Download 3.1 Serious Adverse Events

Laparoscopic peritoneal lavage or resection for generalised peritonitis for
perforated diverticulitis: a nationwide multicenter randomised trial [NTR 2037]
Version 7. First version published on April 12th, 2009
Version date March 15th 2010, protocol according to Good Clinical Practice
Project leaders
Trial coordinators
Prof. dr. W.A. Bemelman
Prof. dr. J.F. Lange
Drs. H.A. Swank
Drs. I. Mulder
1
Contents
Investigator approval...................................................................................................................................... 3
Summary .............................................................................................................................................................. 4
1. Background .................................................................................................................................................... 6
2. Patients and Methods ................................................................................................................................. 8
2.1 Study design: ................................................................................................................................................ 8
2.2 Study population ........................................................................................................................................ 8
2.2.1 Inclusion criteria: ............................................................................................................ 8
2.2.2 Exclusion criteria: ........................................................................................................... 9
2.3 Procedure ...................................................................................................................................................... 9
2.3.1 Intervention(s): ................................................................................................................ 9
2.3.2 Study outline ................................................................................................................... 9
2.4.3 Standardisation of indication for reintervention ........................................................... 10
2.3.3 Stoma reversal ............................................................................................................... 11
2.3.4 Data collection and follow-up ....................................................................................... 11
2.3.5 Patient accrual ............................................................................................................... 11
2.3.6 Patient withdrawal ........................................................................................................ 12
2.3.7 Data sampling ............................................................................................................... 12
2.4 Outcome parameters............................................................................................................................... 13
2.4.1 Primary endpoint ........................................................................................................... 13
2.4.2 Secondary endpoints ..................................................................................................... 13
2.4.3 Economic evaluation ..................................................................................................... 13
2.5 Statistical analysis ................................................................................................................................... 14
2.5.1 Scientific justification for group size calculation ......................................................... 14
2.5.2 Group size calculation................................................................................................... 16
2.5.3 Cost-effectiveness ......................................................................................................... 17
2.5.4 Accounting for missing data ......................................................................................... 18
2.5.5 Data and record keeping ............................................................................................... 18
2.5.6 Deviations from statistical plan .................................................................................... 19
3. Patient Safety............................................................................................................................................... 19
3.1 Serious Adverse Events .......................................................................................................................... 19
3.2.1 Reporting Serious Adverse Events ............................................................................... 19
3.2.2 Predicted Serious Adverse Events ................................................................................ 20
3.3 Adverse events ........................................................................................................................................... 20
3.4 Data safety monitoring committee ................................................................................................... 21
3.5 Termination of the study ....................................................................................................................... 21
3.6 Ethical and legal requirements ........................................................................................................... 22
3.7 Insurance..................................................................................................................................................... 22
4. Quality control ............................................................................................................................................ 22
5. Publication policy ...................................................................................................................................... 22
6. References .................................................................................................................................................... 23
2
Investigator approval
I certify that I have read and understood the protocol of: Laparoscopic peritoneal
lavage or resection for generalised peritonitis for perforated diverticulitis: a
nationwide multicenter randomised trial. I agree to conduct the study in accordance
with this document.
Version 7. First version published on april 12th, 2009
Version date March 15th 2010, protocol according to Good Clinical Practice
3
sigmoid
Summary
Perforated
anastomosis
diverticulitis
generally
requires emergency surgery. Regardless of
selected strategy, sigmoid resections for
acute
perforated
diverticulitis
are
associated with substantial morbidity (up
to 50%) and mortality (15 to 25%). Just
recently, excellent results were reported
with laparoscopic lavage and drainage
only, in patients with purulent peritonitis.
Mortality and morbidity figures were less
than 5%, and a colostomy was avoided in
the majority of these patients. Potentially,
this alternative brings a large gain in
health
and
reduction
of
costs.
Nevertheless, since sigmoidectomy is still
considered the standard of care for
perforated diverticulitis by most surgeons,
implementation might be variable. Some
surgeons will embrace laparoscopic lavage
because of its technical simplicity, other
might be reluctant fearing failure of this
recent strategy. Only a head to head
comparison of the several treatment
options for perforated diverticulitis with
purulent peritonitis will provide sufficient
evidence for implementation (LOLA). If it
is decided to perform a sigmoidectomy for
perforated
resection
diverticulitis,
the
optimal
strategy is still a matter of debate. The
available literature suggest equality of
mortality
with
regarding
and
or
without
postoperative
morbidity.
If
a
sigmoidectomy with anastomosis is done,
a
protective
loop-ileostomy
probably
diminishes the number of anastomotic
leakages
and
its
complications.
The
available literature suggests that the
likelihood of stoma closure is higher after
resection, anastomosis and ileostomy
(90%) in comparison to Hartmann’s with
end-colostomy (60%), but evidence is
lacking.
The first objective of this integrated trial
(LOLA)
is
to
determine
whether
laparoscopic lavage leads to better clinical
outcomes compared to sigmoidectomy in
patients with perforated diverticulitis with
purulent peritonitis in terms of mortality
and morbidity.
The
second
objective
(DIVA)
is
to
determine whether sigmoidectomy with
anastomosis
and
ileostomy
or
sigmoidectomy with end-colostomy is the
superior
perforated
approach
in
diverticulitis
patients
with
with
either
purulent or faecal peritonitis in terms of
stoma free survival. The study is designed
as a multicenter and randomised trial.
Patients diagnosed as having perforated
diverticulitis with free air on plain
abdominal X-ray or CT scan fulfilling the
in- and exclusion criteria are randomised
4
during
laparoscopy
via
a
central test two-sided alpha of 5% and power of
computer. In case of purulent diverticulitis 90%) in favour of the patients with a
patients are randomised to three arms: (a) protective loop ileostomy after primary
laparoscopic lavage, (b) sigmoidectomy anastomosis. More than 35 hospitals have
with colostomy or (c) sigmoidectomy with agreed to participate in this study with an
anastomosis
with
defunctioning
loop estimated total inclusion of 290-431
ileostomy in ratio of 2:1:1 (LOLA). In case patients per year. Inclusion of 100 patients
of
faecal
peritonitis
or
an
overt per year must be realistic over a 4 years
perforation of the sigmoid, the patient will period. Patients will be followed for one
be randomised 1:1 to sigmoidectomy with year.
colostomy
anastomosis
or
sigmoidectomy
with
or
with The study will be executed in concordance
without with the protocol, the Good Clinical
defunctioning loop ileostomy (DIVA). The Practice
guidelines
and
regulatory
first primary outcome parameter consists requirements.
of a combined endpoint consisting of
mortality, and major morbidity (LOLA).
