Hemostasis
Conditions
Keywords
Vascular surgery, Hepatic surgery, Soft tissue surgery, Spinal surgery
Brief summary
This purpose of this clinical trial was to study the safety and efficacy of Topical Thrombin (Human) Grifols as an add-on treatment to help stop bleeding during vascular, liver, soft tissue, and spinal surgical procedures.
Detailed description
This was a prospective, randomized, double-blind, controlled, Phase II study to evaluate the safety and efficacy of Topical Thrombin (Human) Grifols as an adjunct to hemostasis during vascular (IG1202-A), hepatic (IG1202-B), soft tissue (IG1202-C), and spinal (IG1202-D) surgical procedures. Approximately 180 subjects were randomized into 1 of 2 treatment groups in a 2:1 ratio: Topical Thrombin (Human) Grifols (120 subjects) or Bovine Thrombin JMI (60 subjects) among the 4 types of surgeries. Randomized subjects were evaluated for identification of a target bleeding site (TBS) in which control of bleeding by conventional surgical techniques (including suture, ligature and cautery) was ineffective or impractical and required an adjunct treatment to achieve hemostasis. The Investigator rated the intensity of bleeding at the TBS. Topical Thrombin (Human) Grifols or Bovine Thrombin JMI was applied to the TBS and the time to hemostasis was assessed at various timepoints during a 5-minute observation period. Subjects were evaluated by surgery type and by integrated analysis of clinical studies IG1202-A, IG1202-B, IG1202-C, and IG1202-D.
Interventions
BIOLOGICALHuman thrombin
Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges
BIOLOGICALBovine thrombin
Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges
Sponsors
Instituto Grifols, S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Pre-operative (at Baseline Assessments Visit) hemoglobin (Hgb) ≥9.0 g/dL (deciliter) * Pre-operative (at Baseline Assessments Visit) fibrinogen level ≥150 mg/dL (functional method). * Required one of the following procedures: 1. An elective (non-emergency), open (non-laparoscopic; non- endovascular) surgical procedure involving a native artery-graft end-to-side proximal anastomosis utilizing coated or uncoated polytetrafluoroethylene (PTFE) graft (IG1202-A). 2. An elective (non-emergency), open (non-laparoscopic) hepatic resection (anatomic and non-anatomic resections of at least one anatomical hepatic segment or equivalent tissue volume) (IG-1202-B). 3. An elective (non-emergency), open (non-laparoscopic), surgical procedure involving soft (non-parenchymous) tissue (IG1202-C). 4. An elective (non-emergency), spinal surgical procedure in which the epidural venous plexus was exposed (IG1202-D). * A target bleeding site (TBS) was identified according to the Investigator's judgment, and the TBS had mild or moderate bleeding according to the Investigator's judgment.
Exclusion criteria
* Required surgical procedure due to trauma (except for spinal surgery). * Infection in the anatomic surgical area. * History of severe (e.g. anaphylactic) reactions to blood or to any blood-derived (human or animal) product. * Previous known sensitivity to any Topical Thrombin (Human) Grifols component, any Bovine Thrombin JMI component, porcine collagen, and heparin or protamine (vascular surgery only) component. * Received an organ transplant. * Underwent another concurrent major surgical intervention beyond the liver (applied to hepatic surgery \[IG1202-B\] only; concurrent interventions on the pancreas, gall bladder, bile duct, or intestines were allowed). * Underwent a re-operative procedure, which was defined as a second, or successive, surgical procedure on the same anatomic location. * Underwent other vascular procedures during the same surgical session (applied to vascular surgery \[IG1202-A\] only; stenting and/or endarterectomy of the same artery were allowed). * Underwent a therapeutic surgical procedure within 30 days from screening (diagnostic procedures were allowed). * Previously included in this trial (i.e. each subject could only be enrolled once in this study). * TBS could not be identified according to the investigator's judgment. * TBS had a severe bleeding according to the Investigator's judgment. * Occurrence of major intra-operative complications that required resuscitation or deviation from the planned surgical procedure. * Application of any topical haemostatic material on the resection surface of the liver prior to application of the study treatment (applied to hepatic surgery \[IG1202-B\] only). * Radiofrequency precoagulation of the liver resection surface, except focal use of radiofrequency as primary haemostatic treatment (applied to hepatic surgery \[IG1202-B\] only). * Intra-operative change in planned surgical procedure which resulted in subject no longer meeting preoperative inclusion and/or
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | From start of treatment until 5 minutes after treatment start | Subjects achieving hemostasis at the target bleeding site by 5 minutes following the start of treatment without the occurrence of re-bleeding until the completion of surgical closure |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | From start of treatment until 4 minutes after treatment start | Cumulative proportion of subjects having achieved hemostasis by each of the following time points: * At 3 minutes following start of study treatment * At 4 minutes following start of study treatment |
| Prevalence of Treatment Failures | From start of treatment up to surgical closure by layers of the exposed surgical field containing the TBS, a median of 34 minutes | Protocol-defined bleeding at the target bleeding site after the start of treatment or the use of alternative hemostatic treatments or maneuvers at the target bleeding site after the start of treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IG1202-A (Vascular) Human thrombin: Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges
