CLINICAL IMPACT OF SEPRAFILM SAFETY AND EFFICACY

Transcription

1 CLINICAL IMPACT OF Post-surgical ADHESIONS SEPRAFILM SAFETY AND EFFICACY Clinical Reviews

2 Clinical studies contents OVERVIEW 3. REDUCED INCIDENCE AND SEVERITY OF ADHESIONS 3.1 Becker JM et al. (1996) 3.2 Kusunoki M et al. (2005) 3.3 Dupré A et al. (2013) 1. Clinical Impact of Post-Surgical Adhesions 1.1 Beck DE et al. (1999) 1.2 Parker MC et al. (2001) 1.3 van Goor H (2007) 1.4 ten Broek RPG et al. (2013) 2. PRODUCT SAFETY STUDY 2.1 Beck DE et al. (2003) 4. IMPACT OF RE-OPERATION 4.1 Tang C-L et al. (2003) 4.2 Kawamura H et al. (2010) 5. REDUCED RISK OF ADHESIVE SMALL-BOWEL OBSTRUCTION (ASBO) 5.1 Fazio VW et al. (2006) 5.2 Mohri Y et al. (2005) 5.3 Park C-M et al. (2008) 6. REDUCED RISK OF OTHER ADHESION-RELATED COMPLICATIONS 6.1 van der Wal JBC et al. (2011)

3 1. Clinical Impact of Post-Surgical Adhesions 1.1 Beck DE et al. (1999) 1.2 Parker MC et al. (2001) 1.3 van Goor H (2007) 1.4 ten Broek RPG et al. (2013)

4 Clinical Impact of Post-Surgical Adhesions 1.1 Beck DE et al. (1999) Incidence of small-bowel obstruction and adhesiolysis after open colorectal and general surgery Study Type: A retrospective cohort study Patient population: N=18,912 PRIMARY/CONFIRMATORY DIAGNOSIS: Not applicable AMOUNT AND PLACEMENT OF ADHESION PRODUCT: Not applicable Objective(s): Establish the incidence of small-bowel obstruction, adhesiolysis for obstruction, and additional abdominal surgery after open colorectal and general surgery Hypothesis: Not applicable Methodology: Utilised U.S. Health Care Financing Database from the years ; patients were categorised into 4 sub-cohorts based on their index procedures corresponding to ICD-9 codes (45, 46, 48, and 54) A 5% random sample of all Medicare beneficiaries who underwent surgery in 1993 was made; of these, 18,912 had an index abdominal procedure Several types of events occurred within the first 2 years after index procedures and included hospitalisation with one of the following: 1) diagnosis of intestinal obstruction; 2) diagnosis of intestinal obstruction and a procedure for lysis of peritoneal adhesions; or 3) second hospitalisation during which a second colorectal or general surgery was performed Two analyses of the incidence of various events were conducted after index procedure

5 Clinical Impact of Post-Surgical Adhesions 1.1 Beck DE et al. (1999) Incidence of small-bowel obstruction and adhesiolysis after open colorectal and general surgery (cont.) Findings: Within the first 2 years, of patients who underwent abdominal surgery (incision, excision, and anastomosis of intestine), 14.3% presented with a bowel obstruction 2.6% of these patients required adhesiolysis to relieve the bowel obstruction 12.9% underwent additional open colorectal or general surgery (within 2 years of an anastomosis or incision) Results at 2 years post incision, excision, and anastomosis of intestine ICD-9 Code Percent of obstruction Percent requiring adhesiolysis for obstructions Percent requiring additional open colorectal or general surgery 45 (incision of intestine, not otherwise specified) 46 (other operations on intestine) 48 (operations on rectum, rectosigmoid, and perirectal tissue) 54 (other operations on abdominal region) Conclusions: Bowel obstruction, adhesiolysis for obstruction, and additional abdominal surgery occurred more often after abdominal surgery than previously published Additional Findings: Because of the limited follow-up period, for later cases in the series it can be expected that the ultimate rate of reoperation (due to intestinal obstruction in this cohort) will be greater than the reported 3% Reference: Beck DE, Opelka FG, Bailey HR, et al. Incidence of small-bowel obstruction and adhesiolysis after open colorectal and general surgery. Dis Colon Rectum. 1999;42:

6 Clinical Impact of Post-Surgical Adhesions 1.2 Parker MC et al. (2001) Postoperative adhesions: 10-year follow-up of 12,584 patients undergoing lower abdominal surgery Study Type: Retrospective follow-up review Patient population: N=12,584 PRIMARY/CONFIRMATORY DIAGNOSIS: Not applicable AMOUNT AND PLACEMENT OF ADHESION PRODUCT: Not applicable Objective(s): To investigate the impact of adhesion-related readmissions after open surgery on the small intestine, appendix, colon, rectum, and abdominal wall Hypothesis: Not applicable Methodology: Reviewed patient data from the Scottish NHS Medical Record Linkage Database Database identified a cohort of patients undergoing open lower abdominal surgery in 1986 Readmissions for potential adhesion-related disease in the subsequent 10 years were analysed Results: 32.6% of total patients were readmitted an average of 2.2 times in the subsequent 10 years for a potential adhesion-related problem 25.4% (greatest number) of readmissions were in the initial postoperative year 7.3% of all readmissions after lower abdominal surgery were directly related to adhesions 52% of all readmissions were for an adhesion-related problem or for further surgery, which could be complicated by adhesions 430 (n=643) were abdominal surgical interventions for direct adhesion-related disease

7 Clinical Impact of Post-Surgical Adhesions 1.2 Parker MC et al. (2001) Postoperative adhesions: 10-year follow-up of 12,584 patients undergoing lower abdominal surgery (cont.) Conclusions: Study provides sound justification for improved adhesion prevention strategies Additional Findings: Not applicable PATIENT READMISSIONS BY SITE OF SURGERY ACROSS 10-YEAR PERIOD Total number of patients undergoing initial open surgery 12,584 Total number of patients readmitted 4,101 (32.6%) Total number of hospital readmissions 8,861 Readmissions directly adhesion-related 643 (n=8,861) Readmissions possibly related to adhesions 3,596 (n=8,861) Reoperations potentially complicated by adhesions 4,622 (n=8,861) Reference: Parker MC, Ellis H, Moran BJ, et al. Postoperative adhesions: ten-year follow-up of 12,584 patients undergoing lower abdominal surgery. Dis Colon Rectum. 2001;44(6):

