Bleeding (Oozing) in Hepatic Resection
Conditions
Brief summary
The purpose of the study is to compare safety and efficacy of Fibrin Sealant (FS) Vapor Heated (VH) S/D 500 s-apr with manual compression as a supportive treatment of local bleeding (i.e. oozing) in hepatic resection surgery when standard surgical techniques are insufficient.
Interventions
DRUGFibrin Sealant (FS) VH S/D 500 s-apr
Dosage form: spray application; dosage frequency: single application
OTHERManual compression
Dosage form: surgical gauze swab; dosage frequency: single application
Sponsors
Baxter Innovations GmbH
Baxter Healthcare Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Pre-Operative Inclusion Criteria: * Signed informed consent obtained from the subject before any study-related activities * Subject's age is 18 years or above * Subject will undergo planned, elective resection of at least 1 anatomical segment of the liver for any reason by laparotomy * Subject is willing and able to comply with the requirements of the protocol * Female subjects of childbearing potential must present with a negative serum or urine pregnancy test within 72 hours before the elective liver resection * Female subjects of childbearing potential must agree to employ adequate birth control measures for the time of their participation in the study Intra-Operative Inclusion Criteria (before randomization): * Resection of at least 1 anatomical segment of the liver has been performed * Oozing from the cut surface of the liver persists after conventional resection procedure and primary control of arterial and venous bleeding by sutures, ligations, clips, vascular stapler, point electrocautery or focal radiofrequency ablation * Need for additional supportive hemostatic treatment to stop bleeding (i.e. diffuse oozing) of the liver resection area Pre-Operative
Exclusion criteria
* Subject needs emergency liver surgery * Subject will undergo liver resection via laparoscopic procedure * Subject has known congenital coagulation disorder (e.g. hemophilia) * Subject has known hypersensitivity to any ingredient of the investigational medicinal product * Suspected inability or unwillingness of the subject to comply with trial procedures * If female, subject is pregnant or lactating at the time of study enrollment * Subject has already participated in this study (each subject can only be enrolled once) * Subject has participated in another clinical study involving an investigational product or investigational device within 30 days prior to study enrollment or is scheduled to participate in another clinical study involving an investigational product or investigational device during the course of this study Intra-operative
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Intraoperative Hemostasis at 4 Minutes After Treatment Application | 4 minutes post start of treatment application | Hemostasis defined as no visible bleeding on the liver resection surface (liver surgical site) after treatment application. Hemostasis had to be maintained until surgical closure. Time recording started with treatment application, ie, with the start of spraying Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr) or with the application of manual compression. The following were regarded as treatment failures: * No hemostasis achieved at 4 minutes post treatment application (for the FS VH S/D 500 s-apr arm, the time to hemostasis was used; a time window of +5 seconds was acceptable for showing a success) * Additional hemostatic treatment (ie, hemostatics in addition to the randomized treatment) was required * Reapplication of FS VH S/D 500 s-apr after 4 minutes * Intraoperative rebleeding after the first 4 minutes of the observation period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Intraoperative Hemostasis at 8 Minutes After Application of the Randomized Treatment | 8 minutes after start of treatment application | Hemostasis defined as no visible bleeding on the liver resection surface (liver surgical site) after treatment application. Hemostasis had to be maintained until surgical closure. Time recording started with treatment application, ie, with the start of spraying Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr) or with the application of manual compression. |
| Percentage of Participants With Intraoperative Hemostasis at 10 Minutes After Application of the Randomized Treatment | 10 minutes after start of treatment application | Hemostasis defined as no visible bleeding on the liver resection surface (liver surgical site) after treatment application. Hemostasis had to be maintained until surgical closure. Time recording started with treatment application, ie, with the start of spraying Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr) or with the application of manual compression. |
| Percentage of Participants With Intraoperative Rebleeding After Occurrence of Hemostasis | Intraoperative day 0 | Intraoperative rebleeding from the treated liver resection surface after occurrence of hemostasis. |
| Percentage of Participants With Intraoperative Hemostasis at 6 Minutes After Application of the Randomized Treatment | 6 minutes after start of treatment application | Hemostasis defined as no visible bleeding on the liver resection surface (liver surgical site) after treatment application. Hemostasis had to be maintained until surgical closure. Time recording started with treatment application, ie, with the start of spraying Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr) or with the application of manual compression. |
| Percentage of Participants With Transfusion Requirements Until Discharged From Surgical Ward | Intra- and postoperative until discharged from surgical ward | Transfusions administered included whole blood, packed red blood cells, fresh frozen plasma, and thrombocyte concentrate. |
| Median Total Volume of Postoperative Drainage Fluid Within 48 Hours After Surgery | Within 48 hours after surgery | — |
| Percentage of Participants With Postoperative Rebleeding | Postoperative until discharged from surgical ward | Rebleeding until discharged from the surgical ward, defined as any rebleeding from the treated liver resection surface requiring surgical reexploration |
Countries
Germany
Participant flow
Recruitment details
95 participants were enrolled and screened. 23 were screen failures. 2 participants were discontinued due to: 1 was operated on by a surgeon other than the investigator, and the other underwent a prolonged operation- meaning that the investigational product (IP) could not be used. Therefore, 70 of the 95 enrolled were randomized.
