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Trial registered on ANZCTR


Registration number
ACTRN12616000788471
Ethics application status
Approved
Date submitted
29/05/2016
Date registered
16/06/2016
Date last updated
16/06/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Prospective Randomised Controlled Study of Non-operative Management for Appendicitis in Children
Scientific title
A Prospective Randomised Controlled Non-inferiority Study to Evaluate the Safety and Effectiveness of Non-operative Management in Children With Acute Uncomplicated Appendicitis
Secondary ID [1] 289320 0
None
Universal Trial Number (UTN)
Trial acronym
APRES
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Focal Appendicitis 298934 0
Appendicitis 298935 0
Condition category
Condition code
Surgery 299010 299010 0 0
Other surgery
Oral and Gastrointestinal 299114 299114 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Non-operative management group (NOM) Children in the NOM group will receive intravenous Piperacillin with Tazobactam (Tazocin) 100mg/kg/ dose every 8 hours for at least 24 hours, and they will be observed and reassessed within 24 hours after randomisation. A further 24 hours of intravenous Piperacillin with Tazobactam therapy will be offered to children in invariable condition. A clinical decision will be made by the attending surgeon to offer operative management if a patient’s condition deteriorates at any time, or if a patient has failed to improve after 48 hours of intravenous antibiotic therapy. Once the patient is clinically improving and tolerating oral intake, the antibiotic regimen will be changed to oral Amoxicillin plus Clavulanic acid (Augmentin) 22.5mg/kg/dose twice per day to complete a total seven day course of antibiotics. Oral Ciprofloxacin 15mg/kg/dose twice daily and oral Metronidazole 10mg/kg/dose twice daily will be offered to children who are known to have an intolerance or allergy to Amoxicillin or Clavulanic acid.
Intervention code [1] 294886 0
Treatment: Drugs
Comparator / control treatment
Appendectomy group (Operative management, OM). Children allocated to OM may receive preoperative antibiotic prophylaxis as clinically indicated. Appendicectomy will be performed laparoscopically, or via open surgery according to the surgeon’s standard practice. Postoperative antibiotic treatment will be determined on the basis of intraoperative findings in accordance with the institutional practice. The appendix specimen will be examined by a paediatric pathologist, and the formal histopathology report will be recorded.
Control group
Active

Outcomes
Primary outcome [1] 298474 0
Unplanned or unnecessary operation which is assessed by review of medical records and and at post-discharge telephone interviews. An unplanned or unnecessary operation is defined as operation that is not part if study protocol, occurring as a result of failure or complication of study treatment.
Timepoint [1] 298474 0
30 days post-randomisation
Secondary outcome [1] 324256 0
Structural complications including appendiceal perforation, bowel adhesions and/or bowel obstruction. These are clinical diagnoses (with or without tools/tests).
Timepoint [1] 324256 0
30 days post-randomisation
Secondary outcome [2] 324257 0
Length of primary hospital stay (time of randomisation to discharge) from review of medical records and at post-discharge telephone interviews.
Timepoint [2] 324257 0
At discharge from hospital
Secondary outcome [3] 324258 0
Treatment-related complications i.e. complications that are attributed to the intervention received. For those in the non-operative management group, this could include reactions to antibiotic received e.g. hypersensitivity reaction, nausea, vomiting. For those in the operative management group this would include surgical site infection(s), and/or wound dehiscence.

These complications are assessed by clinical examination, tests, review of medical records, and at post-discharge telephone interviews.
Timepoint [3] 324258 0
12 months post hospital discharge
Secondary outcome [4] 324259 0
Infection complications including surgical site infection(s), peritonitis, abscess and/or phlegmon formation . These are clinical diagnoses (with or without tools/tests).

