Clinical trial NCT01096927: Non Operative Treatment for Acute Appendicitis
Official title: Non Operative Treatment for Acute Appendicitis: Study on Efficacy and Safety of Antibiotic Treatment (Amoxicillin and Clavulanic Acid) in Patients With Right Sided Lower Abdominal Pain
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Lower Abdominal Pain
Right Iliac Fossa Pain
Acute Appendicitis
Keywords: Lower Abdominal Pain
Right Iliac Fossa Pain
Acute Appendicitis
Antibiotic Therapy
Conservative Management
Appendectomy
Recurrence
Length of hospital stay
Sick leave time
Short and Long Term Abdominal pain evaluation
Lead sponsor: Maggiore Bellaria Hospital, Bologna
Sponsor class: OTHER
First posted: 2010-03-31
Enrollment: 160
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Case control studies that randomly assign patients to either surgical or non-surgical treatment yield a relapse rate of approximately 14% at one year. It would be useful to know the relapse rate of patients who have, instead, been selected for a given treatment based on a thorough clinical evaluation, including physical examination and laboratory results (all characteristics forming the Alvarado Score) as well as radiological exams if needed or deemed helpful. If this clinical evaluation is useful,the investigators would expect patient selection to be better than chance, and relapse rate lower than 14%. Once the investigators have established the utility of this evaluation, the investigators can begin to identify those components that have predictive value (such as blood chemistry analysis, or CT findings). This is the first step toward developing an accurate diagnostic-therapeutic algorithm which will avoid the risks and costs of needless surgery.

This will be a single-cohort prospective interventional study. It will not interfere with the usual procedures, consisting of clinical examination in the Emergency Department (ED) and execution of the following exams at the physician's discretion: complete blood count with differential, C reactive protein, abdominal ultrasound, abdominal CT. Patients admitted to Emergency Department with Lower Abdominal and suspicion of Acute Appendicitis not needing immediate surgery, are requested by informed consent to undergo observation and non operative treatment with antibiotic therapy (Amoxicillin and Clavulanic Acid). The patients by protocol should not have received any previous antibiotic treatment during the same clinical episode. Patients not undergoing surgery will be physically examined 5 days later. During this follow-up visit, the patient will be given information about the study, will be invited to participate, and will be asked to sign an informed consent form. If the patient is under the age of 18 years, consent will be obtained from a parent or other legal guardian.

Telephone (or email) follow-ups will be conducted at 15 days, 6 months, and 12 months (see attached schedule) to monitor the state of the illness.

Detailed description: Background: Acute appendicitis is one of the most common urgent conditions seen in general surgery practice. Complications can be severe and include perforation and generalized peritonitis. Traditionally, surgical appendectomy has been the primary treatment, even in cases of unconfirmed diagnosis, given the low incidence of major complications. In 15-30% of cases, in fact, the appendix is found to be free of disease upon resection. This procedure, however, is not without risk. It is associated with surgical wound infection, intestinal obstruction due to adhesions, pneumonia, and tubal infertility in females. For this reason, the possibility of using conservative treatment merits investigation. There is considerable debate regarding the utility of conservative treatment over surgical treatment in some cases of acute appendicitis, as few studies have addressed this issue to date. If deemed useful, it will become of utmost importance to make an accurate diagnosis and assessment in every patient in order to select the most appropriate treatment.

Hansson et al conducted a randomized clinical trial investigating the efficacy of conservative treatment compared to surgery for acute appendicitis. They reported that conservative treatment with antibiotics was efficacious in 91% of cases, with a 14% relapse rate at 12 month follow-up. One third of relapses occurred within the first 10 days of hospital discharge, while most of the remaining two thirds occurred between 3 and 16 months following discharge. The rates of minor complications such as diarrhea, vomiting, and nosocomial infections were similar among patients treated conservatively and those treated surgically. The incidence of major complications such as appendiceal abscess, paralytic ileus and pulmonary embolism, however, was significantly higher in those treated surgically (p\<0.05).

A recent prospective randomized study conducted by Ajaz and colleagues compared antibiotic therapy to appendectomy in acute appendicitis. The authors reported that conservative treatment was not only safe and efficacious, but caused the patients less pain than did surgery, reducing the need for analgesic therapy (p\<0.001). Ten percent of conservatively treated patients relapsed within 12 months of discharge.

A multicenter randomized trial conducted in Sweden yielded similar results: the rate of relapse in antibiotic treated patients was 14% at one year after discharge. Interestingly, this was equal to the rate of post-operative complications in patients treated surgically.

