The main goal of the present study is to establish whether antibiotics are necessary in the primary treatment of acute mild diverticulitis, and whether a more liberal strategy without initial antibiotics is more cost-effective with respect to time-to-full recovery.
In daily practice there is an ongoing discussion about the relative benefits and disadvantages of a more conservative treatment strategy embracing the use of intravenous antibiotics. This strategy needs hospital admission and is, at least at the start, an in-hospital treatment regimen. A more liberal strategy, without antibiotics and without the strict requirement of hospital admission, may lead to a shorter hospital stay and reduced costs without compromising outcome.
Our hypothesis is that in uncomplicated (mild) acute diverticulitis, a liberal strategy treatment without antibiotics is a more cost-effective approach than conservative treatment strategy with hospital admission and antibiotics, outcome is measured by time-to-full recovery as primary outcome and diverticulitis-associated complication rates and patient well-being as secondary outcome.
1. Only left-sided and primary (first attack) mild acute diverticulitis.
2. Diagnosis of diverticulitis by US and conditional CT. Diverticulitis-positive US findings are sufficiently accurate compared to CT findings [9
]. In diverticulitis-negative US findings in clinically suspected patients, immediate i.v. contrast-enhanced CT is mandatory for confirmation of diverticulitis and exclusion of other pathology.
3) Staging of diverticulitis by CT. CT is needed for all patients for Hinchey/Ambrosetti classification (which is a CT-based classification system). In diverticulitis-positive US findings CT has to be performed within 24 hours. Staging diverticulitis is defined according the modified Hinchey/Ambrosetti staging. Only modified Hinchey stages 1a and 1b (1a Colonic wall thickening/Confined pericolic inflammation, 1b Confined small pericolic abscess) and Ambrosetti's "mild" diverticulitis stage are included. Figure depicts a flow chart, showing the inclusion criteria and the steps after inclusion [10
4. Informed consent.
Exclusion criteria are summarized in Table .
Patients will be randomly allocated to one of the following two treatment strategies: Conservative strategy including immediate antibiotic treatment or liberal strategy without antibiotics (supportive measures only). (Table ).
In the conservative strategy, the use of antibiotics will be intravenously for at least 48 hours after which route of administration can be switched to orally if tolerated. Hospital admission in the liberal strategy is needed for patients with nausea and vomiting, in need of intravenous fluids or for patients with excessive pain not properly reacting to oral pain medication.
The interval between start of symptoms of the patient and administration of antibiotics will be registered. Also the period after inclusion and the actual first administration of antibiotics will be registered.
In both strategies CT is repeated in case of clinical deterioration. For patients in the liberal strategy treatment arm, clinical deterioration and/or proven subsequent complicated diverticulitis and/or other infectious foci (e.g., pneumonia, infections) may dictate start of antibiotic treatment, instigated by the treating physician. Criteria to start antibiotics in the liberal arm are temperature > 39°C, positive blood cultures and clinical suspicion of bacteraemia (i.e. sepsis). Criteria for sepsis are set by the American College of Chest Physicians and the Society of Critical Care Medicine. Two or more symptoms are required: Body temperature < 36°C or > 38°C, heart rate higher than 100 beats a minute, respiratory rate higher than 20 breaths a minute and white blood cell count < 4 × 109
or > 12 × 109
]. Also another infectious focus (e.g., pneumonia, urinary tract infections) may dictate start of antibiotic treatment, instigated by the treating physician.
The following discharge criteria are applied in both strategies: normal diet (defined by tolerating solid food and more than 1L of fluid orally), temperature < 38.0°C, VAS (Visual Analoge Score) pain score < 4 (with paracetamol only), self support as compared to the pre-illness level, and acceptance by the patient.
All outpatients will daily monitor and register their body temperature. Written and oral instructions at discharge are given, and relevant telephone numbers and contact information will be provided. In case of fever above 38˚C, progression of pain above a VAS of 4 or other clinical signs of deterioration, patients can contact the hospital or emergency department immediately.
