Study setting {9}
This study is performed by the Danish Chronic Subdural Hematoma Study group (DACSUHS), which is a national steering committee with participants from all neurosurgical departments in Denmark. DACSUHS coordinates CSDH management and research in Denmark. All study sites are thus in Denmark, and all Danish neurosurgical departments are participating. There are no private facilities for cranial neurosurgery in Denmark. Patients are admitted to their local neurosurgical department after a computed tomography (CT) has confirmed the diagnosis. Local clinical neurosurgical teams review the patients upon admission and will assess eligibility for the DRAIN-TIME 2 study. The decision for surgery is made on an individual basis by the neurosurgical teams together with the patient (if possible) and their family. The study was approved on two levels by the Danish Regional Committees on Health Research Ethics, so both incapacitated and mentally competent patients can be enrolled.
Eligibility criteria {10}
Screening of patients to determine eligibility for participation in the study will be performed by the neurosurgical team upon admission according to the following criteria.
Inclusion criteria
- Adult patients (≥ 18 years)
- Minimum two weeks’ time span from known head trauma
- Patients with symptomatic CSDH confirmed on CT or magnetic resonance imaging (MRI), admitted to a neurosurgical department for operative treatment
- Patients undergoing a single burr-hole evacuation and placement of a passive subdural drain.
Exclusion criteria
- Patients with abnormalities in their cerebrospinal fluid
- Patients with changes or abnormalities in their normal cerebrospinal fluid dynamics, e.g. ventricular peritoneal shunt
- Patients with additional intracranial pathology that requires neurosurgical treatment
- Patients with recurrent CSDH or with previous craniotomy or other transcranial surgery.
Who will take informed consent? {26a}
Informed consent will be obtained by a member of the research team upon admission or immediately after surgery. The Danish confidentiality law requires that the patient and any relatives are orally informed about the trial, including its rationale and overall purpose. Written patient information and the consent form will also be handed out and reviewed together with the patient. Both oral and written consent must be obtained from the patient before study randomization. The patients will be made aware of the right to a reflection period and that they can withdraw their consent at any stage. Patients who do not wish to take part in the trial will have a postoperative drainage period of 24 hours, which is the current standard treatment in Denmark.
At Odense University Hospital and Rigshospitalet, we will perform an exploratory/mechanistic sub-study. Patients will be given additional patient information and an additional consent form so that they can consider whether they would like to take part in the sub-study.
Patients who are temporarily incapacitated due to severe symptoms can still be enrolled in the trial if oral and written consent is obtained from both A and B (see below) no later than 6 hours post-surgery:
- The patient’s legal representative. If at any stage the patient’s legal representative chooses to withhold or withdraw the consent, the patient will be excluded from the trial.
- A healthcare professional (medical doctor) who is independent of the interests of the persons responsible for the trial and of interests in the project in general. The consent may initially be oral, and the doctor's first and last name must be noted in the medical record.
The patient can then be randomized.
Mentally incapacitated patients relinquish the authority, that is the competent patients’ right, to choose among professionally acceptable alternative treatments or to participate in research projects. While standards to determine intellectual capacity remain unclear, a practical approach is to demonstrate that a patient is able to describe the physician's view of the situation and to understand the physician's opinion as to the best intervention [7]. We consider patients to be incapacitated if they are unable to participate in the medical examination, are not aware of time, place and personal information, or are somnolent or comatose.
Patients who regain capacity post-surgery will be informed about the clinical trial, and consent will be sought. In most cases, this will happen during the stay at the department of neurosurgery. If this is not the case, evaluation of capacity will be performed at 90 days follow-up.
All patients admitted to the neurosurgical departments will receive standard care and will be monitored pre- and postoperatively as per routine clinical practice. Patients will either be discharged to home or transferred to another department or hospital. The Short-Form 36 (SF-36) questionnaire will be used for the 90 days follow-up and will be handed out to patients before discharge. In addition, the patient will receive the questionnaire by mail after 90 days. A member of the research team will contact the patient or the patient’s legal representative by telephone in order to determine their capacity, obtain a modified Rankin Scale score, and guide the patient through the SF-36 questionnaire. If the patient is considered to be incapacitated, then the patient will be deemed as lost to follow-up concerning SF-36.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable.
Interventions
Explanation for the choice of comparators {6b}
Not applicable. A control/placebo group is not a part of the study design.