Based on these reports, conservative treatment seems to represent a valid therapeutic approach to acute appendicitis. Relapse rate is low and comparable to the rate of surgical complications.

Rationale: Case control studies that randomly assign patients to either surgical or non-surgical treatment yield a relapse rate of approximately 14% at one year. It would be useful to know the relapse rate of patients who have, instead, been selected for a given treatment based on a thorough clinical evaluation, including physical examination and laboratory results (all characteristics forming the Alvarado Score) as well as radiological exams if needed or deemed helpful. If this clinical evaluation is useful, the investigators would expect patient selection to be better than chance, and relapse rate lower than 14%. Once the investigators have established the utility of this evaluation, the investigators can begin to identify those components that have predictive value (such as blood chemistry analysis, or CT findings). This is the first step toward developing an accurate diagnostic-therapeutic algorithm which will avoid the risks and costs of needless surgery.

Study Description: This will be a single-cohort prospective interventional study. It will not interfere with the usual procedures, consisting of clinical examination in the Emergency Department (ED) and execution of the following exams at the physician's discretion: complete blood count with differential, C reactive protein, abdominal ultrasound, abdominal CT. Patients admitted to Emergency Department with Lower Abdominal and suspicion of Acute Appendicitis not needing immediate surgery, are requested by informed consent to undergo observation and non operative treatment with antibiotic therapy (Amoxicillin and Clavulanic Acid). The patients by protocol should not have received any previous antibiotic treatment during the same clinical episode. Patients not undergoing surgery will be physically examined 5 days later. During this follow-up visit, the patient will be given information about the study, will be invited to participate, and will be asked to sign an informed consent form. If the patient is under the age of 18 years, consent will be obtained from a parent or other legal guardian.

Telephone (or email) follow-ups will be conducted at 15 days, 6 months, and 12 months (see attached schedule) to monitor the state of the illness. The patient will be asked if he/she has undergone surgery since the first visit (5 days post-ED). If not, the patient will be asked:

1. has your illness improved, stayed the same, or worsened since its onset?
2. have you done any further tests or had additional doctor's visits for your illness?
3. after your initial emergency department visit, how much time did it take to return to your normal activities (physical activity, work, etc)? In the case of patients under the age of 18 years, the phone interview will be conducted with a parent or legal guardian.

Study Objectives:

Main Objective: Evaluate the outcome of patients treated conservatively, assessing the reliability of the initial clinical evaluation in predicting which conservatively-treated patients should have treated surgically.

Primary Outcomes are the following:

1. Short Term Efficacy of Antibiotic Treatment: Failure of the conservative treatment with antibiotic within the period of the Amoxicillin + Clavulanic Acid therapy (7 days), defined as readmission for abscence of clinical improvement and/or worsening abdominal pain and/or localized/diffuse peritonitis
2. Long Term Efficacy of Antibiotic Treatment: Efficacy of antibiotic therapy for acute appendicitis defined as incidence of recurrences of clinical episodes of appendicitis up to 1 year follow up
3. Long Term Efficacy of Antibiotic Treatment (NO need for surgery): Efficacy of antibiotic therapy for acute appendicitis defined as definite improvement without need for surgery within 1 year follow up
4. Safety of Antibiotic treatment: Major side effects/complications drug/treatment-related (i.e. Allergy or other complications treatment related such as abscess formation)

Secondary Outcomes are:

1. Minor Complications: Minor side effects/complications drug/treatment-related (i.e. bloating, diarrhea, gas, headache, heartburn, nausea, and vomiting)
2. Abdominal Pain after discharge: Assessment of abdominal pain / discomfort evaluated by mean of Numerical rating scale (NRS)
3. Length of Hospital stay: Length of clinical observation as inpatient
4. Outpatient clinic checkup: Number of follow up appointments scheduled in outpatient clinic
5. Sick Leave: Number of days of sick leave needed by the patient
6. Cost analysis: Analysis of the costs, including Antibiotic course, Length of Hospital Stay, Outpatient Clinic follow up appointments, sick leave days

Additional Objective: Identify clinical, laboratory or imaging findings that are predictive of relapse and need for appendectomy.

Study Design: Single cohort prospective interventional study. No experimental interventions or treatments will be employed beyond routine clinical care.

Inclusion Criteria: Any patient, male or female, above the age of 14 years (non-pediatric), who returns for the follow-up visit 5 days after the ED visit and consents participation between January 1, 2010 and December 31, 2010.

The investigators estimate a sample size of 160, the number of patients with suspected acute appendicitis we typically receive yearly in the ED.

