Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02029781 |
| Other study ID # |
Apple study 2013 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
January 6, 2014 |
| Last updated |
May 29, 2016 |
| Start date |
September 2013 |
Study information
| Verified date |
May 2016 |
| Source |
University Medical Center Groningen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Netherlands: Medical Ethics Review Committee (METC) |
| Study type |
Interventional
|
Clinical Trial Summary
SUMMARY
Rationale: A diagnostic laparoscopy is a frequently used method to confirm the diagnosis
appendicitis. However until recently evidence-based laparoscopic criteria for determining
appendicitis were not defined. If there is any doubt about the presence of appendicitis the
appendix is usually removed. In a single centre prospective pilot study on 134 patients the
investigators were able to define the Laparoscopic APPendicitis (LAPP) score. In the current
study the investigators will validate the LAPP score in order to decrease the negative
appendectomy rate by 50%. Eventually the score should lead to a decrease in morbidity.
Objective: To decrease the negative appendectomy rate by 50%.
Study design: A multicenter prospective validation study
Study population: All patients, ≥18 years, operated with a diagnostic laparoscopy for the
clinical suspicion appendicitis. Sample size calculation, performed by a statistician/
epidemiologist of the Trial Coordination Centre, showed the need to analyse 778 patients.
Intervention (if applicable): Patients operated on appendicitis in 2008 and 2009 (n=843),
were retrospectively analysed for negative appendectomies. This cohort will serve as the
control group. In this control group no intervention was given, as the LAPP score was not
yet defined.
In the 778 prospective analysed patients, the LAPP score will be used during a diagnostic
laparoscopy. With the LAPP score the investigators intend to halve the number of negative
appendectomies.
Main study parameters/endpoints: A decrease in the negative appendectomy rate from 9% to 5%.
This decrease should not lead to an increase in missed appendicitis (occurring within 30
days), defined as requiring a surgical re-intervention or as an appendicitis or appendicular
infiltrate on an ultrasound or CT-scan.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: The risk of implementation of the LAPP score is minimal. In theory, the use of
the LAPP score might lead to an increase risk in missed appendicitis. This might lead to an
increase in morbidity.
Description:
1. INTRODUCTION AND RATIONALE
During the last decade, a laparoscopic approach for a suspicion of appendicitis has
become more common in surgical practice. In case the appendix looks normal the
guideline of the Dutch Society of Surgeons advices not to remove it. [1] The morbidity
of a negative appendectomy is approximately 6% and it also leads to additional costs.
[2] However, until recently no criteria on how to assess the appendix during a
laparoscopy has been published. In a recently performed pilot study the investigators
defined the Laparoscopic APPendectomy (LAPP) score. [3] The LAPP score is an easy
applicable score that can be used during a diagnostic laparoscopy to evaluate the
appendix on the presence or absence of 5 laparoscopic criteria on appendicitis. In our
prospective cohort, use of the LAPP score would have led to a positive predictive value
of 99% and a negative predictive value of 100%.
The goal of the current study is to validate the LAPP score in a prospective
multicenter validation study. Our hypothesis is that the application of the LAPP score
leads to a reduction of 50% of negative appendectomies compared with a retrospective
cohort in the same centers. The investigators have chosen to compare the negative
appendectomy rate of this prospective multicenter validation study with a retrospective
control group. The control group consists of 843 patients operated in 5 centers in 2008
and 2009 with a negative appendectomy rate of 9%.
The most ideal design would be a clustered center randomized trial. In such a case half
of the hospitals will be asked to use the LAPP score and the other half should assess
the appendix the conventional way. The investigators feel that it is not feasible, as
they already presented the LAPP score at the national congress for surgeons. In
addition, after publication of the results of the LAPP study surgeons might already
start to use the LAPP score or at least will evaluate the appendix differently than
before. [3]
2. OBJECTIVES
Primary Objective: To reduce the negative appendectomy rate with 50% compared with the
retrospective control group.
Secondary Objective(s):
- The percentage of missed appendicitis should not exceed 1%.
- Analyse sensitivity rate.
- Cost from used materials during the operation.
- Cost form the histology review by the pathologist of a removed appendix
3. STUDY DESIGN
Prospective cohort design, multicenter prospective validation study in 778 patients
suspected for appendicitis with an indication for diagnostic laparoscopy. The
investigators expect to fulfill the inclusion within one and half year.
This cohort will be compared with a multicenter historical cohort. Each center will be
its own control group.
