Subjects and Surgical Procedures
Of the 132 subjects who provided informed consent, 29 subjects were screen failures for either intra-operative findings precluding study treatment (16 subjects), failing in- or exclusion criteria (12 subjects), and patient withdrawal prior to surgery (1 subject) (Figure 1). As a result, 103 subjects were included in the ITT set. A total of 100 subjects completed the study as planned, while 2 subjects died during follow-up prior to the 6-month visit and one subject was lost to follow-up. One subject, although treated, had a major protocol deviation due to failing to meet an inclusion criterion and was excluded from the PP set, which resulted in 102 evaluable subjects included in the PP set. There were 8 investigative sites, each having enrolled 2-20 evaluable subjects.
The median (range) age of the study population was 64.0 (33-88) years, the male/female gender distribution was 50.5%/49.5%, and subjects were predominantly Caucasian [93/103 (90.3%)] (Table 1).
The distribution of operative procedures was urological (37.9%), abdominal (32.0%), gynecological (14.6%), cardiothoracic (13.6%) and pelvic (1.9%); open surgery (53.4%) was slightly more frequent than laparoscopic/thoracoscopic surgery (46.6%) (including 7 robotic and 2 thoracoscopic procedures). The TBS tissue types included parenchymatous tissue (19.4% with the majority (19/20) being liver), connective tissue (45.6%) and a separate category of loose areolar tissue (27.2%), as well as a small number of other TBS (7.8%) (Table 1). The median surface area of the TBS was 4 cm2 (range 0.02–72.0) and bleeding was considered mild in 72/103 subjects (69.9%) and moderate in the remaining 31/103 subjects (30.1%) (Table 1).
In 100/103 subjects (97.1%), one single Surgicel®-P applicator was used, and sufficient coverage was obtained in all subjects (100%). At initial Surgicel®-P application, manual compression was applied in 28/102 procedures (27.5%, n=1 data unavailable) (Figure 2). During longitudinal assessment of hemostasis, this rate declined progressively to 2/102 procedures at fascia closure (2%, n=1 data unavailable), while the percentage of bleeding sites showing hemostasis increased from 89/103 procedures (86.4%) at 3 minutes to 96/101 procedures (95%) at fascia closure (Figure 2). In 18 subjects (17.5%), additional Surgicel®-P treatment was administered with/without manual compression or observation, whereas in 7 subjects (6.8%), investigators reverted to standard-of-care using other hemostatic methods including cautery, suture, SURGICEL®-SNoW or TachoSil (Figure 2).
The median total surgical procedure duration was 197 min (range 32-895 min), median total time in the operating room was 244 min (range 81-995 min) and median total postoperative hospital stay was 5 nights (range 0-76 nights, data unavailable for n=1). The median estimated total intra-operative blood loss amounted to 150 mL (range 5-4,000 mL), and blood and blood product transfusions were given in 13/103 subjects (12.6%).
Table 1. Subject Demographics, Surgical Procedure and Target Bleeding Site Characteristics.
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Overall group (N=103)
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Patient Characteristics
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Age at Consent, years
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Mean (SD)
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61.0 (12.8)
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Median (range)
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64.0 (33.0, 88.0)
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Gender, n (%)
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Male
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52 (50.5)
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Female
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51 (49.5)
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Race, n (%)
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Caucasian
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93 (90.3)
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Asian
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2 (1.9)
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Not reported
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8 (7.8)
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Ethnicity, n (%)
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Not Hispanic or Latino
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91 (88.3)
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Not reported
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12 (11.7)
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Prior and/or Concomitant Medical Conditions, n (%)
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103 (100.0)
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Relevant Surgical History, n (%)
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86 (83.5)
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Surgical Procedure Characteristics
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Surgical Approach, n (%)
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Open
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55 (53.4)
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Laparoscopic/thoracoscopic
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48 (46.6)
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Surgical Procedure, n (%)
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Cardiothoracic1
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14 (13.6)
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Abdominal
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33 (32.0)
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Pelvic
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2 (1.9)
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Gynecological
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15 (14.6)
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Urological
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39 (37.9)
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Target Bleeding Site Characteristics
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Primary Method for Hemostasis, n (%)
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None (other methods impractical)
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80 (77.7)
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Suture
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1 (1.0)
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Ligation
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1 (1.0)
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Cautery
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19 (18.4)
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Other
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2 (1.9)
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Type of Bleeding, n (%)
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Mild
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72 (69.9)
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Moderate
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31 (30.1)
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Tissue Type, n (%)
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Connective tissue
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47 (45.6)
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Loose Areolar tissue
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28 (27.2)
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Parenchyma
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20 (19.4)
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Other2
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8 (7.8)
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Size (Area), cm2
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Mean (SD)
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7.58 (10.06)
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Median (range)
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4.00 (0.02, 72.00)
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1 N=12 (11.7%) cardiac and n=2 lung (1.9%)
2 superior vena cava needle holes (n=1), perivascular tissue (n=1), right atrium needle holes (n=1), epicardial dissection on left ventricle(n=1), peri-adrenal tissue (n=3), periprostatic tissue (n=1)
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Effectiveness Endpoints
The primary endpoint analysis (Figure 3) in the ITT set showed the percentage of subjects achieving hemostatic success at 5 minutes to be 90/103 subjects (87.4%; 95%CI [79.4%, 93.1%]). The primary endpoint success rate according to bleeding intensity was 67/72 subjects with mild bleeding (93.1%; 95%CI [84.5%, 97.7%]) versus 23/31 subjects with moderate bleeding (74.2%; 95%CI [55.4%, 88.1%]). According to surgical approach, the success rate was 50/55 subjects (90.9%; 95%CI [80.0%, 97.0%]) for the open procedure group and 40/48 subjects (83.3%; 95%CI [69.8%, 92.5%]) for the laparoscopic/thoracoscopic procedure group (p=0.25, Chi-square test). Endpoint analysis results in the PP set were similar (not shown).
