Our study on aspirin for metal stents in malignant distal CBD obstruction (AIMS) is an investigator-initiated, randomized, multicenter, double-blinded, placebo-controlled prospective comparative study. We will perform the study in accordance with the common guidelines for clinical trials in accordance with the Declaration of Helsinki and International Conference on Harmonisation and World Health Organization Good Clinical Practice (ICH-GCP) standards. This study protocol was approved by the institutional review board of Seoul National University Hospital, South Korea (IRB No. H-1707-161-874). This trial was registered with ClinicalTrials.gov (NCT03279809) on September 5, 2017. Figure 1 shows the overall scheme for the AIMS study and Figure 2 for the SPIRIT checklist and additional file 1 for SPIRIT checklist.
Patients referred to tertiary centers who need endoscopic biliary drainage for malignant distal CBD obstruction will be recruited for the trial. The target sample size is 184 subjects in the tertiary referral centers in South Korea (i.e., Seoul National University Hospital, Wonju Severance Christian Hospital, Myongji Hospital, and Yongin Severance Hospital). Our study will be informed to patients who are considered eligible for the trial. All the eligible candidates will undergo an interview and receive more detailed information regarding the study, the intervention, and the two ways to manage index SEMS placement for malignant distal CBD obstruction. The candidates will then receive either aspirin or a placebo in a double-blind manner since evidence on the effect of aspirin for SEMS maintenance is unclear. The participants’ written informed consent will be obtained and archived securely in document form. The participants will be provided with comprehensive information regarding the study aim, intervention, and potential risks and benefits, and will be able to withdraw from the study at any time without consequence. The trial will commence from November 2017 and conclude six months after the last patient enrollment. All the recruitment procedures will be recorded in a log file.
The participants meeting the following criteria will be included:
- Aged 20 years or older
- Have unresectable malignant distal CBD obstruction
- Technically successful placement of index ERBD with a SEMS
Participants meeting one or more of the following criteria will be excluded from the study:
- Patient refusal
- Patient underwent previous SEMS placement
- Current aspirin user
- History of allergic reaction to aspirin
- Contraindication to aspirin
- Life expectancy less than six months
- Active peptic ulcer or gastrointestinal bleeding
- History of drug (substance) abuse
- Registration for other clinical trials within 30 days
Randomization and blinding, and treatment allocation
The randomization lists will be generated using Random Allocation Software version 1.0.0 (free software developed by M. Saghaei, MD, Isfahan University of Medical Science, Isfahan, Iran ) using the block randomization method developed by a research fellow at Seoul National University Hospital who is not involved in our trial. The patients who meet the selection criteria will be randomized at a 1:1 ratio in each group (test or control). As this is a double-blinded study, the researchers, patients, and other study personnel will be blinded to the treatment.
Interventions and management of the study drug
The enrolled patients will be randomly assigned to the test group or the control group. The drug administration will start within 30 days of successful placement of index ERBD with a SEMS. The specifications of the stent (covered/partially covered/uncovered, caliber, length) were also decided by the physician's discretion, taking into account the feature of obstruction site and patient’s condition. And we allow to use all biliary SEMS available in each institution regardless of manufacturers including WallFlex biliary stent (Boston Scientific, Natick, Mass), Bonastent (Standard SciTech Inc., Seoul, South Korea), Niti-S biliary stent (Taewoong Medical Co, Ltd, Ilsan, South Korea), Zilver biliary self-expanding stent (Wilson-Cook Medical Inc., NC, United states), ARISTENT (CGbio Co, Ltd, Seongnam-si, South Korea), etc. Prophylactic rectal indomethacin for post-procedural pancreatitis will not be used because it is not commercially available in Korea. The patients in the test group will take one 100 mg enteric-coated aspirin tablet (Daewon Pharmaceutical Co., Ltd.) per day before or after meals for six months, which was known to be physiologically equivalent to 75 mg of plain aspirin. And the patients in the control group will take one placebo tablet for six months. We planned longer period of aspirin use with six months in comparison with the previous retrospective study, because known median patency of SEMS in distal CBD obstruction was over 6 months.[1, 5] They will be followed-up in an outpatient clinic irrespective of whether the clinical outcomes, including stent malfunction, occur. Anticancer therapy, which is or will be received, will continue regardless of whether the patient is enrolled to the study.
