Mild or Moderate Surgical Bleeding
Conditions
Keywords
fibrin sealant, thrombin, fibrinogen, hemostasis
Brief summary
The purpose of this study is to confirm the superiority of Fibrocaps plus gelatin sponge, as compared to gelatin sponge alone, for achieving hemostasis. The investigational products were used in participants with mild to moderate surgical bleeding during spine, liver, vascular or soft tissue surgery, when control of mild to moderate bleeding by standard surgical techniques is ineffective and/or impractical.
Interventions
BIOLOGICALFibrocaps
Human fibrinogen and thrombin powder, for topical administration.
BIOLOGICALGelatin sponge
Absorbable gelatin sponge for topical administration.
Sponsors
Mallinckrodt
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
1. Has signed an institutional review board/independent ethics committee (IRB/IEC)-approved informed consent document 2. Is undergoing one of the 4 surgical procedures described 3. Is at least 18 years old at time of consent 4. If female and of child-bearing potential, has negative pregnancy test during screening and is not breast-feeding 5. If able to reproduce, agrees to use a medically accepted form of contraception from the time of consent to completion of all follow-up study visits when engaging in heterosexual intercourse 6. Has not received blood transfusion between screening and study treatment 7. Has mild to moderate surgical bleeding 8. Does not have intra-operative complications 9. Has not used a topical hemostat containing thrombin prior to study treatment 10. Has an approximate bleeding site surface area of less than or equal to 100 cm\^2
Exclusion criteria
1. Has known antibodies or hypersensitivity to thrombin or other coagulation factors 2. Has history of heparin-induced thrombocytopenia (only for vascular subjects where heparin use is required) 3. Has known allergy to gelatin sponge 4. Is unwilling to receive blood products 5. Has liver enzymes appropriate for the study, considering their disease 6. Has appropriate level of platelets per liter (PLT/L) during screening 7. Has any clinically-significant coagulation disorder that may interfere with the assessment of efficacy or pose a safety risk to the subject according to the Investigator, or baseline abnormalities during screening that are not explained by current drug treatment (e.g., warfarin, heparin)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Hemostasis (TTH) for Participants Receiving Soft Tissue Dissection | Within 5 minutes | The measurement of TTH begins at t=0, which is the time the study product is applied to the Target Bleeding Site (TBS) and ends when hemostasis is achieved or 5-minutes, whichever occurs first, based on data collected by surgery type and treatment. |
| Time to Hemostasis (TTH) for Participants Receiving Spinal Surgery | Within 5 minutes | The measurement of TTH begins at t=0, which is the time the study product is applied to the Target Bleeding Site (TBS) and ends when hemostasis is achieved or 5-minutes, whichever occurs first, based on data collected by surgery type and treatment. |
| Time to Hemostasis (TTH) for Participants Receiving Vascular Surgery | Within 5 minutes | The measurement of TTH begins at t=0, which is the time the study product is applied to the Target Bleeding Site (TBS) and ends when hemostasis is achieved or 5-minutes, whichever occurs first, based on data collected by surgery type and treatment. |
| Time to Hemostasis (TTH) for Participants Receiving Hepatic Resection | Within 5 minutes | The measurement of TTH begins at t=0, which is the time the study product is applied to the Target Bleeding Site (TBS) and ends when hemostasis is achieved or 5-minutes, whichever occurs first, based on data collected by surgery type and treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Restricted Mean TTH | Within 5 minutes | Restricted mean TTH over 5 minutes is computed using Irwin's estimator, based on data collected by surgery type and treatment. |
| Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | Within 29 days | An adverse event (AE) is any untoward medical occurrence (including clinically significant changes in laboratory values or other clinical tests) experienced by a participant administered a pharmaceutical product regardless of causal relationship with the treatment. A TEAE is any adverse event reported on the case report form that occurs after start of treatment or any adverse event with a missing start date. |
| Number of Participants Who Require Alternative Hemostatic Agents at 5 Minutes | At 5 minutes | If hemostasis is not achieved within 5 minutes, the treatment is considered to have failed, and the surgeon is to implement additional hemostatic measures. |
| Number of Participants Who Required Red Blood Cells | Within 29 days | Red blood cells are defined as including World Health Organization (WHO) DRUG terms of Blood cells, packed human, Blood, whole, Red blood cells, Red blood cells, concentrated and Red blood cells, leucocyte depleted. |
Countries
Belgium, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled from May 2012 to April 2013 at 57 investigative sites (United States, n = 28; United Kingdom, n = 12; The Netherlands, n = 11; and Belgium, n = 6), and were randomized 2:1 to receive treatment with Fibrocaps plus gelatin sponge or gelatin sponge alone.