4. STUDY POPULATION
Population (base) All patients operated for the suspicion of acute appendicitis. The
preoperative work-up is not standardized for this study; therefore the investigators
stick to the protocol of each hospital. The clinical decision to operate the patient
will be made by the surgeon on call. Only patients that will undergo a (diagnostic)
laparoscopy can be included in this study.
A total of 778 patients must be included. The investigators intend to fulfill inclusion
within one and a half year. This duration is based on prevalence of appendicitis in the
Netherlands. Annually, 16.000 appendectomies are performed, in combination with eight
participating centers, the investigators think this is a feasible period.
Sample size calculation The sample size calculation was performed according to the
methods by William D. Dupont and Walton D. Plummer (PS Power and Sample Size
Calculations). For the sample size calculation the investigators performed a
retrospective cohort analysis in 2008 and 2009 in 5 hospitals in the Netherlands
(Wilhelmina Ziekenhuis Assen, Nij Smellinghe Ziekenhuis Drachten, Universitair Medisch
Centrum Groningen, Medisch Centrum Leeuwarden and Martini Ziekenhuis Groningen). During
this period 843 patients were operated for the suspicion of acute appendicitis with a
diagnostic laparoscopy, 9% of the removed appendices turned out to be normal (appendix
sana). In order to half the negative appendectomy rate with a power of 0.8 and an alpha
of 0.05, 544 patients in the prospective group are needed. Our previous prospective
analysis (the LAPP study) and the retrospective data showed that approximately 15% of
the included patients will have another diagnosis (Crohn's disease, ruptured ovarian
cyst etc.), additionally the investigators expect another 15% of exclusions because for
example no clear laparoscopic view of the appendix (figure 1). Therefore the
investigators need 778 patients in our multicenter prospective validation study.
Important to mention, in the sample size calculation they did not take sensitivity rate
into account, as they expect the sensitivity will be around 100%. However, the
investigators will calculate this percentage and report is in the results section.
5. TREATMENT OF SUBJECTS
5.1 Investigational product/treatment Use of the LAPP score. The LAPP score consists of
5 questions concerning criteria of appendicitis, if 1 or more of these questions are
answered with 'yes' the appendix should be removed, if all questions are answered with
'no' the appendix should not be removed.
The five questions are:
- Is there perforation and/or necrosis of the appendix;
- Is the appendix thickened;
- Is the mesentery of the appendix thickened;
- Is there presence of injected vessels on the serosa of the appendix;
- Are there any adhesions around the appendix.
5.2 Use of co-intervention (if applicable) Not applicable
5.3 Escape medication (if applicable) Not applicable.
6. INVESTIGATIONAL PRODUCT
Not applicable, as this study concerns no research with medicinal products.
7. NON-INVESTIGATIONAL PRODUCT
8. METHODS
8.1 Study parameters/endpoints 8.1.1 Main study parameter/endpoint The main endpoint of
the study is to reduce the negative appendectomy rate with 50%. The gold standard is
the histological examination by the pathologist. The pathologist considers the appendix
as inflamed when at least (local) ulceration with infiltration of polymorphonuclear
neutrophils into the mucosa and submucosa (endo-appendicitis) is present, either or not
in combination with transmural inflammation, necrosis, perforation and
peri-appendicular inflammation. In case of inflammation without mucosal ulceration was
found, the contralateral part of the appendix and more transverse slices were examined.
[4] An appendix is considered as normal when no signs of inflammation are found and
when no other abnormality is found like more rare entities as carcinoid, adenocarcinoma
of the appendix or a parasite infection.
8.1.2 Secondary study parameters/endpoints (if applicable)
- The percentage of missed appendicitis; this should not exceed 1%. In theory the
LAPP score might lead to an increase in missed appendicitis. This might happen
when a patient has an early or mild appendicitis without any of the 5 laparoscopic
criteria for appendicitis. The investigators have defined 'missed appendicitis' as
a confirmed appendicitis or appendicular infiltrate on a CT-scan or during a
re-operation (within 3 months).
- Cost from used material during the operation.
- Cost form the histology review by the pathologist of a removed appendix.
8.1.3 Other study parameters (if applicable) Not applicable
8.2 Randomisation, blinding and treatment allocation All included patients will undergo
a diagnostic laparoscopy, during this procedure the LAPP score will be used and on the
basis of the results the appendix will be removed or not.
8.3 Study procedures There are no additional procedures the patients will undergo
during this study.