8 Clinical Impact of Post-Surgical Adhesions 1.3 van Goor H (2007) Consequences and complications of peritoneal adhesions Study Type: Not applicable: review of multiple studies Patient population: Various undergoing abdominal surgery PRIMARY/CONFIRMATORY DIAGNOSIS: Various AMOUNT AND PLACEMENT OF ADHESION PRODUCT: Not specified Objective(s): Provide overview of intra-abdominal adhesion morbidity Hypothesis: Not applicable as study is a review of multiple studies Methodology: This paper gives an overview of intra-abdominal adhesion morbidity relevant to colorectal surgeons other than adhesive small-bowel obstruction and secondary female infertility Whenever applicable, recent evidence is reviewed and less common features of adhesions, including adhesion-related conversion in laparoscopy and drawbacks of adhesions in peritonitis, are addressed Key Assumptions: Consequences and complications of postsurgical intra-abdominal adhesion formation are substantial (not including small-bowel obstruction and secondary infertility) Inadvertent enterotomy during reopening of the abdomen or subsequent adhesion dissection is a feared complication of surgery after previous laparotomy The incidence can be as high as 20% in open surgery and between 1% and 100% in laparoscopy, depending on the underlying disease

9 Clinical Impact of Post-Surgical Adhesions 1.3 van Goor H (2007) Consequences and complications of peritoneal adhesions (cont.) Key Assumptions (cont.): Adhesions to the ventral abdominal wall are responsible for the majority of trocar injuries Both trocar injuries and inadvertent enterotomies result in conversion from laparoscopy to laparotomy in almost 100% of cases Dissecting adhesions before executing the planned operation takes on average 20 minutes, which is 1/5 of the total operating time in patients having had previous open colorectal surgery There is some evidence that postoperative morbidity and mortality of patients who need adhesiolysis is higher than that of patients with a virgin abdomen The necessity to dissect adhesions is associated with increased hospital stay Postsurgical adhesions are considered a main reason for conversion from laparoscopy to laparotomy in many types of procedures, including laparoscopic colonic resection The high caseloads of gynaecological and some colorectal practises suggest an enormous impact of adhesion-related, chronic, abdominal, and pelvic pain on patients well-being and socioeconomic costs Key Findings: Reoperation through a previous wound can be time-consuming, difficult, and potentially dangerous as a result of adhesion formation. Various adhesion-related aspects of reoperation have been studied in the past decade: 1. Adhesiolysis time to re-enter the abdominal cavity and to reach the site of pathology 2. Intra-operative complications of adhesion dissection 3. Postoperative morbidity and mortality and length of hospital stay of reoperated patients 4. Safe trocar placement at laparoscopy 5. Conversion rates from laparoscopy to laparotomy due to adhesions

10 Clinical Impact of Post-Surgical Adhesions 1.3 van Goor H (2007) Consequences and complications of peritoneal adhesions (cont.) Key findings: publications on adhesiolysis times Median (range) entry time (min) Median (range) other adhesiolysis time (min) Median (range) other adhesiolysis time (min) First author/year Type of surgery Virgin abdomen or no adhesion prevention Reoperation or no adhesion prevention Virgin abdomen or no adhesion prevention Reoperation or no adhesion prevention Virgin abdomen or no adhesion prevention Reoperation or no adhesion prevention Coleman, 2000 Colorectal 5 (3-10) 8 (4-39)* 0 (0-30)* 15 (0-240) 5* 23 Beck, 2000 Colorectal 6 (2-24) 21 (8-45) Beck, 2000 Benign colorectal Unknown Unknown 34 (1-240) Tang, 2003 (phase I) Tang, 2003 (phase II) Salum, 2006 Kusunoki, 2005 Inoue, 2005 Loop ileostomy closure Loop ileostomy closure Loop ileostomy closure Loop ileostomy closure Stomal closure paediatric n/a n/a n/a n/a 32.5 (10-80) 30 (10-125) n/a n/a n/a n/a 20 (10-40) 20 (10-40) n/a n/a n/a n/a 28 (no ranges given) n/a n/a n/a n/a 95 (65-140)* 105 (65-175) Unknown Unknown 41 (20-73)* 82.4 (31-185) Perrone, 2005 Lap ventral hernia repair n/a n/a n/a n/a >45 minute adhesiolysis in 27% of patients *Significant

11 Clinical Impact of Post-Surgical Adhesions 1.3 van Goor H (2007) Consequences and complications of peritoneal adhesions (cont.) Key Findings (continued): Adhesiolysis time Mean time required for lysis of adhesions was about 1/5 of total mean operative time Intra-operative complications More than 50% of enterotomies occurred when adhesions in the lower abdomen and pelvis were divided and 30% when adhesions were divided to enter the abdomen Adhesiolysis was associated with increased blood loss on average 900 ml following extended adhesiolysis in the group of pouch patients having taken part in the Seprafilm Outcome Study Postoperative morbidity and mortality and length of stay of reoperated patients Morbidity and mortality of reoperations seemed higher than in historical control groups Inadvertent enterotomy during adhesiolysis significantly increased morbidity, when taking into account the high ICU admission rate, the necessity for total parenteral nutrition, and longer stay in hospital Safe trocar placement at laparotomy A midline vertical laparotomy induces adhesions to the anterior abdominal wall in about 70% of patients, whereas adhesions are present in about 25% after (suprapubic) transverse incision One-third of the adhesions involve bowel and 2/3 omentum with an increase of this ratio at midline incisions above the umbilicus Conversion from laparoscopy to laparotomy due to adhesions The relative contribution of adhesions to the number of conversions varies with the type of laparoscopic procedure, but exceeds 20% in the majority of reports

12 Clinical Impact of Post-Surgical Adhesions 1.3 van Goor H (2007) Consequences and complications of peritoneal adhesions (cont.) Conclusions: Consequences and complications of postoperative adhesions other than small-bowel obstruction seem to be diverse and many Adhesion-related increased operating time, inadvertent enterotomy, intra-operative bleeding, trocar injury, conversion from laparoscopy to laparotomy, surgical site infection, prolonged length of hospital stay, and chronic abdominal and pelvic pain have major clinical and socioeconomic impact Based on prevalences and physical and emotional consequences, the majority of these complications warrant proper patient counselling and informed consent Awareness of adhesion-related consequences and complications other than small-bowel obstruction by physicians and patients should be stimulated to reduce the morbidity and mortality of postsurgical peritoneal adhesions Reference: van Goor H. Consequences and complications of peritoneal adhesions. Colorectal Dis. 2007; 9(suppl 2):25-34.

