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Safety and Tolerability Study of E-WE Thrombin in Healthy Adult Subjects

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ClinicalTrials.gov Identifier: NCT03453060
Recruitment Status : Completed
First Posted : March 5, 2018
Last Update Posted : January 9, 2019
Sponsor:
Information provided by (Responsible Party):
Aronora, Inc.

Brief Summary:
The purpose of this study is to assess the safety, tolerability and pharmacodynamics of a single iv dose of E-WE Thrombin in healthy adult subjects.

Condition or disease Intervention/treatment Phase
Thrombosis Drug: E-WE Thrombin Other: placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1, Single Ascending Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of E-WE Thrombin as an Intravenous Bolus in Healthy Adult Subjects
Actual Study Start Date : May 30, 2018
Actual Primary Completion Date : November 25, 2018
Actual Study Completion Date : November 25, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Clots

Arm Intervention/treatment
Experimental: E-WE Thrombin Drug: E-WE Thrombin
E-WE Thrombin specified dose on specified day administered as a single intravenous injection

Placebo Comparator: Placebo Other: placebo
placebo specified dose on specified day administered as a single intravenous injection




Primary Outcome Measures :
  1. The number of subjects with treatment-emergent adverse events (TEAEs) and the number of TEAEs will be summarized using frequency counts. [ Time Frame: one month ]
    TEAEs will be determined by symptom driven physical examinations that can include assessment of the skin, head, ears, eyes, nose, throat, respiratory system, cardiovascular system, gastrointestinal system, neurological condition, blood and lymphatic systems, and the musculoskeletal system.

  2. The number of subjects with clinically significant changes in body temperature, frequency, and relation to treatment will be assessed. [ Time Frame: two days ]
    Body temperature will be measured in degrees Celsius.

  3. The number of subjects with clinically significant changes in respiratory rate, frequency, and relation to treatment will be assessed. [ Time Frame: two days ]
    Respiratory rate will be measured in breaths per minute.

  4. The number of subjects with clinically significant changes in blood pressure (systolic and diastolic), frequency, and relation to treatment will be assessed. [ Time Frame: two days ]
    Systolic and diastolic blood pressure will be measured in mmHg.

  5. The number of subjects with clinically significant changes in heart rate, frequency, and relation to treatment will be assessed. [ Time Frame: two days ]
    Heart rate will be measured in beats per minute.

  6. The number of subjects with abnormal electrocardiogram and frequency and/ or adverse events that are related to treatment. [ Time Frame: two days ]
    12-lead electrocardiogram measurement.

  7. The number of subjects with clinically significant changes in activated partial thromboplastin time (aPTT), frequency, and relation to treatment will be assessed as part of a standard coagulation panel. [ Time Frame: one month ]
    Plasma aPTT will be measured in seconds.

  8. The number of subjects with clinically significant changes in prothrombin time, frequency, and relation to treatment will be assessed as part of a standard coagulation panel. [ Time Frame: one month ]
    Prothrombin time will be measured in seconds.

  9. The number of subjects with clinically significant changes in thrombin time, frequency, and relation to treatment will be assessed as part of a standard coagulation panel. [ Time Frame: one month ]
    Thrombin time will be measured in seconds.

  10. The number of subjects with clinically significant changes in plasma fibrinogen, frequency, and relation to treatment will be assessed as part of a standard coagulation panel. [ Time Frame: one month ]
    Plasma fibrinogen levels will be measured in mg/dL.

  11. The number of subjects with injection site reaction and/ or adverse events that are related to treatment. [ Time Frame: two days ]
    Injection site reaction assessment (pain, tenderness, erythema/ redness, and induration/ swelling.

  12. The number of subjects that develop treatment-related immunogenicity. [ Time Frame: one month ]
    Immunogenicity measured by plasma anti-drug antibodies.

  13. The number of subjects with clinically significant changes in blood urea nitrogen levels (BUN) as part of a standard serum chemistry panel, frequency, and relation to treatment will be assessed. [ Time Frame: two days ]
    BUN levels in the blood will be measured in mg/dL.

  14. The number of subjects with clinically significant changes in bilirubin (total and direct) levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    Bilirubin (total and direct) levels in the blood will be measured in mg/dL.

  15. The number of subjects with clinically significant changes in alkaline phosphatase levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    Alkaline phosphatase levels in the blood will be measured in U/L.

  16. The number of subjects with clinically significant changes in aspartate aminotransferase (AST) levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    AST levels in the blood will be measured in U/L.

  17. The number of subjects with clinically significant changes in alanine aminotransferase (ALT) levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    ALT levels in the blood will be measured in U/L.

  18. The number of subjects with clinically significant changes in lactate dehydrogenase (LDH) levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    LDH levels in the blood will be measured in U/L.

