Excessive Bleeding During Surgery
Conditions
Brief summary
The objective of the study is to evaluate if FS Grifols is non-inferior to EVICEL® in terms of the percentage of participants achieving hemostasis at the target bleeding site (TBS) by 4 minutes (T4) from the start of treatment application (TStart) with no occurrence of rebleeding until the completion of the surgical closure by layers of the exposed surgical field containing the TBS (TClosure).
Detailed description
This is a prospective, randomized, active-controlled, single-blind, parallel group clinical trial to evaluate the safety and efficacy of FS Grifols as an adjunct to hemostasis during surgery. Approximately 172 pediatric participants will be enrolled and will be randomly allocated in a 1:1 ratio into 1 of 2 treatment groups: FS Grifols or EVICEL. Enrollment will be monitored by surgery type to ensure at least 50% of the surgical procedures are hepatic. A specific bleeding site will be defined as the TBS when it is determined by the investigator (the surgeon) that control of bleeding by conventional surgical techniques (including suture, ligature, and cautery) is ineffective or impractical and requires an adjunct treatment to achieve hemostasis. When the TBS is identified, the investigator will record the precise anatomical location of the TBS, rate the intensity of the bleeding at the TBS (Grade 1-4 according to a 5-point validated bleeding severity scale), and record the size of the approximate bleeding surface, (small, medium, and large). For soft tissue surgery only, the investigator will also record the type of soft tissue (ie, fat, muscle, or connective tissue). In this clinical trial, only participants with a TBS with bleeding of Grade 1 (mild) or Grade 2 (moderate) intensity will be enrolled. This study includes a Screening Visit to determine participant eligibility, a Baseline Visit, the Surgical Procedure (Day 1), and Post-operative assessments at Days 1, 4, and 30. The total duration of a participant's participation in this study is expected to be no longer than 2 months from the Screening Visit to the Post-operative Day 30 Visit.
Interventions
BIOLOGICALFibrin Sealant Grifols
The FE Grifols solution was applied topically via drip or spray application.
BIOLOGICALEVICEL
The EVICEL solution was applied topically via drip or spray application.
Sponsors
Instituto Grifols, S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
Pre-operative: 1. Less than 18 years of age. 2. Requires an elective (non-emergent), open (non-laparoscopic), pelvic, abdominal, or thoracic (non-cardiac) surgical procedure. 3. Participant and/or participant's legal guardian is willing to give permission for the participant to participate in the clinical trial and provide written informed consent for the participant. In addition, assent must be obtained from pediatric participants who possess the intellectual and emotional ability to comprehend the concepts involved in the clinical trial. Intra-operative: 4. Presence of an appropriate (as defined in inclusion criterion 5) parenchymous or soft tissue TBS identified intra-operatively by the investigator (the surgeon). 5. TBS has Grade 1 (mild) or Grade 2 (moderate) bleeding intensity according to the investigator's (the surgeon's) judgment. The intensity of the bleeding at the TBS will be rated by the investigator using the 5-point validated bleeding severity scale.
Exclusion criteria
Pre-operative: 1. Admitted for trauma surgery. 2. Unwilling to receive blood products. 3. Known history of severe (eg, anaphylactic) reaction to blood products. 4. Known history of intolerance to any of the components of the investigational product (IP). 5. Female participants who are pregnant, breastfeeding or, if of child-bearing potential (ie, adolescent), unwilling to practice a highly effective method of contraception. 6. Previously enrolled in a clinical trial with FS Grifols. 7. Currently participating, or during the study is planned to participate, in any other investigational device or medicinal product study without prior and explicit approval from the sponsor. Intra-operative: 8. An appropriate parenchymous or soft tissue TBS (as defined in
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Hemostasis Within 4 Minutes After Treatment Start (T4) | From start of treatment until 4 minutes after treatment start (Day 1) | Hemostasis is defined as Grade 0 bleeding per 5-point validated bleeding severity scale (0=no bleeding and 4=Unidentified or inaccessible spurting or gush) at the target bleeding site (TBS) according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Percentage of Participants Achieving Hemostasis at the TBS by the 7 Minutes After Treatment Start (T7) | From start of treatment to 7 minutes after start of treatment (Day 1) | Hemostasis is defined as Grade 0 bleeding at the TBS according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin. The cumulative percentage of participants achieving hemostasis at the TBS by the time points of T7 defined as an absence/cessation of bleeding (Grade 0) at the TBS by that time point without occurrence of rebleeding, Grade 3 or Grade 4 bleeding, use of alternative hemostatic treatment, and reapplication of study treatment after T4 and until TClosure. |
| Cumulative Percentage of Participants Achieving Hemostasis at the Target Bleeding Site by 10 Minutes After Treatment Start (T10) | From start of treatment to 10 minutes after start of treatment (Day 1) | Hemostasis is defined as Grade 0 bleeding at the TBS according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin. The cumulative percentage of participants achieving hemostasis at the TBS by the time points of T10 defined as an absence/cessation of bleeding (Grade 0) at the TBS by that time point without occurrence of rebleeding, Grade 3 or Grade 4 bleeding, use of alternative hemostatic treatment, and reapplication of study treatment after T4 and until TClosure. |
| Percentage of Participants With Treatment Failures | From start of treatment to 10 minutes after start of treatment and until the time of completion of surgical closure (Day 1) | Participants were considered treatment failures if there is a. persistent bleeding at the TBS beyond T4 b. Grade 3 or Grade 4 breakthrough bleeding from the TBS that jeopardizes participant safety according to the investigator's judgment at any moment during the 10-minute observational period and until TClosure c. Use of alternative hemostatic treatments or maneuvers (other than the study treatment) at the TBS during the 10-minute observational period and until TClosure, or use of study treatment at the TBS beyond T4 and until TClosure d. Rebleeding (Grade ≥1) at the TBS after the assessment of the primary efficacy endpoint at T4 and until TClosure. |
Countries
Bulgaria, Canada, France, Germany, Hungary, Romania, Serbia, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 18 sites in the United States, Bulgaria, France, Hungary, Romania, Serbia, and United Kingdom, from 18 January 2019 (first participant enrolled to receive the study drug) to 20 May 2022 (last participant completed).