Participants by arm
| Arm | Count |
|---|---|
| FS VH S/D 500 S-apr Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr), not to exceed 20mL per participant. Hemostasis will be assessed at 4, 6, 8 and 10 minutes after application of the study treatment. | 35 |
| Manual Compression - Control A dry surgical gauze swab will be used to apply by hand an even light pressure onto the oozing resection surface of the liver. Hemostasis will be assessed at 4, 6, 8 and 10 minutes after application of the study treatment. | 35 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | FS VH S/D 500 S-apr | Manual Compression - Control | Total |
|---|---|---|---|
| Age Continuous | 54.7 years STANDARD_DEVIATION 14.5 | 59.8 years STANDARD_DEVIATION 12.8 | 57.3 years STANDARD_DEVIATION 13.9 |
| Region of Enrollment Germany | 35 participants | 35 participants | 70 participants |
| Sex: Female, Male Female | 15 Participants | 16 Participants | 31 Participants |
| Sex: Female, Male Male | 20 Participants | 19 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 35 | 23 / 35 |
| serious Total, serious adverse events | 9 / 35 | 11 / 35 |
Outcome results
Primary
Percentage of Participants With Intraoperative Hemostasis at 4 Minutes After Treatment Application
Hemostasis defined as no visible bleeding on the liver resection surface (liver surgical site) after treatment application. Hemostasis had to be maintained until surgical closure. Time recording started with treatment application, ie, with the start of spraying Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr) or with the application of manual compression. The following were regarded as treatment failures: * No hemostasis achieved at 4 minutes post treatment application (for the FS VH S/D 500 s-apr arm, the time to hemostasis was used; a time window of +5 seconds was acceptable for showing a success) * Additional hemostatic treatment (ie, hemostatics in addition to the randomized treatment) was required * Reapplication of FS VH S/D 500 s-apr after 4 minutes * Intraoperative rebleeding after the first 4 minutes of the observation period
Time frame: 4 minutes post start of treatment application
Population: full analysis (data) set (FAS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FS VH S/D 500 S-apr | Percentage of Participants With Intraoperative Hemostasis at 4 Minutes After Treatment Application | 82.9 percentage of participants |
| Manual Compression - Control | Percentage of Participants With Intraoperative Hemostasis at 4 Minutes After Treatment Application | 37.1 percentage of participants |
p-value: <0.001likelihood-ratio chi square test
Secondary
Median Total Volume of Postoperative Drainage Fluid Within 48 Hours After Surgery
Time frame: Within 48 hours after surgery
Population: * Full analysis (data) set~* Participants who received a drain and for whom the volume for the first 48 hours after surgery is available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FS VH S/D 500 S-apr | Median Total Volume of Postoperative Drainage Fluid Within 48 Hours After Surgery | 415.0 mL |
| Manual Compression - Control | Median Total Volume of Postoperative Drainage Fluid Within 48 Hours After Surgery | 410.0 mL |
Secondary
Percentage of Participants With Intraoperative Hemostasis at 10 Minutes After Application of the Randomized Treatment
Hemostasis defined as no visible bleeding on the liver resection surface (liver surgical site) after treatment application. Hemostasis had to be maintained until surgical closure. Time recording started with treatment application, ie, with the start of spraying Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr) or with the application of manual compression.