The second primary endpoint consists of
stoma-free survival one year after initial
surgery (DIVA). Secondary endpoints are
number of days alive and outside the
hospital, health related quality of life,
health care utilisation and associated
costs. A sample size of 132:66:66 patients
per treatment arm will be able to detect a
difference in the combined endpoint of
serious complications and mortality from
25% in the two sigmoidectomy groups
compared to 10% in the lavage group
(two-side alpha of 5% and a power of
90%. In the DIVA part 2x132 patients are
needed to significantly demonstrate a
difference of 30% in stoma-free survival
between both treatment arms (log rank
5
studies in one proposal. A joint effort will
1. Background
improve hospital participation, patient
Diverticular disease is an important
condition in terms of healthcare utilisation
and it is one of the five most costly
gastrointestinal disorders in westernised
countries.[1] Despite this high prevalence,
treatment of all different stages of
diverticular disease is still hardly evidence
based,
hence
containing
a
lot
of
controversies. High quality studies are
lacking which makes clinical decision
making hardly evidence based. Four trials
with different research questions all
involving important issues concerning the
treatment at different manifestations of
diverticulitis have evolved in 2008 in the
Netherlands (flow chart figure 1). This has
led to a joint Dutch initiative the “Dutch
Diverticular Disease Collaborative Study
Group" or the "3D Collaborative Study
Group”. Two of these trials with different,
but correlated research questions aim to
include
patients
with
perforated
diverticulitis. For this reason, the project
leaders of the LOLA trial (purulent
perforated
diverticulitis:
LaparOscopic
LAvage or resection) and the DIVA trial
(faecal
Hartmann
perforated
procedure
DIVerticulitis:
or
primary
Anastomosis with ileostomy) have decided
to cooperate and to combine the two
accrual, data quality and study efficiency
in this nationwide multicenter study. In
the present proposal the study objective
and research questions of both the LOLA
trial and the DIVA trial are incorporated.
Perforated diverticulitis is a perforation of
a diverticulum of the large bowel, mostly
the sigmoid, resulting in either a purulent
or faecal peritonitis (Hinchey stadia 3 and
4). Both conditions require emergency
surgery. [2,3] Regardless of selected
strategy emergency operations for acute
perforated diverticulitis are associated
with substantial morbidity (up to 50%)
and mortality (15 to 25%).[3-8] Primary
sigmoidectomy
with
or
without
an
anastomosis has become the standard
practice for patients with generalised
peritonitis complicating diverticulitis.[610]
For
many
surgeons
Hartmann’s
procedure still remains the favoured
option, meaning that patients will have
end-colostomy. Reversal of stoma after
Hartmann’s however, is only done in 50 to
60% of the patients due to high mortality
and morbidity rates [12,13,19], thereby
compromising
quality
increasing
costs.
laparoscopic
lavage
of
life
[14]
emerged
and
Recently
as
an
effective alternative in patients with
perforated diverticulitis with purulent
6
peritonitis. [18] Laparoscopic lavage for anastomosis
regarding
postoperative
perforated diverticulitis with purulent mortality and morbidity.[5,7,9,29,30] If
peritonitis has first been described by anastomosed,
a
defunctioning
loop-
O'Sullivan in 1996.[22] Just recently, ileostomy might diminish the number of
Myers et al [18] reported excellent results anastomotic
leakages
and
its
in a series of 92 patients. Mortality and complications.[15] The available literature
morbidity figures are less than 5% and a suggests that the likelihood of stoma
(permanent) colostomy was avoided in closure
is
higher
after
resection,
the majority of these patients.[18, 22-28] anastomosis and ileostomy (85%) in
So there is a potential large gain in health comparison to Hartmann’s (60%) (DIVA)
and
costs
to
laparoscopic
be
expected
lavage
for
applying [14,16], but robust evidence is lacking.
perforated The first objective (LOLA) is to determine
purulent diverticulitis. Nevertheless, since whether
laparoscopic
sigmoidectomy is still considered the superior
approach
standard
of
diverticulitis
care
by
for
lavage
is
the
compared
to
perforated sigmoidectomy with end-colostomy or
most
surgeons, with
anastomosis
and
ileostomy
in
implementation might be variable. Some patients with perforated diverticulitis with
surgeons will embrace laparoscopic lavage purulent peritonitis in terms of mortality,
because of its technical simplicity, other morbidity, quality of life, health care
might be reluctant fearing failure of this utilisation and associated costs. The
recent strategy. Only a head to head second objective (DIVA) is to determine
comparison of the several treatment whether sigmoidectomy with anastomosis
options for perforated diverticulitis with and ileostomy or sigmoidectomy with endpurulent peritonitis will provide sufficient colostomy is the superior approach in
evidence to guide surgeons what to do patients with perforated diverticulitis with
(LOLA). In case of faecal peritonitis there purulent and faecal peritonitis in terms of
is no evidence for alternatives other than stoma free survival, quality of life and cost
sigmoidectomy with an ostomy. If it is effectiveness.
decided to perform a sigmoidectomy for
perforated
diverticulitis,
the
optimal
strategy is still a matter of debate. The
available literature suggest equality of
sigmoid
resection
with
or
without
7
eligible for this study. If the in- and
2. Patients and Methods
exclusion criteria are fulfilled, the patient
This multicenter randomised trial will be will have a diagnostic laparoscopy to
executed
in
concordance
protocol,
the
Good
guidelines
and
with
the confirm the diagnosis. In case of purulent
Clinical
Practice peritonitis the patients enters the LOLA
relevant
legal arm of the study, in case of faecal
peritonitis, the patient enters the DIVA
requirements.
arm of the study. Randomisation is
In this study we will compare three performed during laparoscopy via the trial
relevant treatment strategies that exist for website
patients
with
purulent
patients
with
faecal
to
the
attached
perforated flowchart (figure 2).
diverticulitis and two surgical strategies In
for
according
case
of
purulent
diverticulitis
perforated laparoscopic lavage is compared with
diverticulitis. All patients will be followed either sigmoidectomy with colostomy or
up to one year and in the period we will sigmoidectomy with anastomosis with
measure
clinical
relevant
outcomes defunctioning loop ileostomy (LOLA). The
(combined endpoint of mortality and best evidence indicates that the latter two
major morbidity), health related quality of resectional strategies are equal in terms of
life, number of days alive and spent morbidity and mortality in case of
outside the hospital and costs. A specific generalised peritonitis [8]. For this reason
outcome
when
comparing
surgical a three way 2:1:1 randomisation is
strategies is stoma-free survival. For both proposed. In case of faecal peritonitis or
patient groups, we will determine which an overt perforation of the sigmoid, the
treatment strategy is the most cost- patient will be randomised in the DIVA
arm of this study. In this way all patients
effective one.
with perforated diverticulitis fulfilling the
in/exclusion criteria can be included in
2.1 Study design
this study.
The design of the study is randomised and
multicenter.