For the choice and duration of antibiotics the practice guidelines of the Dutch Antibiotic Policy Committee [28
] and the American Society of Colon and Rectal Surgeons [30
] are followed. In both guidelines, a minimum of 7-14 days of broad-spectrum antibiotics is advised. In the present study amoxicillin-clavulanic acid is chosen as broad-spectrum antibiotic; duration of antibiotic treatment is 10 days. The dosage scheme for the study drug is 1200 mg i.v. 4 times daily with subsequent oral administration of 625 mg 3 times daily. In case of allergy (known or newly diagnosed), a switch will be made to the combination of ciprofloxacine and metronidazole; ciprofloxacine 2 times a day 400 mg i.v. and metronidazol 3 times daily 500 mg, with oral doses of ciprofloxacine being 500 mg 2 times a day and of metronidazol 3 times a day 500 mg.
The primary endpoint is time-to-full recovery within a follow-up period of 6 months. Full recovery is defined by the following criteria: discharged from the hospital (out-patient), normal diet (defined by tolerating solid food and more than 1L of fluid orally), temperature < 38.0°C, and VAS pain score < 4, no use of daily pain medication or back to pre-illness pain medication use, and resuming to pre-illness working activities; as assessed by questionnaires and out-patient clinic visits.
The secondary endpoints are: proportion of patients who develop complicated diverticulitis require surgery or non-surgical intervention; number of days outside the hospital in a 6 months period; direct and indirect medical costs at 6 months follow-up; occurrence of complicated diverticulitis defined as abscess, perforation, stricture and/or fistula; predefined side-effects of initial antibiotic treatment (e.g. antibiotic resistance/sensitivity pattern, allergy); morbidity (e.g. pneumonia, myocardial infarction, urinary tract infection); mortality; readmission rate within 6 months and acute diverticulitis recurrence rates at 12 and 24 months follow-up. Changes in health status and valuation over time will be measured using generic and disease specific quality of life questionnaires (Euro-Qol 5D, Short Form 36 (SF-36) and the Gastro-Intestinal Quality of Life Index (Giqli)) on admission and after 3, 6, 12 and 24 months.
A recurrence is defined as ultrasound- or CT-proven acute diverticulitis after complete resolution of symptoms more than 1 month after initial discharge from hospital. If a patient dies during follow-up, the reason for death will be recorded as related or unrelated to diverticular disease.
Computerized block randomization for allocation of treatment group, stratified for center and for Hinchey 1a and 1b, will take place after all inclusion and exclusion criteria have been verified and informed consent has been obtained. A standardized case record from (CRF) will be used. This CRF is partially web-based via a secured internet module. A minimum of 10% of the CRF data will be verified with source data by an independent audit.
Sample size calculation and date analysis
A non-inferiority design was chosen. Time-to-full recovery in the liberal strategy arm must not exceed a clinically relevant difference of more than 5 days compared with the conservative strategy. When this condition is fulfilled, the potential advantages of the liberal (non-antibiotic) strategy become dominant: patient well being when the need of hospital admission can be avoided, less costs, less antibiotic resistance and less other side effects. The study must have the power (superiority) to detect a difference in time-to-full recovery of 5 days.
The median time-to-full recovery is 21 days based on the National Dutch Hospital Registry data with an average of 7 days admission and an assumed additional median 14-day out-patient period to full recovery. To reject the null-hypothesis of a difference in time-to-full recovery of 5 days or less, using a time-to-event analysis with a power of 85% at a confidence level of 95%, an accrual period of 730 days and a follow-up period of 180 days, at least 264 patients need to be included in each treatment arm. With an estimated one percent of the trial patients lost to follow-up, a total 533 patients is needed.
The primary endpoint is time-to-full recovery. Kaplan-Meier curves depicting the proportion of patients with full recovery since randomisation will be constructed for both strategies. The log rank test will be used to test for superiority of one strategy compared with the other. Testing for non-inferiority will be done by calculating the hazard ratio for the liberal strategy compared with the conservative strategy using Cox regression. We will calculate a one-sided 95% confidence interval for this ratio to determine whether it reaches outside the hazard ratio belonging to an equivalence limit of a difference of 5 days in median survival time.
