| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute uncomplicated (simple) appendicitis |
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| E.1.1.1 | Medical condition in easily understood language |
| Acute uncomplicated appendicitis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003011 |
| E.1.2 | Term | Appendicitis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The aim of this study is to compare the effectiveness of initial non-operative treatment strategy (reserving appendectomy for those not responding or with recurrent disease) with immediate appendectomy in children from 7-17 years old, inclusive, with acute simple appendicitis in terms of complications, health related QOL and costs.
Main research question:
What is the difference in proportion of patients experiencing complications within one year between both strategies in children from 7-17 years old, inclusive, with acute simple appendicitis |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives consist of:
Number of days absent from school, social or sport events (patient-level)
Number of days absent from work (parents-level)
Total number of extra visits (not the already scheduled ones) for abdominal pain.
Total length of hospital stay
Level of pain
Pain medication utilization
Proportion of patients with missed diagnosis of complex appendicitis with risk of peritonitis, not having to undergone appendectomy, experiencing recurrent appendicitis.
Proportion of patients experiencing early failure of initial non-operative treatment, that undergo interval appendectomy or experiencing complications
Quality of life measured by the validated CHQ-CF87, EQ-5d-Youth, EQ-5d-Proxy questionnaire.
Medical, non-medical and indirect costs at one year follow up
Patient satisfaction measured by the NET PROMOTOR SCORE and validated Patient Satisfaction Questionnaire (PSQ)18.
Factors influencing implementability
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligible for inclusion are all children from 7 to 17 years old, inclusive, with a radiologically confirmed simple appendicitis. Definition of simple appendicitis is based upon predefined clinical, biochemical and radiological (ultrasound) criteria.
Clinical & biochemical criteria:
- Unwell but not generally ill
- Localized tenderness in the right iliac fossa region
- Normal/hyperactive bowel sounds
- No guarding or palpable mass
- Biochemical signs of infection (Elevated White Blood Cell count (WBC) and/or C-reactive protein (CRP)).
As recommended by the national guideline, all children with a clinical and/or biochemical suspicion should undergo ultrasound studies. Ultrasound criteria to confirm the diagnosis of acute simple appendicitis are:
- An incompressible, painful appendix with an outer diameter > 6 mm
- Secondary signs of inflammation such as surrounding fat infiltration, limited clear free fluid surrounding the appendix, hyperemia within the appendiceal wall.
- No fecolith, no signs of perforation, no signs of intra-abdominal abscess or phlegmone.
In case the ultrasound is inconclusive, additional imaging studies may be obtained. CT-scan is not recommended in the young children (due to its risk of radiation induced malignancy). MRI is recommended in those places with sufficient experience in the interpretation of the results. Only those in whom imaging studies confirm the diagnosis of simple appendicitis can be included. In case there is no certain diagnosis and a “watchful waiting” strategy is chosen, the patient cannot be included.
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| E.4 | Principal exclusion criteria |
Exclusion criteria:
• Generalized peritonitis, complex appendicitis or sepsis (based upon predefined criteria and scoring system). [21,22]
Scoring system: As scoring system was developed determining the risk of complex appendicitis based upon five pre-operative variable. Points have been awarded to each variable. In case the total score is less than 4 points, the patient is likely to have a simple appendicitis. In case the score is 4 or more points, the chance of having complex appendicitis is significant and those children will be excluded from this study. Variables:
Diffuse abdominal guarding (3 points)
CRP level more than 38 mg/L (2 points)
Signs on ultrasound indicative of complex appendicitis (2 points)
More than one day abdominal pain (2 points)
Temperature: more than 37.5 degree Celsius (1 point)
• Fecolith (ultrasound)
• Serious co-morbidity
• Recurrent appendicitis
• Suspicion of an underlying malignancy or inflammatory bowel disease
• Documented type 1 allergy to the antibiotics used.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome is the proportion of patients experiencing complications within one year follow-up. An adjudication committee will be installed to review the complications. They will review all patients with possible complications to determine whether or not they fulfill the criteria for complications. All Complications will be recorded.
Complications are defined as:
• Allergic reaction to antibiotics administered. In case an allergic reaction is suspected, the child will be referred to the allergist for further evaluation.
• Re-admission for an indication other than recurrent appendicitis but related to appendicitis (such as readmission for observation of fever or abdominal pain)
• Complications associated with appendectomy:
- Superficial Site infection
- Intra-abdominal abscess
- Stump leakage/stump appendicitis
- Secondary / prolonged Bowel Obstruction
- Anesthesia Related complications (such us pneumonia)
- Hernia cicatricalis
- Need for other surgical or radiological intervention than appendectomy but related to appendicitis (such as percutaneous drainage of an abscess, surgical intervention for a superficial site infection)
Recurrent appendicitis sometimes referred to as ‘failure of initial non-operative treatment strategy’ should not be regarded as complication, as this is a potential consequence of the initial non-operative treatment strategy in some patients.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| One-year after initial treatment |
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| E.5.2 | Secondary end point(s) |
Day 7
Proportion of patients experiencing early failure of initial non-operative treatment, defined as the need to undergo an appendectomy during the antibiotic course (iv or oral) due to clinical deterioration, lack of improvement or fecolith.
Pain score measured by the Visual Analogue Score (validated for children older than 7 years old) during clinical phase
Pain medication utilization during the first seven days after admission.
After one month:
Proportion of patients with missed diagnosis of complex appendicitis
At one month, six months and one year follow-up:
Number of days absent from school, social or sport events
Number of days absent from work (parents)
Number of extra visits to the outpatient clinic, general practitioners office or emergency department for abdominal pain.
Total number of days as an inpatient in hospital during the one year follow-up period for strategy related treatment or complications
Proportion of patients not having undergone appendectomy
Proportion of patients experiencing recurrent appendicitis, defined as histopathologically confirmed appendicitis after appendectomy
Proportion of patients experiencing complications at six and 12 months follow up
Proportion of patients that undergo interval appendectomy, defined as undergoing an appendectomy with a low clinical and radiological suspicion of recurrent appendicitis and no signs of appendicitis upon histopathological examination.
Health-related Quality of Life measured by the(disease specific) Child Health Questionnaire –Child Form 87 (CHQ-CF87) and the (generic) European Quality of Life-5 Dimensions-Youth (EQ-5d-Y) (Child perspective) and European Quality of life-5 Dimensions-Proxy (EQ-5D-Proxy)(Parents perspective). The CHQ-CF87 is a validated multi-dimensional questionnaire to assess the health related (disease specific) quality of life in children 5-18 years old. It contains the dimensions of physical functioning, role/social limitations-emotional, role/social limitations-behavioral, role/social limitations-physical, bodily pain/discomfort, behavior, mental health, self esteem, general health perception and family activities. The EQ-5D-Y is a modified version of the EQ-5D specific for children. The adult version (EQ-5D) has been designed as a generic instrument for measuring health related quality of life, in particular utility. It is recommended for use in cost-effectiveness and cost-utility studies. For parents’ perspective, the EQ-5D-Proxy will be used.
Medical, non-medical and indirect costs.
iMCQ and iPCQ will be used to measure the direct and indirect costs of health care utilization, and days absent from work and school by both the parents and children. These questionnaires have been adjusted to fit the situation of children and there parents. Costs will be calculated using the answers from the iMCQ and iPCQ. Actual health care costs will be gathered based upon the actual used health care in our study. Variables gathered will be, but not limited to number of follow up out-patient clinic visits, number of general practitioners visits, number of emergency department visits, absenteeism from work and travel expenses.
Patient satisfaction will be measured by the NET PROMOTOR SCORE and Patient Satisfaction Questionnaire (PSQ) 18. Both have been validated in the general population. Proxy-assessments will be obtained from the parents.
Outcomes will be measured at discharge, 7 days, 1, 6, and 12 months after randomization as described above. The follow up measurements at 7 days, 6 and 12 months will be done by email and telephone. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See the above mentioned time points of evaluation |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last follow up by telephone at 12 months after discharge of last subject |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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