Patients presenting
with
signs of generalised peritonitis will have a 2.2 Study population
CT-scan. If there is free intra-abdominal
2.2.1 Inclusion criteria
air with suspicion of perforated - patients suspected of diverticulitis
diverticulitis, the patient is potentially
8
- age in between 18 and 85 years
this way all patients with perforated
- informed consent
diverticulitis fulfilling the in/exclusion
criteria can be included in this study.
with free air on plain abdominal X-ray or
CT-scan
OR
with peritonitis and diffuse gas or fluid on
CT-scan
2.3.2 Study outline
Patients fulfilling the
inclusion
and
exclusion criteria will have a diagnostic
laparoscopy. After the pneumoperitoneum
is installed, two additional 5 mm trocars
2.2.2 Exclusion criteria
- dementia
are inserted in the left and right lower
- prior sigmoidectomy
abdominal cavity particularly the stomach,
- steroid treatment > 20 mg daily
duodenum and sigmoid, is done to localize
- prior pelvic irradiation
the site of perforation. In case of
- preoperative
inotropics
shock:
due
abdomen. A careful inspection of the
requirement
to
of peritonitis
due
to
a
perforated
circulatory diverticulum it must be attempted gently
insufficiency
to locate the site of perforation. Careful
removal of adherent omentum or bowel is
tried. If clearly adherent, it should be left
2.3 Procedure
in place. If no obvious perforation is
2.3.1 Intervention(s)
In case of purulent
diverticulitis
laparoscopic lavage is compared with
either sigmoidectomy with colostomy or
sigmoidectomy with anastomosis with or
without defunctioning loop ileostomy
(LOLA arm). In case of faecal peritonitis or
an overt perforation of the sigmoid, the
patient will be randomised in the DIVA
arm of this study to undergo either
sigmoidectomy
with
colostomy
or
sigmoidectomy with anastomosis with or
without defunctioning loop ileostomy. In
apparent and in the absence of faecal
content, the patient is included in the
LOLA arm. In case of an overt perforation
or intra-abdominal contamination with
faeces, the patients enters the DIVA arm of
the study. Abdominal content is aspirated
for culture and randomisation is done via
the website. When there is doubt on the
peritonitis being purulent or faecal, the
abdominal content should be aspirated
and the colour or the content should be
examined. Only brown-coloured fluid can
be marked as faecal content. When
9
aspiration alone is not sufficient for Leaving a Douglas drain is at the
determining
the
faecal
content,
the discretion of the operating surgeon.
aspirated fluid should be sprayed on a Intravenous
or
oral
antibiotics
are
gauze to see if there are any brown bits on administered for seven days in both
the gauze. If present, there is faecal groups. Postoperatively, oral diet and
peritonitis.
mobilisation are advanced as soon as
Laparoscopic lavage; the abdominal cavity possible. Within four to six weeks after
is irrigated with six litres of warm saline. surgery a sigmoidoscopy is performed to
At the end of the procedure a Douglas exclude malignancy as the underlying
drain is inserted via the right lateral port.
cause of the perforation.
Sigmoidectomy and anastomosis and loop
ileostomy:
Sigmoidectomy
is
done
the 2.3.3 Standardisation of indication for
reintervention
American Society of Colon and Rectal Relaparotomy is indicated in patients with
Surgeons. [31,32] The distal transsection clinical deterioration or lack of clinical
according
to
the
guidelines
of
margin has to be on the proximal rectum, improvement with a likely intrathe proximal margin is determined by the abdominal cause within 48 – 74 hours
absence of wall thickening due to after the index procedure. Other
diverticulitis. The type of anastomosis is (intercurrent)
infectious
foci
(e.g.
done according to the preference of the pneumonia) must be ruled out using
operating surgeon. A loop ileostomy can laboratory tests, imaging modalities, or
be fashioned in order to ensure faecal both. The decision to perform a
deviation, this is upon the discretion of the relaparotomy must be made by the
surgeon.
multidisciplinary medical team. To guide
Sigmoidectomy
(Hartmann’s
with
procedure):
colostomy the decision for reoperation, the
Hartmann's Sequential Organ Failure Assessment
procedure is stated as a two-stage (SOFA) score can be used as help for
procedure with the intention to close the decision making.[33] Prespecified surgical
colostomy in a second stage. During the emergencies
which
might
require
primary surgery, only the perforated reintervention,
are
abdominal
diseased part must be resected. There is compartment syndrome, intra-abdominal
no need of having the distal transsection bleeding with persistent decrease in
line on the proximal rectum.
haemoglobin
despite
replacement,
10
hemodynamic instability, burst abdomen, reinterventions and stoma rate at end of
perforation of visceral organ, anastomotic follow-up. Pre-, per- and postoperative
leakage, intra-abdominal abscess that data have to be filled in online via the trial
cannot be drained percutaneously, and website.
ischemia/necrosis of a visceral organ.
The data will be filled accompanied by the
patients randomisation code. No names or
contact information appears on the Case
2.3.4 Stoma reversal
Record Forms. The trial coordinators do
After sigmoidoscopy is performed and the
not have access to the patients
surgeon finds the patient eligible for
information. The participating hospitals
stoma reversal, the surgeon can offer the
keep the list for decoding the
patient reversal of the stoma. When the
randomisation codes in the investigators
patient accepts, he or she can be planned
site file, located in the participating
for surgery. When a patient does not show
hospital.
to the outpatient department, when the
patient is not eligible for stoma reversal,
when the patient refuses stoma reversal 2.3.6 Patient accrual
or when the anesthesiologist refuses As the ratio between purulent (Hinchey
stoma reversal, the patient can not be III) and faecal (Hinchey IV) peritonitis due
planned for surgery. The reason for not to perforated diverticulitis is estimated
reverting the stoma needs to be filled in in 2:1, it is expected that 396 patients have to
the Case Record Form.
fulfil the in/exclusion criteria. In this way,
264 patients enter the purulent arm and
132 of the patients with faecal peritonitis
2.3.5 Data collection and follow-up
will enter the faecal arm. The patients
Data
collection
includes
patient
having had resectional therapy in purulent
characteristics,
POSSUM
score,
arm together with the patients from the
preoperative APACHE score, surgical
faecal arm with an estimated loss of
parameters, Hinchey score, Mannheim
patients of 20% (due to mortality and lost
peritonitis index, morbidity, length of stay,
in follow-up) will be enough to power for
quality of life at 2, 4, 13 and 26 weeks (SFthe outcome "stoma free survival at one
36, GIQLI, EQ-5D), consumption of
year" (see flow chart).
hospital resources and health care at 4, 13,
26, 39 and 52 weeks, early and late
11
Up to now more than 35 hospitals agreed to that point and all data recorded will be
to participate in this study. Patient accrual included in the final analysis provided the
can be expected to be easy for several surgery was attempted. If the patient
reasons. Patients probably would like to withdraws prior to attempted surgery
enter the study hoping to be allotted in the then this patient will be excluded from the
laparoscopic lavage group avoiding an analysis. Additional patients may be
ostomy. In addition, since all patients with enrolled if patients withdraw from the
free
air
suspected
of
perforated study prior to closure of recruitment, to
diverticulitis can be included in this study, ensure the sample size is maintained.
there is no doubt that patients cannot be
included. Sigmoidectomy for perforated
diverticulitis is not a popular operation
because
its
relative
complexity.
The
procedure is mostly done by the general
surgeon or residents outside of office
hours. A technically simple alternative via
laparoscopic lavage is for this reason very
attractive. Patient inclusion will therefore
be relatively simple because of the
attractive
treatment
alternative
of
laparoscopic lavage both for the patient as
well as for the surgeon. Inclusion of 100
patients per year must be realistic over a 4
years period.