The secondary endpoint analysis (Figure 3) in the overall group showed hemostatic success in 80/103 subjects (77.7%; 95%CI [68.4% - 85.3%]) at 3 minutes and in 95/103 subjects (92.2%; 95%CI [85.3%, 96.6%]) at 10 minutes. In the subgroup analysis according to surgical approach, hemostatic success for the open procedure group was 44/55 subjects (80.0%; 95%CI [67.0%, 89.6%]) at 3 minutes and 53/55 subjects (96.4%; 95%CI [87.5%, 99.6%]) at 10 minutes; for the laparoscopic/thoracoscopic group, hemostatic success was 36/48 subjects (75.0%; 95%CI [60.4%, 86.4%]) at 3 minutes and 42/48 subjects (87.5%, 95%CI [74.8%, 95.3%]) at 10 minutes. In the subgroup analysis according to bleeding severity, hemostatic success for mild bleeding was 61/72 subjects (84.7%; 95%CI [74.3%, 92.1%] at 3 minutes and 69/72 subjects (95.8%; 95%CI [88.3%, 99.1%]) at 10 minutes; for moderate bleeding, hemostatic success was 19/31 subjects (61.3%; 95%CI [42.2%, 78.2%]) at 3 minutes and 26/31 subjects (83.9%, 95%CI [66.3%, 94.6%]) at 10 minutes.
Of note, for two subjects, the 10-minute hemostasis assessment was not performed as the fascia was closed at 5 minutes and 8 minutes; these subjects were considered as successes given the specific clinical bleeding scenarios with hemostatic success at 3 and 5 minutes without rebleeding or the subsequent need for additional treatment.
Safety
Over 6-month follow-up, a total of 257 AEs occurred in 70/103 subjects (68.0%) (safety set), which included 33 SAE in 24 subjects (23.3%) and 19 severe AEs in 15 subjects (14.6%) (Table 2). There were no AEs or SAEs, specifically, no post-operative TBS-rebleeding or thrombo-embolic events, considered by the investigator to be unlikely, possibly, probably or causally related to Surgicel®-P. A total of 64 subjects (62.1%) experienced at least one AE that was categorized as unlikely, possibly, probably or causally related to the study procedure. Seven subjects experienced AEs of ileus, which were considered anticipated for their procedure. All cases of ileus were dynamic/functional and resolved with non-surgical treatment and without sequalae. The AE and SAE occurred most frequently within the system classes of gastro-intestinal disorders (43/103 subjects [41.7%]) and infections and infestations (27/103 subjects [26.2%]). Two subjects (1.9%), both known with pancreatic cancer, died between the day-30 and the month-6 visit: one subject died at 3 months from an undetermined cause, and one subject died at 6 months due to pulmonary embolism after chemotherapy.
Table 2. Adverse Events.
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Surgicel®-P N=103
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Total Number of Adverse Events
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257
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Total Number of Serious Adverse Events
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33
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Number (%) of Subjects with at Least 1 Event in the Category
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AE
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70 (68.0)
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Serious AE
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24 (23.3)
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Severe AE
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15 (14.6)
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AE Related* to Surgicel®-P
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0 (0.0)
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SAE Related* to Surgicel®-P
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0 (0.0)
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AE Related* to Study Procedure
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64 (62.1)
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Subjects with at Least One AE Expected/Anticipated
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55 (53.4)
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Number (%) of Subject Deaths
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2 (1.9)
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*possibly related, probably related, or related
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Surgeon Ease-of-Use Questionnaire
Data were collected for a total of 43 procedures, including 19 open and 22 laparoscopic and 2 thoracoscopic procedures (Supplementary Information 2). For the majority of procedures, investigators either ‘agreed’ or ‘strongly agreed’ that Surgicel®-P was easy and quick to prepare for application [41/43 (95.3%)] and could be easily applied to the TBS [39/43 (90.7%)], that the investigator could exactly control the amount of Surgicel®-P applied to the TBS [30/43 (69.8%)] and could adequately cover a broad area of bleeding [40/43 (93.0%)], and that excess Surgicel®-P was easy to irrigate/aspirate out of surgical site without disturbing the clot at the TBS [29/36 (80.5%)]. Similarly, for the majority of procedures, the investigators ‘agreed’ or ‘strongly agreed’ feeling confident about the ability of the product to achieve and maintain hemostasis [37/43 (86.1%) and 37/43 86.1%), respectively]. A subgroup analysis according to surgical approach (Figure 4) showed a similar response pattern for open and laparoscopic/thoracoscopic procedures; across the different survey items, the proportion of surgeons who ‘strongly agreed’ varied between 42.1% and 84.2% for the open approach (median 63.2%), and between 28.6% and 54.2% for the laparoscopic/thoracoscopic approach (median 45.8%) (Figure 4).