Protocol for a comparison study of 1-day (single dose) versus 2-day prophylactic antibiotic administration in Holmium Laser enucleation of the prostate (HoLEP): a randomized controlled trial

Eligibility criteria

Selection criteria

In the period from May 1^st 2018 to April 30^th 2021, patients 20 years old or older undergoing HoLEP/TUEB without preoperative bacteriuria will be enrolled.

Exclusion criteria

i) Patients who have undergone another procedure such as prostate biopsy or bladder urolithiasis at the time of HoLEP/TUEB. ii) Those with an indwelling urethral catheter. iii) Those with an allergy to CEZ. iv) Hemodialysis patients.

Interventions

Eligible patients will be randomized in equal proportions between 1-day (single dose) and 2-day PAA for HoLEP/TUEB using cefazolin (CEZ).

Outcomes

Primary endpoint

Primary endpoint is to compare SSI occurrence rate in both 2 groups.

Items of postoperative infection complications:

30-days postoperative infectious complications after HoLEP

In this study, UTI and urogenital infection means prostatitis, epididymitis, pyelonephritis and urosepsis. The occurrence date of these infections and the duration (days) until disappearance of pyuria, in those cases with pyuria, will be recorded.

Secondary endpoints

In cases where perioperative infection requires antibiotic therapies, the following information will be recorded. 1) The kind of infection and reasons for the diagnosis; 2) Occurrence data of such infection; 3) Blood culture and urine culture; 4) Identified bacteria; 5) Methods of therapies; 6) Duration of therapies; 7) Other postoperative complications than infectious ones; 8) Drug-induced adverse events.

Feasible purpose

This is a feasible randomized study to investigate the occurrence rate of postoperative UTI or urogenital infection within 30 days after HoLEP/TUEB with an estimated 95% CI, and will be followed by confirmatory studies.

Sample size

For a feasible randomized comparing study, the target sample size is n=180 (1 day (single dose): n=90 and 2 days: n=90). The sample calculation was performed as follows: this study is a feasibility study. We referred to the following study which examined their 164 TURP and HoLEP cases, and found the postoperative infectious complications in 7/72 cases (9.7%) and 2/72 cases (2.8%), respectively. Accordingly, if we estimate 3 or 4 cases of UTI or urogenital infectious complication within 30 days after HoLEP, the occurrence frequencies for a 95% confidence interval (CI) are 0.007-0.094 and 0.012-0.111, respectively. The upper limit of a 95% CI is 10% or so, and it may be useful for planning the next study to set them as in Jhanwar et al.⁷.

Statistical analysis

Analysis of study participants’ background:

The difference between groups will be analyzed by the following methods:

Pearson’s chi-square: nominal variables; Fisher’s direct probability calculation method is performed where the expected frequency of less than 5 is 20% or higher; T-tests will be done for continuous variables. The Significance standard is set as 5% in two-sided tests.

Recruitment strategy

Recruitment will be performed from the patients with indication of HoLEP in those institutions participated in this study. Randomization will be performed by a table of random numbers as a simple randomized study under the control of the responsible party (Dr. Yuzo Nakano, Department of Urology, Kobe University Hospital).

Allocation

Participants will be randomly assigned to either 1-day or 2-day antibiotic group with a 1:1 allocation as per a computer-generated randomization schedule.

Blinding

Assessments regarding clinical recovery will be conducted by Dr. Yuzo Nakano blind to treatment allocation. Due to the nature of the intervention neither participants nor staff can be blinded to allocation, but are strongly inculcated not to disclose the allocation status of the participant at the follow up assessments. An employee outside the research team will feed data into the computer in separate datasheets so that the researchers can analyse data without having access to information about the allocation

Assignment of intervention

Tested antibiotics

1^st generation cephalosporine : Cefazolin Sodium Hydrate (J01DB04)

Method of administration

Patients will be randomly divided into a 1-day (single dose) group (CEZ 1g, once per i.v. just before HoLEP/TUEB) and a 2-day group (CEZ 1g, i.v. just before HoLEP/TUEB with a repeat dose the next morning). Comparison of SSI occurrence in these 2 groups is a feasible randomization study.