Pre-assignment details
After screening, 719 eligible participants had surgery in 1 of 4 surgical indications (i.e., spinal, hepatic, vascular, or soft tissue dissection) on Day 1 according to local standard practice, and received treatment with the investigational product assigned.
Participants by arm
| Arm | Count |
|---|---|
| Fibrocaps + Gelatin Sponge Single application of Fibrocaps plus gelatin sponge. | 482 |
| Gelatin Sponge Single application of gelatin sponge alone. | 239 |
| Total | 721 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 8 | 2 |
| Overall Study | Did Not Receive Treatment | 2 | 0 |
| Overall Study | Lost to Follow-up | 6 | 4 |
| Overall Study | No Day 29 Visit | 0 | 1 |
| Overall Study | Non-compliance | 0 | 1 |
| Overall Study | Withdrew Consent | 1 | 1 |
Baseline characteristics
| Characteristic | Fibrocaps + Gelatin Sponge | Gelatin Sponge | Total |
|---|---|---|---|
| Age, Continuous | 57.4 years STANDARD_DEVIATION 14.44 | 58.1 years STANDARD_DEVIATION 14.12 | 57.6 years STANDARD_DEVIATION 14.33 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 3 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 42 Participants | 20 Participants | 62 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 5 Participants | 14 Participants |
| Race (NIH/OMB) White | 422 Participants | 210 Participants | 632 Participants |
| Sex: Female, Male Female | 214 Participants | 115 Participants | 329 Participants |
| Sex: Female, Male Male | 268 Participants | 124 Participants | 392 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 480 | 2 / 239 |
| other Total, other adverse events | 426 / 480 | 214 / 239 |
| serious Total, serious adverse events | 81 / 480 | 29 / 239 |
Outcome results
Primary
Time to Hemostasis (TTH) for Participants Receiving Hepatic Resection
The measurement of TTH begins at t=0, which is the time the study product is applied to the Target Bleeding Site (TBS) and ends when hemostasis is achieved or 5-minutes, whichever occurs first, based on data collected by surgery type and treatment.
Time frame: Within 5 minutes
Population: Efficacy population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fibrocaps + Gelatin Sponge | Time to Hemostasis (TTH) for Participants Receiving Hepatic Resection | 1.0 minutes |
| Gelatin Sponge | Time to Hemostasis (TTH) for Participants Receiving Hepatic Resection | 2.0 minutes |
p-value: <0.0001Log Rank
Primary
Time to Hemostasis (TTH) for Participants Receiving Soft Tissue Dissection
The measurement of TTH begins at t=0, which is the time the study product is applied to the Target Bleeding Site (TBS) and ends when hemostasis is achieved or 5-minutes, whichever occurs first, based on data collected by surgery type and treatment.
Time frame: Within 5 minutes
Population: Efficacy population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fibrocaps + Gelatin Sponge | Time to Hemostasis (TTH) for Participants Receiving Soft Tissue Dissection | 1.5 minutes |
| Gelatin Sponge | Time to Hemostasis (TTH) for Participants Receiving Soft Tissue Dissection | 2.5 minutes |
p-value: <0.0001Log Rank
Primary
Time to Hemostasis (TTH) for Participants Receiving Spinal Surgery
The measurement of TTH begins at t=0, which is the time the study product is applied to the Target Bleeding Site (TBS) and ends when hemostasis is achieved or 5-minutes, whichever occurs first, based on data collected by surgery type and treatment.