Intervention description {11a}
This trial follows Danish standard clinical care and treatment published by DACSUHS [8]. Placement of a subdural drain is standard treatment, and the only deviation is the drainage time. Blood samples are obtained routinely at admission.
In the sub-study, extra blood will be collected and stored, and CSDH fluid and the surrounding membrane will be removed during surgery. This biological material will be collected and stored for later analyses together with fluid collected from the drain during the postoperative period. Results from the sub-study will be published separately.
Criteria for discontinuing or modifying allocated interventions {11b}
Discontinuing of the study after randomization can occur in the following situations:
- Signs of infection around the drain tube
- Pronounced leakage from the drain canal
- Patient and/or relative (in case of incapacitated patients) request to withdraw from the study
- Deterioration of the condition which thereby requires repeat surgery or craniotomy during primary hospitalization.
Strategies to improve adherence to interventions {11c}
The surgeon will state in the medical record the time at which the envelope with the randomization result must be opened (6 hours after surgery for all patients). This time will also be stated on the board by the patient’s bed. If the drain is to be removed after 12 or 24 hours, the exact time of drain removal is written in the medical journal and on the board after opening of the randomization envelope at the 6 hours timepoint. A member of the research team will continuously monitor whether this process is carried out correctly.
Relevant concomitant care permitted or prohibited during the trial {11d}
All patients receive a standard operation and standard postoperative care. No specific care or interventions are prohibited.
Provisions for post-trial care {30}
Neither provisions for ancillary and post-trial care (if any) nor compensation to those who suffer harm from trial participation (if any) are provided by the neurological departments or the DACSUHS consortium. All care and help needed after discharge is provided by the Danish Health Authorities free of charge.
Everyone who receives treatment or purchases medicine in Denmark is covered by the Patient Compensation Association and can file a claim for an injury sustained as a result of the treatment or medication. This also covers participation in clinical trials.
Outcomes {12}
Primary outcome measure
Recurrence rate of chronic subdural hematoma at three months post-operatively.
Secondary outcome measures
- Mortality rate at 90 days
- Modified Rankin Scale at 90 days (Table 1)
- Patient-reported health status assessed by the SF-36 questionnaire (during admission and at 90 days follow-up)
- Length of hospital stay (at the department of neurosurgery before discharge to home or transfer to another hospital)
- Drain-related complications such as bleeding, pain, general discomfort, infection
- Complications related to immobilization (deep venous thrombosis and/or pulmonary embolism, brain infarction)
- Sub-analyses of patients with recurrence at 90 days: Co-morbidities, medications, age, gender, and evaluation of hematoma subtypes on CT from admission (homogenous, separated, mixed, or membranous [2]).
Exploratory (mechanistic) outcome measure (sub-study)
To explore possible mechanisms and thereby potential therapeutic targets for reducing recurrence risk, the peripheral and central (local) inflammatory response will be assessed by collecting blood samples, CSDH fluid, and a biopsy of the surrounding membranous tissue during surgery together with CSDH fluid from the postoperative draining period. Proteomic analysis and inflammatory marker analysis of the collected material will serve as a descriptive study; results will be compared between recurrent and non-recurrent patients to assess whether differences inflammatory mechanisms play a role in the development of recurrent CSDH. The following activities will be conducted:
- Assess the peripheral (blood) inflammatory response in CSDH patients
- Assess the composition of proteomics, inflammatory and angiogenetic markers in the CSDH fluid from surgery and in the fluid obtained during the draining period
- To do immunohistochemical analyses of inflammatory markers on membranous tissue removed during surgery
- Compare fluid composition with hematoma subtype
- Compare fluid composition between recurrent and non-recurrent patients.
Results from this exploratory sub-study will be presented in a separate paper.
Participant timeline {13}
As part of the routine standard care at hospital admission, all patients will have a medical history taken and a clinical examination. Figure 1 shows a full schedule of trial assessments as per the SPIRIT guidelines.
Sample size {14}
Calculations were based on the primary outcome measure recurrence.
Choice of non-inferiority margin:
The non-inferiority margin was chosen by the fixed-margin method [9] that is recommended by the United States Food and Drug Administration (FDA) [10]. A historical estimate for the effect of the active control (24 hours drainage) compared to no drainage was derived from the meta-analysis from Liu et al. [11]. This publication summarized different surgical procedures including a comparison of drainage vs. no drainage after burr-hole evacuation; drainage times varied between the studies but were typically 48 hours.