  19. The number of subjects with clinically significant changes in albumin levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days. ]
    Albumin levels in the blood will be measured in g/dL.

  20. The number of subjects with clinically significant changes in sodium levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    Sodium levels will be measured in mEq/L.

  21. The number of subjects with clinically significant changes in potassium levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    Potassium levels will be measured in mEq/L.

  22. The number of subjects with clinically significant changes in chloride levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    Chloride levels will be measured in mEq/L.

  23. The number of subjects with clinically significant changes in bicarbonate levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    Bicarbonate levels will be measured in mEq/L.

  24. The number of subjects with clinically significant changes in glucose levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    Blood glucose levels will be measured in mg/dL.

  25. The number of subjects with clinically significant changes in creatinine levels, frequency, and relation to treatment will be assessed as part of a standard serum chemistry panel. [ Time Frame: two days ]
    Creatinine levels will be measured in mg/dL.

  26. The number of subjects with clinically significant changes in hemoglobin levels, frequency, and relation to treatment will be assessed as part of a standard hematology panel. [ Time Frame: two days ]
    Hemoglobin levels will be measured in g/dL.

  27. The number of subjects with clinically significant changes in hematocrit levels, frequency, and relation to treatment will be assessed as part of a standard hematology panel. [ Time Frame: two days ]
    Hematocrit levels will be measured in %.

  28. The number of subjects with clinically significant changes in total leukocyte counts, frequency, and relation to treatment will be assessed as part of a standard hematology panel. [ Time Frame: two days. ]
    Total leukocyte counts will be measured in 10˄3/uL.

  29. The number of subjects with clinically significant changes in differential leukocyte counts, frequency, and relation to treatment will be assessed as part of a standard hematology panel. [ Time Frame: two days. ]
    Differential leukocyte counts will be measured in %.

  30. The number of subjects with clinically significant changes in red blood cell count, frequency, and relation to treatment will be assessed as part of a standard hematology panel. [ Time Frame: two days ]
    Red blood cell count will be measured in 10˄6/uL.

  31. The number of subjects with clinically significant changes in platelet count, frequency, and relation to treatment will be assessed as part of a standard hematology panel. [ Time Frame: two days ]
    Platelet count will be measured in 10˄3/uL.

  32. The number of subjects with clinically significant changes in urine pH, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    pH of the urine will be measured.

  33. The number of subjects with clinically significant changes in urine specific gravity, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Specific gravity of the urine will be evaluated.

  34. The number of subjects with clinically significant changes in urine protein levels, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Protein levels in the urine will be evaluated.

  35. The number of subjects with clinically significant changes in urine glucose levels, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Glucose levels in the urine will be evaluated.

  36. The number of subjects with clinically significant changes in urine ketone levels, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Ketone levels in the urine will be evaluated.

  37. The number of subjects with clinically significant changes in urine bilirubin levels, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Bilirubin levels in the urine will be evaluated.

  38. The number of subjects with clinically significant changes in urine blood levels, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Blood levels in the urine will be evaluated.

  39. The number of subjects with clinically significant changes in urine nitrite levels, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Nitrite levels in the urine will be evaluated.

  40. The number of subjects with clinically significant changes in urine urobilinogen levels, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Urobilinogen levels in the urine will be evaluated.

  41. The number of subjects with clinically significant changes in urine leukocyte esterase levels, frequency, and relation to treatment will be assessed as part of a standard urinalysis panel. [ Time Frame: two days ]
    Leukocyte esterase levels in the urine will be evaluated


Secondary Outcome Measures :
  1. The effect of a single intravenous dose of E-WE Thrombin on generation of activated protein C- protein C inhibitor complexes (APC-PCI). [ Time Frame: two days ]
    Plasma APC-PCI levels will be measured in ng/mL.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy, adult, male and/or female (females of non-childbearing potential only), 18 to 55 years of age, inclusive, at screening.
  2. Continuous non-smoker, who has not used nicotine-containing products for at least 3 months prior to dosing, based on subject self-reporting.
  3. Body mass index (BMI) ≥ 18 and < 29 (kg/m2) at screening and weight between 50 and 125 kg (inclusive) at screening.
  4. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or electrocardiograms, as deemed by the PI or designee.
  5. A female must be of non childbearing potential and must have undergone one of the following sterilization procedures at least 6 months prior to dosing:

    • hysteroscopic sterilization;
    • bilateral tubal ligation or bilateral salpingectomy;
    • hysterectomy;
    • bilateral oophorectomy. or be postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status.
  6. A non vasectomized, male subject must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the dose of study drug. (No restrictions are required for a vasectomized male provided his vasectomy has been performed 4 months or more prior to dosing of study drug. A male who has been vasectomized less than 4 months prior to dosing must follow the same restrictions as a non vasectomized male).
  7. If male, must agree to not donate sperm from dosing until 90 days after dosing.
  8. Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the protocol.