The initial drug distribution and storage will be handled by the clinical trials center pharmacy of Seoul National University Hospital. Thirty-five tablets will be packaged in each medicine bottle, which will have a random number on the front label. After screening and enrollment, a randomization number will be assigned to each patient, and a prescribed number of medications will be given to them based on the randomization number. Each patient will be prescribed one bottle every four weeks according to the follow-up schedule, and the number of drugs remaining at the following outpatient visit will be retrieved to assess patient compliance. A research nurse will conduct frequent telephone monitoring to be prepared for the cases that lose or not to return the drug bottle.
During the follow-up period, the study patients will be instructed not to take medicines that are prohibited in conjunction with aspirin according to the pharmaceutical authorization from the Korean Ministry of Food and Drug Safety. When taking new medicines during the study period, the patients will be required to contact the researchers so that they can evaluate the drugs’ interactions with aspirin and effect on the research sustainability. The detailed principles of the concomitant use of drugs in this study are as follows :
- Anticoagulants, thrombolytics, other platelet aggregation inhibitors, hemostatic agents : De-escalation of dose or careful administration
- Other nonsteroidal anti-inflammatory drugs and salicylic acid preparations: Discontinue administration if possible, do not concomitant use due to increased risk of bleeding or decreased renal function
- High dose methotrexate over 15mg/week : Do not use due to increment of toxicity
- Lithium : Careful administration due to the possibility of lithium poisoning
- Selective Serotonin Reuptake Inhibitors: Careful administration due to increased risk of upper gastrointestinal bleeding
- Digoxin: Careful administration due to increment of plasma digoxin level
- Valproic acid: Careful administration due to increment of toxicity
- Alcohol: Careful use due to increment of gastrointestinal mucosa damage, prolonged bleeding time
Study outcome and assessment
The primary outcome of this study is the rate of stent dysfunction at six months. Stent dysfunction is defined as the presence of symptoms of obstructive jaundice or cholangitis in combination with confirmation of stent obstruction or migration via imaging (i.e., computed tomography and/or magnetic resonance imaging) after index SEMS insertion. Cholangitis will be diagnosed according to the Tokyo Guideline 2013 as follows: fever over 38°C, evidence of an inflammatory response with an abnormal white blood cell level (< 4 000/uL or > 10 000/uL) or a C-reactive protein level ≥ 1 mg/dl, jaundice (total bilirubin ≥ 2 mg/dL), abnormal liver function tests (alkaline phosphatase, gamma-glutamyl transferase, alanine transaminase, aspartate transaminase > 1.5 x standard deviation), and biliary dilatation at imaging tests. The rate of stent dysfunction is defined as the percentage of patients who develop stent dysfunction during the follow-up period.
The secondary outcomes of this study are the duration of stent patency, the rate of reintervention, and any adverse events related to aspirin administration. The duration of stent patency will be evaluated on a day scale as the duration between the index SEMS placement and the occurrence of stent dysfunction, or death in the case of patients without stent dysfunction. The rate of reintervention is defined as the percentage of patients who underwent an additional intervention for biliary drainage during the follow-up period after index SEMS placement. For adverse events, a thorough investigation will be conducted to determine whether the adverse effects were related to aspirin administration.
Baseline characteristics and medical information of patients are also recorded in detail through case report form including information as follows for further analysis: Etiology, stage of disease, histologic feature, Charlson’s cormorbidity index, history of hypertension, diabetes mellitus, pulmonary tuberculosis, cerebrovascular disease, coronary artery disease, liver or bile duct disease, peptic ulcer disease, any bleeding event, drug in current use, smoking, alcohol, family history, prior management including sphincterotomy, any biliary stent, further management including detail information of chemotherapy, radiotherapy, surgery.
The patients will visit the outpatient clinic at four, 12, and 24 weeks after index ERBD where their clinical symptoms will be evaluated and laboratory tests conducted to assess their vital signs, the presence of Charcot’s triad (jaundice, fever, and right upper quadrant abdominal pain), white blood cell count, hemoglobin, platelets, blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, alanine transaminase, aspartate transaminase, C-reactive protein, prothrombin time, and the results of imaging tests such as computed tomography, magnetic resonance imaging, or endoscopic ultrasonography. Additional visits to the outpatient clinic or emergency room at the follow-up center will be allowed if worrisome symptoms or signs become apparent.
