Safety and Efficacy Study of OMS721 in Patients With Atypical Hemolytic Uremic Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the platelet count change from baseline and safety of OMS721 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
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This is a Phase 3, multicenter study of OMS721 in adults and adolescents with atypical hemolytic uremic syndrome (aHUS). The uncontrolled, open-label study will evaluate the effect of OMS721 in subjects with plasma therapy-resistant aHUS and plasma therapy-responsive aHUS. This study has four periods: Screening, Treatment Induction, Treatment Maintenance, and Follow-up. Approximate enrollment is 80 subjects. An interim analysis will be performed after 40 subjects have completed 26 weeks of treatment for potential registration.

Official Title
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A Phase 3 Study to Evaluate the Safety and Efficacy of OMS721 for the Treatment of Atypical Hemolytic Uremic Syndrome (aHUS) in Adults and Adolescents

Conditions
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Thrombotic Microangiopathies, Atypical Hemolytic Uremic Syndrome

Intervention / Treatment
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* Biological: OMS721


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Competent to provide informed consent, or if a minor, have at least one parent or legal guardian to provide informed consent with written assent from the subject. Are at least 12 years old at screening (Visit 1). Have a clinically diagnosis of primary atypical hemolytic uremic syndrome (aHUS), with ADAMTS13 activity greater than 5% in plasma. Plasma therapy-resistant aHUS patients must have a screening platelet count less than 150,000/uL, evidence of microangiopathic hemolysis, and serum creatinine greater than upper limit of normal. Plasma therapy-responsive aHUS patients must have documented history of requiring plasma therapy to prevent aHUS exacerbation and received plasma therapy at least once every 2 weeks at an unchanged frequency for at least 8 weeks before first dose of OMS721. Exclusion Criteria: Have STEC-HUS, a direct positive Coombs test, history of hematopoietic stem cell transplant, and/or HUS from an identified drug. History of vitamin B12 deficiency-related HUS, systemic lupus erythematosus, and/or antiphospholipid syndrome. Active cancer or history of cancer (except non-melanoma skin cancers) within 5 years of screening. Have been on hemodialysis or peritoneal dialysis for greater than or equal to 12 weeks. Have an active systemic bacterial or fungal infection requiring systemic antimicrobial therapy (prophylactic antimicrobial therapy administered as standard of care is allowed). Baseline resting heart rate less than 45 beats per minute or greater than 115 beats per minute. Baseline QTcF greater than 470 milliseconds. Have malignant hypertension (diastolic blood pressure [BP] greater than 120 mm Hg with bilateral hemorrhages or cotton-wool exudates on funduscopic examination). Have a poor prognosis with a life expectancy of less than three months in the opinion of the Investigator. Are pregnant or lactating. Have received treatment with an investigational drug or device within four weeks prior to screening. Have abnormal liver function tests defined as ALT or AST > five times ULN. Have HIV infection. History of cirrhosis of the liver. Have previously completed treatment in an OMS721study.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OMS721<br>Administration of OMS721 | Biological: OMS721<br>* Intravenous loading dose followed by daily subcutaneous injections<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of OMS721 as measured by platelet count change from baseline | The effect of OMS721 will be evaluated in subjects with aHUS by changes in platelet count from baseline | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as measured by incidences of Adverse Events, vital signs, ECG, and clinical laboratory tests | Assessment of safety of OMS721 in subjects with aHUS by incidence of Adverse Events, clinically significant vital sign abnormalities, ECG abnormalities, and clinical laboratory test abnormalities | Pre-dose and up to 771 days post-dose | 
| TMA Response | Complete TMA response defined as normalization of platelet count, normalization of serum 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 | 26 weeks | 
| 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 | 26 weeks | 
| Increase in eGFR | Increase of greater than 15 ml/min/1.73 m2 in eGFR calculated by the MDRD Equation | 26 weeks | 
| Hematological Normalization | Normalization of platelet count and normalization of serum LDH by 2 consecutive measurements over at least 4 consecutive weeks, within the initial 26-week period | 26 weeks | 
| TMA Remission | Platelet count greater than or equal to 150,000/μL over at least 2 consecutive weeks, within the initial 26-week period | 26 weeks | 
| Incidence of antidrug antibodies (ADA) | Incidences of ADA in subjects with aHUS, administered OMS721 | 771 days post-dose | 
| Change from baseline in serum creatinine | Assessment of subject's change from baseline in serum creatinine | 26 weeks | 
| Change from baseline in serum LDH | Assessment of subject's change from baseline in serum LDH | 26 weeks | 
| Change from baseline in haptoglobin | Assessment of subject's change from baseline in haptoglobin | 26 weeks | 
| Pharmacokinetics (PK): Trough plasma concentration, lower limit of quantification (LLOQ) |  | 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) |  | 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) |  | 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 |  | 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 |  | Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TMA, aHUS