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The purpose of this study is to evaluate the safety and immune system response to recombinant thrombin when used to control bleeding in spinal and vascular surgery.
This is a Phase 3b, open-label, single-group, multisite safety and immunogenicity study of recombinant thrombin (rThrombin) in participants who are at least 18 years of age and undergoing spinal or vascular surgery. Eligible participants will receive topical rThrombin during surgery and complete a 1-month follow-up visit.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Experimental | rThrombin |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rThrombin | Biological | 1000 U/mL applied directly or in combination with absorbable gelatin sponge or powder |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Anti-recombinant Thrombin (rThrombin) Product Antibodies at Day 29 in Participants With and Without Anti-bovine Thrombin Product Antibodies at Baseline | Seropositive=with specific anti-bovine thrombin product antibodies; seronegative=without specific anti-bovine thrombin product antibodies. | At Day 29 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs | AE=a new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may or may not have a causal relationship with treatment. SAE=an unfavorable medical event that results in death, persistent or significant incapacity, or drug dependency or abuse; is life-threatening, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=possibly, probably, or certainly related to study drug. Treatment-emergent=onset on or after treatment start. Grade (Gr) 1=mild, Gr 2=moderate, Gr 3=severe, Gr 4=life threatening/disabling, Gr 5=death. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Allan Alexander, MD, CPI | ZymoGenetics | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Huntington Memorial Hospital | Pasadena | California | 91105 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20980172 | Derived | Randleman CD Jr, Singla NK, Renkens KL, Souza S, Pribble JP, Alexander WA. Persistence of antibodies to the topical hemostat bovine thrombin. J Am Coll Surg. 2010 Dec;211(6):798-803. doi: 10.1016/j.jamcollsurg.2010.07.023. Epub 2010 Oct 25. | |
| 19651065 | Derived | Singla NK, Ballard JL, Moneta G, Randleman CD Jr, Renkens KL, Alexander WA. A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis. J Am Coll Surg. 2009 Jul;209(1):68-74. doi: 10.1016/j.jamcollsurg.2009.03.016. Epub 2009 May 28. |
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Of 234 participants enrolled, 209 received study drug. Of those who received study drug, 200 had both baseline and post-baseline immunogenicity evaluations.
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| ID | Title | Description |
|---|---|---|
| FG000 | rThrombin, 1000 IU/mL | Participants received at least 1 application of recombinant thrombin (rThrombin), 1000 IU/mL, during a single surgical procedure. rThrombin was applied, per investigator judgment and standard clinical practice, directly or in combination with an absorbable gelatin sponge or powder. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | rThrombin | Participants who received at least 1 application of rThrombin during spinal or vascular surgery (arterial reconstruction or PAB,or AV vascular access procedure and had seronegative baseline rThrombin antibody status |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Anti-recombinant Thrombin (rThrombin) Product Antibodies at Day 29 in Participants With and Without Anti-bovine Thrombin Product Antibodies at Baseline | Seropositive=with specific anti-bovine thrombin product antibodies; seronegative=without specific anti-bovine thrombin product antibodies. | Participants who received treatment with rThrombin and had results from both baseline and post-baseline antibody assessments | Posted | Number | Participants | At Day 29 |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | rThrombin, 1000 IU/mL | Participants received at least 1 application of recombinant thrombin (rThrombin), 1000 IU/mL, during a single surgical procedure. rThrombin was applied, per investigator judgment and standard clinical practice, directly or in combination with an absorbable gelatin sponge or powder. