<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03234296</url>
  </required_header>
  <id_info>
    <org_study_id>APPAC III</org_study_id>
    <nct_id>NCT03234296</nct_id>
  </id_info>
  <brief_title>Antibiotics vs. Placebo in Acute Uncomplicated Appendicitis</brief_title>
  <acronym>APPACIII</acronym>
  <official_title>Antibiotic Therapy vs. Placebo in the Treatment of Acute Uncomplicated Appendicitis: a Randomized Double-blinded Placebo-controlled Trial - APPAC III Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Turku University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Tampere University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kuopio University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oulu University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Helsinki University Central Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Turku University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Appendicectomy has been the treatment of acute appendicitis for over a hundred years.&#xD;
      Appendicectomy, however, includes operative and postoperative risks despite being a &quot;routine&quot;&#xD;
      operation. At the same time other similar intra-abdominal infections, such as diverticulitis,&#xD;
      are treated with antibiotics. Several studies have proved promising results of the safety and&#xD;
      efficiency of antibiotics in the treatment of acute uncomplicated appendicitis. Our previous&#xD;
      APPAC study, published in 2015 in the Journal of American Medical Association, also proved&#xD;
      promising results with 73% of patients with CT-diagnosed uncomplicated appendicitis treated&#xD;
      successfully with antibiotics within one-year follow-up. None of the patients initially&#xD;
      treated with antibiotics that later had appendectomy had major complications. The results of&#xD;
      the APPAC trial suggest that CT proven uncomplicated acute appendicitis is not a surgical&#xD;
      emergency and antibiotic therapy is a safe first-line treatment option. Reducing unnecessary&#xD;
      appendectomies has also been shown to lead to significant economic savings.&#xD;
&#xD;
      Already in 1886 Fitz noted that 1/3 of patients in a large series of autopsies from the&#xD;
      pre-appendicectomy era had evidence of prior appendices inflammation suggesting spontaneous&#xD;
      resolution of acute appendicitis. Acute appendicitis is thought to be similar to acute&#xD;
      diverticulitis (&quot;left-sided appendicitis&quot;) and this similarity has been shown in&#xD;
      epidemiological studies. Recent studies have shown no benefit of antibiotic treatment in the&#xD;
      treatment of uncomplicated diverticulitis with outpatient management without antibiotics&#xD;
      proving safe and well-functioning.&#xD;
&#xD;
      The aim of this randomised double-blinded study is to compare antibiotic therapy with placebo&#xD;
      to evaluate the role of antibiotic therapy in the resolution of CT-diagnosed uncomplicated&#xD;
      acute appendicitis.&#xD;
&#xD;
      The hypothesis is that antibiotic therapy is necessary in the treatment of acute&#xD;
      uncomplicated appendicitis and that antibiotic therapy is superior to spontaneous resolution&#xD;
      (placebo) with the primary endpoint evaluated at ten days after the intervention.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute appendicitis is the most common cause of abdominal pain in emergency departments and&#xD;
      appendectomy is the most common emergency abdominal surgery. The lifetime risk of acute&#xD;
      appendicitis in males is 8.6% and 6.7% in females.In Finland according to Stakes data there&#xD;
      were 6 377 appendectomies (3242 in males, 3135 in females, median age 35 years) performed in&#xD;
      2010 with a total number of days in hospital care was 16 111 days and the mean length of&#xD;
      hospital stay was three days.&#xD;
&#xD;
      Although acute appendicitis is the most common reason for surgical emergency department&#xD;
      visit, its diagnosis still remains challenging. The clinical diagnosis has previously been&#xD;
      based on patient history, physical examination and laboratory findings as well as the&#xD;
      clinical surgical diagnosis. Several scoring systems have been created to aid in the&#xD;
      diagnosis of acute appendicitis18-20, but the accuracy of clinical diagnosis without&#xD;
      preoperative imaging is about 76 - 80 % for combined patient groups of males and females.&#xD;
&#xD;
      As acute appendicitis has historically been thought to always progress to perforation&#xD;
      requiring emergency appendectomy, high negative appendectomy rates even up to 40 % in some&#xD;
      patient populations have been previously accepted as good surgical practice. For the last two&#xD;
      decades, the use of dedicated imaging in acute abdomen in general and also in acute&#xD;
      appendicitis has led to improved diagnostic accuracy.&#xD;
&#xD;
      Based on large epidemiological studies, it is now known that complicated (perforated) and&#xD;
      uncomplicated (non-perforated) appendicitis have followed different epidemiological trends.&#xD;
      These unassociated epidemiologic trends suggest different pathophysiology for the two form of&#xD;
      appendicitis. The differential diagnosis is essential as patients with an uncomplicated acute&#xD;
      appendicitis may not require surgical intervention and might experience even spontaneous&#xD;
      resolution without perforation. The majority (approximately 80 %) of acute appendicitis cases&#xD;
      are of uncomplicated nature.&#xD;
&#xD;
      Complicated acute appendicitis defined as a finding of a perforation, appendicolith, abscess&#xD;
      or a suspicion of a tumor, requires emergency appendectomy with the exception of cases with&#xD;
      abscess as they are often managed conservatively.&#xD;
&#xD;
      Appendicolith is a calcified fecal concretion in the appendix resulting in internal luminal&#xD;
      obstruction and it is the most common form of complicated acute appendicitis. In the first&#xD;
      randomized study by Vons et al. comparing operative treatment and antibiotic therapy using CT&#xD;
      as a diagnostic inclusion criterion, the presence of an appendicolith in preoperative CT scan&#xD;
      was the only factor that significantly increased the risk of complicated appendicitis and it&#xD;
      was also the only factor associated with the failure of antibiotic therapy for acute&#xD;
      appendicitis. Indeed, if Vons et al had excluded the patients with an appendicolith from&#xD;
      their analysis, no significant difference in the incidence of post-intervention peritonitis&#xD;
      between the treatment groups would have been noticed in their study.&#xD;
&#xD;
      CT imaging is the primary imaging modality and the golden standard in the diagnosis of acute&#xD;
      appendicitis as it establishes the diagnosis with almost perfect diagnostic accuracy. The&#xD;
      advantages of CT imaging are high accuracy, availability, ease of performance and&#xD;
      interpretation, and that it is rarely affected by bowel gas, severe abdominal pain or extreme&#xD;
      body habitus. The main disadvantage of CT is exposure to radiation.&#xD;
&#xD;
      The increased use of preoperative CT imaging has been evaluated thoroughly by evaluating its&#xD;
      impact on the negative appendectomy rate reducing the number of unnecessary appendectomies.&#xD;
      In 2010, a mandatory imaging guideline for suspected acute appendicitis was implemented in&#xD;
      the Netherlands. After implementation the negative appendectomy rate dropped significantly&#xD;
      from 23 % to 6 % (p&lt;0.001) reducing the surgical complication rate from 20% to 14 % and&#xD;
      resulting in average cost-per-patient decrease by 594€.&#xD;
&#xD;
      The favorable diagnostic performance of CT imaging has encouraged optimization of the&#xD;
      protocol to minimize exposure to radiation through the development of low-dose CT protocols.&#xD;
      Low-dose protocols balance with as low as reasonably achievable-principle while maintaining&#xD;
      diagnostic accuracy. However, low-dose protocols with intravenous contrast are still not&#xD;
      implemented in routine clinical practice. These protocols require more advanced optimization&#xD;
      and validation because of the wider need for contrast enhanced assessment. Kim et al showed&#xD;
      that contrast enhanced low-dose CT (median radiation dose 116 mmGy in dose-length product)&#xD;
      was not inferior to standard-dose contrast enhanced CT (median radiation dose 521 mmGy), with&#xD;
      negative appendectomy rates of 3.5% and 3.2% respectively and no statistical significance in&#xD;
      appendiceal perforation rates or patients requiring additional imaging.&#xD;
&#xD;
      The investigators have performed a prospective observational study (OPTICAP trial,&#xD;
      NCT02533869, Ethical committee of Turku University Hospital approval) in order to optimize a&#xD;
      low-dose CT scan for both diagnosing acute appendicitis and to differentiate uncomplicated&#xD;
      acute appendicitis from a complicated acute appendicitis. In this study, phantom imaging with&#xD;
      15 different imaging protocols were performed aiming to minimize radiation with optimal&#xD;
      diagnostic accuracy. The phantom protocols were assessed by blinded evaluation of two&#xD;
      gastrointestinal radiologists and the two best performing protocols were chosen for the&#xD;
      clinical phase. The clinical evaluation included performing both of these imaging protocols&#xD;
      for patients with suspected uncomplicated acute appendicitis evaluated by a senior digestive&#xD;
      surgeon. All of the enrolled patients underwent laparoscopic appendectomy to evaluate the&#xD;
      sensitivity and specificity of the imaging protocols. The two most optimal imaging protocol&#xD;
      were selected for use in the APPAC III trial; one low-dose CT protocol for patients with BMI&gt;&#xD;
      30 and one optimised standard CT for patients with BMI exceeding 30.&#xD;
&#xD;
      For over a century appendectomy has been the standard treatment for all patients with acute&#xD;
      appendicitis. However, the results of our APPAC trial have now shown that the majority (73%)&#xD;
      of patients with uncomplicated acute appendicitis were successfully treated with antibiotics&#xD;
      alone. We also showed that none of the patients treated initially with antibiotics and later&#xD;
      undergoing appendectomy had major complications or increased morbidity defining antibiotic&#xD;
      therapy as a safe first-line treatment. Patients with a complicated acute appendicitis&#xD;
      require emergency appendectomy and early identification of these patients is of vital&#xD;
      importance. Laparoscopic appendectomy has become the golden standard for appendectomy&#xD;
      providing lower morbidity and faster recovery compared with open appendectomy. For patients&#xD;
      with uncomplicated acute appendicitis, the time has come to evaluate abandoning routine&#xD;
      appendectomy and evaluating the optimal use of antibiotic therapy.&#xD;
&#xD;
      Emergency appendectomy was first advocated because of the very high mortality of perforated&#xD;
      appendicitis combined with the assumption of the natural course of acute appendicitis&#xD;
      evolving always to perforated disease. This was first reported in 1886 by Reginald Fitz, who&#xD;
      initially originated the term appendicitis and identified appendix as a cause for right lower&#xD;
      quadrant infections. Fitz also noted that one-third of patients in a large autopsy series&#xD;
      from the pre-appendectomy era had evidence of prior appendiceal inflammation suggesting&#xD;
      spontaneous resolution of acute appendicitis.&#xD;
&#xD;
      Acute appendicitis is similar to acute diverticulitis (&quot;left-sided appendicitis&quot;) and this&#xD;
      similarity has been shown in epidemiological studies suggesting a common underlying&#xD;
      pathogenesis. There is one multicenter randomized trial, one population-based study, one&#xD;
      case-control study and one prospective observational study that have shown no benefit of&#xD;
      antibiotic therapy in uncomplicated acute diverticulitis. The reported complication rates in&#xD;
      these studies is low (approximately 2 %) and even outpatient management without antibiotics&#xD;
      in acute uncomplicated diverticulitis has been shown to be feasible, well-functioning and&#xD;
      safe. The APPAC III trial will first recruit 3-5 pilot patients in order to finalise the&#xD;
      hospital pharmacy procedures in practice.&#xD;
&#xD;
      The aim of the APPAC III study is to compare antibiotic therapy with placebo in the treatment&#xD;
      of uncomplicated acute appendicitis to evaluate the role of antibiotic therapy in the&#xD;
      resolution of acute uncomplicated appendicitis. The study hypothesis is that antibiotic&#xD;
      therapy is necessary in the treatment of acute uncomplicated and that antibiotic therapy is&#xD;
      superior to spontaneous resolution (placebo) with the primary endpoint evaluated at ten days&#xD;
      after the intervention.&#xD;
&#xD;
      Sample size calculations were based on one-sided Pearson's χ2 -test for two proportions.&#xD;
      Sample size was calculated from an estimated success rate of 94% during the hospitalization&#xD;
      in antibiotic group 7. A decrease of 15 percentage points in success rate is considered&#xD;
      clinically important difference leading to estimated 79% success rate in placebo group. We&#xD;
      estimated that to detect a 15 percentage points difference (antibiotics - placebo) between&#xD;
      groups with a power of 0.8 (1-β) and one-sided significance level (α) of 0.05 64 patients per&#xD;
      group is needed. Before the trial initiation, 3-5 pilot patients will be recruited in order&#xD;
      to finalize the hospital pharmacy procedures and drug delivery in clinical practice. Based on&#xD;
      the pilot study enrollment speed and the recognized challenges in conducting trial, in&#xD;
      real-life emergency setting we need to take into account the anticipated enrolment delays to&#xD;
      assure the completion of this trial within reasonable time. These challenges consisting of&#xD;
      emergency surgery patient enrolment dependent on hospital pharmacy services available only&#xD;
      during standard working hours, the requirement for senior surgeon enrolment and the&#xD;
      discrepancy between the admission hours of appendicitis patients and hospital pharmacy&#xD;
      working hours mandated us to create three scenarios for study power analysis and the number&#xD;
      of patients to be enrolled.&#xD;
&#xD;
      In scenario A, a decrease of 15 percentage points in success rate is considered clinically&#xD;
