Abteilung Allgemein- und Viszeralchirurgie Universitätsklinikum Freiburg Pancreatogastrostomy versus Pancreatojejunostomy A randomized controlled trial

Einleitung: Pankreatogastrostomie (PG) vs Pankreatojejunostomie (PJ) Abteilung Allgemein- und Viszeralchirurgie Universitätsklinikum Freiburg Einleitung: Pankreatogastrostomie (PG) vs Pankreatojejunostomie (PJ)

Retrospektive Untersuchung PG vs PJ – eigene Daten Retrospektive Untersuchung n = 229 p < 0.05 Wellner, Keck et al JOGS 2008

Prospektive Untersuchung PG vs PJ – eigene Daten Prospektive Untersuchung POPF im Gesamtkollektiv PJ PG Risikogruppe weiches Pankreas weiches Pankreas hartes Pankreas Wellner, Keck et al DGCH 2009

retrospektiver Studien PG vs PJ – Metaanalyse retrospektiver Studien Wente, Büchler et al AJS 2007

PG vs PJ – Metaanalyse prospektiver Studien Wente, Büchler et al AJS 2007

aktuellste prospektive Studie PG vs PJ aktuellste prospektive Studie Fernandez-Cruz et al Ann Surg 2008

Allgemeine Studieninformation RECOPANC Allgemeine Studieninformation Design Vergleichsstudie ( 2 Gruppen ) randomisiert – kontrolliert – observer blinded multizentrisch (12 Studienzentren) Ziel Vergleich zweier Rekonstruktionstechniken Pankreatogastrostomie (PG) vs Pankreatojejunostomie (PJ) primär bzgl Häufigkeit postoperativer Pankreasfisteln sekundär bzgl perioperative Probleme/Komplikationen langfristig: Pankreasfunktion Lebensqualität

Allgemeine Studieninformation RECOPANC Allgemeine Studieninformation Indikation elektive Pankreatoduodenektomie Patienten to be assessed / allocated / analyzed 400 / 360 / 306 Randomisation 1:1 - Block pro Zentrum - präOP Rekrutierung 2 Jahre Visiten + F/up Screening, OP periOP Tag 3, Entlasstag, Tag 30 langfristig 6Mo, 1J DFG-Antrag assessed / allocated / analyzed 400 / 352 / 306 Änderung von T. Bruckner auf 400 / 360 / 306 Schätzung ca 15% drop-out wegen Inoperabilität

Timeline

Timeline FPI first patient in Juni 2011 LPO last patient out Mai 2014 Final report Ende 2014 Diskussionspunkt voraussichtlicher Zeitpunkt First Patient in

Studienleitung Studienleitung UKF Prof. Dr. Dr. U.T. Hopt UKF Prof. Dr. T. Keck Management SDGC Prof. Dr. C. Seiler Biometrie / IMBI Dr. T. Bruckner Data Management IMBI R. Limprecht Monitoring / SAE ZKS S. Brett analog CHROPAC

Data Safety Monitoring Board Prof. em. Dr. Edgar Brunner Abteilung Medizinische Statistik, Universitätsklinikum Göttingen PD Dr. Roland Croner Geschäftsführender Oberarzt Allgeimeinchirugie, Chirurgische Klinik mit Poliklinik, Universität Erlangen-Nürnberg PD Dr. Robert Gruetzmann Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirgie, Universitätklinikum Dresden gemäß Antrag

Kooperationen Institut für Pathologie, UKF Prof. Dr. Werner Histopathologische Auswertung der Pankreasfibrose gemäß Antrag

Einschlußkriterien 1. Elektive Pankreatoduodenektomie 2. Alter >= 18 Jahre 3. schriftliche Einwilligung

Ausschlußkriterien 1. Teilnahme an einer interferierenden Studie (Ausnahme adjuvante Therapiestudien z.B. Conko) 2. Keine Compliance erwartet

Randomisation zentralisiert web-basiert (Randomizer.at) präoperative Randomisation zentralisiert web-basiert (Randomizer.at) (Blockrandomisation für Zentren) Antrag: Minimizing selection bias. Consecutively screened and eligible patients will be included in the trial at each center after initiation of the study. Patients will be screened on the day of admission and randomized preoperatively using a centralized web based tool which allows block randomization for each center to achieve equal group sizes per center.

Behandlung Arm A jede Form der Pankreatogastrostomie Arm B jede Form der Pankreatojejunostomie mögliche Varianten: PPPD / klassischer Whipple einreihig / zweireihig / duct – mucosa Einzelknopfnaht / fortlaufende / Tabaksbeutelnaht mit / ohne Pankreasgangstent Invaginations – Anastomose End-Seit / End-End PJ gemeinsamer / getrennter jejunaler Schenkel für Pankreasanastomose PG mit / ohne anteriore Gastrotomie offen / laparoskopisch assistiert ...