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial fibrillation | Cardiac disorders |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John Pribble, Vice President, Medical Affairs; Scot Maxon, Scientific Information | ZymoGenetics, a Bristol-Myers Squibb company | (206) 428-2756; (206) 434-3365 | John.Pribble@bms.com; Scot.Maxon@bms.com |
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| ID | Term |
|---|---|
| C513462 | recombinant human thrombin |
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| Day 1 (surgery) to Day 29 (end of study), continuously |
| Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Hemoglobin, low (g/L): Grade 2=<100 Grade 3=<80; Grade 4=<65. Platelets, low: Grade 2=<75*10^9/L; Grade 3=<50*10^9/L; Grade 4=<25*10^9/L. Leukocytes, low: Grade 2=<3.0-2.0*10^9/L; Grade 3=<2.0-1.0*10^9/L; Grade 4=<1.0*10^9/L. Lymphocytes, low: Grade 2=<0.8*10^9/L; Grade 3=<0.5*10^9/L; Grade 4=<0.2*10^9/L. Neutrophils, low: Grade 2=<1.5*10^9/L; Grade 3=<1.0*10^9/L; Grade 4=<0.5*10^9/L. Changes in hematocrit values observed were not graded for severity. | Baseline and Day 29 (end of study) |
| Number of Participants With Elevations in Coagulation Parameters of CTC Grade 3 or Higher at Baseline and Day 29 | Activated partial thromboplastin time (aPTT) elevations: Grade 3=>2*upper limit of normal (ULN). International normalized ratio(INR)elevations: Grade 3=>2*ULN. Changes in prothrombin time were not graded for toxicity. n=Number of participants with assessments available at that visit. | Baseline and Day 29 (end of study) |
| Number of Participants With Abnormal Laboratory Results in Median Levels of Immunoglobulin A, G, and M at Baseline or Day 29 | Abnormal laboratory findings were recorded as AEs when the investigator considered them to be clinically significant (eg, an unusual result for the surgical population or for an individual participant) or when they were associated with symptoms or required treatment or a change in patient management. | Baseline and Day 29 (end of study) |
| Number of Participants With Clinically Significant Changes in Mean Values for Vital Signs (Temperature, Systolic Blood Pressure, Diastolic Blood Pressure, Respiration Rate, Heart Rate) at Baseline and Day 29 | Laboratory findings considered clinically significant by investigator when associated with symptoms, required specific treatment, or required a change in participant management. Clinically significant changes in vital signs were reported as adverse events. | Baseline and Day 29 (end of study) |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs | AE=a new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may or may not have a causal relationship with treatment. SAE=an unfavorable medical event that results in death, persistent or significant incapacity, or drug dependency or abuse; is life-threatening, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=possibly, probably, or certainly related to study drug. Treatment-emergent=onset on or after treatment start. Grade (Gr) 1=mild, Gr 2=moderate, Gr 3=severe, Gr 4=life threatening/disabling, Gr 5=death. | All participants who received at least 1 application of rThrombin during surgery. | Posted | Number | Participants | Day 1 (surgery) to Day 29 (end of study), continuously |
|
|
|
| Secondary | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Hemoglobin, low (g/L): Grade 2=<100 Grade 3=<80; Grade 4=<65. Platelets, low: Grade 2=<75*10^9/L; Grade 3=<50*10^9/L; Grade 4=<25*10^9/L. Leukocytes, low: Grade 2=<3.0-2.0*10^9/L; Grade 3=<2.0-1.0*10^9/L; Grade 4=<1.0*10^9/L. Lymphocytes, low: Grade 2=<0.8*10^9/L; Grade 3=<0.5*10^9/L; Grade 4=<0.2*10^9/L. Neutrophils, low: Grade 2=<1.5*10^9/L; Grade 3=<1.0*10^9/L; Grade 4=<0.5*10^9/L. Changes in hematocrit values observed were not graded for severity. | All participants who who received at least 1 application of rThrombin during surgery and had laboratory test results available for baseline and Day 29 visits. | Posted | Number | Participants | Baseline and Day 29 (end of study) |