2.3.8 Data sampling
Data is sampled by the clinical investigator
in the online Case Record Form at four
times. This data is recorded in a source
document at the centre and will be copied
to the online CRF. The first time is after
informed consent by the patient (preoperative data), the second time is
immediately after surgery (per-operative
data), the third time is at discharge (postoperative data), the fourth time is after the
patients
visit
department.
of
the
All other data
outpatient
will be
retrieved from questionnaires, that are
sent to the patient by the trial coordinator
at 2, 4, 13, 26, 39 and 52 weeks and will be
2.3.7 Patient withdrawal
Any patient maintains the right to revoke recorded in the CRF directly by the trial
their consent at any point and withdraw coordinator
from
the
trial.
In
that
event
or
sent
to
the
data
the management by fax or mail and thereby
investigator would attempt to ascertain recorded automatically.
the reason for withdrawal and record this When the patient does not show up at the
on the patient termination form. As much outpatient department, he or she will be
follow-up data as possible will be collected contacted by telephone by the trial
12
coordinator
to
check
the
patients outcome for the comparison of the
compliance and verify whether the patient resectional strategies (DIVA).
has received medical care from a different
center.
All patients who show bad compliance will
be contacted by the trial coordinator by
telephone. All patients who indicate on the
questionnaire Health Care Use that they
have received medical care from a medical
center different from the primary hospital,
will be contacted by telephone by the trial
2.4.2 Secondary endpoints
Secondary endpoints are operating time,
hospital stay, number of days alive and
outside the hospital, incisional hernia,
reinterventions within twelve months,
health related quality of life, health care
utilisation and associated costs.
coordinator.
2.4.3 Economic evaluation
Background and rationale:
2.4 Outcome parameters
The
key
question in the economic evaluation is to
2.4.1 Primary endpoint
a. The following main outcomes will be assess whether to what extent a more
assessed in this trial to compare the effective surgical strategy also reduces
various strategies: poor clinical outcome health care utilisation and associated
defined as a combined endpoint consisting costs. A more effective strategy in terms of
of mortality, and major morbidity. Major health status is expected to incur less costs
morbidity includes any of the following due to health care utilisation (direct
events
or
conditions:
wound
dehiscence,
reintervention, medical costs) and less productivity loss
incisional
hernia, due to absence from paid work (indirect
abscess needing percutaneous drainage, costs). Comparisons of the different
urosepsis, myocardial infarction, renal surgical
strategies
in
the
economic
failure and respiratory insufficiency. This evaluation will be analogous to the
will be the primary outcome in the lavage analyses of the clinical endpoints. The
vs. resectional intervention comparison economic evaluation will be performed
(LOLA).
from a societal perspective, with the costs
b. Stoma-free survival one year after initial per unit improvement on the primary
surgery, is the only relevant and primary clinical
endpoints,
defined
as
poor
outcome (combined mortality/morbidity)
13
for the LOLA part; and stoma-free survival health care providers, and home care.
for the DIVA trial as the primary outcome Direct non-medical costs are generated by
measure.
The
appropriate
type
of travel to and from health care providers.
economic evaluation is be conditional on Indirect costs are associated with lost
the results (Gold, 1996). We hypothesise productivity due to absence from paid
that a more effective intervention will be work.
associated with less health care utilisation
as
well
absence
(productivity
from
costs).
paid
Therefore,
work
the
2.5 Statistical analysis
cost- 2.5.1 Scientific justification for group
size calculation
effectiveness analysis that evaluates costs A. Systematic review: Mortality of
associated with an improved surgical sigmoidectomy
for
perforated
primary
analysis
will
be
a
outcome in terms of stoma-free survival. diverticulitis.
In addition, a secondary analysis, will “Primary Resection With Anastomosis vs.
evaluate cost differences in relation to Hartmann’s Procedure in Nonelective
differences in quality-adjusted life-years Surgery
(QALY’s).
This
resulting
in
cost-utility
an
analysis, for Acute
incremental cost- Systematic
Colonic
Diverticulitis:
Review.
Vasilis
A
A.
effectiveness ratio expressed in costs per Constantinides et al. Diseases of the Colon
QALY, will be included to allow and Rectum 2006 Jul;49(7):966-81.[8]”
comparison with other health-related Search terms: comparative studies and
interventions or programs. With a study diverticular disease / diverticulitis,
horizon of twelve months, no discounting comparative studies and peritonitis,
will be applied. We will differentiate diverticular disease / diverticulitis and
between direct medical, direct non- primary and resection / anastomosis, onemedical and indirect costs. Direct medical stage and diverticular disease /
costs are associated with health care diverticulitis and operation / resection,
utilisation
related
to
surgical diverticular disease / diverticulitis and
interventions,
diagnostic
percutaneous
procedures,
drainages, Hartmann’s and procedure / operation.
medications, Population: Fifteen studies matched the
materials (blood products, gauze packing), selection criteria and were suitable for
readmissions and reinterventions, visits to meta-analysis. These included a total of
outpatient, primary care and paramedical 963
adult
patients,
of
which
547
14
underwent
anastomosis
primary
(PRA
resection
57%)
and
and for
emergency
operations
showed
416 significantly decreased mortality with
Hartmann’s procedure (HP 43%). The primary resection and anastomosis (7.4
study design was retrospective in 13 vs. 15.6 percent; odds ratio = 0.44). No
studies and prospective, nonrandomized significant difference in mortality was
in 2.
observed in trials matched for severity of
Outcome: The primary end point was peritonitis Hinchey > 2 (14.1 vs. 14.4
postoperative
mortality.
Secondary percent; odds ratio = 0.85). Overall
endpoints included surgical and medical morbidity was 29% for PRA and 33% for
morbidity, operative time, and length of HP.
postoperative hospitalisation.
Conclusions: Patients selected for primary
Methodological filters: Comparative filters
resection and anastomosis have a lower
Databases used and number of manuscripts mortality
than
those
treated
by
retrieved: A MEDLINE, Ovid, Embase, and Hartmann’s procedure in the emergency
Cochrane database search was performed setting and comparable mortality (14%)
on all studies published between 1984 and under conditions of generalised peritonitis
2004.
Twenty-four
studies
published (Hinchey > 2). The retrospective nature of
between 1984 and 2004 matched the the
included
studies
allows
for
a
search criteria, comparing PRA vs. HP and considerable degree of selection bias that
reporting the incidence of mortality, limits
postoperative
complications,
robust
and
clinically
sound
operative conclusions.
time, or length of postoperative hospital
stay. Nine studies were excluded because B. Probability of mortality and morbidity
they contained a patient group undergoing analysis of sigmoidectomy for perforated
PRA vs. HP that was indistinguishably diverticulitis:
mixed for cancer as well as diverticulitis.
“Operative
strategies
for
diverticular
Selection procedure, validity assessment: peritonitis: a decision analysis between
Two reviewers (VC and PT) independently primary resection and anastomosis versus
extracted the data
Hartmann's procedures. Constantinides
Results: Overall mortality was significantly VA et al. Ann. Surg. 2007, 245: 94-103.” [9]
reduced with primary resection and Summary of results: A total of 135 primary
anastomosis (4.9 vs. 15.1%; odds ratio = resection and anastomosis (PRA), 126
0.41). Subgroup analysis of trials matched primary anastomoses with defunctioning
15
stoma (PADS), and 6619 Hartmann’s Results: A weighted mean mortality and
procedures (HP) were considered. The morbidity rate was calculated amounting
probability of morbidity and mortality was resp. 1.3% and 6.7%.