13 Clinical Impact of Post-Surgical Adhesions 1.4 ten Broek RPG et al. (2013) Burden of adhesions in abdominal and pelvic surgery: systematic review and met-analysis Study Type: Systematic review and meta-analyses Patient population: Outcomes review of patients undergoing abdominopelvic surgery PRIMARY/CONFIRMATORY DIAGNOSIS: Various, including inflammatory bowel disease AMOUNT AND PLACEMENT OF ADHESION PRODUCT: Not applicable Objective(s): Estimate the disease burden of the most important complications of postoperative abdominal adhesions: small-bowel obstruction, difficulties at reoperation, infertility, and chronic pain Hypothesis: A more valid estimate of the disease burden of adhesions will increase the awareness of this complication, which can be used in counselling and clinical practise Methodology: Two researchers (RPGtB and YI) searched the Cochrane Central Register of Controlled Trials, PubMed, and Embase from January 1990 to December 2012 using the search terms for small-bowel obstruction, incidence and morbidity of small-bowel obstruction, female infertility, chronic pain, and history of abdominal surgery listed 196 eligible papers were identified The incidence of the four most important complications of postoperative adhesion formation was studied: small-bowel obstruction, difficulties at repeated abdominal surgery, female infertility, and chronic pain Subgroup and sensitivity analyses were done to study the robustness of the results A random effects model was used to account for heterogeneity between studies

14 Clinical Impact of Post-Surgical Adhesions 1.4 ten Broek RPG et al. (2013) Burden of adhesions in abdominal and pelvic surgery: systematic review and met-analysis (cont.) Primary Outcome: The primary outcome was the incidence of adhesive small-bowel obstruction in patients with a history of abdominal surgery Secondary Outcome: Secondary outcomes were the incidence of small-bowel obstruction by any cause, difference in operative time, enterotomy during adhesiolysis, and pregnancy rate after abdominal surgery Key Findings: Heterogeneity was considerable for almost all meta-analyses, yet its origin could not be explained by study design, study quality, publication date, anatomical site of operation, or operative technique The incidence of small-bowel obstruction by any cause after abdominal surgery was 9% (95% confidence interval 7% to 10%; I 2 =99%) The incidence of adhesive small-bowel obstruction was 2% (2% to 3%; I 2 =93%); presence of adhesions was generally confirmed by emergent reoperation In patients with a known cause of small-bowel obstruction, adhesions were the single most common cause (56%, 49% to 64%; I 2 =96%) Operative time was prolonged by 15 minutes (95% confidence interval 9.3 to 21.1 minutes; I 2 =85%) in patients with previous surgery Use of adhesiolysis resulted in a 6% (4% to 8%; I 2 =89%) incidence of iatrogenic bowel injury The pregnancy rate after colorectal surgery in patients with inflammatory bowel disease was 50% (37% to 63%; I 2 =94%), which was significantly lower than the pregnancy rate in medically treated patients (82%, 70% to 94%; I 2 =97%) Conclusions: This review provides detailed and systematically analysed knowledge of the disease burden of adhesions Complications of postoperative adhesion formation are frequent, have a large negative effect on patients health, and increase workload in clinical practise The quantitative effects should be interpreted with caution, owing to large heterogeneity of the studies Reference: ten Broek RPG, Issa Y, van Santbrink EJP, et al. Burden of adhesions in abdominal and pelvic surgery: systematic review and met-analysis [published online October 3, 2013]. BMJ. 2013;347:f5588. doi: /bmj.f5588.

15 2. Product Safety Study 2.1 Beck DE et al. (2003)

16 Product Safety Study 2.1 Beck DE et al. (2003) A prospective, randomized, multicenter, controlled study of the safety of Seprafilm Adhesion Barrier in abdominopelvic surgery of the intestine Study Type: Prospective, randomised, multicenter, single-blind, controlled, multinational Patient population: N=1,791 randomised to receive Seprafilm or no treatment prior to abdomen closure PRIMARY/CONFIRMATORY DIAGNOSIS: Ulcerative colitis, Crohn s disease, diverticular disease, fistula, and polyps AMOUNT AND PLACEMENT OF ADHESION PRODUCT: Patients in the Seprafilm-treatment group received a mean of 4.4 (range, ) sheets; additional sheets used for additional surgeries Seprafilm was applied to adhesiogenic tissues throughout the abdomen Objective(s): To evaluate the safety of Seprafilm in a population of patients undergoing abdominopelvic surgery To evaluate concurrently the postoperative incidence of abdominal and pelvic abscess and pulmonary embolism Hypothesis: Seprafilm is not associated with a higher incidence of abdominal and pelvic abscess or pulmonary embolism Methodology: Patients were randomised to either the Seprafilm (n=882) or control group (n=909) after completion of the main portion of the operation just before abdominal closure Occurrence of complications and death were assessed 1 month after surgery Each parameter was evaluated on the occurrence of leak, abscess, fistula, peritonitis, sepsis, or 1 or more of these adverse events

17 Product Safety Study 2.1 Beck DE et al. (2003) A prospective, randomized, multicenter, controlled study of the safety of Seprafilm Adhesion Barrier in abdominopelvic surgery of the intestine (cont.) Primary Endpoint(s): Occurrence of abdominal abscess, pulmonary embolism, and foreign body reaction within first month of surgery Secondary Endpoint(s): Not applicable Safety Results: Safety was measured across the following parameters Parameter Seprafilm (n=882) Control (n=909) P Value Total abscess 37 (4) 29 (3) Abdominal abscess 27 (3) 17 (2) Pelvic abscess 11 (1) 12 (1) 1 Pulmonary embolism 4 (<1) 3 (<1) Foreign body reaction 0 (0) 0 (0) 1 Serious adverse events 249 (28) 223 (25)