Pre-assignment details
Paediatric participants with excessive bleeding during surgery were randomized into 1: 1 ratio to receive Fibrin Sealant (FS) Grifols and EVICEL. A total of 197 participants were screened, out of which 186 participants were randomized (Intent-to-treat population), 178 received study treatment (modified intent-to-treat population), 171 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Fibrin Sealant Grifols Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder. | 95 |
| EVICEL Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically. | 91 |
| Total | 186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent Withdrawn by Participant | 0 | 1 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Reason not Specified | 1 | 3 |
| Overall Study | Screen Failure | 3 | 1 |
Baseline characteristics
| Characteristic | EVICEL | Total | Fibrin Sealant Grifols |
|---|---|---|---|
| Age, Continuous | 8.84 years STANDARD_DEVIATION 6.32 | 8.63 years STANDARD_DEVIATION 6.199 | 8.43 years STANDARD_DEVIATION 6.108 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 24 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 80 Participants | 162 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 8 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 89 Participants | 175 Participants | 86 Participants |
| Sex: Female, Male Female | 30 Participants | 70 Participants | 40 Participants |
| Sex: Female, Male Male | 61 Participants | 116 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 91 | 2 / 87 |
| other Total, other adverse events | 20 / 91 | 13 / 87 |
| serious Total, serious adverse events | 8 / 91 | 9 / 87 |
Outcome results
Primary
Percentage of Participants Achieving Hemostasis Within 4 Minutes After Treatment Start (T4)
Hemostasis is defined as Grade 0 bleeding per 5-point validated bleeding severity scale (0=no bleeding and 4=Unidentified or inaccessible spurting or gush) at the target bleeding site (TBS) according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin.
Time frame: From start of treatment until 4 minutes after treatment start (Day 1)
Population: Modified ITT (mITT) population included all participants in the ITT population who meet the intra-operative enrollment criteria, and thus treated with any amount of investigational product (IP). Overall number analyzed are the number of participants with haemostasis by 4 minutes. Number analyzed are the number of participants with parenchymous and soft tissue surgery with data available for analysis. Percentage are rounded off the single decimal point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fibrin Sealant Grifols | Percentage of Participants Achieving Hemostasis Within 4 Minutes After Treatment Start (T4) | Parenchymous Surgery | 100.0 percentage of participants |
| Fibrin Sealant Grifols | Percentage of Participants Achieving Hemostasis Within 4 Minutes After Treatment Start (T4) | Soft Tissue Surgery | 93.3 percentage of participants |
| EVICEL | Percentage of Participants Achieving Hemostasis Within 4 Minutes After Treatment Start (T4) | Parenchymous Surgery | 100.0 percentage of participants |
| EVICEL | Percentage of Participants Achieving Hemostasis Within 4 Minutes After Treatment Start (T4) | Soft Tissue Surgery | 90.9 percentage of participants |
Comparison: Hemostasis by 4 Minutes (Parenchymous)p-value: <0.00195% CI: [0.92, 1.09]Cochran-Mantel-Haenszel
Comparison: Hemostasis by 4 Minutes (Soft Tissue)p-value: <0.00195% CI: [0.91, 1.16]Cochran-Mantel-Haenszel
Secondary
Cumulative Percentage of Participants Achieving Hemostasis at the Target Bleeding Site by 10 Minutes After Treatment Start (T10)
Hemostasis is defined as Grade 0 bleeding at the TBS according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin. The cumulative percentage of participants achieving hemostasis at the TBS by the time points of T10 defined as an absence/cessation of bleeding (Grade 0) at the TBS by that time point without occurrence of rebleeding, Grade 3 or Grade 4 bleeding, use of alternative hemostatic treatment, and reapplication of study treatment after T4 and until TClosure.
