Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03236961 |
| Other study ID # |
APPAC II |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 3, 2017 |
| Est. completion date |
April 1, 2029 |
Study information
| Verified date |
November 2020 |
| Source |
Turku University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Appendicectomy has been the treatment of acute appendicitis for over a hundred years.
Appendicectomy, however, includes operative and postoperative risks despite being a routine
procedure. Several studies have proved promising results of the safety and efficiency of
antibiotics in the treatment of acute uncomplicated appendicitis. The APPAC study by the
investigators, published in 2015 in the Journal of American Medical Association, also proved
promising results with 73% of patients with uncomplicated appendicitis treated successfully
with antibiotics. None of the patients initially treated with antibiotics that later had
appendectomy had major complications. The results of the APPAC trial suggest that CT proven
uncomplicated acute appendicitis is not a surgical emergency and antibiotic therapy is a safe
first-line treatment option. Reducing unnecessary appendectomies has also been shown to lead
to significant economic savings.
The aim of this randomized prospective study is to optimize antibiotic therapy for
uncomplicated acute appendicitis by comparing different antibiotic regimens; intravenous
antibiotic (ertapenem) followed by per oral antibiotic (levofloxacin and metronidazole) with
only per oral antibiotics (moxifloxacin). Before randomization, the diagnosis of acute
uncomplicated appendicitis is confirmed with a CT scan.
The hypothesis is that broad-spectrum intravenous antibiotics requiring additional hospital
resources are not necessary for the treatment of uncomplicated acute appendicitis and that
per oral mono therapy is non-inferior to the combination of intravenous and per oral
antibiotic therapy.
Description:
Acute appendicitis is the most common cause of abdominal pain in emergency departments and
appendectomy is the most common emergency abdominal surgery. The lifetime risk of acute
appendicitis in males is 8.6% and 6.7% in females. In Finland according to Stakes data there
were 6 377 appendectomies (3242 in males, 3135 in females, median age 35 years) performed in
2010. The total number of days in hospital care was 16 111 days and the mean length of
hospital stay was three days.
Although acute appendicitis is the most common reason for surgical emergency department
visit, its diagnosis still remains challenging. The clinical diagnosis has previously been
based on patient history, physical examination and laboratory findings as well as the
clinical surgical diagnosis. Several scoring systems have been created to aid in the
diagnosis of acute appendicitis18-20, but the accuracy of clinical diagnosis without
preoperative imaging is about 76 - 80 % for combined patient groups of males and females.
As acute appendicitis has historically been thought to always progress to perforation
requiring emergency appendectomy, high negative appendectomy rates even up to 40 % in some
patient populations have been previously accepted as good surgical practice. For the last two
decades, the use of dedicated imaging in acute abdomen in general and also in acute
appendicitis has led to improved diagnostic accuracy.
Based on large epidemiological studies, it is now known that complicated (perforated) and
uncomplicated (non-perforated) appendicitis have followed different epidemiological trends.
These unassociated epidemiologic trends suggest different pathophysiology for the two form of
appendicitis. The differential diagnosis is essential as patients with an uncomplicated acute
appendicitis may not require surgical intervention and might experience even spontaneous
resolution without perforation. The majority (approximately 80 %) of acute appendicitis cases
are of uncomplicated nature.
Complicated acute appendicitis defined as a finding of a perforation, appendicolith, abscess
or a suspicion of a tumor, requires emergency appendectomy with the exception of cases with
abscess as they are often managed conservatively.
Appendicolith is a calcified fecal concretion in the appendix resulting in internal luminal
obstruction and it is the most common form of complicated acute appendicitis. In the first
randomized study by Vons et al. comparing operative treatment and antibiotic therapy using CT
as a diagnostic inclusion criterion, the presence of an appendicolith in preoperative CT scan
was the only factor that significantly increased the risk of complicated appendicitis and it
was also the only factor associated with the failure of antibiotic therapy for acute
appendicitis. Indeed, if Vons et al had excluded the patients with an appendicolith from
their analysis, no significant difference in the incidence of post-intervention peritonitis
between the treatment groups would have been noticed in their study.