18 Product Safety Study 2.1 Beck DE et al. (2003) A prospective, randomized, multicenter, controlled study of the safety of Seprafilm Adhesion Barrier in abdominopelvic surgery of the intestine (cont.) Efficacy Results: Efficacy results were reported by Fazio et al in the following: Fazio V, Cohen Z, Fleshman J, et al. Reduction in adhesive small-bowel obstruction by Seprafilm Adhesion Barrier after intestinal resection. Dis Colon Rectum 2005;49:1-11 Safety Results: There was no difference between the Seprafilm and control groups in the incidence of abscess (4% versus 3%, respectively) or pulmonary embolism (1% in each group) In addition, there were no reports of foreign body reaction in either study group In a subgroup analysis, incidences of fistula, leak, and peritonitis were statistically greater in the Seprafilm group incidence of each event was low (2%-4% in the Seprafilm group versus <1%-2% in the control group) Since there was no difference between the groups when Seprafilm was not wrapped, additional controlled studies are needed to explore the positive/negative aspects of wrapping an anastomosis with Seprafilm Conclusions: This study confirmed the safety of Seprafilm adhesion barrier with respect to abdominal abscess, pelvic abscess, and pulmonary embolism when administered to patients undergoing abdominopelvic surgery Foreign body reaction was not reported for any patient However, wrapping the suture or staple line of a fresh bowel anastomosis with Seprafilm should be avoided, because the data suggest that this practise may increase the risk of sequelae associated with anastomotic leak Reference: Beck DE, Cohen Z, Fleshman JW, Kaufman HS, van Goor H, Wolff BG; Adhesion Study Group Steering Committee. A prospective, randomised, multicenter, controlled study of the safety of Seprafilm adhesion barrier in abdominopelvic surgery of the intestine. Dis Colon Rectum. 2003;46(10):

19 3. Reduced Incidence and Severity of Adhesions 3.1 Becker JM et al. (1996) 3.2 Kusunoki M et al. (2005) 3.3 Dupré A et al. (2013)

20 Reduced Incidence and Severity of Adhesions 3.1 Becker JM et al. (1996) Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomised, double-blind multicenter study Study Type: Controlled, prospective, randomised, multicenter, double-blind Patient population: N=183 randomised to receive Seprafilm or no treatment prior to abdomen closure PRIMARY/CONFIRMATORY DIAGNOSIS: Chronic ulcerative colitis or familial adenomatous polyposis AMOUNT AND PLACEMENT OF ADHESION PRODUCT: Patients in the Seprafilm-treatment group received an average of 2 sheets placed directly over the omentum and small bowel Objective(s): To assess the incidence of post-operative adhesions after a standardised, major, abdominal operation using direct laparoscopic peritoneal imaging To determine the safety and efficacy of Seprafilm in preventing or reducing postoperative adhesions Hypothesis: Seprafilm safely and effectively reduces the incidence, extent, and severity of postoperative formation of adhesions at placement sites in the abdomen Methodology: Patients were randomised immediately before closure of the abdomen An evaluator at each study site, blinded to the patients and random assignments, evaluated adhesions by laparoscopic imaging to assess the incidence, extent, and severity of postoperative adhesions to the midline incision

21 Reduced Incidence and Severity of Adhesions 3.1 Becker JM et al. (1996) Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomised, double-blind multicenter study (cont.) Primary Endpoint(s): Incidence, extent, and severity of postoperative abdominal adhesion formulation Secondary Endpoint(s): Determine the safety and effectiveness of the sodium hyaluronate-based bioresorbable membrane in preventing post-operative adhesions Adhesion classification Seprafilm n=86 Control group n=90 No adhesions 43 5 Grade Grade Grade

22 Reduced Incidence and Severity of Adhesions 3.1 Becker JM et al. (1996) Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomised, double-blind multicenter study (cont.) Efficacy Results: The incidence of patients with 1 or more adhesions to the midline incision was significantly reduced from 94% in the control group to 49% in the Seprafilm group The mean extent of adhesions to the incision line was 63% in the control group versus 23% in the Seprafilm group In those patients who received Seprafilm and developed adhesions, the incidence of dense adhesions was only 15% (compared to 58% in the non-seprafilm group) Safety Results: Alterations in vital signs, complete blood cell counts, electrolytes, liver function, and renal function were similar between study groups No statistically significant difference in the incidence of adverse events between study groups Conclusions: The reduced incidence, extent, and severity of adhesions in patients receiving Seprafilm demonstrated that it acts effectively as an adhesion barrier Seprafilm did not compromise patient safety Additional Findings: Despite the fact that by study design the omentum was preserved, 63% of patients in the control group had a portion of small intestine adhered to the midline incision Reference: Becker JM, Dayton MT, Fazio VW, et al. Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomised, double-blind multicenter study. J Am Coll Surg. 1996;183(4):

23 Reduced Incidence and Severity of Adhesions 3.2 Kusunoki M et al. (2005) Bioresorbable hyaluronate-carboxymethylcellulose membrane (Seprafilm) in surgery for rectal carcinoma: a prospective randomised clinical trial Study Type: Long-term follow-up of a randomised clinical trial Patient population: N=62 enrolled, and n=59 analysed: 30 patients had Seprafilm and 29 did not have Seprafilm PRIMARY/CONFIRMATORY DIAGNOSIS: Rectal carcinoma over stage II AMOUNT AND PLACEMENT OF ADHESION PRODUCT: Under the midline incision (mean 1.9 units) and in the pelvis (mean 1.3 units) Objective(s): To determine the long-term effect of Seprafilm on the incidence of adhesions and subsequent smallbowel obstruction and chronic abdominal complaints after colorectal surgery Hypothesis: Seprafilm may play a role in the prevention of abdominal adhesions after chemotherapy and radiotherapy without affecting tumour implantation Methodology: All patients received preoperative radiotherapy, followed by a 2-stage operation and systemic chemotherapy Adhesion formation was assessed when patients returned for ileostomy closure using laparoscopic imaging (midline incision and peristomal areas) The stoma incision was closed around a laparoscopic cannula and the abdominal cavity was insufflated to allow visualisation of the previous incision