Time frame: 10 minutes after start of treatment application
Population: Full analysis (data) set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FS VH S/D 500 S-apr | Percentage of Participants With Intraoperative Hemostasis at 10 Minutes After Application of the Randomized Treatment | 94.3 percentage of participants |
| Manual Compression - Control | Percentage of Participants With Intraoperative Hemostasis at 10 Minutes After Application of the Randomized Treatment | 74.3 percentage of participants |
p-value: 0.017likelihood ratio chi-square test
Secondary
Percentage of Participants With Intraoperative Hemostasis at 6 Minutes After Application of the Randomized Treatment
Hemostasis defined as no visible bleeding on the liver resection surface (liver surgical site) after treatment application. Hemostasis had to be maintained until surgical closure. Time recording started with treatment application, ie, with the start of spraying Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr) or with the application of manual compression.
Time frame: 6 minutes after start of treatment application
Population: Full analysis (data) set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FS VH S/D 500 S-apr | Percentage of Participants With Intraoperative Hemostasis at 6 Minutes After Application of the Randomized Treatment | 91.4 percentage of participants |
| Manual Compression - Control | Percentage of Participants With Intraoperative Hemostasis at 6 Minutes After Application of the Randomized Treatment | 57.1 percentage of participants |
p-value: <0.001likelihood ratio chi-square test
Secondary
Percentage of Participants With Intraoperative Hemostasis at 8 Minutes After Application of the Randomized Treatment
Hemostasis defined as no visible bleeding on the liver resection surface (liver surgical site) after treatment application. Hemostasis had to be maintained until surgical closure. Time recording started with treatment application, ie, with the start of spraying Fibrin Sealant, Vapor Heated, Solvent/Detergent treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr) or with the application of manual compression.
Time frame: 8 minutes after start of treatment application
Population: Full analysis (data) set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FS VH S/D 500 S-apr | Percentage of Participants With Intraoperative Hemostasis at 8 Minutes After Application of the Randomized Treatment | 91.4 percentage of participants |
| Manual Compression - Control | Percentage of Participants With Intraoperative Hemostasis at 8 Minutes After Application of the Randomized Treatment | 71.4 percentage of participants |
p-value: 0.028likelihood ratio chi-square test
Secondary
Percentage of Participants With Intraoperative Rebleeding After Occurrence of Hemostasis
Intraoperative rebleeding from the treated liver resection surface after occurrence of hemostasis.
Time frame: Intraoperative day 0
Population: Full analysis (data) set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FS VH S/D 500 S-apr | Percentage of Participants With Intraoperative Rebleeding After Occurrence of Hemostasis | 2.9 percentage of participants |
| Manual Compression - Control | Percentage of Participants With Intraoperative Rebleeding After Occurrence of Hemostasis | 8.6 percentage of participants |
p-value: 0.293likelihood ratio chi-square test
Secondary
Percentage of Participants With Postoperative Rebleeding
Rebleeding until discharged from the surgical ward, defined as any rebleeding from the treated liver resection surface requiring surgical reexploration
Time frame: Postoperative until discharged from surgical ward
Population: Full analysis (data) set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FS VH S/D 500 S-apr | Percentage of Participants With Postoperative Rebleeding | 2.9 Percentage of participants |
| Manual Compression - Control | Percentage of Participants With Postoperative Rebleeding | 0.0 Percentage of participants |
p-value: 0.237likelihood ratio chi-square test
Secondary
Percentage of Participants With Transfusion Requirements Until Discharged From Surgical Ward
Transfusions administered included whole blood, packed red blood cells, fresh frozen plasma, and thrombocyte concentrate.
Time frame: Intra- and postoperative until discharged from surgical ward
Population: Full analysis (data) set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FS VH S/D 500 S-apr | Percentage of Participants With Transfusion Requirements Until Discharged From Surgical Ward | 40.0 percentage of participants |
| Manual Compression - Control | Percentage of Participants With Transfusion Requirements Until Discharged From Surgical Ward | 42.9 percentage of participants |
p-value: 0.808likelihood ratio chi-square test