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Trial registered on ANZCTR


Registration number
ACTRN12619001760167
Ethics application status
Approved
Date submitted
8/10/2019
Date registered
11/12/2019
Date last updated
11/12/2019
Date data sharing statement initially provided
11/12/2019
Date results information initially provided
11/12/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of three different analgesic methods for patients undergoing transrectal ultrasound-guided prostate biopsy: a prospective, randomized controlled trial.
Scientific title
Efficacy and safety of three different analgesic methods for patients undergoing transrectal ultrasound-guided prostate biopsy: a prospective, randomized controlled trial.
Secondary ID [1] 299330 0
Nil known
Universal Trial Number (UTN)
U1111-1240-5658
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate cancer 314472 0
Pain relief 314474 0
Condition category
Condition code
Cancer 312808 312808 0 0
Prostate
Renal and Urogenital 312809 312809 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Urologist on duty for prostate biopsy procedure administered an intramuscular injection of Tramadol 100mg/ml, one hour prior to prostate biopsy procedure as adjunct regimen to the current gold standard of care method for preventing pain during transrectal ultrasound-guided biopsy, known as periprostatic nerve block (PPNB) anesthesia by injecting 10ml of Lidocaine 1% bilaterally at neurovascular bundles of prostate gland five minutes prior the actual biopsy process (obtaining of prostate cores) of prostate biopsy procedure.
Arm 2: Urologist on duty for prostate biopsy procedure administered the intramuscular injections of Tramadol 100mg/ml and Parecoxib 40mg/ml, one hour prior to prostate biopsy procedure as adjunct regimens to the current gold standard of care method for preventing pain during transrectal ultrasound-guided biopsy, known as periprostatic nerve block (PPNB) anesthesia by injecting 10ml of Lidocaine 1% bilaterally at neurovascular bundles of prostate gland five minutes prior the actual biopsy process (obtaining of prostate cores) of prostate biopsy procedure.
Intervention code [1] 315599 0
Treatment: Drugs
Intervention code [2] 315600 0
Prevention
Comparator / control treatment
Bilateral injection of 10ml of Lidocaine 1% at neurovascular bundles of prostate gland, known as periprostatic nerve block (PPNB) anesthesia. The injection was performed five minutes before the actual biopsy process of prostate biopsy procedure.
Control group
Active

Outcomes
Primary outcome [1] 321430 0
The efficacy of examined drugs (Tramadol alone or in combination with Parecoxib) as adjunct regimens to PPNB anesthesia. The efficacy was assessed by the difference in mean value of numeric rating scale (NRS) of pain, ranging from 0 to 10 points, with zero corresponding to no pain or discomfort and 10 corresponding to worst possible pain or discomfort.
Timepoint [1] 321430 0
Immediately after completion of each particular step of prostate biopsy procedure, participants were asked to assess the pain experienced at three consecutive time-periods: (i) at the time of probe insertion (NRS1), (ii) at the time of PPNB anesthesia (NRS2) and (iii) at the time of actual biopsy itself (NRS3), on a numeric rating scale (NRS) of pain.
Secondary outcome [1] 374931 0
The safety evaluated by occurrence of post-procedural complications and adverse effects related to each analgesic study protocol alone, as well as, compared to the current gold standard technique (PPNB).
Complications and adverse effects were graded as:
(i )Severe, including: syncope episode or hypotension requiring intravenous fluid and/or atropine, allergic reactions, hematuria and rectal bleeding requiring hospitalization, acute urinary retention, urosepsis or any kind of intervention.
(ii) Mild, including: self-limiting hematuria, fever (>38,0C) and rectal bleeding.
Post-procedural complications and adverse effects were presented in total counts and percentages.
Timepoint [1] 374931 0
Participants were monitored up to 2 hours after biopsy completion in order to record any potential severe complication and/or adverse effect related to the study interventions,
Post-procedural complications and adverse effects related to the prostate biopsy procedure were interviewed by telephone 72 hours later. The questions were phrased in the same manner for all participants to minimize any bias during data collection.
Secondary outcome [2] 374932 0
The difference in anxiety feeling of participants, experienced during the pre- and post-procedural period, The anxiety test (Likert Anxiety Scale) evaluated the intensity of nine similar symptoms on a linear analogue scale, ranging from 0 to 10 points, with zero corresponding to no intensity and 10 corresponding to extreme intensity feeling. Results of anxiety test were presented in mean values.
Timepoint [2] 374932 0
Upon enrollment of participants in the trial, a questionnaire (Pre-procedural Likert Anxiety Scale) was provided in order to assess the intensity of anxiety feeling experienced before any interventional procedure.
Participants were interviewed 2 hours after biopsy completion in order to complete a questionnaire regarding their anxiety feeling (Post-procedural Likert Anxiety Scale).
Secondary outcome [3] 374933 0
The satisfaction of participants related to the pain relief, experienced during each analgesic study arm. The satisfaction of pain relief was assessed by “Post-procedural Questionnaire”. Post-procedural Questionnaire was composed by four questionson with five possible answers for each question on a linear analogue scale, ranging from the least to the greatest extent of satisfaction. Results of satisfaction test were presented in total counts and percentages.
1) What word best describes the pain experienced during the biopsy?
No pain Mild discomfort Distressing Horrible Excruciating
2) Which word best describes the pain experienced after the biopsy?
No pain Mild discomfort Distressing Horrible Excruciating
3) Overall, how comfortable was the entire procedure?
Not at all easy Not very easy Easy Fairly easy Very easy
4) If medically necessary, how willing would you be to return for this procedure?
Not at all easy Not very easy Easy Fairly easy Very easy
Timepoint [3] 374933 0
Participants were interviewed 2 hours after biopsy completion in order to complete a questionnaire regarding their satisfaction in relation to pain relief (Post-procedural Questionnaire).