Bovine thrombin: Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges | 31 |
| IG1202-B (Hepatic) Human thrombin: Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges
Bovine thrombin: Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges | 30 |
| IG1202-C (Soft Tissue) Human thrombin: Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges
Bovine thrombin: Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges | 35 |
| IG1202-D (Spinal) Human thrombin: Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges
Bovine thrombin: Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges | 85 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 2 |
| Overall Study | Subject did not have transportation | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | IG1202-A (Vascular) | IG1202-B (Hepatic) | IG1202-C (Soft Tissue) | IG1202-D (Spinal) |
|---|---|---|---|---|---|
| Age, Continuous Bovine Thrombin | 56.39 years STANDARD_DEVIATION 16.464 | 71.82 years STANDARD_DEVIATION 9.857 | 56.50 years STANDARD_DEVIATION 14.455 | 47.67 years STANDARD_DEVIATION 12.434 | 54.04 years STANDARD_DEVIATION 17.24 |
| Age, Continuous Human Thrombin | 55.54 years STANDARD_DEVIATION 16.017 | 66.30 years STANDARD_DEVIATION 12.427 | 57.50 years STANDARD_DEVIATION 13.987 | 47.52 years STANDARD_DEVIATION 13.885 | 54.32 years STANDARD_DEVIATION 16.733 |
| Age, Customized 12-17 Bovine Thrombin | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Customized 12-17 Human Thrombin | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Customized 18-64 Bovine Thrombin | 41 Participants | 3 Participants | 8 Participants | 11 Participants | 19 Participants |
| Age, Customized 18-64 Human Thrombin | 82 Participants | 9 Participants | 13 Participants | 20 Participants | 40 Participants |
| Age, Customized >=65 Bovine Thrombin | 19 Participants | 8 Participants | 2 Participants | 1 Participants | 8 Participants |
| Age, Customized >=65 Human Thrombin | 37 Participants | 11 Participants | 7 Participants | 3 Participants | 16 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native Bovine Thrombin | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native Human Thrombin | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian Bovine Thrombin | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian Human Thrombin | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American Bovine Thrombin | 7 Participants | 2 Participants | 1 Participants | 4 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American Human Thrombin | 19 Participants | 6 Participants | 5 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander Bovine Thrombin | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander Human Thrombin | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other Bovine Thrombin | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other Human Thrombin | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White (Caucasian) Bovine Thrombin | 50 Participants | 9 Participants | 6 Participants | 8 Participants | 27 Participants |
| Race/Ethnicity, Customized White (Caucasian) Human Thrombin | 97 Participants | 14 Participants | 13 Participants | 15 Participants | 55 Participants |
| Sex: Female, Male Bovine Thrombin Female | 42 Participants | 4 Participants | 9 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Bovine Thrombin Male | 19 Participants | 7 Participants | 1 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Human Thrombin Female | 70 Participants | 8 Participants | 10 Participants | 23 Participants | 29 Participants |
| Sex: Female, Male Human Thrombin Male | 50 Participants | 12 Participants | 10 Participants | 0 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 1 / 11 | 0 / 20 | 0 / 10 | 0 / 23 | 0 / 12 | 0 / 57 | 1 / 28 | 0 / 120 | 2 / 61 |
| other Total, other adverse events | 12 / 20 | 7 / 11 | 20 / 20 | 9 / 10 | 23 / 23 | 12 / 12 | 49 / 57 | 24 / 28 | 104 / 120 | 52 / 61 |
| serious Total, serious adverse events | 3 / 20 | 2 / 11 | 2 / 20 | 1 / 10 | 1 / 23 | 0 / 12 | 4 / 57 | 3 / 28 | 10 / 120 | 6 / 61 |
Outcome results
Primary
Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS
Subjects achieving hemostasis at the target bleeding site by 5 minutes following the start of treatment without the occurrence of re-bleeding until the completion of surgical closure
Time frame: From start of treatment until 5 minutes after treatment start
Population: Data are presented for subjects in the Human Thrombin and Bovine Thrombin treatment groups in the modified intent-to-treat (mITT) population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IG1202-A (Vascular) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Human Thrombin | 75.0 percent of subjects achieving hemostasis |
| IG1202-A (Vascular) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Bovine Thrombin | 54.5 percent of subjects achieving hemostasis |
| IG1202-B (Hepatic) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Human Thrombin | 75.0 percent of subjects achieving hemostasis |
| IG1202-B (Hepatic) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Bovine Thrombin | 80.0 percent of subjects achieving hemostasis |
| IG1202-C (Soft Tissue) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Human Thrombin | 73.9 percent of subjects achieving hemostasis |
| IG1202-C (Soft Tissue) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Bovine Thrombin | 91.7 percent of subjects achieving hemostasis |
| IG1202-D (Spinal) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Bovine Thrombin | 85.7 percent of subjects achieving hemostasis |