Time frame: Within 5 minutes
Population: Efficacy population consists of all participants who were randomized, received study treatment, and had a TTH assessment. Number analyzed is the number of participants in the efficacy population who receive each type of surgery.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fibrocaps + Gelatin Sponge | Time to Hemostasis (TTH) for Participants Receiving Spinal Surgery | 1.0 minutes |
| Gelatin Sponge | Time to Hemostasis (TTH) for Participants Receiving Spinal Surgery | 2.5 minutes |
p-value: <0.0001Log Rank
Primary
Time to Hemostasis (TTH) for Participants Receiving Vascular Surgery
The measurement of TTH begins at t=0, which is the time the study product is applied to the Target Bleeding Site (TBS) and ends when hemostasis is achieved or 5-minutes, whichever occurs first, based on data collected by surgery type and treatment.
Time frame: Within 5 minutes
Population: Efficacy population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fibrocaps + Gelatin Sponge | Time to Hemostasis (TTH) for Participants Receiving Vascular Surgery | 2.0 minutes |
| Gelatin Sponge | Time to Hemostasis (TTH) for Participants Receiving Vascular Surgery | 4.0 minutes |
p-value: <0.0001Log Rank
Secondary
Number of Participants Who Require Alternative Hemostatic Agents at 5 Minutes
If hemostasis is not achieved within 5 minutes, the treatment is considered to have failed, and the surgeon is to implement additional hemostatic measures.
Time frame: At 5 minutes
Population: Efficacy population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fibrocaps + Gelatin Sponge | Number of Participants Who Require Alternative Hemostatic Agents at 5 Minutes | 6 Participants |
| Gelatin Sponge | Number of Participants Who Require Alternative Hemostatic Agents at 5 Minutes | 7 Participants |
Secondary
Number of Participants Who Required Red Blood Cells
Red blood cells are defined as including World Health Organization (WHO) DRUG terms of Blood cells, packed human, Blood, whole, Red blood cells, Red blood cells, concentrated and Red blood cells, leucocyte depleted.
Time frame: Within 29 days
Population: Efficacy population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fibrocaps + Gelatin Sponge | Number of Participants Who Required Red Blood Cells | 40 Participants |
| Gelatin Sponge | Number of Participants Who Required Red Blood Cells | 22 Participants |
Secondary
Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)
An adverse event (AE) is any untoward medical occurrence (including clinically significant changes in laboratory values or other clinical tests) experienced by a participant administered a pharmaceutical product regardless of causal relationship with the treatment. A TEAE is any adverse event reported on the case report form that occurs after start of treatment or any adverse event with a missing start date.
Time frame: Within 29 days
Population: Safety population, defined as all participants who were randomized and received study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fibrocaps + Gelatin Sponge | Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | 426 Participants |
| Gelatin Sponge | Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | 214 Participants |
Secondary
Restricted Mean TTH
Restricted mean TTH over 5 minutes is computed using Irwin's estimator, based on data collected by surgery type and treatment.
Time frame: Within 5 minutes
Population: Efficacy population. Number analyzed is the number of participants with data available for analysis in each surgery type.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fibrocaps + Gelatin Sponge | Restricted Mean TTH | Spinal Surgery | 1.2 minutes | Standard Error 0.08 |
| Fibrocaps + Gelatin Sponge | Restricted Mean TTH | Vascular Surgery | 2.4 minutes | Standard Error 0.14 |
| Fibrocaps + Gelatin Sponge | Restricted Mean TTH | Hepatic Resection | 1.5 minutes | Standard Error 0.09 |
| Fibrocaps + Gelatin Sponge | Restricted Mean TTH | Soft Tissue Dissection | 1.5 minutes | Standard Error 0.09 |
| Gelatin Sponge | Restricted Mean TTH | Soft Tissue Dissection | 3.1 minutes | Standard Error 0.19 |
| Gelatin Sponge | Restricted Mean TTH | Spinal Surgery | 2.7 minutes | Standard Error 0.19 |
| Gelatin Sponge | Restricted Mean TTH | Hepatic Resection | 2.5 minutes | Standard Error 0.21 |
| Gelatin Sponge | Restricted Mean TTH | Vascular Surgery | 3.5 minutes | Standard Error 0.2 |