CT imaging is the primary imaging modality and the golden standard in the diagnosis of acute
appendicitis as it establishes the diagnosis with almost perfect diagnostic accuracy. The
advantages of CT imaging are high accuracy, availability, ease of performance and
interpretation, and that it is rarely affected by bowel gas, severe abdominal pain or extreme
body habitus. The main disadvantage of CT is exposure to radiation.
The increased use of preoperative CT imaging has been evaluated thoroughly by evaluating its
impact on the negative appendectomy rate reducing the number of unnecessary appendectomies.
In 2010, a mandatory imaging guideline for suspected acute appendicitis was implemented in
the Netherlands. After implementation the negative appendectomy rate dropped significantly
from 23 % to 6 % (p<0.001) reducing the surgical complication rate from 20% to 14 % and
resulting in average cost-per-patient decrease by 594€.
The favorable diagnostic performance of CT imaging has encouraged optimization of the
protocol to minimize exposure to radiation through the development of low-dose CT protocols.
Low-dose protocols balance with as low as reasonably achievable-principle while maintaining
diagnostic accuracy. However, low-dose protocols with intravenous contrast are still not
implemented in routine clinical practice. These protocols require more advanced optimization
and validation because of the wider need for contrast enhanced assessment. Kim et al showed
that contrast enhanced low-dose CT (median radiation dose 116mmGy in dose-length product) was
not inferior to standard-dose contrast enhanced CT (median radiation dose 521 mmGy), with
negative appendectomy rates of 3.5% and 3.2% respectively and no statistical significance in
appendiceal perforation rates or patients requiring additional imaging.
The investigators have performed a prospective observational study (OPTICAP trial,
NCT02533869, Ethical committee of Turku University Hospital approval) in order to optimize a
low-dose CT scan for both diagnosing acute appendicitis and to differentiate uncomplicated
acute appendicitis from a complicated acute appendicitis. In this study, phantom imaging with
15 different imaging protocols were performed aiming to minimize radiation with optimal
diagnostic accuracy. The phantom protocols were assessed by blinded evaluation of two
gastrointestinal radiologists and the two best performing protocols were chosen for the
clinical phase. The clinical evaluation included performing both of these imaging protocols
for patients with suspected uncomplicated acute appendicitis evaluated by a senior digestive
surgeon. All of the enrolled patients underwent laparoscopic appendectomy to evaluate the
sensitivity and specificity of the imaging protocols. The most optimal imaging protocols were
selected for use in the APPAC II trial; one low-dose CT protocol for patients with BMI under
30 and one optimised standard CT protocol for patients with BMI exceeding 30.
For over a century appendectomy has been the standard treatment for all patients with acute
appendicitis. However, the results of our APPAC trial have now shown that the majority (73%)
of patients with uncomplicated acute appendicitis were successfully treated with antibiotics
alone. We also showed that none of the patients treated initially with antibiotics and later
undergoing appendectomy had major complications or increased morbidity defining antibiotic
therapy as a safe first-line treatment. Patients with a complicated acute appendicitis
require emergency appendectomy and early identification of these patients is of vital
importance. Laparoscopic appendectomy has become the golden standard for appendectomy
providing lower morbidity and faster recovery compared with open appendectomy. For patients
with uncomplicated acute appendicitis, the time has come to evaluate abandoning routine
appendectomy and evaluating the optimal use of antibiotic therapy.
The aim of study is to optimize the antibiotic therapy for uncomplicated acute appendicitis
by evaluating the success of treatment in both study groups and by comparing intravenous
antibiotic therapy followed by per oral antibiotics with per oral antibiotic monotherapy. The
study hypothesis is that broad-spectrum intravenous antibiotics requiring additional hospital
resources are not necessary for the treatment of uncomplicated acute appendicitis and that
per oral monotherapy is non-inferior to the combination of intravenous and per oral
antibiotic therapy. The secondary aim is to evaluate the results of the randomized APPAC
trial in a prospective patient cohort by implementing antibiotic therapy as the first-line
treatment for uncomplicated acute appendicitis in clinical practice.
