) | TMA Event-free Status | 2 Participants |
Secondary
TMA Remission
Platelet count greater than or equal to 150,000/μL on at least 2 consecutive measures over at least 2 consecutive weeks, within the initial 26-week period
Time frame: 26 weeks
Population: Any patient who received drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OMS721 (Narsoplimab) | TMA Remission | 2 Participants |