Trial Outcomes & Findings for Immunogenicity and Safety Study of Topical Recombinant Thrombin in Surgical Hemostasis (NCT NCT00491608)

NCT ID: NCT00491608

Last Updated: 2012-01-13

Results Overview

Seropositive=with specific anti-bovine thrombin product antibodies; seronegative=without specific anti-bovine thrombin product antibodies.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 234 participants
• Primary outcome timeframe: At Day 29
• Results posted on: 2012-01-13

Participant Flow

Of 234 participants enrolled, 209 received study drug. Of those who received study drug, 200 had both baseline and post-baseline immunogenicity evaluations.

Participant milestones

Measure	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.
Overall Study STARTED	209
Overall Study COMPLETED	206
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Measure	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.
Overall Study Death	2
Overall Study Withdrawal by Subject	1

Baseline Characteristics

Immunogenicity and Safety Study of Topical Recombinant Thrombin in Surgical Hemostasis

Baseline characteristics by cohort

Measure	rThrombin n=209 Participants 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
Age, Customized Overall (All status)	64 Years n=5 Participants
Sex: Female, Male Female	99 Participants n=5 Participants
Sex: Female, Male Male	110 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	25 participants n=5 Participants
Race/Ethnicity, Customized Asian	2 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	22 participants n=5 Participants
Race/Ethnicity, Customized White	160 participants n=5 Participants

PRIMARY outcome

Timeframe: At Day 29

Population: Participants who received treatment with rThrombin and had results from both baseline and post-baseline antibody assessments

Seropositive=with specific anti-bovine thrombin product antibodies; seronegative=without specific anti-bovine thrombin product antibodies.

Outcome measures

Measure	rThrombin, 1000 IU/mL n=200 Participants 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.
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
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
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 outcome

Timeframe: Day 1 (surgery) to Day 29 (end of study), continuously

Population: All participants who received at least 1 application of rThrombin during surgery.

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.

Outcome measures

Measure	rThrombin, 1000 IU/mL n=209 Participants 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.
Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs Deaths	2 Participants
Number of Participants With Death as Outcome, Serious Adverse Events, Treatment-related Adverse Events (AEs), and Treatment-emergent AEs Serious adverse events	47 Participants
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
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
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 outcome

Timeframe: 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.

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.

Outcome measures

Measure	rThrombin, 1000 IU/mL n=209 Participants 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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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 outcome

Timeframe: 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.

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.

Outcome measures

Measure	rThrombin, 1000 IU/mL n=209 Participants 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.
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
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
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
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

SECONDARY outcome

Timeframe: Baseline and Day 29 (end of study)

Population: All participants who received rThrombin and had both baseline and postbaseline antibody assessments available.

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.

Outcome measures

Measure	rThrombin, 1000 IU/mL n=200 Participants 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.
Number of Participants With Abnormal Laboratory Results in Median Levels of Immunoglobulin A, G, and M at Baseline or Day 29	0 Participants

SECONDARY outcome

Timeframe: Baseline and Day 29 (end of study)

Population: All participants who received at least 1 application of rThrombin during surgery.

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.

Outcome measures

Measure	rThrombin, 1000 IU/mL n=209 Participants 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.
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