      important difference leading to estimated 79% success rate in placebo group. We estimated&#xD;
      that to detect a 15-percentage points difference (antibiotics - placebo) between groups 64&#xD;
      patients per group is needed. With an estimated dropout rate of 10% total of 142 patients, 71&#xD;
      patients per group will be enrolled in the study. In scenario B, clinically important&#xD;
      difference is 20 percentage points, estimated success rate in placebo group is 74% and to&#xD;
      detect this difference 41 patients per group is needed. With an estimated dropout rate of 10%&#xD;
      total of 92 patients, 46 patients per group will be enrolled in the study. In scenario C,&#xD;
      clinically important difference is 25 percentage points, estimated success rate in placebo&#xD;
      group is 69% and to detect this difference 29 patients per group is needed. With an estimated&#xD;
      dropout rate of 10% total of 64 patients, 32 patients per group will be enrolled in the&#xD;
      study. Targeted minimum sample size per study hospital will be 10 patients. One-sided test&#xD;
      will be used as our hypothesis is that antibiotic treatment is more effective treatment than&#xD;
      placebo. Sample size calculations were performed using Power procedure in SAS System for&#xD;
      Windows, Version 9.4 (SAS Institute Inc., Cary, NC).&#xD;
&#xD;
      On April 1st, 2019, a study committee consisting of the outside safety monitoring committee&#xD;
      and the core research group will assess which one of these scenarios is most feasible based&#xD;
      on patient enrolment with plan A being the target scenario. Active recruitment at this point&#xD;
      will be continued until a decision is made on the clinically realistic enrolment scenario.&#xD;
      The date of evaluation is set exactly one year after the last study hospital has initiated&#xD;
      enrolment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">August 9, 2017</start_date>
  <completion_date type="Anticipated">August 30, 2029</completion_date>
  <primary_completion_date type="Actual">September 15, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Anticipated enrollment delays &gt; three alternate scenarios for sample size calculations, please see prtocol for details.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Double-blinded RCT, no care providers, patients or researchers are aware of the randomised treatment. Separate safety monitoring committee and preplanned interim analysis.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Success of the randomized treatment</measure>
    <time_frame>10 days after treatment initiation</time_frame>
    <description>Resolution of acute appendicitis with study group treatment resulting in discharge from the hospital without the need for surgical intervention and treatment efficacy evaluated at ten days after initiation of the randomized treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Late recurrence of appendicitis</measure>
    <time_frame>10 years</time_frame>
    <description>Late recurrence of acute appendicitis after study treatment defined as clear clinical suspicion of acute appendicitis evaluated at follow-up of one, three, five and ten years</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Post-intervention complications</measure>
    <time_frame>10 years</time_frame>
    <description>Complications according to the Clavien-Dindo classification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital stay</measure>
    <time_frame>1 month</time_frame>
    <description>Duration of hospital stay in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VAS score (visual analogue score)</measure>
    <time_frame>10 years</time_frame>
    <description>Pain as defied by the VAS pain score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sick leave</measure>
    <time_frame>1 month</time_frame>
    <description>Duration of sick leave</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment costs</measure>
    <time_frame>10 years</time_frame>
    <description>Costs resulting from laboratory costs, imaging costs, treatments costs, hospital stay, and treatment of complications and possible operative treatment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">147</enrollment>
  <condition>Acute Appendicitis</condition>
  <arm_group>
    <arm_group_label>Antibiotic treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Ertapenem 1 g x 1 intravenously for 3 days, followed by per oral levofloxacin 500 mg x 1 and metronidazole 500 mg x 3 for 4 days, duration of treatment 7 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intravenous placebo once a day for 3 days, followed by per oral placebo for 4 days with similar p.o. tablets as in the antibiotic group.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ertapenem</intervention_name>
    <description>Intravenous antibiotic followed by per oral antibiotics</description>
    <arm_group_label>Antibiotic treatment</arm_group_label>