55% and 30% for PRA, 40% and 25% for Conclusions: Mortality and morbidity rates
PADS, and 35% and 20% for HP, are low for laparoscopic lavage for
respectively.
generalised purulent peritonitis due to
perforated diverticulitis. The retrospective
C.
Systematic
Laparoscopic
review
lavage
(unpublished): design of most studies inevitably causes
for
generalised bias. A prospective study comparing
peritonitis due to perforated diverticulitis. lavage with the standard of care e.g.
[18, 22-28]
sigmoidectomy is warranted.
Search terms:
diverticulitis
laparoscopy,
diverticulitis
diverticular
and
disease
peritonitis
diverticular
and
disease
peritonitis
/
and
/
and
laparoscopy and lavage
Outcome: The primary end point was
postoperative mortality. Secondary end
points included surgical and medical
morbidity.
Databases used and number of manuscripts
retrieved: A MEDLINE, Ovid, Embase, and
Cochrane database search was performed
on all studies published between 1984 and
2009.
Population: Eight studies matched the
selection criteria and were suitable for
analysis.
The
retrospective
study
design
was
six
studies
and
in
prospective in two. These studies included
in total 207 patients.
2.5.2 Group size calculation
Combined
endpoint
of
serious
complications and mortality (LOLA arm):
A sample size of 132:66:66 patients per
treatment arm will be able to detect a
difference in the combined endpoint of
serious complications and mortality from
25% in the two sigmoidectomy groups
compared to 10% in the lavage group with
a two-sided significance level of 5% and a
power of 90%. The test statistic used is the
two-sided Likelihood Ratio test. The
significance level of the test was targeted
at 0.05. The significance level actually
achieved by this design is 0.0509. [34-36]
With a group size of a hundred patients
per arm it is also possible to find a
significant difference (alfa=0.05, beta=0.1)
of at least 10% in subscales of the SF-36, a
validated Quality of life Questionnaire.
16
One year stoma free survival (DIVA arm): quality of life) will be also collected at each
using log rank statistics with a power of visit with the EQ-5D (Brooks, 2004).
90% and a type I error of 5%, 212 patients Health state utilities to estimate QALY’s
are needed to significantly demonstrate a will
be
derived
from
an
EQ-5D
difference in stoma-free survival between measurement at baseline, as well as the
both treatment arms. The power analysis follow-up assessments. Utility values for
is based on the existing literature, in EQ-5D scores will be based on UKwhich
the
suspected
postoperative estimates (Dolan,1997). Utility scores will
mortality after Hartmann’s procedure and be
sigmoid
resection
with
uniformly
interpolated,
assuming
primary constant health state between subsequent
anastomosis are equally high (+ 15%).[7] assessments.
About 60% of the patients that had Unit costs: unit costs will be estimated
undergone Hartmann’s will have their according to the Dutch guideline on (unit)
stoma reversed.[12,13]. Corrected for costing in
health
care (Oostenbrink,
expected mortality before reversal results Bouwmans, Koopmanschap, & Rutten,
in + 50%. Patients with a protective loop 2004).
For
surgical
and
diagnostic
ileostomy after primary anastomosis will procedures, we will estimate unit costs for
have their enterostomy reversed in over one academic and one non-academic
85%.[13] Corrected for expected mortality hospital. GP visits, medical specialist visits,
before reversal results in 72% of the initial paramedical
patients.
care,
home
care,
and
travelling will be valued based on the
guideline prices. Medication costs will be
valued by their market prices (van
2.5.3 Cost-effectiveness
Loenen, 2007). The friction cost method
Measurements: health care utilisation,
will be used to estimated the duration of
travel and lost productivity due to absence
lost productivity, age adjusted average
from work or decreased performance at
daily wages will be used to value this
work will be collected with a clinical
duration.
report form, complemented with a patient
Statistical analysis: as most volumes of
questionnaire based on the Trimbos/iMTA
resource utilisation follow a skewed
Labour
and
Health
questionnaire
distribution, differences between the two
(Hakkaart-van
Rooijen,
2000)
study groups will be statistically evaluated
administered at each follow-up visit. Data
with bias-corrected accelerated bootstrap
on general well-being (health-related
17
analyses (Barber, 2000). Mean total costs 2.5.4 Accounting for missing data
for the two groups will be reported, as All clinical data will be entered by the
mean costs per patient are relevant from a clinical investigator in an online Case
Record Form. Data from questionnaires
societal perspective.
Economic evaluation: cost-effectiveness sent to the patients will be entered by the
will be evaluated by calculating trial coordinator in the online Case Record
incremental the cost-effectiveness ratios From. Missing data will be revealed by
(costs /effects), with proportion of poor data validation of the CRF and will be
outcome as the effect parameter. In delivered for resolution with Data
addition, in a cost-utility analysis, costs Clarification Forms (DCFs). The trial
per QALY will be estimated based on costs coordinator will receive this form and
/ QALY’s. A cost-acceptability curve will be hereafter contact the clinical investigator
generated to indicate the probability that to complete the online CRF by means of
the more effective treatment is also cost- the DCF. Completed DCFs will be returned
effective for a range of willingness-to-pay by fax or mail to data management for
values. Robustness of the results for updating the database.
uncertainty in the assumptions will be Missing data on the sent questionnaires
evaluated in sensitivity analyses, including will be solved by the trial coordinator
2005) contacting the patient by telephone and
instead of the UK based model in the main hereafter completing the CRF.
Dutch
health
states
(Lamers,
analyses; a linear interpolation between
EQ-5D measurements instead of uniform
2.5.5 Data and record keeping
interpolation; and varying unit costs for The clinical investigator is asked to keep a
pertinent volumes of health care list with full names and addresses of all
utilisation (e.g. therapy costs, productivity patients participating in the trial, giving
costs). In model-based analyses using data reference to the patient records. All
from literature about these middle to long- investigation-related essential documents
term effects and costs associated with will be retained by the clinical investigator
PTSD patients we will extrapolate the for at least five years. The structure of the
results to estimate the effectiveness and database will be based on the online Case
cost-effectiveness
for
both
treatment Record Form. Discrepancies revealed by
options on long-term (3 to 5 years).
data validation will be delivered for
resolution with a Data Clarification Form
18
(DCF). Completed DCFs will be returned
Any other important medical event that is
by fax or mail to data management for
not mentioned above but can threaten the
updating the database. The clean database
patient or requires intervention to prevent
will be locked after all detected
any of the above, is considered a SAE.
discrepancies have been solved and
database has been updated accordingly.
Only authorised and documented updates
are possible after the database lock.
3.2.1 Reporting Serious Adverse Events
The principal investigator is required to
report to the Medical Ethics Committee, to
all participating centres and to competent
authorities all findings that can
2.5.6 Deviations from statistical plan
When certain data is missing and can not
- threat the safety of the patients,
be completed by the procedure described
-
threat the continuation of the study
above, the initial statistical plan must be
-
likely change the initial positive
deviated to be able to perform statistical
advice from the Medical Ethics
analysis. Deviations from the statistical
Committee on continuation of the
plan will be recorded in the notes to file
study.
section of the Trial Master File.
