Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT03234296 |
| Other study ID # |
APPAC III |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 9, 2017 |
| Est. completion date |
August 30, 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"
operation. At the same time other similar intra-abdominal infections, such as diverticulitis,
are treated with antibiotics. Several studies have proved promising results of the safety and
efficiency of antibiotics in the treatment of acute uncomplicated appendicitis. Our previous
APPAC study, published in 2015 in the Journal of American Medical Association, also proved
promising results with 73% of patients with CT-diagnosed uncomplicated appendicitis treated
successfully with antibiotics within one-year follow-up. 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.
Already in 1886 Fitz noted that 1/3 of patients in a large series of autopsies from the
pre-appendicectomy era had evidence of prior appendices inflammation suggesting spontaneous
resolution of acute appendicitis. Acute appendicitis is thought to be similar to acute
diverticulitis ("left-sided appendicitis") and this similarity has been shown in
epidemiological studies. Recent studies have shown no benefit of antibiotic treatment in the
treatment of uncomplicated diverticulitis with outpatient management without antibiotics
proving safe and well-functioning.
The aim of this randomised double-blinded study is to compare antibiotic therapy with placebo
to evaluate the role of antibiotic therapy in the resolution of CT-diagnosed uncomplicated
acute appendicitis.
The hypothesis is that antibiotic therapy is necessary in the treatment of acute
uncomplicated appendicitis and that antibiotic therapy is superior to spontaneous resolution
(placebo) with the primary endpoint evaluated at ten days after the intervention.
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 with a 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 116 mmGy 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 two most optimal imaging protocol
were selected for use in the APPAC III trial; one low-dose CT protocol for patients with BMI>
30 and one optimised standard CT 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.
Emergency appendectomy was first advocated because of the very high mortality of perforated
appendicitis combined with the assumption of the natural course of acute appendicitis
evolving always to perforated disease. This was first reported in 1886 by Reginald Fitz, who
initially originated the term appendicitis and identified appendix as a cause for right lower
quadrant infections. Fitz also noted that one-third of patients in a large autopsy series
from the pre-appendectomy era had evidence of prior appendiceal inflammation suggesting
spontaneous resolution of acute appendicitis.
Acute appendicitis is similar to acute diverticulitis ("left-sided appendicitis") and this
similarity has been shown in epidemiological studies suggesting a common underlying
pathogenesis. There is one multicenter randomized trial, one population-based study, one
case-control study and one prospective observational study that have shown no benefit of
antibiotic therapy in uncomplicated acute diverticulitis. The reported complication rates in
these studies is low (approximately 2 %) and even outpatient management without antibiotics
in acute uncomplicated diverticulitis has been shown to be feasible, well-functioning and
safe. The APPAC III trial will first recruit 3-5 pilot patients in order to finalise the
hospital pharmacy procedures in practice.
The aim of the APPAC III study is to compare antibiotic therapy with placebo in the treatment
of uncomplicated acute appendicitis to evaluate the role of antibiotic therapy in the
resolution of acute uncomplicated appendicitis. The study hypothesis is that antibiotic
therapy is necessary in the treatment of acute uncomplicated and that antibiotic therapy is
superior to spontaneous resolution (placebo) with the primary endpoint evaluated at ten days
after the intervention.
Sample size calculations were based on one-sided Pearson's χ2 -test for two proportions.
Sample size was calculated from an estimated success rate of 94% during the hospitalization
in antibiotic group 7. A decrease of 15 percentage points in success rate is considered
clinically important difference leading to estimated 79% success rate in placebo group. We
estimated that to detect a 15 percentage points difference (antibiotics - placebo) between
groups with a power of 0.8 (1-β) and one-sided significance level (α) of 0.05 64 patients per
group is needed. Before the trial initiation, 3-5 pilot patients will be recruited in order
to finalize the hospital pharmacy procedures and drug delivery in clinical practice. Based on
the pilot study enrollment speed and the recognized challenges in conducting trial, in
real-life emergency setting we need to take into account the anticipated enrolment delays to
assure the completion of this trial within reasonable time. These challenges consisting of
emergency surgery patient enrolment dependent on hospital pharmacy services available only
during standard working hours, the requirement for senior surgeon enrolment and the
discrepancy between the admission hours of appendicitis patients and hospital pharmacy
working hours mandated us to create three scenarios for study power analysis and the number
of patients to be enrolled.
In scenario A, a decrease of 15 percentage points in success rate is considered clinically
important difference leading to estimated 79% success rate in placebo group. We estimated
that to detect a 15-percentage points difference (antibiotics - placebo) between groups 64
patients per group is needed. With an estimated dropout rate of 10% total of 142 patients, 71
patients per group will be enrolled in the study. In scenario B, clinically important
difference is 20 percentage points, estimated success rate in placebo group is 74% and to
detect this difference 41 patients per group is needed. With an estimated dropout rate of 10%
total of 92 patients, 46 patients per group will be enrolled in the study. In scenario C,
clinically important difference is 25 percentage points, estimated success rate in placebo
group is 69% and to detect this difference 29 patients per group is needed. With an estimated
dropout rate of 10% total of 64 patients, 32 patients per group will be enrolled in the
study. Targeted minimum sample size per study hospital will be 10 patients. One-sided test
will be used as our hypothesis is that antibiotic treatment is more effective treatment than
placebo. Sample size calculations were performed using Power procedure in SAS System for
Windows, Version 9.4 (SAS Institute Inc., Cary, NC).
On April 1st, 2019, a study committee consisting of the outside safety monitoring committee
and the core research group will assess which one of these scenarios is most feasible based
on patient enrolment with plan A being the target scenario. Active recruitment at this point
will be continued until a decision is made on the clinically realistic enrolment scenario.
The date of evaluation is set exactly one year after the last study hospital has initiated
enrolment.