Eligibility
Key inclusion criteria
All consecutive patients referred to Urology Department for early detection of prostate cancer due to increased serum PSA, and/or abnormal digital rectal examination or transrectal ultrasound-guided findings were considered eligible for the present study.
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria were: history of previous prostate biopsy, active anorectal pathology (anal fissures, strictures, hemorrhoids), chronic prostatitis/pelvic pain syndrome, concomitant analgesic medication, known allergy to investigating analgesic regimens, contraindications to NSAIDs such as gastric or duodenal ulcers, patients with bleeding diathesis and those with impaired intellectual ability.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All consecutive patients that were referred to Urology Department for prostate biopsy and that had had fullfilled inclusion criteria were randomly allocated into three study-arms, by the use of an electronic platform generator of randomized permuted blocks.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary outcome was the evaluation of efficacy as assessed by the difference in mean NRS score between the three study groups. The secondary outcomes were the evaluation of safety, anxiety and satisfaction of participants in comparison between the three study groups. To detect statistically significant differences of such magnitude with 81% power and a 2-sided 5% significance level using ANOVA with 2 df contrasts approximately 11 patients per group were required. All continuous variables of participants’ characteristics were found to be normally distributed according to Shapiro-Wilk test and they were reported as the mean ± SD and Min-Max values. Differences in patient characteristics for continuous variables were calculated by the use of one-way analysis of variance (ANOVA) with a =0.05. Categorical variables were reported as frequencies and relative frequencies. Cochran's rule was accepted therefore the chi-square test with a = 0.05 was used.
The assess of normality for NRS scores between participants in group 1, 2 and 3 was suggested that data were not normally distributed, thus the non-parametric Mann-Whitney U test was used. Differences in complication rate were reported with frequencies and relative frequencies and they were assessed by the use of Fisher’s exact test because Cochran's rule was not accepted. The Bonferroni correction with a = 0.0167 was used for adjusting the p-values.
The assess of normality for anxiety scores between participants in group 1, 2 and 3 suggested that data were normally distributed, thus the parametric two-way analysis of variance (ANOVA) with a = 0.05 was used. The Paired t-test was further used to determine which specific pairs of group demonstrate statistically significant differences. Differences in satisfaction of participants related to prostate biopsy procedure were reported with frequencies and relative frequencies and they were assessed by the use of chi-squared test because Cochran's rule was accepted. The Mann-Whitney U test was further used to determine which specific pairs of group demonstrates statistically significant differences between all four questions. The Bonferroni correction with a = 0.0167 was used for adjusting the p-values. All analysis was performed using R, version 3.5.0.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 21878 0
Greece
State/province [1] 21878 0
Thessaloniki

Funding & Sponsors
Funding source category [1] 303846 0
Self funded/Unfunded
Name [1] 303846 0
Xenofon Ouzounidis
Address [1] 303846 0
General Hospital of Thessaloniki "Papageorgiou", Ring Road, N.Eykarpias, Thessaloniki, Greece, 56429
Country [1] 303846 0
Greece
Primary sponsor type
Individual
Name
Xenofon Ouzounidis
Address
General Hospital of Thessaloniki "Papageorgiou", Ring Road, N.Eykarpias, Thessaloniki, Greece, 56429
Country
Greece
Secondary sponsor category [1] 304018 0
Individual
Name [1] 304018 0
Konstantinos Hatzimouratidis
Address [1] 304018 0
General Hospital of Thessaloniki "Papageorgiou", Ring Road, N.Eykarpias, Thessaloniki, Greece, 56429
Country [1] 304018 0
Greece
Secondary sponsor category [2] 304164 0
Individual
Name [2] 304164 0
Kiriakos Moysidis
Address [2] 304164 0
General Hospital of Thessaloniki "Papageorgiou", Ring Road, N.Eykarpias, Thessaloniki, Greece, 56429
Country [2] 304164 0
Greece

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304359 0
Hellenic Republic, Ministry of Health, Macedonian 3rd District Health Administration, Human Resources Development Unit, Health and Social Solidarity Units, Continuing Education and International Partnerships
Ethics committee address [1] 304359 0
Aristotelous 16, Thessaloniki, Greece, 54623
Ethics committee country [1] 304359 0
Greece
Date submitted for ethics approval [1] 304359 0
20/06/2018
Approval date [1] 304359 0
02/08/2018
Ethics approval number [1] 304359 0
D3ß/28896