The local investigator is required to notify
3. Patient Safety
the principal investigator in every case of
a Serious Adverse Event, within 24 hours
3.1 Serious Adverse Events
In accordance to the guidelines for Good
after becoming aware of the event. These
Clinical Practice, all Serious Adverse
mortality and major morbidity:
Events (SAEs) need to be reported to the
- mortality
Medical Ethics Committee in the Academic
- reintervention
Medical Center. SAEs are specified as any
- wound dehiscence
medical event that
- incisional hernia
SAEs include the previously defined
-
leads to death
- abscess needing percutaneous drainage
-
is life-threatening
- urosepsis
-
makes admission to a hospital or an
- myocardial infarction
extended hospital stay inevitable.
- renal failure
leads to serious or persistent
- respiratory insufficiency
-
disability (for work).
19
This can be done at the online CRF, by
filling in the SAE section. The principal
The consequences of all SAEs will need to
investigator gets notified and will inform
be reported in the Case Record Form. This
the medical ethics committee from the
consequences can be reported as:
Academic Medical Center within 24 hours.
additional therapy, reintervention, ICUadmission and result:
3.2.2 Predicted Serious Adverse Events
Not every SAE needs to be reported.
-
patient died from SAE
-
patient is left with permanent
damage from SAE
Predicted SAEs need to be filled in in the
regular Case Record Form, at the time of
-
patient is cured from SAE
discharge of the patient, or 14 days after
initial surgery, whichever comes first.
These SAEs will not need to be directly
3.3 Adverse events
Adverse events will only be recorded at
reported. Based on the Case Record
the visit of the outpatient department.
Forms, the principal investigator will
Adverse events that occurs during the
create linelisting and report predicted
clinical episodes, will not be recorded,
SAE’s to the Medical Ethics Committee
because this group of events is not
every six months.
relevant for patient safety nor for final
Predicted SAEs include:
analysis of trial data. The group of
- wound infection
investigated patients is highly ill.
- non-septical urinary tract infection
Therefore recording of all signs and
- pneumonia without respiratory
symptoms will put a high amount of
insufficiency
administrative labour to the clinical
- cardiac disease
investigators, while the patients safety will
- abscess without drainage
not benefit from these recordings.
- ileus without reintervention
At the visit of the outpatient department
- thrombosis
postoperatively, adverse events can be
- delirium
recorded by the clinical investigator in the
- decubitus
online CRF. At this time remaining signs
- urine retention
and symptoms deem relevant.
- cellulitis as a consequence of infusion
- electrolyte disorder with suppletion
- overhydration with diuretic use
20
3.4 Data safety monitoring committee
A data safety monitoring committee
baseline characteristics from the included
(DSMC) will guard the safety of the
adverse events, classified as:
included patients, give advice on
patients, and an overview from the major
-
continuation of the study upon superiority
of one of the types of treatment, and will
guard the methodological quality of the
mortality within four weeks after
initial surgery
-
major morbidity as defined in the
protocol.
study.
The DSMC will write a short report in
The DSMC will consist of clinical,
which the considerations are summarised.
epidemiological and statistical experts,
This report will be sent to the project
that are independent and have no
leaders.
personal interest in the results of the trial.
Reports on meetings from the committee
are confidential to prevent influence on
the course of the trial.
De DSMC of the Ladies trial will consist of
- Prof.dr. D. Legemate (surgeon and
clinical epidemiologist)
- Prof.dr. J.F. Bartelsman
(gastroenterologist)
- Dr. D.W. Meijer (contract research
organisator)
- Dr. J.B. Reitsma (clinical epidemiologist)
The clinical epidemiologist of the Ladies
trial will create a report on the study after
every 25 included patients, and present
this tot the DSMC in an initial face-to-face
meeting. Following reports will be written,
unless the committee decides to organise a
face-to-face meeting. The report consist on
the number of included patients, in
relation to elapsed time and specified per
3.5 Termination of the study
The entire clinical investigation will be
terminated if a serious treatment-related
adverse event occurs, making it
impossible to recruit new patients or to
continue the treatment of patients already
recruited for medical or ethical reasons.
The clinical investigation in an individual
patient will be terminated in case of
1. insufficient compliance
2. a patients request
3. investigators request because of
the onset of life-threatening
adverse event.
4. changes in health status
incompatible with continued
participation in the clinical
investigation, as judged by the
clinical investigator.
participating hospital. Further on the
21
3.6 Ethical and legal requirements
The protocol will be submitted to the
4. Quality control
appropiately structured Ethics Committe.
Monitoring will ensure that the
Approval for the clinical investigation plan
investigation is conducted in accordance
at each center has to be obtained prior to
with this protocol, including all
start of enrollment.
amendments, Good Clinical Practice and
relevant regulatory requirements.
3.7 Insurance
All patients participating in this study
Monitoring will involve frequent visits to
participating centers to verify good
need to be insured for death or injury
management of patients and the clinical
caused by the study that has occured
investigation treatment, to observe
within four years after participation.
procedures, to supervise the investigation
Patients included in one of the
for quality control purposes, to check
participating centers are to be ensured by
presence of required documents, informed
the Academic Medical Center, unless the
consent and for purpose of source data
participating center is attached to the
verification. There will also be frequent
ensurance company CentraMed B.V. or is a
telephone contact and written
university medical center.
communication between monitor and
The insurance certificate is provided by
clinical investigator. The participating
the Academic Medical Center Medical
centers will permit trial related
Research bureau or by the participating
monitoring, audits, IRB/EC review, and
center (for CentraMed members and
regulatory inspections, providing direct
university medical centers), and is issued
access to source data and documents.
to the Medical Ethics Committee of the
Academic Medical Center by the
investigator. The Medical Ethics
Committee can only agree on participation
of a center upon receival of this certificate
and a positive advice of the board of
directors from the participating center.
5. Publication policy
The project leaders are committed to
presenting the results of this trial in an
appropiate scientific peer reviewed
journal. No single center data will be
published prior to the publication of the
clinical trial data in its entirety.
22
6. References
1. Sandler
RS,
Everhart
JE,
Donowitz M, Adams E, Cronin K,
Goodman C, Gemmen E, Shah S,
Avdic A, Rubin R. The burden of
selected digestive diseases in
the
United
States.
Gastroenterology
2002;122:1500-11
2. Kang JY, Hoare J, Tinto A,
Subramanian S, Ellis C, Majeed
A, Melville D, Maxwell JD.
Diverticular disease of the
colon--on the rise: a study of
hospital admissions in England
between
1989/1990
and
1999/2000. Aliment Pharmacol
Ther 2003;17:1189-1195
3. Morris CR, Harvey IM, Stebbings
WSL, Hart AR. Incidence of
perforated diverticulitis and risk
factors for death in a UK
population.
Br
J
Surg.
