Clinical Trial Results:
Antibiotic treatment alone for children with acute appendicitis; a prospective cohort study part of the Antibiotic versus Primary Appendectomy for Children with acute appendicitis; the APAC trial.
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Summary
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EudraCT number |
2011-004495-12 |
Trial protocol |
NL |
Global end of trial date |
10 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Jul 2021
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First version publication date |
14 Jul 2021
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Other versions |
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Summary report(s) |
Study rapport APAC pilot study |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
KCA2011/APAC
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01356641 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
VU University medical center
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Sponsor organisation address |
de Boelelaan 1117, Amsterdam, Netherlands, 1081HV
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Public contact |
Ramon Gorter, VU University medical center, 0031 204442424, rr.gorter@vumc.nl
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Scientific contact |
Ramon Gorter, VU University medical center, 0031 204442424, rr.gorter@vumc.nl
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Oct 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Jan 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Jan 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
1. To investigate the feasibility of a non inferiority multicenter randomized controlled trial, in order to evaluate the cost -effectiveness of initial antibiotic treatment strategy compared to appendectomy in The Netherlands?
2. To evaluate the safety and outcome (in terms of complications) of initial antibiotic treatment strategy for children aged 7-17 years with simple appendicitis.
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Protection of trial subjects |
Multiple gastrointestinal infections including appendicitis (with the most severe types) can be treated with antibiotics. The medication used in this study (augmentin/gentamicin) are already registered for this indication. However for protection of the trial subjects several measurements were taken into account in the protocol:
1. Patients were admitted to the paediatric (surgical) ward for intensive (clinical and biochemical) monitoring in order to detect clinical deterioration at an early stage
2. After 48 hours an additional ultrasound was performed in order to make sure, no signs of complex appendicitis were missed
3. After reconsideration, it was decided to make small protocol modicifications such as an reduction of the restriction on oral intake and length of hospital stay in order to minimise discomfort with patients and parents
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Background therapy |
All patients participating in this study and undergoing the initial antibiotic treatment strategy were administered besides the antibiotics the following medications: Diet; during the first 12 hours, no oral intake was permitted. Intravenous administration of fluids (Dextrose 3.75% with Sodium chloride 0,225% 0-10 kg 100 ml/kg 10-20 kg 50 ml/kg extra >20 kg 20 ml/kg For instance when a child weighs 20 kilogram the daily intake should be 10x100ml + 10x50 ml 1.5 litre Own medication: patients were allowed to use their regular prescribed medication. Pain medication (common practice): According to the local pain protocol of the Paediatric surgical centre, management of pain consisted of the following medication (doses adjusted to the www.kinderformularium.nl): Acetaminophen (i.v.) Start dose: 20 mg/kg. Afterwards: 60 mg/kg/day (in 4 doses) Acetaminophen (rectal) Start dose: 40 mg/kg. Afterwards: 90 mg/kg/day (in three doses) Diclofenac 1-3 mg/kg/day (in 3 doses) Morphine (rectal) 1.2-2.4 mg/kg/day (in 6 doses) Morphine (I.v.) Start dose: 0.1 mg/kg (in 10 minutes. Afterwards continuous administration. Dose:0.25 mg/kg/day In most cases, acetaminophen either intravenously or rectally, was administered. When this turned out to be inadequate (defined as a VAS score > 4), additional pain medication could be given following a step-up/step down principle, starting with diclofenac and in addition morphine. When the VAS score became < 4, attempts were made to remove additional pain medication. | ||
Evidence for comparator |
All patients participating in this study underwent the initial antibiotic treatment strategy. It was decided (later on the study) that eligible patients not participating in this study will form a control group in the future. | ||
Actual start date of recruitment |
01 Nov 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Scientific research | ||
Long term follow-up duration |
15 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 50
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Worldwide total number of subjects |
50
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EEA total number of subjects |
50
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
11
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Adolescents (12-17 years) |
39
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited at the emergency departments of the participating hospitals. Information regarding this pilot study was provided to the child as well as their legal guardians (age specific information letters). Verbal explanation by treating physician. Informed consent after confirmation of diagnosis | ||||||||||
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Pre-assignment
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Screening details |
Inclusion criteria: • Age 7-17 years • Radiologically confirmed simple appendicitis Exclusion criteria • Generalized peritonitis / severe sepsis / complex appendicitis • Faecalith / associated conditions / allergy. Screened: N= 278 Excluded: N= 228 a. Complex (138) b. No ultrasound (33) c. No IC (57) Included: N=50 | ||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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Initial Antibiotic Treatment strategy | ||||||||||
Arm description |
1. Admission of patients under paediatric surgical responsibility and 2. Administration of intravenous antibiotics (amoxicillin/clavulanic acid 25/2.5 mg/kg 6-hourly (total 100/10mg/kg daily; maximum doses: 6000/600mg a day) and gentamicin 7mg/kg once daily) for the first 48 hours (Appendix 13.4 &13.5). 3. intravenous administration was continued. If administration was changed to oral antibiotics, the patient was discharged (maximum doses: 1500/375mg a day) (for a total of seven days). | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Amoxicillin/clavulanic acid
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Investigational medicinal product code |
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Other name |
Augmentin
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Pharmaceutical forms |
Concentrate for solution for injection/infusion, Concentrate for oral suspension
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Routes of administration |
Intravenous use, Enteral use
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Dosage and administration details |
Intravenous administration of amoxicillin/clavulanic acid 25/2.5 mg/kg 6-hourly (total 100/10 mg/kg daily; maximum doses 6000/600 mg a day) 48 hours
Gentamicin 7 mg/kg once daily iv 48 hours
Oral amoxicillin/clavulanic acid 50/12,5 mg/kg in three times (maximum doses: 1500/375mg a day) for a total of 5 days.
