Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06210269 |
| Other study ID # |
APPAC IV |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 2024 |
| Est. completion date |
December 2045 |
Study information
| Verified date |
January 2024 |
| Source |
Turku University Hospital |
| Contact |
Paulina Salminen, Professor |
| Phone |
+358407181896 |
| Email |
paulina.salminen[@]tyks.fi |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
APPAC IV, a randomized double-blind multicenter clinical trial comparing once daily oral
moxifloxacin with placebo in an outpatient setting aims to evaluate whether antibiotics and
hospitalization or both can be omitted in the treatment of uncomplicated appendicitis further
significantly increasing cost savings and patient satisfaction. This is a direct research
continuum to the previous trial triad: APPAC, APPAC II and APPAC III, which have already
established that the majority of patients with uncomplicated acute appendicitis can be safely
treated without surgery. The APPAC IV trial is based on a novel concept and approach to
further optimize the nonoperative treatment of uncomplicated acute appendicitis with a high
potential in resulting in major health care cost savings and potentially also in significant
reduction of antibiotic use in an extremely common surgical emergency.
Description:
Acute appendicitis is one of the most common surgical emergencies worldwide. For over a
century, surgical removal of the appendix has been considered the only possible treatment
option with appendectomy still being one of the most common emergency surgeries. Although
appendectomy is generally well tolerated, it is a major surgical intervention and can be
associated with postoperative morbidity. Since the time Fitz described the relationship
between the appendix and pelvic abscess and McBurney demonstrated reduced morbidity from
pelvic infections attributable to appendectomy, it has been thought that acute appendicitis
invariably progresses to perforation strengthening the belief that emergency appendectomy is
always required for acute appendicitis. However, it is now acknowledged that complicated and
uncomplicated appendicitis are two different diseases both epidemiologically and clinically
also suggesting different pathophysiology and the majority of the cases are uncomplicated.
The differential diagnosis is essential as patients presenting with an uncomplicated acute
appendicitis may not require surgical intervention and might experience even spontaneous
resolution without perforation.
APPAC IV builds on trials by the APPAC (APPendicitis ACuta) study group showing that imaging
confirmed uncomplicated acute appendicitis is in fact not a surgical emergency. Antibiotic
therapy alone has been shown to be a safe and effective treatment option for patients with
computed tomography (CT) confirmed uncomplicated acute appendicitis also in other randomized
clinical trials (RCTs). A major knowledge gap on the role of antibiotics still exists.
Changing the over century-old dogma of appendectomy for all appendicitis cases into current
knowledge where the majority of patients with uncomplicated acute appendicitis can be treated
with antibiotics alone if not only with symptomatic therapy, protecting patients from
potential adverse effects of antibiotics. In any case, nonoperative treatment, i.e., avoiding
unnecessary surgeries will result in major cost and resource savings as the majority of
appendicitis cases are uncomplicated. In addition to direct cost savings demonstrated by the
APPAC trial at both short- and long-term follow-up, the non-operative treatment approach in
this very common surgical emergency allows for the re-allocation of limited health care
resources.
Implementing the best available knowledge and current state-of-the-art diagnostics for
uncomplicated acute appendicitis using uniform and standardized diagnostic criteria
optimizing the pre-intervention patient selection, the investigators anticipate APPAC IV
trial to have an even higher success rate of antibiotic treatment for imaging confirmed
uncomplicated acute appendicitis compared to the previous trial. Future research should focus
on determining both standardized uniform definitions differentiating between appendicitis
severity ruling out complicated acute appendicitis and factors predicting non-responsiveness
to antibiotics. Further optimizing the patient selection for non-operative treatment would
enable potential outpatient management of uncomplicated acute appendicitis resulting in major
hospital resource and cost savings. With the current knowledge provided by the landmark APPAC
trials and other recent RCTs, initial antibiotic management is consistently associated with a
lower complication rate and an at least 70% chance of avoiding surgery within the first year.
This information should form the basis of shared informed decision-making.
Aims of the study and study hypothesis
APPAC IV, a randomized double-blind multicenter clinical trial comparing once daily oral
moxifloxacin with placebo in an outpatient setting, assesses whether antibiotics and
hospitalization or both can be omitted in the treatment of uncomplicated appendicitis further
significantly increasing cost savings and patient satisfaction. This is a direct and
ambitious research continuum to the previous three APPAC trials, which still have not solved
the role and necessity of antibiotics. The APPAC IV is based on a novel concept of
symptomatic treatment only further optimizing the possibilities of nonoperative treatment for
uncomplicated acute appendicitis. After APPAC IV, it will be known whether antibiotics are
needed. Bridging this knowledge gap will lay the foundation for clinical guidelines of
nonoperative appendicitis treatment. In any outcome, there is a very high potential of both
major health care cost and resource savings. If antibiotics are not needed, this will
additionally result in significant reduction of antibiotic use in an extremely common
surgical emergency. In addition, as AMR is a major global threat, the APPAC IV trial will
include a translational MAPPAC II substudy at TUCH and UTU assessing the effects of
antibiotics on gut microbiota, gut health, and correlation to serum cytokines in this
real-life randomized patient cohort. As a part of ethical conduct of clinical trials, the
investigators will use this unique opportunity of placebo vs. antibiotics randomized patients
with the same disease in similar environments to investigate the development of AMR and the
underlying bacterial defence mechanisms in Escherichia coli and across the microbiome.