As the meta-analysis by Liu et al. [11] reports effect sizes as odds ratios (OR) but our sample size calculations required risk differences (RD), we reanalyzed the data used by Liu et al. [11]. This was done as individual participant data analysis using a logistic regression model with cluster robust standard errors. To transform ORs into RDs, we used the multivariate delta method and obtained an approximate 95% confidence interval for either a 7% or 17% difference in recurrence risk between no drainage and drainage. Consequently, 7% was chosen as the non-inferiority margin.
Sample size calculations
Sample sizes for the five stages of the applied adaptive design were calculated using stage-specific, decreasing significance levels of alpha=0.5, 0.3, 0.2, 0.1, and 0.025 together with stage-specific power levels of 0.9 for the first three stages and 0.95 for the last two stages. Stage parameters were chosen such that the overall power for the final comparison of each experimental arm (6 hours or 12 hours drainage) to control (24 hours drainage) is approximately equal to 0.8. The familywise error rate corresponding to the design is approximately 0.028.
Assuming a recurrence rate of 16.3% on the basis of previous DACSUHS studies in all treatment arms (both experimental and control), equal allocation to all treatment arms, and a non-inferiority margin of 7%, we obtained the following cumulative sample sizes.
|
Stage 1
|
Stage 2
|
Stage 3
|
Stage 4
|
Stage 5
|
Cumulative sample size per treatment arm reaching the respective stage
|
91
|
182
|
344
|
477
|
724
|
New samples per continued treatment arm and per stage
|
91
|
91
|
162
|
133
|
247
|
Overall cumulative sample size if no arm is dropped in any stage
|
273
|
546
|
1032
|
1431
|
2172
|
After each stage, an interim analysis will be done where non-inferiority of both arms is tested at the chosen stage-specific significance levels. Significant arms continue to the next stage, whereas non-significant arms can be dropped (non-binding). Together with the chosen stage-specific significance levels, the overall pairwise type-1 error rate (for the comparison of one experimental arm to control) equals 0.025 if stopping guidelines (i.e. for dropping of arms before the final stage) are ignored. If stopping guidelines are followed, 0.025 is an upper bound for the overall pairwise type-1 error rate.
The expected sample size for the design if all arms have an identical recurrence rate of 16.3% (implying non-inferiority of both experimental arms) and stopping guidelines are followed is 1928. If both experimental arms are inferior (with recurrence rates exceeding 16.3% by at least 7%, i.e. the non-inferiority margin) and stopping guidelines are respected, the expected sample size is 690.
Sample size calculations were done in STATA17.0 using nstagebin [6, 12]. Corresponding software output is shown in supplementary material A. Reanalysis of the meta-analysis was done in R [13] together with the package miceadds [14].
Recruitment {15}
Expectations for the recruitment rate are based on data from the first multicenter national study conducted by DACSUHS (DRAIN-TIME 1, ISRCTN 17021467) that terminated in April 2020. In this study, only patients who were able to give informed consent were enrolled. A total of 37 patients with CSDH were operated per month in Denmark, and the study recruitment rate was 21 patients per month. It took 20 months to include the total number of 420 patients in DRAIN-TIME 1 (two arms). In contrast to DRAIN TIME 1, both capable and incapacitated patients are enrolled in this DRAIN-TIME 2 study. Depending on whether one of the drainage groups is excluded as a result of the interim analysis, the inclusion period will most likely be 2-4 years.
Assignment of interventions: allocation
Sequence generation {16a}
Participants will be randomly assigned to one of the three draining groups no later than 6 hours postoperatively. Online randomization with a 1:1:1 allocation rate will be performed in each center using the REDCap randomize module in the REDCap database. Randomization is done separately in each center.
Concealment mechanism {16b}
Participants will be randomized using REDCap as described above. Allocation concealment will be ensured as the REDCap system will not release the randomization code until the patient has been recruited into the trial. This takes place after the medical history is taken and the clinical examination is performed. The drainage time group randomization is first released after the patient’s data and the signed consent form are uploaded to the database.