Primärer Endpunkt Postoperative Pancreatic Fistula (POPF) Grade B or C ISGPS Definition (2005) mit Spezifikationen nach Hashimoto & Traverso 2010 (Studienprotokoll S.15) Hashimoto Y, Traverso LW. Incidence of pancreatic anastomotic failure and delayed gastric emptying after pancreatoduodenectomy in 507 consecutive patients: use of a web-based calculator to improve homogeneity of definition. Surgery 2010;147:503-15. Antrag: Postoperative pancreatic fistula (POPF) is present by definition if on or after postoperative day 3, amylase activity in the peritoneal drain secretion exceeds threefold the upper normal limit of serum amylase activity. Individual values can vary depending on local laboratory standards. POPF is of grade A if criteria of grade B or C are not fulfilled. POPF is of grade B or C if because of POPF - abdominal drains have to be left in place for 30 days** or more (**Bassi: persistent drainage for 3 weeks or more) - hospital stay is prolonged - readmission is necessary - oral food intake is restricted and partial or total parenteral nutrition is necessary - application of antibiotics is necessary - invasive treatment is necessary (percutaneous drainage, reoperation)

Primärer Endpunkt - Analyse Statistische Analyse des Primären Endpunktes Univariat: POPF Grad B/C Multivariat: Pankreastextur Patienten-Alter Erfahrung des Chirurgen Zentrum Subgruppenanalyse: Patienten mit weichem Pankreas Antrag: A binary logistic regression model will be applied for the comparison of fistula rates in both arms adjusting for age, center, surgeon's experience, texture of pancreatic tissue. Analysis of a high-risk subgroup: Patients with a soft pancreas have a higher risk of developing POPF and constitute a high-risk subpopulation. Therefore the question will be, if the POPF rate after PG or PJ is different when only this subgroup is regarded. This is evaluated in a subgroup analysis. Binary logistic regression will be applied for these subgroup analyses.

Sekundäre Endpunkte Mortality death due to any cause during follow-up Surgical Site Complications SSC - POPF postoperative pancreatic fistula of grade A - DGE delayed gastric emptying of grade B or C (ISGPS definition) - PPH postpancreatectomy hemorrhage (ISGPS definition ) - intraabdominal fluid collection requiring invasive treatment - relaparotomy - necessity of completion total pancreatectomy - anastomotic leak other than POPF - wound infection requiring invasive treatment Antrag: Surgical site complications (SSC): - operation time from cut to suture, in minutes (rational scale) - postoperative pancreatic fistula of grade A (ISGPS definition , yes or no) - delayed gastric emptying of grade B or C (ISGPS definition, yes or no) - postpancreatectomy hemorrhage (ISGPS definition, yes or no) - intraabdominal fluid collection or abscess requiring invasive treatment (yes or no) - relaparotomy (yes or no) - necessity of completion total pancreatectomy (yes or no) - anastomotic leak (other than POPF) (yes or no) wound infection requiring invasive treatment (yes or no) Non-surgical site complications (NSSC): - postoperative mortality, due to any cause (yes or no) - perioperative septic shock = sepsis requiring catecholamine treatment (yes or no) - perioperative respiratory failure requiring invasive mechanical ventilation (yes or no) - perioperative deep venous thrombosis (yes or no) - perioperative lung embolism (yes or no) - perioperative myocardial infarction (yes or no) - perioperative stroke (yes or no) - postoperative hospital stay until discharge, in days (rational scale) The following long-term outcome measures are assessed 30 days, 6 months and 12 months after the operation by telephone visit: - Quality of Life questionaire: EORTC QLQ-C30 and PAN 26 subscores (ordinal scale) - pancreatic function questionnaire: necessity of oral antidiabetic medication (yes or no) necessity of insulin therapy (units per day) necessity of pancreatic enzyme medication (yes or no, units per day) clinical signs of exocrine pancreatic insufficiency (yes or no) Analysis of secondary endpoints: Exploratory data analysis will be performed calculating appropriate summary measures for the empirical distribution as well as calculation of descriptive two-sided p-values. Sensitivity analyses will be conducted for the per-protocol population as well as for appropriate subgroups. Possible learning curve effects will be evaluated

Sekundäre Endpunkte Non-surgical site complications (NSSC) - perioperative septic shock = sepsis requiring catecholamine treatment - perioperative respiratory failure requiring invasive mechanical ventilation - perioperative deep venous thrombosis - perioperative lung embolism - perioperative myocardial infarction perioperative stroke

