2.1 Objective
The aim is to assess the effectiveness of preemptive analgesia with Ketoprofen 10 mg 2 hours before hemorrhoidectomy per os with spinal anesthesia to decrease postoperative pain and the amount of used analgesics.
2.2 Study design and setting
This is a prospective, randomized, double-blind, unicenter, superiority, parallel group 2-arm study with 1:1 allocation ratio conducted in Clinic of coloproctology and minimally invasive surgery of Sechenov University and surgical department of University Clinic of Moscow State University. It is on the recruitment stage. We are anticipating 144 patients of all genders from 18 to 75 years old in total who come to clinicы. Thus, in this case, a double-center design can assure sufficient patient recruitment.
2.3 Eligibility criteria
Every patient included in the study must meet the following criteria:
- Symptomatic haemorrhoids grade III-IV
- Planned surgery: Milligan-Morgan hemorrhoidectomy
Patients who had contraindication or technical inability to perform subarachnoid anesthesia or decompensated somatic diseases, or refused to participate and pregnant women are not included. The written voluntary informed consent to participate is obtained from all eligible patients before randomization.
2.4 Interventions
2.4.1 Preoperative preparation.
2 hours before procedure every patient receives a medication. The research group receives Ketoprofen 10 mg per os; the control group receives a placebo.
2.4.2 Surgical technique
Under a spinal anesthesia the patient is placed in a modified lithotomy position on the back, with legs spread apart on supports. The operative field is treated with an antiseptic solution twice and draped. A complex of external and internal haemorrhoid or internal haemorrhoid only is excised with monopolar electrocautery or bipolar electrosurgery device. Haemorrhoid pedicle is tied with absorbable polyfilament suture. One, two or three nodes can be removed per a procedure.
2.5 The main outcome measures
The trial is conducting to evaluate the primary outcome of the opioid administration intake per day during first week postoperatively that are necessary to hold pain level no more than 3-4 VAS points in every patient. The study also assesses the following secondary outcomes: (1) the pain severity before and after defecation according to VAS on the 6, 12 and 24 hours after the procedure, then 2 times per day up to 7th postoperative day, (2) duration and (3) frequency of other analgesics intake (systemically and topically) during the first week postoperatively, (4) readmission rate and (5) overall quality of life on the 7th and 30th days, (6) time from the procedure to returning to work and (7) the complications rate (i.e. bleeding, retention of urine, infectious complications) in early postoperative period (30 days after procedure). Overall quality of life will be assessed with patient-reported questionnaire Short Form 36 (SF-36). A total score in each of 8 sections will be calculated and transformed into a 0-100 scale with a score of zero equivalents to maximum disability and a score of 100 equivalents to no disability.
All patients are scheduled to return to the ambulatory clinic on 7 and 30 days after the surgery. During these visits, postoperative data is collected and digital rectal examination is performed. If a patient fails to follow-up, the researcher may contact the patient by all means available (phone, email, or mail) to ascertain whether the patient has had any complications and/or adverse events that were treated at another hospital. If the researcher is unsuccessful in contacting the patient, the patient will be considered as lost to follow-up.
2.6 Participant timeline
For schedule of enrolment, interventions, and assessments see Table 1.
2.7 Sample size
Considering that this is a superiority study, the sample size was calculated using 1-sided Blackweder test. According to published data, the incidence of opioids intake after hemorrhoidectomy is varies from 20 to 30% [22]. The expected incidence of opioids intake after hemorrhoidectomy with preemptive analgesia is not more than 10%. The purpose of this study is to show that the opioids intake in patients with preemptive analgesia is lower than without it. Considering that a = 0.05; the statistical power of the study is 80%; the patients are randomized into 2 groups with 1:1 allocation ratio; the noninferiority margin D = 5%, the required sample size is 144 patients (72 patients in each of the 2 groups).
2.8 Recruitment
All patients diagnosed with HD II-III stage will be considered for this study.
2.9 Assignment of interventions
Participants will be randomly assigned to either control or experimental group with a 1:1 allocation ratio using cluster randomization with a computerized random number generator. All subjects will be allocated any interventions. The experimental group receives a tablet with 10 mg Ketoprofen, the control one receives a tablet containing starch per os 2 hours before surgery (72 participants per arm). [see Figure1] The investigator who doesn’t operate generates the allocation sequence, enrolls participants and obtain the informed consent, and assigns participants to interventions. The surgeon and the anesthesiology team are blinded.
All relevant data from patient chart except patients’ names will be transferred into an electronic case report form (eCRF). The eCRF should contain results of all the screening procedures, including patient history and demographics, imaging studies, filled-out questionnaires, operation note, and postoperative rounds during patient stay in in the surgical ward.
2.10 Data collection, management, and analysis
All data will be collected prospectively using eCRFs designed for this trial. The reasons for withdrawal will be documented. The investigator will attempt to contact each participant at least 3 times during each follow-up window before declaring them lost for observation. The study exit form will be recorded in the eCRF. All prior data will be analyzed within the research.
All patients will receive clarifications of all the study procedures, and will be able to discuss them with the primary investigator. All patient data will be handled according to the principles of doctor–patient confidentiality, the subjects will be anonymized and analyzed with individual identifier numbers transcribed into eCRF.
2.11 Statistics
Quantitative variables are described as means with standard deviations, medians, range or interquartile range as appropriate. Categorical variables are described in absolute numbers and percentages. The statistical analysis of the quantitative variables, with independent groups, is performed with the parametric Student’s t-test, provides that its conditions for application are met. Otherwise, the non-parametric Mann-Whitney U-test is used. Statistical analysis for categorical variables is performed using the Pearson χ2 test or the Fisher exact test. Specifically, the above methods are used to compare the two groups in terms of baseline characteristics in order to assess whether the randomization has been effective.
2.12 Data monitoring.
There is no data monitoring committee designated to this trial. Any adverse and serious adverse events will be immediately reported to the principal investigator and the primary sponsor.
2.13 Ethical approval
This study is conducted in accordance to the principles of the Declaration of Helsinki. The study protocol is approved by the Local Ethics committee of Sechenov University. [see Additional file1]
2.14 Protocol amendments
Any protocol amendments that may influence the conduct of the study, will be communicated to the local ethics committee and study director, and will be uploaded to clinical trials.
2.15 Consent or assent
A member of the research team will obtain the consent form. All participants will be able to address their questions about the study to one of the members of the research team.
2.16 Confidentiality
All patient data will be secured at the study site. No one apart from the members of the research team will have access to any patient data, including anonymized eCRFs with a coded ID, as well as filled out questionnaires.
2.17 Declaration of interests.
The authors declare they have no competing interests.
2.18 Access to data.
No one apart from the members of the research team will have access to the final trial dataset.
2.19Dissemination policy.
Trial results will be e-mailed to all participants of the trial. Trial results will be disseminated to healthcare professionals via publication in a peer-reviewed scientific journal and by mass media, as well as conference papers to inform the public and stakeholders, and will be uploaded to the primary registry. We have no intention of granting public access to the full protocol, participant-level dataset, and statistical code.