Time frame: From start of treatment to 10 minutes after start of treatment (Day 1)
Population: mITT population included all participants in the ITT population who meet the intra-operative enrollment criteria and thus treated with any amount of IP. Overall number analyzed are the number of participants with haemostasis by 4 minutes. Number analyzed are the number of participants with parenchymous and soft tissue surgery with data available for analysis. Percentages are rounded off a single decimal point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fibrin Sealant Grifols | Cumulative Percentage of Participants Achieving Hemostasis at the Target Bleeding Site by 10 Minutes After Treatment Start (T10) | Parenchymous Surgery | 97.8 percentage of participants |
| Fibrin Sealant Grifols | Cumulative Percentage of Participants Achieving Hemostasis at the Target Bleeding Site by 10 Minutes After Treatment Start (T10) | Soft Tissue Surgery | 100.0 percentage of participants |
| EVICEL | Cumulative Percentage of Participants Achieving Hemostasis at the Target Bleeding Site by 10 Minutes After Treatment Start (T10) | Parenchymous Surgery | 100.0 percentage of participants |
| EVICEL | Cumulative Percentage of Participants Achieving Hemostasis at the Target Bleeding Site by 10 Minutes After Treatment Start (T10) | Soft Tissue Surgery | 100.0 percentage of participants |
Comparison: Hemostasis by 10 Minutes (Parenchymous)p-value: <0.00195% CI: [0.94, 1.02]Cochran-Mantel-Haenszel
Comparison: Hemostasis by 10 Minutes (Soft tissue)p-value: <0.00195% CI: [0.92, 1.09]Cochran-Mantel-Haenszel
Secondary
Cumulative Percentage of Participants Achieving Hemostasis at the TBS by the 7 Minutes After Treatment Start (T7)
Hemostasis is defined as Grade 0 bleeding at the TBS according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin. The cumulative percentage of participants achieving hemostasis at the TBS by the time points of T7 defined as an absence/cessation of bleeding (Grade 0) at the TBS by that time point without occurrence of rebleeding, Grade 3 or Grade 4 bleeding, use of alternative hemostatic treatment, and reapplication of study treatment after T4 and until TClosure.
Time frame: From start of treatment to 7 minutes after start of treatment (Day 1)
Population: mITT population included all participants in the ITT population who meet the intra-operative enrollment criteria, and thus treated with any amount of IP. Overall number analyzed are the number of participants with haemostasis by 4 minutes. Number analyzed are the number of participants with parenchymous and soft tissue surgery with data available for analysis. Percentages are rounded off a single decimal point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fibrin Sealant Grifols | Cumulative Percentage of Participants Achieving Hemostasis at the TBS by the 7 Minutes After Treatment Start (T7) | Parenchymous Surgery | 100.0 percentage of participants |
| Fibrin Sealant Grifols | Cumulative Percentage of Participants Achieving Hemostasis at the TBS by the 7 Minutes After Treatment Start (T7) | Soft Tissue Surgery | 100.0 percentage of participants |
| EVICEL | Cumulative Percentage of Participants Achieving Hemostasis at the TBS by the 7 Minutes After Treatment Start (T7) | Parenchymous Surgery | 100.0 percentage of participants |
| EVICEL | Cumulative Percentage of Participants Achieving Hemostasis at the TBS by the 7 Minutes After Treatment Start (T7) | Soft Tissue Surgery | 100.0 percentage of participants |
Comparison: Hemostasis by 7 Minutes (Parenchymous)p-value: <0.00195% CI: [0.92, 1.09]Cochran-Mantel-Haenszel
Comparison: Hemostasis by 7 Minutes (Soft tissue)p-value: <0.00195% CI: [0.92, 1.09]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Treatment Failures
Participants were considered treatment failures if there is a. persistent bleeding at the TBS beyond T4 b. Grade 3 or Grade 4 breakthrough bleeding from the TBS that jeopardizes participant safety according to the investigator's judgment at any moment during the 10-minute observational period and until TClosure c. Use of alternative hemostatic treatments or maneuvers (other than the study treatment) at the TBS during the 10-minute observational period and until TClosure, or use of study treatment at the TBS beyond T4 and until TClosure d. Rebleeding (Grade ≥1) at the TBS after the assessment of the primary efficacy endpoint at T4 and until TClosure.
Time frame: From start of treatment to 10 minutes after start of treatment and until the time of completion of surgical closure (Day 1)
Population: mITT population included all participants in the ITT population who meet the intra-operative enrollment criteria and thus treated with any amount of IP. Overall number analyzed are the number of participants with haemostasis by 4 minutes. Number analyzed are the number of participants with parenchymous and soft tissue surgery with data available for analysis. Percentages are rounded off a single decimal point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fibrin Sealant Grifols | Percentage of Participants With Treatment Failures | Parenchymous Surgery | 0 percentage of participants |
| Fibrin Sealant Grifols | Percentage of Participants With Treatment Failures | Soft Tissue Surgery | 0 percentage of participants |
| EVICEL | Percentage of Participants With Treatment Failures | Parenchymous Surgery | 0 percentage of participants |
| EVICEL | Percentage of Participants With Treatment Failures | Soft Tissue Surgery | 0 percentage of participants |