|
|
|
| Secondary | Number of Participants With Elevations in Coagulation Parameters of CTC Grade 3 or Higher at Baseline and Day 29 | Activated partial thromboplastin time (aPTT) elevations: Grade 3=>2*upper limit of normal (ULN). International normalized ratio(INR)elevations: Grade 3=>2*ULN. Changes in prothrombin time were not graded for toxicity. n=Number of participants with assessments available at that visit. | All participants who received at least 1 application of rThrombin during surgery and had laboratory test results available for assessment. | Posted | Number | Participants | Baseline and Day 29 (end of study) |
|
|
|
| Secondary | Number of Participants With Abnormal Laboratory Results in Median Levels of Immunoglobulin A, G, and M at Baseline or Day 29 | Abnormal laboratory findings were recorded as AEs when the investigator considered them to be clinically significant (eg, an unusual result for the surgical population or for an individual participant) or when they were associated with symptoms or required treatment or a change in patient management. | All participants who received rThrombin and had both baseline and postbaseline antibody assessments available. | Posted | Number | Participants | Baseline and Day 29 (end of study) |
|
|
|
| Secondary | Number of Participants With Clinically Significant Changes in Mean Values for Vital Signs (Temperature, Systolic Blood Pressure, Diastolic Blood Pressure, Respiration Rate, Heart Rate) at Baseline and Day 29 | Laboratory findings considered clinically significant by investigator when associated with symptoms, required specific treatment, or required a change in participant management. Clinically significant changes in vital signs were reported as adverse events. | All participants who received at least 1 application of rThrombin during surgery. | Posted | Number | Participants | Baseline and Day 29 (end of study) |
|
|
|
| 47 |
| 209 |
| 197 |
| 209 |
| Deep vein thrombosis | Vascular disorders |
|
| Hyperkaleamia | Metabolism and nutrition disorders |
|
| Myocardial infarction | Cardiac disorders |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders |
|
| Wound secretion | Injury, poisoning and procedural complications |
|
| Cardiac failure congestive | Cardiac disorders |
|
| Hematoma | Vascular disorders |
|
| Nausea | Gastrointestinal disorders |
|
| Postoperative wound infection | Infections and infestations |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders |
|
| Renal failure | Renal and urinary disorders |
|
| Wound dehiscence | Injury, poisoning and procedural complications |
|
| Abdominal wall hematoma | Gastrointestinal disorders |
|
| Acute polyneuropathy | Nervous system disorders |
|
| Anemia | Blood and lymphatic system disorders |
|
| Arteriovenous fistual occlusion | Injury, poisoning and procedural complications |
|
| Arteriovenous fistula site complication | Injury, poisoning and procedural complications |
|
| Arteriovenous fistula site haematoma | Injury, poisoning and procedural complications |
|
| Arteriovenous graft site haematoma | Vascular disorders |
|
| Arthralgia | Musculoskeletal and connective tissue disorders |
|
| Back pain | Musculoskeletal and connective tissue disorders |
|
| Bacteremia | Infections and infestations |
|
| Cardiac arrest | Cardiac disorders |
|
| Cerebrovascular accident | Nervous system disorders |
|
| Cholecystitis | Hepatobiliary disorders |
|
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders |
|
| Drug hypersensitivity | Immune system disorders |
|
| Gastroenteritis viral | Infections and infestations |
|
| Graft thrombosis | Injury, poisoning and procedural complications |
|