To achieve this, the APPAC IV study including the substudy on microbiology (MAPPAC II) has
four specific Aims:
I. Can antibiotics be omitted in the treatment of uncomplicated acute appendicitis? APPAC IV
will be a non-inferiority trial with the study hypothesis that oral placebo is noninferior to
oral antibiotics in the treatment of CT-confirmed uncomplicated acute appendicitis evaluated
at 30 days after the intervention. The primary outcome will be treatment success defined
similarly as in the previous APPAC trials in order to enhance comparability and
generalizability. This study hypothesis is supported by the APPAC III pilot feasibility trial
results where antibiotics were not superior to placebo warranting a large noninferiority
trial to truly assess the role of antibiotics in the treatment of uncomplicated acute
appendicitis. The expected outcome according to the study hypothesis is that still the
majority of patients can be treated without surgery and even antibiotics could perhaps be
omitted having a major impact on the antibiotic usage in this very common disease. The
successful nonoperative treatment with either antibiotics or symptomatic therapy will in any
case result in significant cost savings as almost 60-70% of all appendectomies could be
avoided - for example, in the US this would mean approximately almost 200.000 appendectomies
and in Europe approximately 550.000 avoided surgeries allowing re-allocation of this major
health care resource.
To further improve patient selection and subsequently the success rate of nonoperative
treatment for uncomplicated acute appendicitis, accurate differential diagnosis between
uncomplicated and complicated acute appendicitis ruling out the former is essential.
Potential pre-intervention findings associated with primary non-responsiveness to antibiotics
in the APPAC II trial were assessed and appendiceal diameter ≥ 15mm on CT and a body
temperature of > 38°C on admission were associated with primary non-responsiveness to
antibiotic therapy. For the APPAC IV trial, the additional novel findings of the appendiceal
diameter and body temperature have been added to the trial exclusion criteria.
II. Is outpatient treatment of uncomplicated acute appendicitis safe - can hospitalization be
avoided? The hospitalization in the previous RCTs was quite long to ensure patient safety. As
the current available trials have shown nonoperative treatment to be safe for both oral
antibiotics and also for symptomatic therapy in patients with CT-confirmed uncomplicated
acute appendicitis, the second aim of APPAC IV trial will be to assess the safety and
feasibility of outpatient treatment significantly reducing the need for hospital resources.
The patients will be discharged from the emergency room with the oral double-blind
medications with no hospital stay unless they are evaluated to require follow-up at the
hospital based on the surgeon decision or patient related factors. In order to ensure patient
safety, the study coordinator will contact all patients at day 1 after randomization and at
3-4 days together with recommended laboratory tests (leukocyte count and CRP). The hypothesis
is that hospitalization in most cases can be avoided having a phenomenal impact on the used
health care resources - avoiding hospitalization in most patients will increase the potential
high gain and significant impact of the trial in both cost savings, but also allows
re-allocation of limited hospital resources.
III. Is there an effect of oral antibiotic treatment on gut microbiota and its antibiotic
resistance reservoir (APPAC IV substudy at Turku University hospital: Microbiology
APPendicitis Acuta, MAPPAC II) Our initial MAPPAC study has evaluated the differences of
appendiceal microbiota between uncomplicated and complicated acute appendicitis showing that
these two forms of acute appendicitis have different appendiceal microbiome profiles further
supporting the disconnection between these two different forms of acute appendicitis. The aim
of the MAPPAC II is to assess the effect of moxifloxacin on gut microbiota in a longitudinal
single center prospective cohort study as a part of the APPAC IV clinical trial at the main
research center Turku University Hospital. Our hypothesis is that antibiotics will have a
notable effect on gut microbiota composition, functional capacity of gut microbiota and its
resistome. Effects will be studied from rectal and fecal samples collected both pre- and
post-treatment time points by modern, up to date metagenomic shotgun sequencing methodology.
Antibiotic resistant bacterial strains by selective bacterial isolation, phenotypic
antimicrobial susceptibility testing and whole genome sequencing are studied. Further, the
development of antibiotic resistance within gut microbiota will be evaluated in Escherichia
coli and across the microbiome using a very recently developed single-cell technology. The
investigators will also detect resistance genes from the microbiome with metagenomic
sequencing to evaluate the impact of the antibiotic treatment to the whole gut microbiome to
show if the results from the E. coli can be extrapolated to the wider community. This will
also show if the resistance genes (on plasmids) are from the E. coli population or from other
resistant bacteria in the microbiome.
In addition, MAPPAC II will explore the metagenomic data to trace the activity of bacterial
CRISPR defense systems in order to address their role in mobile antibiotic resistance.
IV. The effect of oral antibiotic treatment on gut microbiota, development of dysbiosis and
related systemic low-grade inflammation and immune response. Gut microbiota correlation to
serum cytokine profiles (MAPPAC II).
Cytokines regulate the quantity and quality of inflammatory responses to maintain gut
homeostasis. Our recent findings indicate that patients diagnosed with the complicated form
of acute appendicitis show a significant increase in several serum cytokines compared with
patients diagnosed with the uncomplicated form of appendicitis. This suggests that serum
cytokines may serve as diagnostic biomarkers for differentiating uncomplicated and
complicated appendicitis. Since antibiotics dramatically change the gut flora and cause at
least a transient unbalanced state possibly leading to dysbiosis and systemic low-grade
inflammation, we will investigate how serum cytokines and other inflammatory markers and
metabolomics profiles are affected by the moxifloxacin treatment, and how this correlates
with gut microbiota composition.