Implementation {16c}
All patients who give consent to participation and who fulfil the inclusion criteria will be randomized. Randomization will be performed by the on-call neurosurgeon who has operated on the patient and no later than 6 hours postoperatively. The randomization result will be placed in a closed envelope.
Both in the medical record and on the envelope, the surgeon will state the time at which the envelope must be opened (6 hours after end of surgery for all patients). Identical information will be stated on the board by the patient’s bed. If the drain is to be removed after 12 or 24 hours, the exact time of drain removal is written in the medical journal and on the board after opening of the envelope (after 6 hours of drainage). A member of the research team will continuously monitor whether this process is carried out correctly.
Assignment of interventions: Blinding
Who will be blinded {17a}
Except for the on-call neurosurgeon who operates on the patient, everyone will be blinded to the randomization until 6 hours post-surgery. The envelope will be opened by the nurse at exactly 6 hours after surgery to determine whether the drain should be removed at that time or after 12 or 24 hours. It is a passive drain, and the production rate cannot be affected by any external circumstances, which is why unblinding after 6 hours is not considered an issue.
Procedure for unblinding if needed {17b}
There are no circumstances where emergency unblinding would be absolutely essential for further management of the patient. Any clinical deterioration or need for repeat surgery would terminate the patient’s participation in the study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Primary outcome
The overall primary clinical outcome is recurrence of CSDH within 90 days after initial surgery and drainage. Recurrence is defined as neurological deterioration leading to hospitalization, confirmed recurrent CSDH on cranial imaging (e.g. CT/MRI), and a need for repeat surgery. A retrospective review of the electronic medical record will be used to clarify whether the patient has experienced a recurrence.
Recurrence or no recurrence will be registered in REDCap by a member of the research team after 90 days.
Secondary outcomes
A retrospective review of the electronic medical record will be used to clarify whether the patient has died during the observation period, and if so, for what reason.
The modified Rankin Scale (mRS) is a clinician-reported measure of the patient’s degree of disability. It is widely applied for evaluating outcome for stroke patients and as an endpoint in most of the randomized clinical trials [15]. It is a 7-level scale covering the entire range of functional outcomes from no symptoms to death. There is extensive evidence for the validity of the mRS, and the mRS categories correlate with functional outcome within the spectrum of stroke pathologies [16]. A limitation of the mRS is the subjective assignment of categories and the reproducibility of the score by examiners and patients [17]. A systematic review and meta-analysis of studies describing interobserver variability of the mRS reported pooled reliability (across 10 studies, n=587 patients) of κ=0.46 and weighted κ of 0.90 [18]. To reduce interobserver variability, all members of the research group will be certified in the use of the mRS (http://rankinscale.org/).
The Short Form-36 Health Survey is a validated, 36-item, patient-reported measure of health-related quality of life (HRQOL) that has been used in a wide spectrum of medical conditions [19-21]. It is one of the most extensively used tool to measure health-related quality of life. It covers eight dimensions of HRQOL (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health) and has an item on general health perception. Dimension scores can be summed together with differing weightings to generate two summary scores—a physical component score and a mental component score. Higher scores indicate higher HRQOL, and the SF-36 scores range from 0 (worst) to 100 (best) [21]. In the DRAIN-TIME 2 study, the first SF-36 is completed during the initial hospital stay with assistance from a member of the research group. The questionnaire is completed electronically in the REDCap database, via a computer or tablet (Ipad). A second SF-36 questionnaire is given to the patient at discharge and is also sent by secure electronic post (E-boks) to the patient 85 days after surgery. A member of the research group will ring the patient and assist with the completion of this questionnaire after three months (approx. 90 days). The responses are entered directly into the online REDCap database.
Using the electronic medical record system, we will collect several data points of interest throughout the study period: Number of hours post-surgery before the patient is mobilized; Length of hospital stay (i.e. at the department of neurosurgery before discharge to home or transfer to another hospital).
The following will be assessed by direct daily observation: Complications related to immobilization (back pain, deep venous thrombosis and/or pulmonary embolism, constipation); Drain-related complications such as bleeding, pain, general discomfort, infection.
Plans to promote participant retention and complete follow-up {18b}
Time to follow-up is 90 days, which we believe is a sufficiently short follow-up period to minimize patient attrition and maximize completeness of data collection. Most symptomatic recurrent CSDH cases related to the primary operation are expected to occur within this time frame [22]. The primary outcome data (CSDH recurrence at 90 days) will be obtained through the electronic medical record. To limit participant burden related to follow-up visits, we will contact each participant by phone after 90 days. Here we will assist the patient in completing the SF-36 questionnaire (which they will have received via e-mail/E-boks) and determine the mRS category.