24 Reduced Incidence and Severity of Adhesions 3.2 Kusunoki M et al. (2005) Bioresorbable hyaluronate-carboxymethylcellulose membrane (Seprafilm) in surgery for rectal carcinoma: a prospective randomised clinical trial (cont.) Primary Endpoint(s): Severity and extent of adhesions at the time of ileostomy closure Secondary Endpoint(s): Recurrence of tumours, late complication, complications, and outcome Midline adhesions Severity Seprafilm n=30 Control group n=29 Grade Grade Grade Grade Extent Seprafilm n=30 Control group n=29 Grade Grade Grade Grade 3 0 7

25 Reduced Incidence and Severity of Adhesions 3.2 Kusunoki M et al. (2005) Bioresorbable hyaluronate-carboxymethylcellulose membrane (Seprafilm) in surgery for rectal carcinoma: a prospective randomised clinical trial (cont.) Peristomal adhesions Severity Seprafilm n=30 Control group n=29 Grade Grade Grade Grade Extent Seprafilm n=30 Control group n=29 Grade Grade Grade Grade

26 Reduced Incidence and Severity of Adhesions 3.2 Kusunoki M et al. (2005) Bioresorbable hyaluronate-carboxymethylcellulose membrane (Seprafilm) in surgery for rectal carcinoma: a prospective randomised clinical trial (cont.) EFFICACY RESULTS Seprafilm n=30 Control group n=29 P value Midline incision 26 (8%) 4 (13.8%) <0.001 Stomal incision 4 (13%) 0 (%) Safety Results: Seprafilm was not associated with any postoperative complications or chemoradiation-related toxicity Seprafilm did not affect recurrence of tumours and the 5-year survival rate Conclusions: Seprafilm effectively reduced abdominal adhesions in chemoradiated patients and had no adverse events on the oncologic results Additional Findings: Operation time, blood loss, and necessity to extend the skin incision were significantly reduced by the use of Seprafilm, indicating that Seprafilm makes repeated laparotomy easier Reference: Kusunoki M, Ikeuchi H, Yanagi H, et al. Bioresorbable hyaluronate-carboxymethylcellulose membrane (Seprafilm) in surgery for rectal carcinoma: a prospective randomised clinical trial. Surg Today. 2005;35(11):

27 Reduced Incidence and Severity of Adhesions 3.3 Dupré A et al. (2013) Use of bioresorbable membranes to reduce abdominal and perihepatic adhesions in 2-stage hepatectomy of liver metastases from colorectal cancer Study Type: Prospective, randomised, controlled phase II Patient population: N=54, randomised 3:1 ratio to receive Seprafilm or non-use prior to second hepatectomy PRIMARY/CONFIRMATORY DIAGNOSIS: Metastatic colorectal cancer with liver involvement AMOUNT AND PLACEMENT OF ADHESION PRODUCT: 2 (12.7x15.2 cm) sheets applied to anterosuperior surface of liver; 2 half sheets to inferior surface of liver and hepatic pedicle; fourth sheet to surface of stomach, colon, and intestine under the abdominal wound Objective(s): To assess the feasibility, safety, and efficacy of using Seprafilm to prevent abdominal and perihepatic adhesions in metastatic colorectal cancer patients Hypothesis: The use of Seprafilm may facilitate second-stage hepatectomies by reducing difficulties in access and dissection, operative time, blood loss, and risk of organ injury and other peri- and postoperative complications Methodology: 41 patients were randomised into the Seprafilm group, 13 into the control group Patients were assessed by clinical examination, CT scan, liver ultrasonography, and serum tumour markers 1 month postoperatively, then every 3 months for 2 years, and every 6 months thereafter Incidence, extent, and severity of midline adhesions were evaluated when the abdomen was open at the start of the second hepatectomy Abdominal and perihepatic adhesions were graded by extent and severity Postoperative 30- and 90-day morbidity and mortality were recorded Postoperative complications were classified according to severity

28 Reduced Incidence and Severity of Adhesions 3.3 Dupré A et al. (2013) Use of bioresorbable membranes to reduce abdominal and perihepatic adhesions in 2-stage hepatectomy of liver metastases from colorectal cancer (cont.) Primary Endpoint(s): Time to achieve complete liver mobilisation at second hepatectomy Secondary Endpoint(s): Incidence, extent, and severity of adhesions at second hepatectomy; blood loss during initial phase of liver mobilisation; perioperative morbidity at first and second hepatectomy Adhesion(s): Of the 54 patients randomised before abdominal closure at first hepatectomy, 13 were ineligible for second procedure Adhesion classification at second hepatectomy Seprafilm n=30 Control group n=11 Extent grade % 54.5% Severity grade % 45.5% Grade extent of abdominal or perihepatic adhesions for treatment group 0 None 1 Minor, covering up to 25% of the total liver surface or length of abdominal scar 2 Moderate, covering 26% 50% of the total liver surface or length of abdominal scar 3 Severe, covering 51% 75% of the total liver surface or length of abdominal scar 4 Major, covering more than 75% of the total liver surface or length of abdominal scar Grade severity of abdominal or perihepatic adhesions for control group 0 None 1 Filmy adhesion, easy to divide by blunt dissection 2 Stronger adhesion, but easily divided by sharp dissection, beginning of vascularisation 3 Thick vascular adhesion, lysis possible by sharp dissection only 4 Strong and dense adhesion; at risk of organ injury with division