2008;95:876-81
4. Vermeulen J, Gosselink MP, Hop
WCJ, Lange JF, Coene PPLO,
Harst E van der, Weidema WF,
Mannaerst GHH. Prognostische
factoren voor ziekenhuissterfte
na een spoedoperatie van acuut
geperforeerde diverticulitis. Ned
Tijdschr Geneeskd 2009 [in
press]
5. Constantinides VA, Tekkis PP,
Senapati
A.
Prospective
multicentre
evaluation
of
adverse outcomes following
treatment
for
complicated
diverticular
disease.
BJS
2006;93:1503-13
6. Abbas S. Resection and primary
anastomosis
in
acute
complicated diverticulitis, a
systematic review of the
literature. Int J Colorectal Dis.
2007
Apr;22(4):351-7.
1:
Chirurgie. 1998 Sep;123(4):35862.
7. Salem L, Flum DR. Primary
anastomoss or Hartmann’s
procedure for patients with
diverticular
peritonitis?
A
systematic review. Dis Colon
Rectum 2004;47:1953-64
8. Constantinides VA, Tekkis PP,
Athanasiou
T,
Aziz
O,
Purkayastha S, Remzi FH, Fazio
VW, Aydin N, Darzi A, Senapati
A. Primary resection with
anastomosis vs. Hartmann's
procedure
in
nonelective
surgery for acute colonic
diverticulitis:
a
systematic
review. Dis Colon Rectum. 2006
Jul;49(7):966-81.
9. Constantinides VA, Heriot A,
Remzi F, Darzi A, Senapati A,
Fazio VW, Tekkis PP. Operative
strategies
for
diverticular
peritonitis: a decision analysis
between primary resection and
anastomosis versus Hartmann's
procedures.
Ann
Surg.
2007;245:94-103
10. Gooszen AW, Tollenaar RA,
Geelkerken RH, Smeets HJ,
Bemelman
WA,
Van
Schaardenburgh P, Gooszen HG.
Prospective study of primary
anastomosis following sigmoid
resection for suspected acute
complicated
diverticular
disease. Br J Surg. 2001
May;88(5):693-7.
11. Gooszen AW, Geelkerken RH,
Tollenaar RA, Timmermans DR,
Kievit J, Gooszen HG. Operatieve
strategie bij de acute of electieve
sigmoidresectie in Nederland;
enquete op basis van een
marketing
model.
NTVG
1994;138:2005-10
12. Maggard MA, Zingmond D,
O’Connell JB, Ko CY (2004).
What proportion of patients
with
an
ostomy
(for
23
diverticulitis) get reversed? Am
Surg;70:928-31
13. Vermeulen J, Coene PP, Van
Hout NM, van der Harst E,
Gosselink MP, Mannaerts GH,
Weidema
WF,
Lange
JF.
Restoration of Bowel Continuity
after
Surgery
for
Acute
Perforated Diverticulitis Should
Hartmann's
procedure
be
considered
a
one-stage
procedure? Colorectal Dis. 2008
Aug 21 [Epub ahead of print]
14. Banerjee S. Leather AJM, Rennie
JA, Samano N, Gonzalez JG,
Papagrigoriadis S. Feasibility
and morbidity of reversal of
Hartmann’s.
Colorectal
Dis
2005;7:454-9
15. Gooszen AW, Geelkerken RH,
Hermans J, Lagaay MB, Gooszen
HG. Quality of life with a
temporary stoma: ileostomy vs.
colostomy. Dis Colon Rectum.
2000;43:650-5
16. Matthiessen P, Hallböök O,
Rutegård J, Simert G, Sjödahl R.
Defunctioning stoma reduces
symptomatic
anastomotic
leakage after low anterior
resection of the rectum for
cancer:
a
randomized
multicenter trial. Ann Surg.
2007;246:207-14
17. Bell C, Asolati M, Hamilton E,
Fleming J, Nwariaku F, Sarosi G,
Anthony T. A comparison of
complications associated with
colostomy
reversal
versus
ileostomy reversal. Am J Surg.
2005;190:717-20
18. Myers E, Hurley M, O'Sullivan
GC, Kavanagh D, Wilson I,
Winter
DC.
Laparoscopic
peritoneal
lavage
for
generalised peritonitis due to
perforated diverticulitis. Br J
Surg. 2008 Jan;95(1):97-101.
19. Dutch hospital statistics at
www.prismant.nl
20. Janes S, Meagher A, Frizelle F.
Management of diverticulitis.
BMJ 2006;332:271-5
21. Makela J, Kiviniemi H, Laitinen S.
Prevalence
of
perforated
sigmoid
diverticulitis
is
increasing. Dis Colon Rectum
2002;45:955-961
22. O'Sullivan GC, Murphy D,
O'Brien
MG,
Ireland
A.
Laparoscopic management of
generalised peritonitis due to
perforated colonic diverticula.
Am
J
Surg.
1996
Apr;171(4):432-4.
23. Da Rold AR, Guerriero S,
Fiamingo P, Pariset S, Veroux M,
Pilon F, Tosato S, Ruffolo C,
Tedeschi
U.
Laparoscopic
colorrhaphy, irrigation and
drainage in the treatment of
complicated acute diverticulitis:
initial experience. Chir Ital. 2004
Jan-Feb;56(1):95-8.
24. Franklin ME Jr, Portillo G,
Treviño JM, Gonzalez JJ, Glass JL.
Long-term experience with the
laparoscopic
approach
to
perforated diverticulitis plus
generalised peritonitis. World J
Surg. 2008 Jul;32(7):1507-11.
25. Faranda C, Barrat C, Catheline
JM, Champault GG. Two-stage
laparoscopic management of
generalised peritonitis due to
perforated sigmoid diverticula:
eighteen cases. Surg Laparosc
Endosc Percutan Tech. 2000
Jun;10(3):135-8;
discussion
139-41
26. Bretagnol F, Pautrat K, Mor C,
Benchellal Z, Huten N, de Calan
L.
Emergency
laparoscopic
management
of
perforated
sigmoid
diverticulitis:
a
promising alternative to more
24
radical procedures. J Am Coll
Surg. 2008 Apr;206(4):654-7.
27. Mutter D, Bouras G, Forgione A,
Vix M, Leroy J, Marescaux J.
Two-stage totally minimally
invasive approach for acute
complicated
diverticulitis.
Colorectal
Dis.
2006
Jul;8(6):501-5.
28. Taylor CJ, Layani L, Ghusn MA,
White
SI.
Perforated
diverticulitis
managed
by
laparoscopic lavage. ANZ J Surg.
2006 Nov;76(11):962-5
29. Schilling MK, Maurer CA,
Kollmar O, Buchler MW. Primary
vs. secondary anastomosis after
sigmoid colon resection for
perforated
diverticulitis
(Hinchey Stage III and IV): a
prospective outcome and cost
analysis. Dis Colon Rectum
2001;44:699-703
30. Richter S, Lindemann W,
Kollmar O, Pistorius GA, Maurer
CA, Schilling MK. One-stage
sigmoid colon resection for
perforated
diverticulitis
(Hinchey stages III and IV).
World J Surg 2006;30:1027-32
31. Rafferty J, Shellito P, Hyman NH,
Buie WD; Standards Committee
of American Society of Colon
and Rectal Surgeons. Practice
parameters
for
sigmoid
diverticulitis.Dis Colon Rectum.