Adverse Events

rThrombin, 1000 IU/mL

Serious events: 47 serious events

Other events: 197 other events

Deaths: 0 deaths

Serious adverse events

Measure	rThrombin, 1000 IU/mL n=209 participants at risk 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.
Cardiac disorders Atrial fibrillation	1.4% 3/209
Vascular disorders Deep vein thrombosis	1.4% 3/209
Metabolism and nutrition disorders Hyperkaleamia	1.4% 3/209
Cardiac disorders Myocardial infarction	1.4% 3/209
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.4% 3/209
Injury, poisoning and procedural complications Wound secretion	1.4% 3/209
Cardiac disorders Cardiac failure congestive	0.96% 2/209
Vascular disorders Hematoma	0.96% 2/209
Gastrointestinal disorders Nausea	0.96% 2/209
Infections and infestations Postoperative wound infection	0.96% 2/209
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.96% 2/209
Renal and urinary disorders Renal failure	0.96% 2/209
Injury, poisoning and procedural complications Wound dehiscence	0.96% 2/209
Gastrointestinal disorders Abdominal wall hematoma	0.48% 1/209
Nervous system disorders Acute polyneuropathy	0.48% 1/209
Blood and lymphatic system disorders Anemia	0.48% 1/209
Injury, poisoning and procedural complications Arteriovenous fistual occlusion	0.48% 1/209
Injury, poisoning and procedural complications Arteriovenous fistula site complication	0.48% 1/209
Injury, poisoning and procedural complications Arteriovenous fistula site haematoma	0.48% 1/209
Vascular disorders Arteriovenous graft site haematoma	0.48% 1/209
Musculoskeletal and connective tissue disorders Arthralgia	0.48% 1/209
Musculoskeletal and connective tissue disorders Back pain	0.48% 1/209
Infections and infestations Bacteremia	0.48% 1/209
Cardiac disorders Cardiac arrest	0.48% 1/209
Nervous system disorders Cerebrovascular accident	0.48% 1/209
Hepatobiliary disorders Cholecystitis	0.48% 1/209
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.48% 1/209
Immune system disorders Drug hypersensitivity	0.48% 1/209
Infections and infestations Gastroenteritis viral	0.48% 1/209
Injury, poisoning and procedural complications Graft thrombosis	0.48% 1/209
Vascular disorders Hemorrhage	0.48% 1/209
Injury, poisoning and procedural complications Hip fracture	0.48% 1/209
Metabolism and nutrition disorders Hypoglycemia	0.48% 1/209
Vascular disorders Hypotension	0.48% 1/209
General disorders Impaired healing	0.48% 1/209
Infections and infestations Incision site infection	0.48% 1/209
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.48% 1/209
Injury, poisoning and procedural complications Postoperative respiratory distress	0.48% 1/209
Renal and urinary disorders Renal failure acute	0.48% 1/209
Nervous system disorders Sedation	0.48% 1/209
Infections and infestations Sepsis	0.48% 1/209
Injury, poisoning and procedural complications Spinal cord injury lumbar	0.48% 1/209
Vascular disorders Steal syndrome	0.48% 1/209
Injury, poisoning and procedural complications Stent-graft endoleak	0.48% 1/209
Cardiac disorders Supraventricular tachycardia	0.48% 1/209
Nervous system disorders Syncope	0.48% 1/209
Nervous system disorders Presyncope	0.48% 1/209
Injury, poisoning and procedural complications Transfusion-related circulatory overload	0.48% 1/209
Nervous system disorders Transient ischemic attack	0.48% 1/209
Gastrointestinal disorders Vomiting	0.48% 1/209
Infections and infestations Wound infection	0.48% 1/209

Other adverse events

Measure	rThrombin, 1000 IU/mL n=209 participants at risk 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.
Gastrointestinal disorders Nausea	26.8% 56/209
Gastrointestinal disorders Constipation	20.1% 42/209
Gastrointestinal disorders Vomiting	9.1% 19/209
General disorders Pyrexia	9.6% 20/209
General disorders Edema peripheral	7.7% 16/209
Injury, poisoning and procedural complications Incision site pain	45.0% 94/209
Injury, poisoning and procedural complications Procedural pain	39.2% 82/209
Injury, poisoning and procedural complications Wound secretion	6.2% 13/209
Metabolism and nutrition disorders Hypokalemia	5.7% 12/209
Musculoskeletal and connective tissue disorders Muscle spasms	12.4% 26/209
Musculoskeletal and connective tissue disorders Pain in extremity	8.1% 17/209
Nervous system disorders Headache	8.1% 17/209
Psychiatric disorders Insomnia	5.3% 11/209
Skin and subcutaneous tissue disorders Pruritus	7.2% 15/209
Vascular disorders Hypotension	11.0% 23/209
Blood and lymphatic system disorders Anemia	16.7% 35/209
Cardiac disorders Sinus tachycardia	5.7% 12/209
Cardiac disorders Tachycardia	5.7% 12/209

Additional Information

John Pribble, Vice President, Medical Affairs; Scot Maxon, Scientific Information

ZymoGenetics, a Bristol-Myers Squibb company

Phone: (206) 428-2756; (206) 434-3365

Email: John.Pribble@bms.com; Scot.Maxon@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER