The PSP Appendix Trial is a prospective, multi-center, cohort study to assess the value of PSP in the diagnostic workup of acute appendicitis. Two hundred and forty five patients will be recruited. Interim analysis will be performed once 123 patients are recruited [ Additional file 1]. A power analysis will be performed on the actual and precise data collected. At interim analysis the potential need to modify the sample size will be investigated. If any changes are suggested by the external data monitoring committee, the principal investigators will decide on the feasibility of the potential changes and submit a formal addendum to the ethics committee. No changes will be made to the protocol or study design unless first approved by the ethics committee. Any changes to the protocol approved by the ethics committee will be updated at clinicaltrials.gov [NCT01610193].
The primary endpoint of the study is histopathological diagnosis of appendicitis on the specimen after appendectomy in order to assess the diagnostic accuracy of PSP calculated in predicting acute appendicitis. Secondary endpoints concern:
1. Grade of appendicitis detected intraoperatively:
G0: Appendix without any abnormalities detected introperatively
G1: Acute appendicitis
G2: Gangrenous appendicitis
G3: Perforated or phlegmon
G4: Periappendicular abscess
2. Alvarado Score elements which are obtained from the patient’s history, the physical examination and from laboratory tests. A score below 5 is strongly against a diagnosis of appendicitis, while a score of 7 or more is strongly predictive of acute appendicitis. In patients with an equivocal score of 5 or 6, a CT scan is used to further reduce the rate of negative appendectomy .
3. Pancreatic Stone Protein (PSP) blood serum/plasma levels will be correlated with this score. Surgical complications defined according to the Clavien-Dindo Classification will be monitored .
Data collection and statistics
The assessment for patient recruitment starts in the very beginning as soon as the patient attends the emergency room (ER), receives a consultation and a doctor’s assessment of the patient’s condition Additional file 2. If there is a clinical suspicion of appendicitis, the patient should be assessed for eligibility (inclusion and exclusion criteria) to participate in the PSP Appendicitis Trial Additional file 3. If any patient is assessed for eligibility of inclusion in this trial but was found to meet any of the exclusion criteria, the reason and explanation of the exclusion should be also documented in the Clinical Trial Management System (CTMS) https://www.PSPtrail.com.
Once a patient is assessed for eligibility and is found to meet the inclusion criteria, the patient should immediately enter the trial before any investigations have ordered blood tests, imaging, etc. The consent forms and patient information have to be provided to the patient. If the patient does not agree to participate in the trial, this should be documented in the online CTMS. If the patient agrees to participate in this trial, blood has to be taken for Pancreatic Stone Protein (PSP) measurement (1 tube of 5-10 ml, for serum determination in clinical chemistry). This tube has to be labelled as B1 followed by the patient trial number (B1_II_YYYY). The letter “B” stands for blood” and “1” as the first blood collection. The patient trial number should be the name initials (II) followed by the year of birth (YYYY). As part of the standard care, blood has to be taken for analysis for full blood count and CRP measurement at participating institutions. In particular, the White Blood Cell Count (WBC), Neutrophil Granulocytes (%) and C-reactive Protein (CRP) will have to be entered into the CTMS. The blood has to be taken at the same time for PSP, WBC and CRP as soon as the patient signs the consent form while still at the emergency department. A pregnancy test (beta hCG) has to be also performed and information entered into the CTMS. The investigators are free to perform any other blood tests deemed necessary.
The investigators are free to use any kind of imaging as part of the routine management of patients. Ultrasound Scan (USS) or Computed Tomography (CT) data will be entered in the CTMS.
The physician will then decide whether the patient should be subject to further diagnostics, referred to another inpatient or outpatient department or be discharged home [ Additional file 4]. If the patient is admitted for an operation, this has also to be documented in the CTMS. If the physician decides to take blood to assess the progress of the patient before an operation or discharge, an additional tube for PSP measurement is taken (see above). This tube has to be labelled as (B2_II_YYYY, e.g. B2_DR1978, see example above, “2” stands for second blood test for PSP). The same centrifugation process has to be performed to sample B2 as for B1.
Then the investigators will be asked to indicate the type of the operation and the intra-operative findings, if the patient was operated. During hospitalisation, the physician should document any complication according to the Clavien-Dindo Classification of surgical complications. For the patients that were operated, the physician will need to document the date of discharge. Once the histopathology report of the resected specimen has been received, the diagnosis will be entered in the CTMS. To ensure standardized reporting, all centers will adhere to the above classification of appendicitis.
Continuous variables will be compared with the Student t, Mann–Whitney U, one-way ANOVA, and Kruskal-Wallis tests, where appropriate. Differences among proportions derived from categorical data will be compared using the Fischer’s Exact or the Pearson χ2 tests, where appropriate. All p values will be two-sided and considered statistically significant if p ≤ 0.05. Sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR), Yuden’s index (YI), diagnostic odds ratio (OR), and the receiver operator characteristic (ROC) curve will be calculated. Data will be presented as mean (SD), median (i.q.r.) and Odds Ratios (95% CI) where appropriate. Reproducibility of PSP measurements will be performed by duplicating the samples and the variability assessed by the Pearson’s Correlation Coefficient. Statistical analysis will be performed using SPSS Statistics version 20 (SPSS: An IBM Company, Chicago IL, 2011).