These complications are assessed by review of medical records and at post-discharge telephone interviews.
Timepoint [4] 324259 0
30 days post-randomisation
Secondary outcome [5] 324260 0
Cost of treatment in Australian Dollars (AUD). It will be based on fees registered in Medicare Benefits Schedule (MBS), Pharmaceutical Benefits Scheme (PBS) and institution standard pre-determined admission costing. It is calculated as a fee per day of in-hospital care, a fee for use of the operating room, the cost of a course of intravenous and oral antibiotics, and the cost for total analgesic use. Cost for any additional admission will be calculated the same way when it is applicable.
Timepoint [5] 324260 0
12 months post hospital discharge
Secondary outcome [6] 324261 0
Return to school from time of randomisation using parent reports (acquired through regular post-discharge interviews).
Timepoint [6] 324261 0
At post-discharge telephone interviews conducted at 1 week, 2 weeks, 3 months, 6 months and 12 months after discharge, as well as the outpatient clinic at 4 to 6 weeks after discharge as per standard practice.
Secondary outcome [7] 324262 0
Return to normal activities from time of randomisation using parent reports (acquired through regular post-discharge interviews).
Timepoint [7] 324262 0
At post-discharge telephone interviews conducted at 1 week, 2 weeks, 3 months, 6 months and 12 months after discharge, as well as the outpatient clinic at 4 to 6 weeks after discharge as per standard practice.
Secondary outcome [8] 324533 0
Emergency Department presentation with readmission acquired through medical records and parent reports through post-discharge interviews.
Timepoint [8] 324533 0
At 12 months after discharge.
Secondary outcome [9] 324534 0
Total analgesia requirement acquired through medical records, information such as types, route and dosage (mg/kg).
Timepoint [9] 324534 0
At discharge from hospital, and at post-discharge telephone interviews conducted at 1 week, 2 weeks, 3 months, 6 months and 12 months after discharge, as well as the outpatient clinic at 4 to 6 weeks after discharge as per standard practice.
Secondary outcome [10] 324688 0
Emergency Department presentation (without readmission) acquired through medical records and parent reports through post-discharge interviews.
Timepoint [10] 324688 0
At 12 months after discharge.

Eligibility
Key inclusion criteria
1. Age between 5 and 16 years;
2. Clinical diagnosis by at least one paediatric surgeon (or duty surgical registrar)
of acute uncomplicated appendicitis based on with a combination of clinical, laboratory and/or imaging findings; that before the study would have led to the decision to recommend been subjected to an appendicectomy.
Minimum age
5 Years
Maximum age
16 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
If one or more of the following is assessed to be present:
1. Suspicion of perforated appendicitis on the basis of generalised peritonitis and/ or imaging studyA diagnosis of perforated or complicated appendicitis (e.g. peritonitis, appendiceal mass) is made on the basis of clinical, laboratory and/or imaging findings;
2. Previous non-operative treatment of acute appendicitis;
3. Age younger than 5 years or older than 16 years;
4. Known intolerance or allergy to Piperacillin with Tazobactam;
5. Known history of inflammatory bowel disease, or other chronic abdominal pain
syndrome;
6. Known concurrent significant illness;
7. Unable to obtain informed consent from parents or guardian;
8. Known to have a cognitive impairment, an intellectual disability or a mental illness that would impair participation.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Blocked weighted minimisation using the following criteria: age (5-8 years or 9-16 years), gender (male or female), and duration of symptoms (<48 hours or >48 hours)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The main analyses will be based on the intention-to-treat principle, but both intention-to-treat and per-protocol analyses will be performed. The intention-to-treat population will include all randomised participants who commence on a treatment, excluding consent withdrawals. The per-protocol population will include all participants who complete the study at 1year follow-up. Subgroup analysis will be performed to compare outcomes of children enrolled on the study after clinically diagnosed appendicitis to those enrolled after appendicitis diagnosed on medical imaging using the same outcome measures. A non-inferiority analysis will be performed to compare both the primary and secondary outcomes. Based on current adult literature, the treatment efficacy difference between operative and non-operative treatment is about 25-35%. The most recent randomised controlled trial in adults used 25% as its non-inferiority margin. In children, a 10% failure rate of NOM has been noted in the pilot study. Thus, a non-inferiority margin of 15% will be used in this study.

Sample size based on the reported post-appendicectomy complication rate of 1.9-8.8% and negative appendicectomy rate of 6-15% we would expect a treatment efficacy of 90% in the control OM group. Based on the reported treatment efficacy of 63-73% in adults treated with NOM and 87.5-98.7% in children ], we would expect a possible difference of treatment efficacy between control and treatment group to be between 15-25%. Thus the failure rate in the OM group is assumed to be 10% and a failure rate of 25% or more in the antibiotic group would be considered unacceptably high. For the non-inferiority study, the null hypothesis is that the antibiotic treatment is inferior and we wish to have an 80% power at 5% significance to rule out inferiority if the failure rate difference is 15% or lower (assuming the stated estimate of 10% failure rate in the surgery group). This requires a sample size of approximately 80 per group, however we plan to recruit 110 patients per group to allow for up to 25% loss to follow up. Each study site treats approximately 300 cases of appendicitis each year (600 in total) of which approximately 60% will be uncomplicated, resulting in a total of 360 eligible cases. Assuming a recruitment rate of 30%, we would recruit 110 per annum, thus aiming to recruit over a period of 2-3 years.