29 Reduced Incidence and Severity of Adhesions 3.3 Dupré A et al. (2013) Use of bioresorbable membranes to reduce abdominal and perihepatic adhesions in 2-stage hepatectomy of liver metastases from colorectal cancer (cont.) Efficacy Results: At second hepatectomy, patients in the Seprafilm group required 33% less time to achieve complete liver stabilisation The risk of hepatectomy adhesions was reduced in the Seprafilm group (31% had grade 3-4 adhesions versus 55% in the control group) Adhesion severity was reduced in the Seprafilm group (17% thick and hypervascular adhesions versus 46% in control group) Safety Results: Proportion of patients having at least 1 complication after second hepatectomy was 23.3% in the Seprafilm group versus 54.6% in the control group Additional Information: Good hemostasis is required for optimum bioresorbable membrane positioning on the liver, and it is possible that the need to achieve this contributed to the lower rate of postoperative adhesions This study is the first randomised controlled trial to investigate the use of Seprafilm in staged hepatectomy Conclusions: Use of 4 Seprafilm sheets at the end of the first hepatectomy reduced the extent and severity of adhesions and facilitated the second hepatectomy A larger study to confirm these findings is warranted Reference: Dupré A, Lefranc A, Buc E, et al. Use of bioresorbable membranes to reduce abdominal and perihepatic adhesions in 2-stage hepatectomy of liver metastases from colorectal cancer: results of a prospective, randomised controlled Phase II trial. Ann Surg. 2013;258(1):30-36.

30 4. Impact on Re-Operation 4.1 Tang C-L et al. (2003) 4.2 Kawamura H et al. (2010)

31 Impact on Re-Operation 4.1 Tang C-L et al. (2003) Bioresorbable adhesion barrier facilitates early closure of the defunctioning ileostomy after rectal excision Study Type: Randomised, prospective trial Procedure Type: Closure of defunctioning ileostomy PRIMARY/CONFIRMATORY DIAGNOSIS: Rectal cancer, rectosigmoid cancer, radiation stricture/proctitis, rectal prolapse/cap polyposis 2, diverticular disease, rectal metastasis, endometriosis and rectal stricture, rectal carcinoid; any colorectal pathology that required elective rectal resection and a defunctioning ileostomy PATIENT POPULATION: Patients undergoing elective resection of rectum requiring loop ileostomy Phase I: n=105; phase II: n=70 AMOUNT OF ADHESION PRODUCT USED: Two 12 cm strips, with one cut in half lengthwise ADHESION PLACEMENT SITE: Around the serosal surface of the two limbs of the loop ileostomy Objective(s): Determine the incidence of peristomal adhesions at the time of stomal mobilisation Determine the impact of bioresorbable membrane to minimise peristomal adhesions and facilitate earlier closure Hypothesis: Small intestinal-wall oedema from the initial surgery typically resolves to allow mobilisation and early closure after 3 weeks (as opposed to the 6 to 12-week standard of practise) Reduction in peristomal adhesions will facilitate early closure at 3 to 4 weeks after surgery (without anastomotic dehiscence)

32 Impact on Re-Operation 4.1 Tang C-L et al. (2003) Bioresorbable adhesion barrier facilitates early closure of the defunctioning ileostomy after rectal excision (cont.) Primary Endpoint(s): Reduced postoperative peristomal adhesions through the use of a bioresorbable adhesion barrier membrane as an aid in early closure of the defunctioning ileostomy at 3 weeks after surgery Secondary Endpoint(s): N/A Methodology: The study was conducted in two phases. Phase I: n=105 (Seprafilm treatment group=51; control group=54) Patients undergoing creation of a defunctioning ileostomy were randomised in phase I either to have an adhesion barrier membrane wrapped around the limbs of the ileostomy (with closure at 3 weeks) or to the control group (with no barrier membrane and closure at 6+ weeks) Subsequent phase II trial examined efficacy of the barrier membrane compared in a similar manner with a control group at ileostomy reversal after 3 weeks The results of phase I prompted subsequent observer blinded trial (phase II) comparing the use of the adhesion barrier (HAL-II) at 3 weeks (34 patients) versus another control group (36 patients) with ileostomy closure within 3 weeks without use of the barrier (CON-II) Footnote: HAL-II = treatment group using adhesion barrier; CON-II = control group in phase 2

33 Impact on Re-Operation 4.1 Tang C-L et al. (2003) Bioresorbable adhesion barrier facilitates early closure of the defunctioning ileostomy after rectal excision (cont.) Efficacy Results: Phase I: No statistically significant differences in the mean adhesion scores between the 2 groups (7.42 versus 7.28) Efficacy Results: Phase II: Significant reduction in the overall mean adhesion scores with and without adhesion barrier placement (5.81 versus 7.82, respectively) Ease of closure (as evidenced by a lower incidence of perioperative complications) was noted in the adhesion barrier group Stomal retraction related to reduction in peristomal adhesions was more common in the adhesion barrier groups in the 2 phases of the trial (12.5% versus 5% in the entire study period) The number of patients with dense adhesions was also reduced in the adhesion barrier group There was no significant difference in the time taken and the difficulty encountered during ileostomy closure in the 2 groups Safety Results: Problems encountered and additional work at closure of ileostomy (per protocol patients only; see summary table) The CON-II group appeared to have a higher incidence of severe postoperative complications, such as enterocutaneous fistula and leak, than did the HAL-II group Footnote: HAL-II = treatment group using adhesion barrier; CON-II = control group in phase 2 (with no barrier membrane and closure at 6+ weeks)

34 Impact on Re-Operation 4.1 Tang C-L et al. (2003) Bioresorbable adhesion barrier facilitates early closure of the defunctioning ileostomy after rectal excision (cont.) Summary of perioperative outcome of ileostomy closure: problems encountered/ additional work at closure of ileostomy (per protocol patients only) Summary: Phase I Summary: Phase II Barrier 3 weeks (HAL-I) Control >6 weeks (CON-I) Barrier 3 weeks (HAL-II) Control 3 weeks (CON-II) None Dense adhesions (>5 serosal tears ± enterotomy with repair) Dense adhesions with extension of incision for mobilisation Conclusions: A slightly greater number of patients in the treatment group who had problems (such as enterotomies, the need for bowel resection, extension of the surgical incision, and adhesiolysis) at closure were encountered in the early part of phase I; this was probably a result of the initial learning curve for placement of the adhesion barrier membrane Phase II results showed that an adhesion barrier membrane placed around the limbs of a defunctioning loop ileostomy reduces peristomal adhesion Phase II showed early closure possible at 3 weeks with minimal complications compared with that of conventional closure at 6+ weeks Secure membrane placement can be assured pending the absence of any post-lavage fluid in the peritoneal cavity Reference: Tang C-L, Seow-Choen F, Fook-Chong S, Eu K-W. Bioresorbable adhesion barrier facilitates early closure of the defunctioning ileostomy after rectal excision: a prospective, randomised trial. Dis Colon Rectum. 2003;46(9):