    <other_name>Levofloxacin</other_name>
    <other_name>Metronidazole</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Intravenous placebo followed by per oral placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 18-60 years&#xD;
&#xD;
          -  CT confirmed uncomplicated acute appendicitis&#xD;
&#xD;
          -  Ability to give informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age under 18 or over 60 years&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Allergy to contrast media or iodine&#xD;
&#xD;
          -  Allergy or contraindication to antibiotic therapy&#xD;
&#xD;
          -  Metformin medication&#xD;
&#xD;
          -  Renal insufficiency&#xD;
&#xD;
          -  Severe systemic illness (for example malignancy, medical condition requiring&#xD;
             immunosuppressant medication)&#xD;
&#xD;
          -  Complicated acute appendicitis confirmed by CT scan&#xD;
&#xD;
          -  Inability to cooperate or give informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paulina Salminen, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Turku University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Turku University Hospital</name>
      <address>
        <city>Turku</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Finland</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>November 9, 2020</last_update_submitted>
  <last_update_submitted_qc>November 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Turku University Hospital</investigator_affiliation>
    <investigator_full_name>Paulina Salminen</investigator_full_name>
    <investigator_title>Primary investigator</investigator_title>
  </responsible_party>
  <keyword>uncomplicated acute appendicitis</keyword>
  <keyword>complicated acute appendicitis</keyword>
  <keyword>antibiotic therapy</keyword>
  <keyword>spontaneous resolution</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Appendicitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metronidazole</mesh_term>
    <mesh_term>Levofloxacin</mesh_term>
    <mesh_term>Ertapenem</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03234296
org study id: APPAC III
nct id: NCT03234296
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Anticipated enrollment delays > three alternate scenarios for sample size calculations, please see prtocol for details.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Double-blinded RCT, no care providers, patients or researchers are aware of the randomised treatment. Separate safety monitoring committee and preplanned interim analysis.
measure: Success of the randomized treatment
time frame: 10 days after treatment initiation
description: Resolution of acute appendicitis with study group treatment resulting in discharge from the hospital without the need for surgical intervention and treatment efficacy evaluated at ten days after initiation of the randomized treatment.
measure: Late recurrence of appendicitis
time frame: 10 years
description: Late recurrence of acute appendicitis after study treatment defined as clear clinical suspicion of acute appendicitis evaluated at follow-up of one, three, five and ten years
measure: Post-intervention complications
time frame: 10 years
description: Complications according to the Clavien-Dindo classification
measure: Hospital stay
time frame: 1 month
description: Duration of hospital stay in days
measure: VAS score (visual analogue score)
time frame: 10 years
description: Pain as defied by the VAS pain score
measure: Sick leave
time frame: 1 month
description: Duration of sick leave
measure: Treatment costs
time frame: 10 years
description: Costs resulting from laboratory costs, imaging costs, treatments costs, hospital stay, and treatment of complications and possible operative treatment
arm group label: Antibiotic treatment
arm group type: Active Comparator
description: Ertapenem 1 g x 1 intravenously for 3 days, followed by per oral levofloxacin 500 mg x 1 and metronidazole 500 mg x 3 for 4 days, duration of treatment 7 days.
arm group label: Placebo
arm group type: Active Comparator
description: Intravenous placebo once a day for 3 days, followed by per oral placebo for 4 days with similar p.o. tablets as in the antibiotic group.
intervention type: Drug
intervention name: Ertapenem
description: Intravenous antibiotic followed by per oral antibiotics
arm group label: Antibiotic treatment
other name: Levofloxacin
other name: Metronidazole
intervention type: Other
intervention name: Placebo
description: Intravenous placebo followed by per oral placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Paulina Salminen, MD,PhD
role: Principal Investigator
affiliation: Turku University Hospital
facility: 
country: Finland
responsible party type: Principal Investigator
investigator affiliation: Turku University Hospital
investigator full name: Paulina Salminen
investigator title: Primary investigator
mesh term: Appendicitis
mesh term: Metronidazole
mesh term: Levofloxacin
mesh term: Ertapenem
sharing ipd: No