| IG1202-D (Spinal) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Human Thrombin | 82.5 percent of subjects achieving hemostasis |
| Overall (IG1202-A, IG1202-B, IG1202-C, and IG1202-D) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Human Thrombin | 78.3 percent of subjects achieving hemostasis |
| Overall (IG1202-A, IG1202-B, IG1202-C, and IG1202-D) | Proportion of Subjects Achieving Hemostasis by Five Minutes After Treatment Start at the TBS | Bovine Thrombin | 80.3 percent of subjects achieving hemostasis |
Secondary
Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points
Cumulative proportion of subjects having achieved hemostasis by each of the following time points: * At 3 minutes following start of study treatment * At 4 minutes following start of study treatment
Time frame: From start of treatment until 4 minutes after treatment start
Population: Data are presented for subjects in the Human Thrombin and Bovine Thrombin treatment groups in the mITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IG1202-A (Vascular) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Human Thrombin | 40.0 percent of subjects achieving hemostasis |
| IG1202-A (Vascular) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Bovine Thrombin | 36.4 percent of subjects achieving hemostasis |
| IG1202-A (Vascular) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Human Thrombin | 50.0 percent of subjects achieving hemostasis |
| IG1202-A (Vascular) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Bovine Thrombin | 45.5 percent of subjects achieving hemostasis |
| IG1202-B (Hepatic) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Human Thrombin | 45.0 percent of subjects achieving hemostasis |
| IG1202-B (Hepatic) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Bovine Thrombin | 70.0 percent of subjects achieving hemostasis |
| IG1202-B (Hepatic) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Bovine Thrombin | 60.0 percent of subjects achieving hemostasis |
| IG1202-B (Hepatic) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Human Thrombin | 65.0 percent of subjects achieving hemostasis |
| IG1202-C (Soft Tissue) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Bovine Thrombin | 91.7 percent of subjects achieving hemostasis |
| IG1202-C (Soft Tissue) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Bovine Thrombin | 75.0 percent of subjects achieving hemostasis |
| IG1202-C (Soft Tissue) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Human Thrombin | 73.9 percent of subjects achieving hemostasis |
| IG1202-C (Soft Tissue) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Human Thrombin | 73.9 percent of subjects achieving hemostasis |
| IG1202-D (Spinal) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Human Thrombin | 70.2 percent of subjects achieving hemostasis |
| IG1202-D (Spinal) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Bovine Thrombin | 71.4 percent of subjects achieving hemostasis |
| IG1202-D (Spinal) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Bovine Thrombin | 78.6 percent of subjects achieving hemostasis |
| IG1202-D (Spinal) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Human Thrombin | 78.9 percent of subjects achieving hemostasis |
| Overall (IG1202-A, IG1202-B, IG1202-C, and IG1202-D) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Bovine Thrombin | 73.8 percent of subjects achieving hemostasis |
| Overall (IG1202-A, IG1202-B, IG1202-C, and IG1202-D) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 4 minutes: Human Thrombin | 70.8 percent of subjects achieving hemostasis |
| Overall (IG1202-A, IG1202-B, IG1202-C, and IG1202-D) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Bovine Thrombin | 63.9 percent of subjects achieving hemostasis |
| Overall (IG1202-A, IG1202-B, IG1202-C, and IG1202-D) | Cumulative Proportion of Subjects Having Achieved Hemostasis at the Target Bleeding Site by Specified Time Points | Hemostasis by 3 minutes: Human Thrombin | 61.7 percent of subjects achieving hemostasis |
Secondary
Prevalence of Treatment Failures
Protocol-defined bleeding at the target bleeding site after the start of treatment or the use of alternative hemostatic treatments or maneuvers at the target bleeding site after the start of treatment
Time frame: From start of treatment up to surgical closure by layers of the exposed surgical field containing the TBS, a median of 34 minutes
Population: Data are presented for subjects in the Human Thrombin and Bovine Thrombin treatment groups in the mITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IG1202-A (Vascular) | Prevalence of Treatment Failures | Human Thrombin | 25.0 percent of subjects |
| IG1202-A (Vascular) | Prevalence of Treatment Failures | Bovine Thrombin | 45.5 percent of subjects |
| IG1202-B (Hepatic) | Prevalence of Treatment Failures | Human Thrombin | 25.0 percent of subjects |
| IG1202-B (Hepatic) | Prevalence of Treatment Failures | Bovine Thrombin | 20.0 percent of subjects |
| IG1202-C (Soft Tissue) | Prevalence of Treatment Failures | Human Thrombin | 26.1 percent of subjects |
| IG1202-C (Soft Tissue) | Prevalence of Treatment Failures | Bovine Thrombin | 8.3 percent of subjects |
| IG1202-D (Spinal) | Prevalence of Treatment Failures | Bovine Thrombin | 14.3 percent of subjects |
| IG1202-D (Spinal) | Prevalence of Treatment Failures | Human Thrombin | 17.5 percent of subjects |
| Overall (IG1202-A, IG1202-B, IG1202-C, and IG1202-D) | Prevalence of Treatment Failures | Human Thrombin | 21.7 percent of subjects |
| Overall (IG1202-A, IG1202-B, IG1202-C, and IG1202-D) | Prevalence of Treatment Failures | Bovine Thrombin | 19.7 percent of subjects |