Outline of study

i) One-day dosing (single dose): i.v. initiation of CEZ (1g) 30 min prior to surgery, completed in 30–60 min (with no any other antibiotic administration)

ii) Two-day dosing: i.v. initiation of CEZ (1g) 30 min prior to surgery, completed in 30–60 min, repeated every 12 hours for 2 days including the surgery day. Additional dosing is necessary in cases with 3 hours or longer of surgery time. Test items and schedule of this study is shown in Table 1.

Study therapy

To investigate the inhibiting effect of cefazolin (CEZ) 1-day (single dose) and 2-day administration on perioperative infectious complications in HoLEP with a calculated 95% CI.

Combination medicine

Exclusion criteria include use of other antibiotics or cases requiring an additional antibiotic.

Termination of antibiotic administration

Cases exhibiting or suspicious for drug-induced allergy.

Assignment of interventions (for controlled trials)

Management and delivery of study drug

Applicants will be contacted by fax or e-mail and then given either 1-day (single dose) or 2-day CEZ under randomization as described above.

Post-test treatments

In cases where the attending physician diagnoses a perioperative infectious complication, the doctor can treat at discretion, including i.v. for severe cases and oral antibiotics for mild cases.

Evaluating items

We will gather the following data from the medical records.

i) Patients’ background factors

Age, Body Mass Index (BMI), Preoperative IPSS/QOL・Qmax・residual urine volume (ml), Estimated prostate volume(ml), Preoperative PSA, ASA-PS, Diabetes mellitus (HbA1c, blood sugar control), Chemotherapy and immune-suppressants

ii) Surgery-related categories

Surgical time (min, including morcellation), Resected prostate weight (g), Catheterized period (days), Post-operative residual urine volume (ml): until 30 days after surgery, Duration of antibiotic administration (1 day (single dose) or 2 days)

iii) Postoperative infectious complications

Investigation for 30 days after surgery (need to record), UTI or urogenital infection (prostatitis, epididymitis or pyelonephritis), Postoperative complication other than infectious ones, Occurrence date, Cases with infectious complications requiring additional antibiotic therapy, Detail of infection and the diagnosing evidence, Infection occurrence date, Urine culture and blood culture, Detected bacteria, Therapy, Therapeutic duration, and Days needed to reduce pyuria

Screening tests

Screening tests will be done to check the following criteria i) and ii).

i) Enrollment criteria

Those patients who are older than 20 years old undergoing HoLEP for benign prostate hyperplasia (BPH) without bacteriuria preoperatively and with informed consent.

ii) Exclusion criteria: see above

Information on participants

The following information will be recorded at the time of informed consent acquisition and screening tests.

i) Date of informed consent acquisition; ii) Class card number of study participants; iii) Backgrounds of study participants, birth date, age, height, body weight, past history, complication (underlying disease), iv) Present illness: date of definitive diagnosis, risk scoring, family history

Subjective symptom/ objective findings

Observation of adverse events including infectious complication, blood pressure, heart rate, body weight, hematology examination, blood biochemical examination, urinalysis, chest X-ray, ECG, urine culture

Patients’ background

Age, body mass index (BMI), preoperative PSS/QOL・Qmax・residual urine volume (ml) estimated prostate weight (ml), preoperative PSA, ASA-PS, diabetes mellitus (HbA_1c, blood sugar control), chemotherapy or immune-suppressants,

Surgery-related items

Surgical time (min; including morcellation time), resected prostate weight (g), duration (days) to removal of urethral catheter postoperatively, Postoperative residual urine volume (ml) till 30-days after surgery, duration of prophylactic antibiotic administration (CEZ) : 1-day (single dose) or 2-days group

Items for postoperative perioperative infection and complications: Examination till 30-days after surgery

UTI and urogenital infection (prostatitis, epididymitis and pyelonephritis), postoperative adverse events including infectious ones, except postoperative infection, occurrence date.