35 Impact on Re-Operation 4.2 Kawamura H et al. (2010) A sodium hyaluronate carboxymethylcellulose bioresorbable membrane prevents postoperative small-bowel adhesive obstruction after distal gastrectomy Study Type: Retrospective PATIENT POPULATION: N=282 randomised to receive Seprafilm or no treatment prior to abdomen closure for open distal gastrectomy (DG) PRIMARY/CONFIRMATORY DIAGNOSIS: Gastric cancer AMOUNT OF ADHESION PRODUCT USED: One sheet of Seprafilm was used and placed directly under the surgical wounds Objective(s): Compare incidence of adhesive small-bowel obstruction in Seprafilm versus non-seprafilm group Hypothesis: Since distal gastrectomy (DG) with Billroth I anastomosis generally involves a median incision up to 20 cm long and does not involve any structure beyond the transverse colon, it is predicted that the main cause of adhesive obstruction originates from the surgical wound DG is therefore an appropriate operation to demonstrate the efficacy of Seprafilm when it is placed under the incision Methodology: Retrospective comparison of the incidence of adhesive obstructions in the Seprafilm group (n=113) and the non-seprafilm group (n=169) Primary Endpoint(s): Incidence of adhesive obstruction requiring additional surgery Secondary Endpoint(s): Costs incurred (JPN ) related to adhesive obstruction after DG in the 10 last cases

36 Impact on Re-Operation 4.2 Kawamura H et al. (2010) A sodium hyaluronate carboxymethylcellulose bioresorbable membrane prevents postoperative small-bowel adhesive obstruction after distal gastrectomy (cont.) Efficacy Results: The incidences of adhesive obstruction 2 years after surgery were 0.9% in the Seprafilm group versus 6.5% in the non-seprafilm group (P=0.021) The cumulative incidence of adhesive obstruction was significantly lower in the Seprafilm group than in the non-seprafilm group (P=0.021) Multivariate analysis of the occurrence of adhesive obstruction revealed no significant differences in sex, age, body mass index, operation time, blood loss, or degree of lymph-node dissection; however, it did reveal a significant difference in relation to the use of Seprafilm (P=0.049) Overall there were 16 cases of adhesive obstruction: 1 in the Seprafilm group and 15 in the non-seprafilm group Four (25%) of these patients required abdominal surgery, all of whom were in the non-seprafilm group The cost performance of Seprafilm related to the decreased incidence of surgical obstruction was deemed negligible (JPN 6,851 additional cost for procedures where Seprafilm is used) Safety Results: There were no significant differences in anastomotic leakage, intra-abdominal infection, wound infection, or pancreatic leakage between the groups Conclusion: Seprafilm reduced the incidence of adhesive obstruction after DG significantly; however, a prospective randomised study will be necessary to confirm this result Reference: Kawamura H, Yokota R, Yokota K, et al. A sodium hyaluronate carboxymethylcellulose bioresorbable membrane prevents postoperative small-bowel adhesive obstruction after distal gastrectomy. Surg Today. 2010;40(3):

37 5. Reduced Risk of Adhesive small-bowel Obstruction (asbo) 5.1 Fazio VW et al. (2006) 5.2 Mohri Y et al. (2005) 5.3 Park C-M et al. (2008)

38 Reduced Risk of Adhesive Small-Bowel Obstruction (asbo) 5.1 Fazio VW et al. (2006) Reduction in adhesive small-bowel obstruction (ASBO) by Seprafilm adhesion barrier after intestinal resection Study Type: Prospective, randomised, multicentre, single-blind, controlled, multinational Patient population: N=1,791 randomised to receive Seprafilm or no treatment prior to abdomen closure PRIMARY/CONFIRMATORY DIAGNOSIS: Ulcerative colitis, Crohn s disease, diverticular disease, fistula, and polyps AMOUNT AND PLACEMENT OF ADHESION PRODUCT: Patients in the Seprafilm treatment group received a mean of 4.4 (range, ) sheets; additional sheets used for additional surgeries Seprafilm was applied to adhesiogenic tissues throughout the abdomen Objective(s): Compare incidence and type of bowel obstruction between intestinal resection patients who received Seprafilm and those who did not Hypothesis: A relative reduction of 25% bowel obstruction with Seprafilm was assumed to constitute a clinically meaningful benefit Sample size calculations were based on a 2-year incidence of 20% of all classes of bowel obstruction combined in the no-treatment control group Methodology: Patients undergoing intestinal resection were randomised to receive Seprafilm or no treatment before closure Patients undergoing additional procedure for closure of temporary ileostomy received an additional sheet of Seprafilm at the site of the stoma Incidence and type of bowel obstruction was compared between treatment/non-treatment groups

39 Reduced Risk of Adhesive Small-Bowel Obstruction (asbo) 5.1 Fazio VW et al. (2006) Reduction in adhesive small-bowel obstruction (ASBO) by Seprafilm adhesion barrier after intestinal resection (cont.) Primary Endpoint(s): To compare the incidence of all types of bowel obstruction between the treatment and control groups Secondary Endpoint(s): Predictive factors for reducing adhesive small-bowel obstructions that require additional operation(s) Bowel-obstruction Classifications: Class I: Confirmatory requirement a: Definitive evidence from surgery or autopsy (adhesive and non-adhesive) b: Indirect assessment from X-ray or CT scan Class II: Indirect assessment indicates or fails to rule out clinical symptoms, and X-ray or CT indicates or fails to rule out, and medical records suspect or confirm Efficacy Results: No difference found between treatment and control groups in the overall rate of bowel obstruction The incidence of adhesive small-bowel obstruction requiring reoperation was 1.8% for Seprafilm versus 3.4% in patients with no-treatment (P< 0.05) (reduction rate in ASBO requiring reoperation of 1.6% and a relative reduction of 47%) Seprafilm was the only predictive factor for reducing ASBO requiring reoperation (P=0.043) For additional data on bowel obstruction, please see the Seprafilm preliminary results: bowel obstruction (BO) chart Safety Results: Safety results were reported by Beck et al in the following: Beck DE, Cohen Z, Fleshman JW, Kaufman HS, van Goor H, Wolff BG; Adhesion Study Group Steering Committee. A prospective, randomised, multicenter, controlled study of the safety of Seprafilm Adhesion Barrier in abdominopelvic surgery of the intestine. Dis Colon Rectum. 2003;46(10):