Exclusion Criteria:

  1. Subject is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.
  2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the PI or designee.
  3. History of any illness that, in the opinion of the PI or designee, might confound the results of the study or poses an additional risk to the subject by their participation in the study.
  4. History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.
  5. Consumes 3 units or more of alcohol per day (e.g., 1 unit is equivalent to 240 mL of wine, 1 bottle of beer [12 oz.], or 1 shot of liquor [1 oz.]).
  6. History or presence of hypersensitivity or idiosyncratic reaction to the study drug and excipients or related compounds.
  7. History or presence of a disease or disorder, acquired or inherited, that is active, or could be reasonably expected to become active during the study, including but not limited to:

    • Hypersensitivity to ß-lactam / penicillin derivatives;
    • Bleeding and blood coagulation disorders, including stroke, hemophilias, thrombophilias, or heparin-induced thrombocytopenia;
    • Ischemic disorders, including stroke, heart attack, coronary artery disease;
    • Gastrointestinal disorders, including gastrointestinal bleeds, gallstones, ulcers, diseases or dysfunction of the liver and excluding appendectomy and/or cholecystectomy;
    • Genitourinary disorders, including renal disease;
    • Cardiovascular disorders, including aneurysms, vasculitis;
    • All conditions that are associated with taking medications for pain;
    • Infection of any organ or system within 30 days of dosing;
    • Malignant and cancerous neoplasms of any organ or system;
    • Psychiatric and behavioral disorders;
    • A clinically significant hematological disorder of any type;
    • Inflammation and inflammatory diseases of any organ system.
  8. Females of childbearing potential.
  9. Females who are pregnant or who are lactating.
  10. Positive urine drug or alcohol results at screening or check in.
  11. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV).
  12. Supine blood pressure is less than 90/50 mmHg or greater than 140/90 mmHg at screening.
  13. Supine heart rate is lower than 40 bpm or higher than 99 bpm at screening.
  14. QTcF interval > 450 msec for males or > 460 msec for females, or history of prolonged QT syndrome at screening.
  15. Estimated creatinine clearance < 90 mL/minutes at screening using the Cockcroft Gault estimation.
  16. Unable to refrain from or anticipates the use of:

    • Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements beginning approximately 14 days prior to dosing and throughout the study.
    • Any oral or injectable anticoagulant (e.g., warfarin, heparin, low molecular weight heparin, etc.), coagulants (aprotinin, tranexamic acid, epsilon‐aminocaproic acid, and aminomethylbenzoic acid), anti-platelet (e.g., clopidogrel), nonsteroidal anti-inflammatory drugs (NSAIDs) and/or acetylsalicylic acid (ASA) beginning approximately 10 days prior to dosing and throughout the study.
    • Any drugs known to be significant inducers of cytochrome P-450 enzymes and/or P glycoprotein, including St. John's Wort, for 28 days prior to dosing and throughout the study.

    Appropriate sources (e.g., Flockhart TableTM) will be consulted to confirm lack of pharmacokinetic/ pharmacodynamic interaction with study medication. Acetaminophen (up to 2 g per 24 hour period) or any other treatment of an adverse event, drug related or not, and considered appropriate and allowable by the PI or designee may be permitted after dosing.

  17. Has been on a diet incompatible with the on study diet, in the opinion of the PI or designee, within the 30 days prior to dosing and throughout the study.
  18. Has participated in strenuous exercise or physical activity within 72 hours prior to Day 1, unless deemed acceptable by the PI or designee.
  19. Donation of blood or significant blood loss within 56 days prior to dosing.
  20. Plasma donation within 7 days prior to dosing.
  21. Has been hospitalized within 2 months of Day -1.
  22. Participation in another clinical study within 30 days prior to dosing. The 30-day window will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of the current study.
  23. Surgery within the past 90 days prior to dosing which in the opinion of the PI or designee is clinically relevant.
  24. Presence of any scars, or tattoos which may obscure the injection site, as deemed by PI or designee.
  25. Any condition or circumstance, in the opinion of the PI or designee, which may make the subject unlikely to complete the study or comply with study procedures and requirements, or may pose a risk to the subject's safety.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03453060


Locations
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United States, Arizona
Celerion
Tempe, Arizona, United States, 85283
Sponsors and Collaborators
Aronora, Inc.
Investigators
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Principal Investigator: Danielle Armas, MD Celerion

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Responsible Party: Aronora, Inc.
ClinicalTrials.gov Identifier: NCT03453060     History of Changes
Other Study ID Numbers: EWE-17-01
First Posted: March 5, 2018    Key Record Dates
Last Update Posted: January 9, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Thrombosis
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Thrombin
Hemostatics
Coagulants