Data management {19}
All patients admitted to one of the neurosurgical departments with a CSDH will be registered in REDCap, which is a worldwide online system developed specifically for non-commercial clinical research. REDCap is administered by the Open Patient data Explorative Network (OPEN) at Odense University Hospital, Odense, Denmark. The data entered will be stored on secure servers in the Region of Southern Denmark. Data are entered via an encrypted connection, are anonymized, and fulfil the demands for data protection. All data entries and changes are logged in REDCap and meet the Good Clinical Practice (GCP) requirements for use of the Electronic Case Report Form (eCRF) in medical trials. Members of the research team are responsible for all data entry. Baseline data obtained from the medical record are registered at admission. After patient consent, online randomization is performed in REDCap. The database is updated when the patient is discharged. At three months follow-up, an electronic copy of the SF-36 questionnaire is automatically distributed via E-boks, which is an online secure digital mailbox linked to the patient’s personal Danish registration number
Confidentiality {27}
All study-related information will be stored securely at the study site. All participant information will be stored in locked filing cabinets in areas with limited access. All laboratory specimens, data collection, and administrative forms will be identified by a coded ID [identification] number to maintain participant confidentiality. All records that contain names or other personal identifiers, such as informed consent forms, will be stored separately from study records identified by code number. The electronic database (REDCap) is secured with password-protected access. Forms, lists, and any other listings that link participant ID numbers to other identifying information will be stored in a separate, locked filing cabinet in an area with limited access. Access to the electronic database (REDCap) and to the locked cabinets in areas with limited access is reserved exclusively to members of the national steering committee, DACSUHS. Data processing and statistical work will be performed by exporting the data from REDCap to a secure server. Participant confidentiality will be maintained at all times.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
A sub-study at Odense University Hospital and Rigshospitalet will be carried out. The biological specimens from this sub-study will be collected and stored in a biobank.
Overall objectives and background:
Regardless of the choice of surgical procedure, there is a risk of spontaneous recovery/recurrence of the hematoma. Patients who develop recurrence experience significantly greater morbidity and mortality than patients who are cured after the first operation. In recent years, there has been an increasing interest in the composition of the hematoma fluid and in the systemic response as it is likely that the causes of hematoma expansion and recurrence will be found here. Therefore, we will collect hematoma fluid and hematoma membrane during the operation and will collect fluid from the drainage bag when the drain is removed after 6, 12, or 24 hours. Furthermore, a blood sample before and after the operation will be obtained for the investigation of systemic changes. The biological material will be used for analysis of pro- and anti-inflammatory as well as vascular (blood vessel-associated) proteins and peptides. A study of specific neuron and glia (markers of brain impact) will also be performed.
We hope that the study results will shed light on some of the crucial cerebral and systemic processes behind hematoma expansion and whether elimination (leaching) of particular proteins and peptides during surgery influences recurrence risk and postoperative neurological status. Finally, we hope to identify markers that can predict the risk of recurrence.
A) Plasma – collection procedures (methods)
A blood sample will be routinely taken at the time of admission and again on the first postoperative day. At the same time, an additional 10 ml of blood will be collected and distributed in five Sarstedt tubes (2x serum, 1x EDTA-coated, 1x citrate-coated, and 1x buffy-coated). The blood samples will be handled at the respective Departments of Clinical Biochemistry and Pharmacology, where pipetting, freezing, and storage will take place.
B) Chronic subdural hematoma fluid – collection procedures (methods)
Hematoma fluid will be collected from the subdural cavity using a 10 ml syringe. In the operating room, the fluid will be distributed into one Nunc tube of 3.6 ml and two Sarstedt EDTA tubes of 2 ml.
Postoperatively, hematoma fluid from the drainage bag will be retrieved using a 10 ml syringe. Bedside, the fluid will be distributed into one Nunc tube of 3.6 ml and two Sarstedt EDTA tubes of 2 ml.
The material will be picked up by relevant staff and transferred to the respective Departments of Clinical Biochemistry and Pharmacology, where further handling, freezing, and storage will take place.