Summary
Brief summary
Recent studies have found that PPNB anesthesia effectively relieves pain due to insertion of the biopsy needle into the prostate gland (actual biopsy) but it is ineffective in reducing the pain caused by probe insertion into the rectum during TRUS-guided prostate biopsy procedure. In this regard, if adjunct regimens are added prior to PPNB anesthesia, pain experienced during TRUS-guided prostate biopsy may be alleviated. The study purpose is to investigate the efficacy and safety of Tramadol alone or in combination with Parecoxib as adjuncts regimens to PPNB anesthesia in the management of pain during TRUS-guided prostate gland biopsy and compared to current gold standard procedure, PPNB anesthesia, alone.
Trial website
Trial related presentations / publications
Public notes
Ethics approval was requested prior to enrollment of the first participant in the study protocol by the responsible department of ethics issues in the corresponding hospital which requested a further approval by the Hellenic Republic, Ministry of Health, Macedonian 3rd District Health Administration, Human Resources Development Unit, Health and Social Solidarity Units, Continuing Education and International Partnerships. Bureaucratic process takes long time.

Contacts
Principal investigator
Name 96678 0
Mr Xenofon Ouzounidis
Address 96678 0
General Hospital of Thessaloniki "Papageorgiou", Ring Road, N.Eykarpias, Thessaloniki, Greece, 56429
Country 96678 0
Greece
Phone 96678 0
+302313323150
Fax 96678 0
Email 96678 0
xenofonouzounidis@hotmail.com
Contact person for public queries
Name 96679 0
Mr Xenofon Ouzounidis
Address 96679 0
General Hospital of Thessaloniki "Papageorgiou", Ring Road, N.Eykarpias, Thessaloniki, Greece, 56429
Country 96679 0
Greece
Phone 96679 0
+302313323150
Fax 96679 0
Email 96679 0
xenofonouzounidis@hotmail.com
Contact person for scientific queries
Name 96680 0
Mr Xenofon Ouzounidis
Address 96680 0
General Hospital of Thessaloniki "Papageorgiou", Ring Road, N.Eykarpias, Thessaloniki, Greece, 56429
Country 96680 0
Greece
Phone 96680 0
+302313323150
Fax 96680 0
Email 96680 0
xenofonouzounidis@hotmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial except of personal information (e.g. ID number, name, date of prostate biopsy, telephone number).
When will data be available (start and end dates)?
Immediately following publication, no end date determined
Available to whom?
Only researchers who provide a methodologically sound proposal
Available for what types of analyses?
Only to achieve the aims in the approved proposal, especially for those with IPD meta-analyses purposes
How or where can data be obtained?
Data will be provided to the corresponding journal for publishing my research study and will be available upon request to the corresponding journal
What supporting documents are/will be available?
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 4988 0
Ethical approval
Citation [1] 4988 0
Link [1] 4988 0
Email [1] 4988 0
xenofonouzounidis@hotmail.com
Other [1] 4988 0
Type [2] 4989 0
Informed consent form
Citation [2] 4989 0
Link [2] 4989 0
Email [2] 4989 0
xenofonouzounidis@hotmail.com
Other [2] 4989 0
This is the "inform consent form" for participants that consent to participate in the study
Type [3] 4990 0
Informed consent form
Citation [3] 4990 0
Link [3] 4990 0
Email [3] 4990 0
xenofonouzounidis@hotmail.com
Other [3] 4990 0
This is the "inform consent form" for participants that consent to undergone TRUS-guided prostate biopsy
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Yes
Other publication details
Citation type [1] 4993 0
Thesis/dissertation
Citation/DOI/link/details [1] 4993 0
Results – plain English summary
The pain during TRUS-guided biopsy of prostate gland is cumulative in nature and has a
3-fold origin: (i) the pain during insertion of the ultrasonography probe into the rectum, which is due to the stretching of the anal sphincter; (ii) the pain during needle puncture while depositing the local anesthetic at the PPNB site, as well as (iii) the pain during insertion of biopsy needle into prostate gland for the collection of multiple prostate biopsy cores (actual biopsy). Recent studies have found that PPNB anesthesia effectively reduces the pain due to the insertion of the biopsy needle into prostate gland (actual biopsy) but it is ineffective in reducing the pain during insertion of ultrasound probe into the rectum. Another study has shown that the pain caused by anesthetic infiltration at PPNB site can be comparable to or even worse than that of actual biopsy itself. In this regard, if adjunct regimens are added prior to PPNB anesthesia, pain due to aforementioned reasons might be alleviated. Therefore, we investigated the efficacy and safety of Tramadol alone or in combination with Parecoxib, as adjunct regimens to PPNB anesthesia for the management of pain during TRUS-guided biopsy of prostate gland and we compared it to the current gold standard method, PPNB, alone.
Our findings indicate that intramuscular injection of 100 mg tramadol as adjunct regimen to PPNB anesthesia is a simple and safe technique that provides significant analgesic effect during TRUS-guided prostate biopsy, especially at the time of ultrasound probe insertion into rectum and at lidocaine infiltration at PPNB site. The effect size was proved to be even higher when tramadol is combined to intramuscular injection of 40 mg parecoxib before the PPNB anesthesia.