40 Reduced Risk of Adhesive Small-Bowel Obstruction (asbo) 5.1 Fazio VW et al. (2006) Reduction in adhesive small-bowel obstruction (ASBO) by Seprafilm adhesion barrier after intestinal resection (cont.) Incidence of SBO (%) Control NS 12 Seprafilm 12% Control: n=903 SBO+LBO events=106 All Patients: n=1,791 SBO+LBO n=215 12% Seprafilm: n=888 SBO+LBO events=109 Incidence of SBO (%) Control NS 2.0 Seprafilm 3.3% Class Ia: n=903 Adhesive SBO events=30 Class Ia: n=903* SBO+LBO events=36 Class I: n=903 SBO+LBO events=43 Class Ia: n=903 Non-adhesive SBO+LBO events=6 Class Ib: n=903** SBO+LBO events=12 2% Class II: n=903 SBO+LBO events=63 Class Ia: n=888 Adhesive SBO events=18 Class Ia: n=888* SBO+LBO events=24 Class I: n=888 SBO+LBO events=37 Class Ia: n=888 Non-adhesive SBO+LBO events=6 Class Ib: n=888* SBO+LBO events=15 Class II: n=888 SBO+LBO events=72 Incidence of SBO (%) Control P< Seprafilm Colorectal resections: n=861 Adhesive SBO events=29 Adhesiolysis for SBO: n=42 Adhesive SBO events=1 Colorectal resections: n=840 Adhesive SBO events=15 3.4% 1.8% Adhesiolysis for SBO: n=48 Adhesive SBO events=3 * Class Ia= adhesive or non-adhesive bowel obstruction confirmed by surgery or autopsy; Class 1b=bowel obstruction confirmed radiologically; **Class Ia and Ib are not mutually exclusive.

41 Reduced Risk of Adhesive Small-Bowel Obstruction (asbo) 5.1 Fazio VW et al. (2006) Reduction in adhesive small-bowel obstruction (ASBO) by Seprafilm adhesion barrier after intestinal resection (cont.) Conclusions: This study establishes Seprafilm as the first adhesion barrier device proven safe and effective for reducing the incidence of postoperative adhesions and ASBO associated with intestinal resections Study revealed a surprisingly low incidence of overall and adhesive SBO after intestinal resection and anastomosis There was no significant difference between treatment and control groups in the overall rate of small-bowel obstruction The use of Seprafilm was the only predictive factor for reducing adhesive small-bowel obstruction requiring reoperation While the trial was designed with the assumption that there is a 20% incidence of bowel obstruction, the trial determined this to be 12% for both the Seprafilm and control arms Additional Findings: In both groups, 50% of first ASBO episodes occurred within 6 months nearly 30% occurring within the first 30 days The most accurate determination of SBO was a second surgery (class Ia type of obstruction) Reference: Fazio VW, Cohen Z, Fleshman JW, et al. Reduction in adhesive small-bowel obstruction by Seprafilm adhesion barrier after intestinal resection. Dis Colon Rectum. 2006;49(1):1-11.

42 Reduced Risk of Adhesive Small-Bowel Obstruction (asbo) 5.2 Mohri Y et al. (2005) Hyaluronic acid-carboxycellulose membrane (Seprafilm) reduces early postoperative small-bowel obstruction in gastrointestinal surgery Study Type: Retrospective Patient population: N=367 (184 Seprafilm group of patients undergoing elective gastrointestinal surgery versus 183 patients in a comparative control group) PRIMARY/CONFIRMATORY DIAGNOSIS: Patients undergoing elective gastrointestinal surgery AMOUNT AND PLACEMENT OF ADHESION PRODUCT: 1 to 2 sheets placed before fascial closure under the incision Objective(s): To evaluate the efficacy of Seprafilm on early postoperative small-bowel obstruction (EPSBO); examine whether Seprafilm affects surgical site infection rates in gastrointestinal surgery Hypothesis: The use of Seprafilm may reduce the incidence of EPSBO Methodology: Patients in the Seprafilm group were compared with a matched control group of patients operated on without Seprafilm All patients were retrospectively assessed for EPSBO and surgical site infections Follow-up means of days in the Seprafilm group and days in the control group

43 Reduced Risk of Adhesive Small-Bowel Obstruction (asbo) 5.2 Mohri Y et al. (2005) Hyaluronic acid-carboxycellulose membrane (Seprafilm) reduces early postoperative small-bowel obstruction in gastrointestinal surgery (cont.) Primary Endpoint(s): Incidence of EPSBO, incidence of surgical site infections Secondary Endpoint(s): Not applicable Efficacy Results: Incidence of EPSBO was significantly lower (P<0.05) in the Seprafilm group (12/184; 6.5%) than the control group (26/183; 14.2%) Safety Results: Incidence of surgical site infections between the Seprafilm (15.2%) and control (13.7%) groups was not statistically significant no statistically significant difference in incidence of wound infection, intra-abdominal abscess, anastomotic dehiscence Conclusions: Seprafilm reduced the incidence of EPSBO after gastrointestinal surgery and did not bring about other complications Additional Findings: The observed incidence of EPSBO in the control group was 14.2%, which is higher than incidences reported by other authors; the large number of colorectal cases may have yielded a higher incidence Reference: Mohri Y, Uchida K, Araki T, et al. Hyaluronic acid carboxycellulose membrane (Seprafilm) reduces early postoperative small-bowel obstruction in gastrointestinal surgery. Am Surg. 2005;71(10):