Means of follow-up assessment: telephone interview (or e-mail)

Eligibility criteria: Inclusion Criteria:

1. Age \>14 years
2. Lower / RIF Abdominal Pain
3. Clinical Suspicion of Acute Appendicitis:

   i.e.
   * Alvarado Score 5-6 (equivocal for acute appendicitis)
   * Alvarado Score 7-8 (probably appendicitis)
   * Alvarado Score 9-10 (highly likely appendicitis)
4. Informed consent (patient or legal representative)

Exclusion Criteria:

1. Diffuse peritonitis
2. Antibiotic (Penicillin) documented allergy
3. Ongoing previously started antibiotic therapy
4. Previous appendectomy
5. Positive pregnancy test
6. IBD history or suspicion of IBD recrudescence

Primary outcomes:
measure: Short Term Efficacy of Antibiotic Treatment
timeFrame: within 7 days (Antibiotic treatment course)
measure: Long Term Efficacy of Antibiotic Treatment
timeFrame: 1 year
measure: Long Term Efficacy of Antibiotic Treatment (NO need for surgery)
timeFrame: 1 year
measure: Safety of Antibiotic treatment
timeFrame: 7 days
Secondary outcomes:
measure: Minor Complications
timeFrame: 15 days
measure: Abdominal Pain after discharge
timeFrame: 15 days
measure: Length of Hospital stay
timeFrame: 7 days
measure: Outpatient clinic checkup
timeFrame: 15 days
measure: Sick Leave
timeFrame: 1 year
measure: Cost analysis
timeFrame: 1 year
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: Maggiore Bellaria Hospital
Study officials:
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Gregorio Tugnoli, MD
role: STUDY_CHAIR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Gregorio Tugnoli, MD
role: STUDY_DIRECTOR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Nicola Antonacci, MD
role: STUDY_DIRECTOR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Salomone Di Saverio, MD
role: STUDY_DIRECTOR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Franco Baldoni, MD
role: STUDY_DIRECTOR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Andrea Biscardi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Silvia Villani, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Eleonora Giorgini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Gianluca Senatore, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emergency and Trauma Surgery Unit, Department of Emergency, Maggiore Hospital
name: Nicola Clemente, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Malik AA, Bari SU. Conservative management of acute appendicitis. J Gastrointest Surg. 2009 May;13(5):966-70. doi: 10.1007/s11605-009-0835-5. Epub 2009 Mar 10.
citation: Deutsch AA, Shani N, Reiss R. Are some some appendectomies unnecessary? An analysis of 319 white appendices. J R Coll Surg Edinb. 1983 Jan;28(1):35-40. No abstract available.
citation: Pieper R, Kager L, Nasman P. Acute appendicitis: a clinical study of 1018 cases of emergency appendectomy. Acta Chir Scand. 1982;148(1):51-62. No abstract available.
citation: Styrud J, Eriksson S, Nilsson I, Ahlberg G, Haapaniemi S, Neovius G, Rex L, Badume I, Granstrom L. Appendectomy versus antibiotic treatment in acute appendicitis. a prospective multicenter randomized controlled trial. World J Surg. 2006 Jun;30(6):1033-7. doi: 10.1007/s00268-005-0304-6.
citation: Eriksson S, Granstrom L. Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg. 1995 Feb;82(2):166-9. doi: 10.1002/bjs.1800820207.
citation: Hansson J, Korner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg. 2009 May;96(5):473-81. doi: 10.1002/bjs.6482.
citation: Di Saverio S, Sibilio A, Giorgini E, Biscardi A, Villani S, Coccolini F, Smerieri N, Pisano M, Ansaloni L, Sartelli M, Catena F, Tugnoli G. The NOTA Study (Non Operative Treatment for Acute Appendicitis): prospective study on the efficacy and safety of antibiotics (amoxicillin and clavulanic acid) for treating patients with right lower quadrant abdominal pain and long-term follow-up of conservatively treated suspected appendicitis. Ann Surg. 2014 Jul;260(1):109-17. doi: 10.1097/SLA.0000000000000560.
citation: Tugnoli G, Giorgini E, Biscardi A, Villani S, Clemente N, Senatore G, Filicori F, Antonacci N, Baldoni F, De Werra C, Di Saverio S. The NOTA study: non-operative treatment for acute appendicitis: prospective study on the efficacy and safety of antibiotic treatment (amoxicillin and clavulanic acid) in patients with right sided lower abdominal pain. BMJ Open. 2011 Feb 23;1(1):e000006. doi: 10.1136/bmjopen-2010-000006.