For other endpoints data will be compared by the Student's t test, Wilcoxon rank sum test, Chi square test or Fischer exact test as appropriate. In superiority tests a two-tailed P value ≤ 0.05 will be considered statistically significant, whereas one-sided tests will be performed in non-inferiority testing. The main analyses will be based on the intention to treat principle. Predefined subgroup analyses to investigate whether treatment effects are different in subgroups will be performed for Hinchey classification 1a versus 1b and for participating center.
All related costs will be estimated based on the actual input terms of resource use and personnel in the 6-month follow-up period after randomization. For all cost-items such as hospital admission, medication used, diagnostic tests, unit costs will be derived from the Dutch costing manual or determined in cooperation with the hospital administration. Direct medical costs will be recorded in the case record forms. Indirect costs arising from losses in productivity will be assessed by means of the Health and Labor questionnaire and will be calculated by means of the friction cost method.
The economic evaluation will be performed from a societal perspective as a cost-effectiveness and cost-utility analysis. The main analyses include costs per day reduction to achieve full recovery and costs per QALY gained. Additional sensitivity analyses, regarding differences in possible subgroups, will be performed.
Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial, whether or not considered related to the investigational drug. All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death; is life threatening (at the time of the event); requires hospitalization or prolongation of existing inpatients' hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; is a new event of the trial likely to affect the safety of the subjects, such as an unexpected outcome of an adverse reaction, major safety finding from a newly completed animal study, etc. All SAEs will be reported to the accredited Medical Ethical Committee (MEC) that approved the protocol, according to the requirements of that MEC.
Suspected unexpected serious adverse reactions (SUSAR) are all untoward and unintended responses to an investigational product related to any dose administered.
Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not consistent with the applicable product information.
The sponsor will report expedited the following SUSARs to the MEC; SUSARs that have arisen in the clinical trial that was assessed by the MEC; SUSARs that have arisen in other clinical trial of the same sponsor and with the same medicinal product, and that could have consequences for the safety of the subjects involved in the clinical trial that was assessed by the MEC. The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every half year to the MEC. This line listing provides an overview of all SUSARs from the study medicine, accompanied by a brief report highlighting the main points of concern.
The sponsor will report expedited all SUSARs to the competent authority, the Medicine Evaluation Board and the competent authorities in other Member States. The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report. There is no need to break any code in case of a SUSAR because due to the nature of the study in which neither participant nor treating physician are blinded.
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout the clinical trial, a safety report to the accredited MEC, competent authority, Medicine Evaluation Board and competent authorities of the concerned Member States. This safety report consists of: a list of all suspected (unexpected or expected) serious adverse reactions, along with an aggregated summary table of all reported serious adverse reactions, ordered by organ system, per study; a report concerning the safety of the subjects, consisting of a complete safety analysis and an evaluation of the balance between the efficacy and the harmfulness of the medicine under investigation.
An independent data and safety monitoring committee will evaluate the progress of the trial and will examine safety parameters at regular intervals (every 25 patients). The committee can unblind the data whenever deemed necessary based on reported adverse events. All involved physicians will repetitively be asked to report any potential adverse events caused by the study protocol. These adverse events will be listed and discussed with the monitoring committee. The monitoring committee can ask for a full report in order to discuss a specific adverse event. A copy of this report will be send to the central ethics board and to the involved physicians. All deceased patients will be evaluated by the safety committee for cause of death and possible trial related serious adverse effects. Every death will be reported to the central ethics board and the local ethics board. The Data Safety Monitoring Board will consist of an epidemiologist/statistician who is the chairman, an independent surgeon and an independent radiologist.
This study is conducted in accordance with the principles of the Declaration of Helsinki and 'good clinical practice' guidelines. The Medical Ethical Committee of the Academic Medical Center in Amsterdam has approved the protocol. The Ethical Committees of the participating centers is applied for local feasibility. Prior to randomization, written informed consent will be obtained from all patients.