| Hemorrhage | Vascular disorders |
|
| Hip fracture | Injury, poisoning and procedural complications |
|
| Hypoglycemia | Metabolism and nutrition disorders |
|
| Hypotension | Vascular disorders |
|
| Impaired healing | General disorders |
|
| Incision site infection | Infections and infestations |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders |
|
| Postoperative respiratory distress | Injury, poisoning and procedural complications |
|
| Renal failure acute | Renal and urinary disorders |
|
| Sedation | Nervous system disorders |
|
| Sepsis | Infections and infestations |
|
| Spinal cord injury lumbar | Injury, poisoning and procedural complications |
|
| Steal syndrome | Vascular disorders |
|
| Stent-graft endoleak | Injury, poisoning and procedural complications |
|
| Supraventricular tachycardia | Cardiac disorders |
|
| Syncope | Nervous system disorders |
|
| Presyncope | Nervous system disorders |
|
| Transfusion-related circulatory overload | Injury, poisoning and procedural complications |
|
| Transient ischemic attack | Nervous system disorders |
|
| Vomiting | Gastrointestinal disorders |
|
| Wound infection | Infections and infestations |
|
| Constipation | Gastrointestinal disorders |
|
| Vomiting | Gastrointestinal disorders |
|
| Pyrexia | General disorders |
|
| Edema peripheral | General disorders |
|
| Incision site pain | Injury, poisoning and procedural complications |
|
| Procedural pain | Injury, poisoning and procedural complications |
|
| Wound secretion | Injury, poisoning and procedural complications |
|
| Hypokalemia | Metabolism and nutrition disorders |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders |
|
| Headache | Nervous system disorders |
|
| Insomnia | Psychiatric disorders |
|
| Pruritus | Skin and subcutaneous tissue disorders |
|
| Hypotension | Vascular disorders |
|
| Anemia | Blood and lymphatic system disorders |
|
| Sinus tachycardia | Cardiac disorders |
|
| Tachycardia | Cardiac disorders |
|
ZymoGenetics (ZG) agreements vary by trial, but each states that presentation/publication (p/p) cannot disclose Confidential Information (CI), excluding trial results; p/p may not begin until the earlier of 18 months after study end, ZG/lead investigator publishes, or ZG notification that multicenter publication is not planned; ZG has specified time for draft review before submission/presentation and may delay or modify content, require CI removal, and delay p/p for patent application filing.
| Title | Measurements |
|---|---|
|
| Treatment-emergent AEs ≥ Grade 3 |
|
| AEs leading to discontinuation |
|
| Title | Measurements |
|---|---|
|
| Hemoglobin, low: Day 29, Grade 3 (n=196) |
|
| Hemoglobin, low: Baseline, Grade 4 (n=199) |
|
| Hemoglobin, low: Day 29, Grade 4 (n=196) |
|
| Platelets, low: Baseline Grade 2 (n=196) |
|
| Platelets, low: Day 29, Grade 2 (n=194) |
|
| Platelets, low: Baseline, Grade 3 (n=196) |
|
| Platelets, low: Day 29, Grade 3 (n=194) |
|
| Platelets, low: Baseline, Grade 4 (n=196) |
|
| Platelets, low: Day 29, Grade 4 (n=194) |
|
| Leukocytes, low: Baseline, Grade 2 (n=199) |
|
| Leukocytes, low: Day 29, Grade 2 (n=196) |
|
| Leukocytes, low: Baseline, Grade 3 (n=199) |
|
| Leukocytes, low: Day 29, Grade 3 (n=196) |
|
| Leukocytes, low: Baseline, Grade 4 (n=199) |
|
| Leukocytes, low: Day 29, Grade 4 (n=196) |
|
| Lymphocytes, low: Baseline, Grade 2 (n=199) |
|
| Lymphocytes, low: Day 29, Grade 2 (n=196) |
|
| Lymphocytes, low: Baseline, Grade 3 (n=199) |
|
| Lymphocytes, low: Day 29, Grade 3 (n=196) |
|
| Lymphocytes, low: Baseline, Grade 4 (n=199) |
|
| Lymphocytes, low: Day 29, Grade 4 (n=196) |
|
| Neutrophils, low: Baseline, Grade 2 (n=199) |
|
| Neutrophils, low: Day 29, Grade 2 (n=196) |
|
| Neutrophils, low: Baseline, Grade 3 (n=199) |
|
| Neutrophils, low: Day 29, Grade 3 (n=196) |
|
| Neutrophils, low: Baseline, Grade 4 (n=199) |
|
| Neutrophils, low: Day 29, Grade 4 (n=196) |
|
| Title | Measurements |
|---|---|
|
| INR: Day 29: Grade 3 (n=198) |
|