Total duration of antibiotic treatment: 7 days
Rationale for this treatment and doses were based upon the SPC from the antibiotics administered and in line with doses reported on www.kinderformularium.nl
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Investigational medicinal product name |
Gentamicin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Gentamicin 7 mg/kg once daily iv for 48 hours
Rationale for this treatment and doses were based upon the SPC from the antibiotics administered and in line with doses reported on www.kinderformularium.nl
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
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Subject analysis sets
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Subject analysis set title |
Initial non-operative treatment strategy
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
A total of 49 children aged between 7-17 years old with radiological proven simple appendicitis, who have been treated with the initial antibiotic treatment strategy as part of the pilot study.
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End points reporting groups
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Reporting group title |
Initial Antibiotic Treatment strategy
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Reporting group description |
1. Admission of patients under paediatric surgical responsibility and 2. Administration of intravenous antibiotics (amoxicillin/clavulanic acid 25/2.5 mg/kg 6-hourly (total 100/10mg/kg daily; maximum doses: 6000/600mg a day) and gentamicin 7mg/kg once daily) for the first 48 hours (Appendix 13.4 &13.5). 3. intravenous administration was continued. If administration was changed to oral antibiotics, the patient was discharged (maximum doses: 1500/375mg a day) (for a total of seven days). | ||
Subject analysis set title |
Initial non-operative treatment strategy
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
A total of 49 children aged between 7-17 years old with radiological proven simple appendicitis, who have been treated with the initial antibiotic treatment strategy as part of the pilot study.
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End point title |
Percentage of patients willing to participate [1] | ||||||||||||
End point description |
In the result section, we are displaying the percentage of patients willen to participate including a 95% CI.
In total 49/108 patients were willing to participate: 45% 95%CI: 37-55%
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End point type |
Primary
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End point timeframe |
Start of the study - till inclusion of the 50th patient
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis are displayed |
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| Notes [2] - 1 withdrew consent |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of patients with an appendectomy [3] | |||||||||
End point description |
Number of patients who underwent an appendectomy during the one year follow up after the initial start of the initial non-operative treatment strategy. .
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End point type |
Primary
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End point timeframe |
Inclusion - One year follow up
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis are displayed |
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| Notes [4] - 1 withdrew consent |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of patient who underwent an appendectomy for histological proven recurrent appendicitis [5] | |||||||||
End point description |
Number of patients who underwent an appendectomy for the recurrent appendicitis that was proven by histological examination
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End point type |
Primary
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End point timeframe |
Inclusion - One year follow up
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis are displayed |
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| Notes [6] - 1 withdrew consent |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of patient with complications [7] | |||||||||
End point description |
Number of patients that suffered from complications.
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End point type |
Primary
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End point timeframe |
Inclusion - One year follow up
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis are displayed |
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| Notes [8] - 1 withdrew consent |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of patients who underwent an appendectomy during initial treatment (early failure) [9] | |||||||||
End point description |
Number of patients that underwent an appendectomy during the initial treatment with antibiotics due to clinical deterioration(early failure).
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End point type |
Primary
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End point timeframe |
Inclusion - One year follow up
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis are displayed |
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| Notes [10] - 1 withdrew consent |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of patients with post-appendectomy complications [11] | |||||||||
End point description |
Number of patients who suffered from a post-appendectomy complication.
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End point type |
Primary
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End point timeframe |
Inclusion - One year follow up
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis are displayed |
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| Notes [12] - 1 withdrew consent |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of patients undergoing interval appendectomy [13] | |||||||||
End point description |
Number of patients that underwent an interval appendectomy based upon request of parents
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End point type |
Primary
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End point timeframe |
Inclusion - One year follow up
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| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis are displayed |
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| Notes [14] - 1 withdrew consent |
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
The timeframe for reporting adverse events was from inclusion - one year follow up.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
Initial non-operative (antibiotic) treatment group
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Reporting group description |
Children aged 7-17 years old with a radiological proven simple appendicitis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Aug 2012 |
Increasing the number of participating centers
AMC: 21-08-2012 |
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03 Sep 2012 |
Increasing the number of participating centers
RKZ: 03-09-2012 |
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16 Jul 2013 |
Expanding age group: Based upon preliminary results it was decided to expand our inclusion group (starting with 12-17 year old children) to 7-17 year old children. This was decided to increase generalizability and due to the fact that based upon interim descriptive methods, it was shown that this strategy was safe in the 12-17 age group (N=10). Date: 16-07-2013 |
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04 Sep 2013 |
Increasing the number of participating centers
Flevoziekenhuis: 04-09-2013 |
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13 Oct 2014 |
Reducing the duration of the clinical phase: Based upon results from our interim analyses (N=25) it was decided to discharge the patients if they fulfilled the discharge criteria after 48 hours instead of monitoring them for another 24 hours in-hospital. Date: 13-10-2014
Reducing the duration of the “no oral intake“ period: Based upon results of our interim analysis (N=25) it was decided to reduce the “ no oral intake” period from 24 hours to 12 hours. Date: 13-10-2014 |
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13 Oct 2014 |
Proposal was made to use the eligible patients who did not wanted to undergo the initial non-operative treatment protocol as a control group in the future (also those eligible in the past). This protocol was implemented in February 2015 (last inclusion was on 24-11-20-15) Then 50th patient undergoing the initial nonoperative treatment strategy was included since the start of the study and inclusion was stopped as per protocol. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| 1. Small patient group 2. Only patients who underwent the initial non-operative treatment strategy | |||
