Spinal Surgery, Vascular Surgery
Conditions
Keywords
Phase 3b, rThrombin, spine surgery, vascular surgery, hemostasis, immunogenicity, safety
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALrThrombin
1000 U/mL applied directly or in combination with absorbable gelatin sponge or powder
Sponsors
ZymoGenetics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Currently undergoing cervical, thoracic, or lumbar discectomy; corpectomy, laminectomy, lateral or interbody fusion, including both anterior and posterior approaches (not including minimally invasive procedures; arterial reconstruction; peripheral artery bypass (PAB) grafting; or arteriovenous (AV) vascular access procedures * History of surgery with high likelihood of exposure to bovine thrombin within the past 3 years. Prior surgery must have been 1 of the following open procedures: open procedures involving the spine or cranium, PAB grafting, AV vascular access procedures, autologous skin grafting, or other surgical procedure accompanied by documented treatment with bovine thrombin * Age of 18 years or younger at time of informed consent * If female and of child-bearing potential: Negative pregnancy test result within 14 days prior to treatment * Use of a medically accepted form of contraception from the time of informed consent to completion of all follow-up study visits, if sexually active male or a sexually active female of childbearing potential * Signed IRB/independent ethics committee-approved informed consent document
Exclusion criteria
* Currently undergoing procedures requiring cardiopulmonary bypass or involving the aortic arch * Known hypersensitivity to rThrombin or any of its components * Presence of medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures * Breastfeeding * Receipt of treatment with any experimental agent within 30 days of study enrollment or treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | At Day 29 | Seropositive=with specific anti-bovine thrombin product antibodies; seronegative=without specific anti-bovine thrombin product antibodies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs | Day 1 (surgery) to Day 29 (end of study), continuously | 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. |
| Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Baseline and Day 29 (end of study) | 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. |
| Number of Participants With Elevations in Coagulation Parameters of CTC Grade 3 or Higher at Baseline and Day 29 | Baseline and Day 29 (end of study) | 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. |
| Number of Participants With Abnormal Laboratory Results in Median Levels of Immunoglobulin A, G, and M at Baseline or Day 29 | Baseline and Day 29 (end of study) | 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. |
| 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 | Baseline and Day 29 (end of study) | 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. |
Countries
United States
Participant flow
Pre-assignment details
Of 234 participants enrolled, 209 received study drug. Of those who received study drug, 200 had both baseline and post-baseline immunogenicity evaluations.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 209 |
| Total | 209 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | rThrombin |
|---|---|
| Age, Customized Overall (All status) | 64 Years |
| Race/Ethnicity, Customized Asian | 2 participants |
| Race/Ethnicity, Customized Black or African American | 22 participants |
| Race/Ethnicity, Customized Hispanic | 25 participants |
| Race/Ethnicity, Customized White | 160 participants |
| Sex: Female, Male Female | 99 Participants |
| Sex: Female, Male Male | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 197 / 209 |
| serious Total, serious adverse events | 47 / 209 |
Outcome results
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.
Time frame: At Day 29
Population: Participants who received treatment with rThrombin and had results from both baseline and post-baseline antibody assessments
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rThrombin, 1000 IU/mL | 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 at baseline (n=31) | 0 Participants |
| rThrombin, 1000 IU/mL | 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 | Seronegative at baseline (n=169) | 0 Participants |
| rThrombin, 1000 IU/mL | 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 | Total (all participants) | 0 Participants |
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.
Time frame: Baseline and Day 29 (end of study)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Hemoglobin, low: Baseline, Grade 2 (n=199) | 13 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Hemoglobin, low: Day 29, Grade 2 (n=196) | 12 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Hemoglobin, low: Baseline, Grade 3 (n=199) | 3 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Hemoglobin, low: Day 29, Grade 3 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Hemoglobin, low: Baseline, Grade 4 (n=199) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Hemoglobin, low: Day 29, Grade 4 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Platelets, low: Baseline Grade 2 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Platelets, low: Day 29, Grade 2 (n=194) | 1 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Platelets, low: Baseline, Grade 3 (n=196) | 1 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Platelets, low: Day 29, Grade 3 (n=194) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Platelets, low: Baseline, Grade 4 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Platelets, low: Day 29, Grade 4 (n=194) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Leukocytes, low: Baseline, Grade 2 (n=199) | 1 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Leukocytes, low: Day 29, Grade 2 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Leukocytes, low: Baseline, Grade 3 (n=199) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Leukocytes, low: Day 29, Grade 3 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Leukocytes, low: Baseline, Grade 4 (n=199) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Leukocytes, low: Day 29, Grade 4 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Lymphocytes, low: Baseline, Grade 2 (n=199) | 6 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Lymphocytes, low: Day 29, Grade 2 (n=196) | 6 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Lymphocytes, low: Baseline, Grade 3 (n=199) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Lymphocytes, low: Day 29, Grade 3 (n=196) | 2 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Lymphocytes, low: Baseline, Grade 4 (n=199) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Lymphocytes, low: Day 29, Grade 4 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Neutrophils, low: Baseline, Grade 2 (n=199) | 1 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Neutrophils, low: Day 29, Grade 2 (n=196) | 1 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Neutrophils, low: Baseline, Grade 3 (n=199) | 1 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Neutrophils, low: Day 29, Grade 3 (n=196) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Neutrophils, low: Baseline, Grade 4 (n=199) | 0 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Hematology Laboratory Results of Common Terminology Criteria (CTC) Grade 2 or Higher at Baseline and Day 29 | Neutrophils, low: Day 29, Grade 4 (n=196) | 0 Participants |
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.
Time frame: Baseline and Day 29 (end of study)
Population: All participants who received rThrombin and had both baseline and postbaseline antibody assessments available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rThrombin, 1000 IU/mL | Number of Participants With Abnormal Laboratory Results in Median Levels of Immunoglobulin A, G, and M at Baseline or Day 29 | 0 Participants |
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.
Time frame: Baseline and Day 29 (end of study)
Population: All participants who received at least 1 application of rThrombin during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rThrombin, 1000 IU/mL | 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 | 0 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.
Time frame: Day 1 (surgery) to Day 29 (end of study), continuously
Population: All participants who received at least 1 application of rThrombin during surgery.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rThrombin, 1000 IU/mL | Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs | Deaths | 2 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs | Serious adverse events | 47 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs | Treatment-related adverse events (AEs) | 4 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs | Treatment-emergent AEs ≥ Grade 3 | 76 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs | AEs leading to discontinuation | 0 Participants |
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.
Time frame: Baseline and Day 29 (end of study)
Population: All participants who received at least 1 application of rThrombin during surgery and had laboratory test results available for assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rThrombin, 1000 IU/mL | Number of Participants With Elevations in Coagulation Parameters of CTC Grade 3 or Higher at Baseline and Day 29 | aPTT: Baseline, Grade 3 (n=197) | 6 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Elevations in Coagulation Parameters of CTC Grade 3 or Higher at Baseline and Day 29 | aPTT: Day 29: Grade 3 (n=199) | 7 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Elevations in Coagulation Parameters of CTC Grade 3 or Higher at Baseline and Day 29 | INR: Baseline, Grade 3 (n=197) | 1 Participants |
| rThrombin, 1000 IU/mL | Number of Participants With Elevations in Coagulation Parameters of CTC Grade 3 or Higher at Baseline and Day 29 | INR: Day 29: Grade 3 (n=198) | 1 Participants |