Safety and Efficacy of Topical Thrombin (Human) Grifols as an Adjunct to Hemostasis During Surgery

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Prospective, Randomized, Double-blind, Phase II Study to Evaluate the Safety and Efficacy of Topical Thrombin (Human) Grifols as an Adjunct to Hemostasis During Vascular, Hepatic, Soft Tissue, and Spinal Open Surgeries

Conditions
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Hemostasis

Intervention / Treatment
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* Biological: Human thrombin
* Biological: Bovine thrombin


Participation Criteria
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Eligibility Criteria
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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: 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). 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). An elective (non-emergency), open (non-laparoscopic), surgical procedure involving soft (non-parenchymous) tissue (IG1202-C). 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 exclusion criteria. Application of any topical haemostatic material on the cut soft tissue surface prior to application of the study treatment (applied to soft tissue surgery [IG1202-C] only).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IG1202-A (Vascular)<br> | Biological: Human thrombin<br>* Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges<br>Biological: Bovine thrombin<br>* Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges<br>|
| Experimental: IG1202-B (Hepatic)<br> | Biological: Human thrombin<br>* Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges<br>Biological: Bovine thrombin<br>* Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges<br>|
| Experimental: IG1202-C (Soft Tissue)<br> | Biological: Human thrombin<br>* Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges<br>Biological: Bovine thrombin<br>* Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges<br>|
| Experimental: IG1202-D (Spinal)<br> | Biological: Human thrombin<br>* Thrombin purified from human plasma reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges<br>Biological: Bovine thrombin<br>* Thrombin of bovine origin reconstituted as a 1000 IU/mL solution in blinded syringes and applied using Gelfoam® sponges<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From start of treatment until 5 minutes after treatment start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From start of treatment until 4 minutes after treatment start | 
| 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 | From start of treatment up to surgical closure by layers of the exposed surgical field containing the TBS, a median of 34 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vascular surgery, Hepatic surgery, Soft tissue surgery, Spinal surgery