In cases with perioperative infection who need antibiotic therapies, the details include bacterial information (see above).

Cancelation criteria

i) Those cases who are not willing to continue this study and/or wish to withdraw informed consent. ii) Those cases who are found not to be satisfied about their applicability to this study or who cannot continue the study owing to the occurrence of complications and/or exacerbation. iii) Those cases who cannot continue the study owing to study-related adverse events. iv) The study itself is canceled. v) Cases with uncontrollable infectious complications postoperatively. vi) PIs or the members of this research judge that cancelation is needed owing to other reasons.

Study period

May 1^st 2018 to April 30^th 2021; the follow-up period is 1 year afterwards.

Main analysis

We will estimate the difference in postoperative infection occurrence rate at the 95% CI and do the 5% two-sided test for Significant for such differences.

Interim analysis

This study needs interim analysis because it is planned as a feasible randomized study.

That is, once 45 cases are completed, the occurrence rate of postoperative infection can be compared in the 2 groups and to determine if there is less than a 5% of difference and then to continue if the difference is 5% or less.

Ethics and dissemination

Ethical consideration and consent

This protocol was approved by the Institutional review board of the Kobe University Graduate School of Medicine (C180043). All procedures were in compliance with the relevant laws and guidelines in accordance with the ethical standards of the Declaration of Helsinki.

This study was registered in the University Hospital Medical Information Network-Clinical Trial Registry (UMIN000027955) based on recommendations from the International Committee of Medical Journal Editors (ICMJE) on July 1^st 2017.

Protocol amendments

Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol. Such amendment will be approved by the Ethics Committee/IRB (institutional review board) prior to implementation and notified to the health authorities in accordance with local regulations. Administrative changes of the protocol are minor corrections and/or clarifications that have no effect on the way the study is to be conducted. These administrative changes will be agreed upon by Ethics Committee/IRB, and will be documented in a memorandum. The Ethics Committee/IRB may be notified of administrative changes at the discretion of Helsinki Declaration.

Consent of assent

A trained research doctor will introduce the trial to patients who will be shown an informed consent form regarding the main aspects of the trial. Research doctors will discuss the trial with patients in light of the information provided in information sheets. Patients will then be able to have an informed discussion with the participating consultant. Research doctors will obtain written consent from patients willing to participate in the trial. Information sheets and consent forms are provided for all patients (Extended data⁸). All information sheets and consent forms transcripts have been translated into Japanese.

Confidentiality

All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. All laboratory specimens, reports, data collection, process, and administrative forms will be identified by a coded ID number only to maintain participant confidentiality. All records that contain names or other personal identifiers, such as locator forms and informed consent forms, will be stored separately from study records identified by code number. All local databases will be secured with password-protected access systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID numbers to other identifying information will be stored in a separate, locked file in an area with limited access.

Access to data

The Data Management Coordinating Center will oversee the intra-study data sharing process, with input from the Data Management Subcommittee.

All Principal Investigators will be given access to the cleaned data sets. Project data sets will be housed on the Project Accept Web site and/or the file transfer protocol site created for the study, and all data sets will be password protected. Project Principal Investigators will have direct access to their own site’s data sets, and will have access to other sites data by request. To ensure confidentiality, data dispersed to project team members will be blinded of any identifying participant information.

Ancillary and post-trial care

Patients that are enrolled into the study are covered by national health insurance in all the tests and treatments including the ones performed additionally owing to the adverse events of this study.

Dissemination policy

We plan to disseminate the information of this study through the UMIN and our department homepage.

Study status

The study is now undergoing pre-recruitment for participants (recruitment started May 1^st, 2018).

Underlying data

All data underlying the results are available as part of the article and no additional source data are required

Extended data

The consent form and information sheet that will be used in this study is available from Harvard Dataverse

Harvard Dataverse: Extended data. Replication data for Protocol for a comparison study of 1-day versus 2-day prophylactic antibiotic administration in Holmium Laser enucleation of the prostate (HoLEP): a randomized controlled trial https://doi.org/10.7910/DVN/SGTWJN⁸

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