8.4 Withdrawal of individual subjects Subjects can leave the study at any time for any
reason if they wish to do so without any consequences. The investigator can decide to
withdraw a subject from the study for urgent medical reasons.
8.4.1 Specific criteria for withdrawal (if applicable) For whatever reason the patient
is free to withdraw from the study. After the patient is asked to participate in the
study in the emergency department or on the surgical ward and has signed the informed
consent form, he/she will usually have to wait for some time before he/she is operated
on. In theatre the LAPP score will be used. Postoperatively the patient can still
decide to withdraw from the study, although the decision to remove or not to remove the
appendix has already been made. The patient will be prospective followed for 12 months
and during this period the patient can still decide to withdraw from the study, then
all saved data and forms will be deleted from the database.
8.5 Replacement of individual subjects after withdrawal There is no need to replace a
patient that has withdrawn. In our sample size calculation the investigators
anticipated a 40% rate of withdrawal for several reasons.
8.6 Follow-up of subjects withdrawn from treatment These patients will have the usual
follow-up for patients operated on for the suspicion of appendicitis. In most case
patients will be seen postoperatively once or twice in the outpatient clinics.
8.7 Premature termination of the study
- At 2 different time intervals, when 50 and 75% of the total number of patients are
included in the study an interim analysis will be performed. The percentage of
missed appendicitis will be evaluated. When the percentage of missed appendicitis
exceeds 2%, the study will be terminated.
- The percentage of missed appendicitis leading to a serious adverse event (like
persistent or significant disability or incapacity, life threatening or death)
should not exceed 1%. This will be evaluated at any time during the study.
9. SAFETY REPORTING
9.1 Section 10 WMO event In accordance to section 10, subsection 1, of the WMO, the
investigator will inform the subjects and the reviewing accredited METC if anything occurs,
on the basis of which it appears that the disadvantages of participation may be
significantly greater than was foreseen in the research proposal. The study will be
suspended pending further review by the accredited METC, except insofar as suspension would
jeopardise the subjects' health. The investigator will take care that all subjects are kept
informed.
9.2 AEs, SAEs and SUSARs 9.2.1 Adverse events (AEs) See also section 8.7. Serious adverse
events caused by a missed appendicitis will be reported immediately when they occur. If a
missed appendicitis leads to a prolongation of hospitalization of less than 10 days the
investigators will consider this as an adverse event and take no further action unless this
exceeds 2% after inclusion of every quartile of patients.
Adverse events like persistent or significant disability or incapacity, life threatening or
death will be reported immediately or at least within 7 days to the web portal
ToetsingOnline.
Adverse events are defined as any undesirable experience occurring to a subject during the
study, whether or not considered related to [the investigational product / the experimental
intervention]. All adverse events reported spontaneously by the subject or observed by the
investiga¬tor or his staff will be recorded.
9.2.2 Serious adverse events (SAEs)
A serious adverse event is any untoward medical occurrence or effect that at any dose:
- results in death;
- is life threatening (at the time of the event);
- requires hospitalisation or prolongation of existing inpatients' hospitalisation;
- results in persistent or significant disability or incapacity;
- is a congenital anomaly or birth defect;
- Any other important medical event that may not result in death, be life threatening, or
require hospitalization, may be considered a serious adverse experience when, based
upon appropriate medical judgement, the event may jeopardize the subject or may require
an intervention to prevent one of the outcomes listed above.
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited
METC that approved the protocol, within 15 days after the sponsor has first knowledge of the
serious adverse reactions.
SAEs that result in death or are life threatening should be reported expedited. The
expedited reporting will occur not later than 7 days after the responsible investigator has
first knowledge of the adverse reaction. This is for a preliminary report with another 8
days for completion of the report.
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) Not applicable for this study.
9.3 Annual safety report Not applicable for this study.
9.4 Follow-up of adverse events All AEs will be followed until they have abated, or until a
stable situation has been reached. Depending on the event, follow up may require additional
tests or medical procedures as indicated, and/or referral to the general physician or a
medical specialist.
SAEs need to be reported till end of study within the Netherlands, as defined in the
protocol.
9.5 [Independent Data Monitoring Committee (IDMC) / Safety Committee] The following doctors
will take place in the Independent Data Monitoring Committee;
- Prof. dr. H.W. Nijman, gynaecologist
- Drs. T.H. van Dijk, pediatric surgeon
- Dr. J. Niesing, statistician