Categorical variables will be characterised using frequencies and percentages. Statistical significance for categorical data will be tested using the Pearson X2 test. Continuous variables will be characterised as means and standard deviations or medians and interquartile range for non-parametric data. Differences between groups for normally distributed variables will be tested using the independent sample t test. The Mann-Whitney test will be used for variables not normally distributed. Non-inferiority for NOM will be tested using the 1-sided Wald tests with an alpha level of 0.05. Statistical analyses will be performed using the SPSS Statistics Program.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 5863 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 5864 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 13303 0
2031 - Randwick
Recruitment postcode(s) [2] 13304 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 293706 0
Hospital
Name [1] 293706 0
The Children's Hospital at Westmead
Address [1] 293706 0
Postal address: The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145
Street address: Corner Hawkesbury Road and Hainsworth Street, Westmead, NSW, 2145.
Country [1] 293706 0
Australia
Funding source category [2] 293758 0
Hospital
Name [2] 293758 0
Sydney Children's Hospital, Randwick
Address [2] 293758 0
High Street, Randwick, NSW, Australia, 2031
Country [2] 293758 0
Australia
Primary sponsor type
Hospital
Name
The Sydney Children's Hospital Network
Address
The Children's Hospital at Westmead
Postal address: The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia, 2145
Street address: Corner Hawkesbury Road and Hainsworth Street, Westmead, NSW, Australia, 2145.

Sydney Children's Hospital, Randwick
High Street, Randwick, NSW, Australia, 2031
Country
Australia
Secondary sponsor category [1] 292539 0
None
Name [1] 292539 0
None
Address [1] 292539 0
None
Country [1] 292539 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295142 0
Sydney Children's Hospital Network HREC
Ethics committee address [1] 295142 0
Cnr Hawkesbury Road and Hainsworth Street, Westmead, NSW Australia
Locked Bag 4001, Westmead 2145, NSW Australia
Ethics committee country [1] 295142 0
Australia
Date submitted for ethics approval [1] 295142 0
04/08/2015
Approval date [1] 295142 0
03/05/2016
Ethics approval number [1] 295142 0
HREC/15/SCHN/266

Summary
Brief summary
This study is designed to determine the safety and efficacy of non-operative antibiotic management of clinically diagnosed acute uncomplicated appendicitis in children. Enrolled patients will be randomised and an allocation ratio of 1:1 will be made
via weighted minimisation, where half of the patients will receive non-operative management with intravenous Piperacillin with Tazobactam, while the other half will have an appendicectomy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66238 0
Dr Jonathan Karpelowsky
Address 66238 0
Department of Paediatric Surgery
The Children's Hospital at Westmead
Hawkesbury Road & Hainsworth Street
Westmead
NSW
2145
Country 66238 0
Australia
Phone 66238 0
+61, 2, 98453235
Fax 66238 0
Email 66238 0
jonathan.karpelowsky@health.nsw.gov.au
Contact person for public queries
Name 66239 0
Dr Susan Adams
Address 66239 0
Department of Paediatric Surgery
Sydney Children's Hospital
High Street
Randwick
NSW
2031
Country 66239 0
Australia
Phone 66239 0
+61, 2, 93821776
Fax 66239 0
+61, 2, 93821787
Email 66239 0
susan.adams@unsw.edu.au
Contact person for scientific queries
Name 66240 0
Dr Jonathan Karpelowsky
Address 66240 0
Department of Paediatric Surgery
The Children's Hospital at Westmead
Hawkesbury Road & Hainsworth Street
Westmead
NSW
2145
Country 66240 0
Australia
Phone 66240 0
+61, 2, 98453235
Fax 66240 0
Email 66240 0
jonathan.karpelowsky@health.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
No Results