2006 Jul;49(7):939-44.
32. Practice parameters for the
treatment
of
sigmoid
diverticulitis. The Standards
Task Force. The American
Society of Colon and Rectal
Surgeons.Dis Colon Rectum.
2000 Mar;43(3):289.
33. Vincent JL, Moreno R, Takala J et
al. The SOFA (Sepsis-related
Organ Failure Assessment)
score
to
describe
organ
dysfunction/failure. On behalf of
the Working Group on SepsisRelated Problems of the
European Society of Intensive
Care Medicine. Intensive Care
Med 1996;22:707-710.
34. Chow, S.C.; Shao, J.; Wang, H.
2003. Sample Size Calculations
in Clinical Research. Marcel
Dekker. New York. D'Agostino,
R.B., Chase, W., Belanger, A.
1988.'The Appropriateness of
Some Common Procedures for
Testing the Equality of Two
Independent
Binomial
Populations', The American
Statistician,
August
1988,
Volume 42 Number 3, pages
198-202.
35. Fleiss, J. L., Levin, B., Paik, M.C.
2003. Statistical Methods for
Rates and Proportions. Third
Edition. John Wiley & Sons. New
York. Lachin, John M. 2000.
Biostatistical Methods. John
Wiley & Sons. New York.
36. Machin, D., Campbell, M., Fayers,
P., and Pinol, A. 1997. Sample
Size Tables for Clinical Studies,
2nd Edition. Blackwell Science.
Malden,
Mass.
25
26
Participating centers and its clinical investigators
Currently participating:
1. Albert Schweitzer Ziekenhuis
2. Alysis Zorggroep, Rijnstate
3. AMC
4. Amphia Ziekenhuis
5. Atrium MC Parkstad
6. Catharina Ziekenhuis
7. Deventer Ziekenhuis
8. Diaconessenhuis Leiden
9. Erasmus MC
10. Flevo Ziekenhuis
11. Groene Hart Ziekenhuis
12. Haga Ziekenhuis
13. IJsselland Ziekenhuis
14. Ikazia Ziekenhuis
15. Isala Klinieken
16. Jeroen Bosch Ziekenhuis
17. Kennemer Gasthuis
18. LUMC
19. Maasstad Ziekenhuis
20. Máxima MC
21. Meander Medisch Centrum
22. Medisch Spectrum Twente
23. OLVG
24. Orbis MC
25. Reinier de Graaf Gasthuis
26. Rode Kruis Ziekenhuis
27. Slotervaart Ziekenhuis
28. Spaarne Ziekenhuis
29. St. Antonius Ziekenhuis
30. St. Franciscus Gasthuis
31. St. Lucas Andreas Ziekenhuis
32. Tergooi Ziekenhuizen
33. Twee Steden Ziekenhuis
34. UMC Utrecht
35. Universiteitsziekenhuis Leuven
36. Vie Curi Medisch Centrum
37. VUmc
38. Westfries Gasthuis
39. Zaans Medisch Centrum
40. Ziekenhuis Gelderse Vallei
Dr. J.A.B. van der Hoeven
Dr. C. Blanken-Peeters
Prof.dr. W.A. Bemelman
Dr. R.M.P.M. Crolla
Dr. E. Belgers
Dr. S.W. Nienhuijs
Drs. R.J.I. Bosker
Dr. W. Hueting
Prof.dr. J.F. Lange
Dr. M. Boom
Dr. D.J. Swank
Dr. J.J. Wever
Dr. E.J.R. de Graaf
Dr. B.R. Toorenvliet
Dr. E.G.J.M. Pierik
Dr. H. Prins
Dr. H.B.A.C. Stockmann
Prof.dr. J.H. van Bockel
Dr. P.P.L.O. Coene
Dr. G.D. Slooter
Dr. E.C.J. Consten
Drs. E.B. van Duyn
Dr. M.F. Gerhards
Dr. A.G.M. Hoofwijk
Dr. T.M. Karsten
Dr. H.A. Cense
Drs. S.C. Bruin
Dr. Q.A.J. Eijsbouts
Dr. M.J. Wiezer
Dr. G.H.H. Mannaerts
Dr. B.A. van Wagensveld
Dr. A.A.W. van Geloven
Dr. D.J.K. Maring
Dr. W.M.U. van Grevenstein
Prof.dr. A. D'Hoore
Dr. J.L.M. Konsten
Dr. D.L. van der Peet
Drs. M.J.P.M. Govaert
Dr. A.F. Engel
Drs. Ph.M. Kruyt
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Contact information
Project leaders
Prof. dr. W.A. Bemelman
Surgeon
T: +3120566818
E: [email protected]
Academic Medical Center
Department of Surgery
Postbus 22660
1100 DD AMSTERDAM
Prof. dr. J.F. Lange
Surgeon
T: 0652123555
E: [email protected]
Erasmus Medical Center
Department of Surgery
Postbus 2040
3000 CA ROTTERDAM
Trial coordinators
Drs. H.A. Swank
Research fellow
T: 0644206408
E: [email protected]
Academic Medical Center
Department of Surgery G4-144
Postbus 22660
1100 DD AMSTERDAM
Drs. I. Mulder
Research fellow
T: 0646241956
E: [email protected]
Erasmus Medical Center
Department of Surgery
Postbus 2040
3000 CA ROTTERDAM
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Co-investigators
Dr. J. Vermeulen
Surgeon
T: 06-52123555
E: [email protected]
Erasmus Medical Center
Department of Surgery
Postbus 2040
3000 CA ROTTERDAM
Dr. M. Boermeester
Surgeon / Clinical Epidemiologist
T: +31205669111
Academic Medical Center
Department of Surgery
Postbus 22660
1100 DD AMSTERDAM
Drs. B.C. Opmeer
Economist
T: 020-5669111
Academic Medical Center
Epidemiology and Statistics
Postbus 22660
1100 DD AMSTERDAM
Independent advisor
Prof. dr. O.R.C. Busch
Surgeon
T: 020 - 5669111, 62770
Academisch Medisch Centrum
Department of Surgery
Postbus 22660
1100 DD AMSTERDAM
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Project committee
Dr. P.P.L.O. Coene
Surgeon
T: 0624606284
Maasstad Hospital
Groene Hilledijk 315
3075 EA ROTTERDAM
Project advisors
Prof. dr. J.J. Busschbach
HTA professional
T: 0107040704
Erasmus Medical Center
Medical Psychology and Psychotherapy
Postbus 1738
3000 DR ROTTERDAM
Dr. W.C. Hop
Clinical Epidemiologist
T: 0104081111
Erasmus Medical Center
Epidemiology and Statistics
Postbus 2040
3000 CA ROTTERDAM
Dr. J.B. Reitsma
Clinical Epidemiologist
T: 020-5669111
Academic Medical Center
Epidemiology and Statistics
Postbus 22660
1100 DD AMSTERDAM
Monitor
M. de Brouwer
Monitor
T +31(0)20 5668555
Academic Medical Center
Clinical Research Unit J1B-111
Postbus 22660
1100 DD AMSTERDAM
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