TOPARPILOT

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Christoph M. Seiler 2. KKSN-Symposium, November
10th, 2007
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Medical Problem

• Current status Broad variety of surgical
  techniques for resection of the pancreatic
  tail
• Dilemma Morbidity 10 - 40
• Pancreatic Fistula 3 - 40
• Objective To define the surgical method with
  least pancreatic fistulas

Andren-Sandberg A, Wagner M, Tihanyi T, Lofgren
P, Friess H. Technical aspects of left-sided
pancreatic resection for cancer. Dig Surg.
199916(4)305-12
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Meta-Analysis
Knaebel HP, Diener MK, Wente MN, Buchler MW,
Seiler CM. Systematic review and meta-analysis of
technique for closure of the pancreatic remnant
after distal pancreatectomy. Br J Surg. 2005
May92(5)539-46
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Interventions
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Specific challenges of a surgical trial
Population Chronic pancreatitis versus
pancreatic malignancies? Outcome
definition What is a pancreatic fistula? Effect
sizes What are the expected (Sample
Size) frequencies of the outcome? Time of
randomization Expected versus real
findings Performance Surgeons and centre
experience Protocol adherance Concomitant
treatment
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Population

• Stratification before randomization
• High risk for fistula malignant, non-malignant
  and neuroendocrine tumors
• Low risk for fistula chronic pancreatitis and
  pseudocysts
• Analysis
• Tissue from patient analyzed and classified
  according to grade of fibrosis

Sledzianowski JF, Duffas JP, Muscari F, Suc B,
Fourtanier F. Risk factors for mortality and
intra-abdominal morbidity after distal
pancreatectomy. Surgery. 2005 Feb137(2)180-5.
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Primary endpoint
Intraoperative or postoperative death due to any
cause until day 7
Bassi C. et al. Postoperative pancreatic fistula
an international study group (ISGPF)
definition Surgery 2005 138(1)8-13
Drain output of any measurable volume of fluid on
or after postoperative day 3 with an amylase
content greater than 3 times the serum amylase
activity.
And /or
Grade A "transient fistula" with no clinical
impact. Grade B minor change in management (e.g.
partial parenteral nutrition interventional
drainage, leukocytosis, antibiotics...) Grade
C major change in clinical management (e.g.
total parenteral nutrition, i.v. antibiotics,
somatostatin analogues, sepsis, organ
dysfunction, intervention, revision of
anastomosis, and delay in hospital discharge)
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Design Issues

• True effect size of pancreatic fistula
• remains uncertain
• Superiority design based on MA (n302)
• Adaptive design
• (interims analysis after n224)
• Rare surgical procedure
• Multicentre European approach
• Inclusion of centres with at least
• 10 resections per year

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When should we randomize?

• General rule time of randomization as
  close as possible to intervention
• Before surgery many patients will be excluded
  after exploration due to metastatic
  disease
• After laparotomy Randomization may be driven
  by the surgeon
• What causes more bias?

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Investigators Meeting DISPACT

• Rationale and acceptance of protocol
• and interventions
• Training of interventions and materials
• (animal model)
• Harmonization of procedures
• Instructions of quality procedures
• Good Clinical Practice
• Agreement about concomitant treatment

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Evaluation
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Intraoperative Monitoring
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Contracts

• Time minimum 6-8 weeks
• delay of several months
• Reasons
• no workflow in clinical sites for administrative
  issues of clinical trials
• change of responsible investigator
• questions concerning responsibilities,
  remuneration, disposal of surgical materials

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Contract Changes
General issues place of court indemnities
for centres Germany patent issues remunerat
ion additional contract for camera
equipment Europe role of sponsor patient
indemnities / insurance

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Approval Ethics Committees

• Time 12 95 days
• (Mean 47 Germany, 42 Europe)
• Costs 585,- (Cologne)
• Administration 1 10 copies of documents
• Insurance Belgium, Great Britain

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Impact of Ethics Committees

• Patient information
• - wording (risks, side effects G/E, language E)
• Informed consent
• - wording and formatting of data protection /
  privacy paragraph (many EC in Germany)
• - 1 EC obligation for regular SAE reports (G)
• - protocol information on review process
  deman- ded (E), no modification of protocol
  required!
• Others
• - letter to general practioner (E)

G Germany, E Europe, EC Ethics committee
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Ethics approval in Europe (United Kingdom)
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Documentation and Monitoring

• eCRF (MacroTM) - short training necessary
• - less paperwork, but still time
  consuming
• - study nurse is essential at sites
• Photo-upload - special web-based tool
• - easy to work with
• Monitoring - initiation paperwork (CV,
  lab.certificates) - training (eCRF,
  Randomizer, Photo)
• - source data verification 1st patient 100
  and 10 of subsequent trial data

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Milestones

• ? Grant Federal Ministry for Education and
  Research (BMBF)
• ? Registration ISRCTN 18452029
  controlled-trials.com
• ? Approval ethics committees
• ? Contracts
• At present
• - Patient Recruitment
• - Documentation, Photo-upload
• - Follow-up until 12 months after surgery
• Future
• - Interim analysis approx. November 2008

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Timelines
Patient recruitment

• Recruitment 36 months
• Interim-Analysis 21 months
• Follow-up 12 months
• Final Analysis 6 months
• Overall Duration 54 months

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Participating Centres
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CONTACT
Study Centre of the German Surgical Society
(SDGC) Im Neuenheimer Feld 110 69120
Heidelberg Germany Tel. [phone] Fax
49 6221-56-6988 SDGC_at_med.uni-heidelberg.de www.s
dgc.de