Safety and adverse events
An adverse event is an undesirable medical event that occurs in a patient who is receiving a medication or is being studied, irrespective of whether the event is related to the treatment. In our study, any adverse events, regardless of the seriousness, underlying disease, or association with the test drug, will be noted on the appropriate page of the case record. The classification of the adverse events and their severity will be evaluated according to the National Cancer Institute Common Toxicity Criteria (version 3.0) and will be described in the case record in detail. The causality between any adverse reactions and the intervention will be determined based on the judgement of the researchers. If any unanticipated adverse events related to the research, these will be reported to the institutional review board.
The bleeding that occurs after aspirin is the most commonly expected adverse event. We believe that it is rarely to occur the major bleeding with six-months aspirin use in this study, because a recent published meta-analysis reported that the major gastrointestinal bleeding or hemorrhagic stroke events occurred 1.71 for hemorrhagic stroke per 1000 person-years of low-dose aspirin exposure as primary prevention. We anticipated that the expected effect of aspirin on inhibiting stent dysfunction would be of sufficient benefit to patients from this inference. Also, we tried to exclude cases with higher risk of bleeding due to aspirin use via exclusion criteria. In addition, endoscopic biliary stenting was known as a low risk procedure in the ASGE guideline. To add proton pump inhibitor is decided with the discretion of the physician when necessary.
We calculated the sample size for this study based on the results of a previous retrospective study with a similar clinical situation and purpose. In the study, stent occlusion occurred in 15.3% of the patients in the aspirin group and 23.4% of the patients in the non-aspirin group at a mean of three months during the follow-up period. Based on the findings of other studies, we assumed a 40% stent occlusion rate of SEMS in malignant distal CBD obstruction after six months.[9, 25-27] Furthermore, we assumed the rate of stent dysfunction on the basis of a recent study that reported the hazard ratio (0.49; 95% confidence interval, 0.32–0.75) was lower in the patients in the aspirin test group as opposed to 20% in the non-aspirin group. Our calculations were performed using 80% power and a two-sided 5% significance level to verify the null hypothesis and the alternative hypothesis. The sample size required to demonstrate this was calculated as 82 patients in each group and 184 patients in the total sample (92 patients per 10% dropout rate).
Blinding will remain in place until the statistician codes the statistical analyses of the primary and secondary outcomes. The statistical analyses will be done using the full analysis set according to the intention-to-treat principle, meaning all the randomized patients will be analyzed in their allocated groups regardless of any protocol violations or early treatment discontinuations. We will also evaluate the outcomes through a per-protocol analysis set that will consider only the subjects who followed the protocol effectively. No formal interim analysis is planned.
We will compare the rate of stent dysfunction using Pearson’s chi-squared test with Fisher’s exact test and calculate the odds ratio of the event. The secondary outcomes (i.e., the duration of stent patency, the rate of reintervention, and the adverse events related to aspirin administration) will be analyzed using Pearson’s chi-squared test with Fisher’s exact test, Student’s t-test, and Kaplan–Meier curves stratified by drug and the hazard ratios between two groups using the Cox proportional hazards. We also plan to identify the further affecting factors for stent dysfunction by univariate and multivariate logistic regression analysis.
Quality assurance and control
The research institutes will be monitored centrally and via on-site visits by a research nurse from Seoul National University Hospital who will follow the ICH-GCP guidelines. The trial institutes will also be visited regularly by the study coordinator and the study sponsor to ensure compliance with the study protocol and ICH-GCP guidelines. Complete source data verification will be performed by independent monitors. All the data collected during the trial will be stored in a secure electronic data capture system according to the ICH-GCP guidelines. A central study coordinator will coordinate the study. The Seoul National University Hospital will monitor the study’s progress and quality and the completeness of the study data.
Access to data
The principal investigators and co-investigators will have access to the final trial dataset.
Dissemination of data
Results of this study will be disseminated via professional journals, national, and international conferences. A lay summary of study results will be provided on ClinicalTrials.gov upon study completion.
Major protocol modifications are not anticipated. If any important modifications occurred, there will be requested through a modification request form to the institutional review board of Seoul National University Hospital and communicated to all study personnel.
Authorship will be given to those who make considerable contributions to the study.