A study to investigate the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical activity of study drug OMS721 in adults with thrombotic microangiopathies.

Phase 1

Conditions: Three forms of thrombotic microangiopathies (TMA):- atypical hemolytic uremic syndrome (aHUS) - hematopoietic stem cell transplant (HSCT)-associated TMA- thrombotic thrombocytopenic purpura (TTP)
MedDRA version: 18.0Level: PTClassification code 10043645Term: Thrombotic microangiopathySystem Organ Class: 10005329 - Blood and lymphatic system disorders
Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Registration Number: EUCTR2014-001032-11-BE

Lead Sponsor: Omeros Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 89

Inclusion Criteria

1. Competent to provide informed consent.
2. Voluntarily provide informed consent in accordance with regulations and governing ethics committee requirements prior to any procedures or evaluations performed specifically for the sole purpose of the study.
3. Are age =18 at screening (Visit 1).
4. Have a diagnosis of TMA in accordance with one of the following three categories:
• Primary aHUS, diagnosed clinically and having ADAMTS13 activity >10% in plasma. Patients are eligible with or without a documented complement mutation or anti-CFH antibody. Patients are categorized according to their response to plasma therapy (plasma exchange or plasma infusion):
o Plasma therapy-resistant aHUS patients must have all of the following: 1) screening platelet count < 150,000/µL despite at least four plasma therapy treatments prior to screening; 2) evidence of microangiopathic hemolysis (presence of schistocytes, serum lactate dehydrogenase (LDH) > upper limit of normal (ULN), or haptoglobin < LLN); and 3) serum creatinine > ULN.
o Chronic plasma therapy-responsive aHUS patients (plasma therapy-sensitive) must require at least once-per-week plasma therapy for four weeks before first dose of OMS721 with serum creatinine >ULN.
• TTP defined as having all of the following:
o Platelet count < 150,000/µL
o Evidence of microangiopathic hemolysis (presence of schistocytes, serum LDH > ULN, or haptoglobin < LLN)
o ADAMTS13 activity = 10% during the current episode of TTP or historically
• Persistent HSCT-associated TMA defined as having all of the following at least two weeks following modification or discontinuation of calcineurin inhibitor treatment or at least 30 days after the transplant:
o Platelet count < 150,000/µL
o Evidence of microangiopathic hemolysis (presence of schistocytes, serum LDH > ULN, or haptoglobin < LLN)
o Renal dysfunction (doubling of serum creatinine from pre-transplant).
5. No clinically apparent alternative explanation for thrombocytopenia and anemia.
6. 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 70
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 19

Exclusion Criteria

Subjects will be excluded from the study for any of the following reasons:
1. Had eculizumab therapy within three months prior to screening.
2. Have STEC-HUS.
3. Have a positive direct Coombs test.
4. Have an active systemic bacterial or fungal infection requiring antimicrobial therapy (prophylactic antimicrobial therapy administered as standard of care is allowed).
5. Baseline resting heart rate < 45 beats per minute or > 115 beats per minute.
6. Baseline QTcF > 470 milliseconds.
7. Have malignant hypertension (diastolic blood pressure [BP] > 120 mm Hg with bilateral hemorrhages or cotton-wool” exudates on funduscopic examination).
8. Have a poor prognosis with a life expectancy of less than three months in the opinion of the investigator.
9. Are pregnant or lactating.
10. Have received treatment with an investigational drug or device within four weeks prior to screening.
11. Have abnormal liver function tests defined as ALT or AST > five times ULN.
12. Have a positive test for human immunodeficiency virus (HIV) antibodies.
13. Are an employee of Omeros, an investigator, a study staff member, or their immediate family member.
14. Have a known hypersensitivity to any constituent of the product.
15. Presence of any condition that the Investigator believes would put the subject at risk.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The co-primary objectives of this study are to:<br>• Assess the safety and tolerability of multiple-dose administration of OMS721 in subjects with TMA<br>• Evaluate the clinical activity of multiple-dose administration of OMS721 in subjects with TMA;Secondary Objective: • Determine the pharmacokinetics (PK) of multiple-dose administration of OMS721 in subjects with TMA<br>• Determine the pharmacodynamics (PD) of multiple-dose administration of OMS721 in subjects with TMA<br>• Determine the immunogenicity of multiple-dose administration of OMS721 in subjects with TMA;Primary end point(s): • Safety as assessed by AEs, vital signs, ECG and clinical laboratory tests<br>• Clinical activity as assessed by platelet count;Timepoint(s) of evaluation of this end point: from baseline across all evaluations/visits

Secondary Outcome Measures

Name	Time	Method
Timepoint(s) of evaluation of this end point: pre-dose, 5 min, 2 hours, 24 hours, 48 hours, 72 hours;Secondary end point(s): • TMA clinical activity<br> o Serum LDH<br> o Serum haptoglobin<br> o Hemoglobin<br> o Serum creatinine<br> o TMA-related symptoms<br> o Need for plasma therapy (plasma exchange or plasma infusion)<br> o Need for dialysis<br>• PK parameters including maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (t½), area under time-concentration curve (AUC), clearance (CL), and volume of distribution (Vz)<br>• PD measure of inhibition of ex vivo lectin pathway activation<br>• Presence of ADA response

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