Sekundäre Endpunkte Quality measures - operation time from skin incision to suture - postoperative hospital stay until discharge - learning curve effects Perioperative Mortalität ist für die Studie wichtiger als die Overall, also vielleicht unterscheiden

Sekundäre Endpunkte Long Term Outcome - Quality of Life questionaire: EORTC QLQ-C30 and PAN 26 - pancreatic function questionnaire: necessity of oral antidiabetic medication necessity of insulin therapy necessity of pancreatic enzyme medication clinical signs of exocrine pancreatic insufficiency

Methods against Learning Curve Bias Min. 5 PG/PJ in the last year before initiation or Min. total experience of 25 PG/PJ per center

Verblindung verblindet: Patient Hausarzt Observer für primären Endpunkt Entblindung: wenn für Notfallbehandlung nötig Antrag: Blinding. Patients and observers are blinded towards the study intervention: The operating surgeon cannot be blinded. Therefore, blinded assessment of the primary endpoint 30 days after the surgical procedure will be performed by independent observers (not aware of the respective surgical procedure) of the participating centres. Patients will be kept blind to the randomized and performed procedure. Unblinding will be possible in situations requiring re-interventions.

Withdrawal Criteria allgemein - auf Patientenwunsch wenn Nachteile durch Studienteilnahme entstehen speziell keine Pankreatoduodenektomie (geschätzt 15% drop-out wegen Inoperabilität) ! PG / PJ nicht entsprechend der Randomisation -> Intention to Treat Principle, kein drop-out -> nach Möglichkeit vermeiden Antrag: 3.9 STOPPING RULES Withdrawal criteria for the individual patient : * wish of the patient to be withdrawn from the study * pancreatoduodenectomy not performed (because of technical irresectability, metastatic disease, necessity of total pancreatectomy) * a serious threat to the subject’s well-being is suspected by the investigator if the trial is continued pancreatogastrostomy or pancreatojejunostomy not performed according to randomization result Stopping rules for the whole trial : In order to to monitor the safety of the trial, an adaptive interim analysis is planned according to Bauer & Köhne. For the exact stopping rules based on statistical calculations see 4.

Serious Adverse Events Definition Jedes unerwünschte medizinische Ereignis, welches während des Studienzeitraumes - zum Tode führt - lebensbedrohlich ist - zu signifikanten oder bleibenden Schäden führt - Verlängerung der stationären Behandlung / Wiederaufnahme nötig macht

SAE-Meldung innerhalb von 5 Tagen an Studienleitung (Prof. Hopt, Prof. Keck) -> ggfs. Weiterleitung an Ethikkommission Freiburg DSMB regelmäßiges Review aller SAE Studienleitung DSMB (mind alle 12 Mo) Antrag: SAEs are reported immediately (i.e. within 5 days after acknowledgement) by the investigator to the coordinating investigator. SAEs and other safety issues that might materially alter the current risk-benefit assessment should be reported by the coordinating investigator to the responsible ethics committee and an independent data and safety monitoring board (DSMB) according to the study protocol and the applicable regulatory requirements. This includes a regularly listing of all SAEs. DSMB Members are listed under 9. Serious adverse events will be closely monitored and regularly reported to the data and safety monitoring board. The DSMB will assess risks and give recommendations concerning continuation of the trial for an individual centre or the trial as a whole.

Monitoring Monitor-Visiten pro Zentrum Pre-Study Initiation Interim-Visiten Close-out 100% Überprüfung Alter, Geschlecht Ein/Ausschlußkriterien Informed Consent primärer Endpunkt Komplikationen, SAE Antrag: The pre-study visit and all other visits will be performed by the clinical trials center Freiburg in accordance with the established quality management system (SOPs). The results of the pre-study visits will be documented and reported back to the funding agency. Insufficient results may lead to discontinuation of funding. During a monitor visit, year of birth, gender, complications and serious adverse events (SAEs), main inclusion/exclusion criteria, informed consent, and primary endpoints will be checked by 100%. The rest will be controlled according to the clinical trial protocol and the monitor manual. Due to the recruited patients the site will be visited every 2,5 months. Financial Plan: number of visits per site: 20 (1 Pre-Study, 1 Initiation, 18 Interim, 1 Close-out) mean number of days per visit: 2,5 monitoring costs per day: 250 € total no of visits 251 x 2,5 days à 250 € each

Voraussetzungen für Initiation Unterschriften Vertrag Trial Protocol Ethikvotum Freiburg (liegt vor) lokale Ethikkommission EDV MACRO Zugang (eCRF) Randomizer.at Registrierung analog CHROPAC

Recruiting and additional centers Evaluation of recruitment after 6 Mon by Study Board Steering Committee Replacement option to fulfill recruitment criteria by DFG

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