C) Chronic subdural hematoma membrane – collection procedures (methods)
The hematoma membrane from the subdural cavity will be removed/biopsied (if possible) using appropriate instruments and divided so that half the tissue is fixed in formalin (buffered formaldehyde solution 4 %) and the other half is frozen without fixation (-80 degrees).
All above samples will be logged in, and aliquots will be bar coded with a unique storage ID generated by the REDCap system. The scientists who carry out analyses on these materials will not have access to personal identifiers and will not be able to link the results of these tests to personal identifier information. No individual results will be presented in publications or other reports. Participants will not be informed on an individual basis of any results from these studies.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Primary outcome:
We will use logistic regression with treatment assignment (6 hours vs. 12 hours vs. 24 hours drainage time) as categorical covariate and taking the different trial centers into account. Adjusted odds ratios with 95% confidence intervals for recurrence rate will be reported. We investigate a non-inferiority hypothesis with a non-inferiority margin of 7% (see Section 14 on Sample size). We will use a one-sided test together with stage-specific significance thresholds equaling 0.5, 0.3, 0.2, 0.1, and 0.025 for each of the five stages.
Secondary outcomes:
Mortality at three months will be analyzed by logistic regression as with the primary outcome. SF-36, mRS, hours until mobilization, and length of hospital stay will be analyzed by linear or ordinal regression. The occurrence of different types of complications amongst the three study groups will be analyzed with a log-linear Poisson regression model.
For all secondary outcome measures, we investigate superiority of each of the two experimental arms compared to the active control arm at the final analysis.
We use two-sided tests with a significance threshold of 0.05.
Interim analyses {21b}
Interim analyses of the primary outcome will be conducted at the end of each stage (see Section 14 on Sample size). Early dropping of an experimental arm (6 or 12 hours of drainage) can be chosen if stage-specific significance is not achieved by the respective arm. Secondary outcome measures will only be considered during the final analysis.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Patients with CSDH recurrence at 90 days will be considered separately. Descriptive tables of CT-based hematoma subtypes, frequency of comorbidities, medications, gender, and descriptive summaries of patient age will be created.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Loss to follow-up is expected to be rare, and analyses will be done as complete case analyses. All outcomes will be analyzed using intention-to-treat analyses. For the primary outcome, this will be supplemented by an as-treated sensitivity analysis in which the observed drainage times will be used as continuous covariate instead of the randomly assigned drainage times.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
We have no plans for granting public access to protocol, dataset, or statistical code.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Principal investigator:
- Preparation of protocol and revisions
- Preparation of written patient information
- Applying for ethical approval
- Organizing steering committee meetings
- Publication of study reports
- Member of steering committee DACSUHS
Steering committee:
(see title page for all members)
- Agreement of final protocol
- All investigators will be steering committee members; one lead investigator per department will be nominated as local coordinator
- Recruitment of patients
- Reviewing progress of study and, if necessary, agreeing changes to the protocol
- Data verification
- Randomization
Data Manager:
- External person from OPEN
- Maintenance of the trial IT system (REDCap)
- Data verification
Person responsible for data monitoring
- An external, independent biostatistician will perform all the statistical analyses throughout the study
Composition of the data monitoring committee, its role and reporting structure {21a}
A data monitoring committee (DMC) is not established. However, an external, independent biostatistician will monitor the study data and will be responsible for all the statistical work. The biostatistician is blinded and independent of the study organizers. During the period of recruitment to the study, interim analyses will be supplied together with any other analyses that the committee may request. In the light of these interim analyses (three interim analyses and one final analysis), the biostatistician will advise the steering committee based on the previously defined stopping guidelines.
Adverse event reporting and harms {22}
Interim analysis is performed as illustrated in Section 14. If one of the arms is associated with higher recurrence rate, death, or any other unexpected adverse effect, the steering committee will decide what precautions are to be made.
Otherwise, the operations and postoperative care and handling all follow standard procedures.
Frequency and plans for auditing trial conduct {23}
The steering committee will meet one month after trial initiation to evaluate all the aspects related to inclusion and data collection during hospital stay. The committee will be in constant dialogue throughout the study period. Planned meetings will take place after each interim analysis.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
No changes will be made in the present study protocol.
Dissemination plans {31a}
A final trial report will be written for publication, and trial results will be presented at international meetings.