This was a single blind, randomized non-inferiority trial which compared 2% lidocaine gel to a shea lubricant, eliciting patients’ response to anal pain, discomfort, peri-anal pruritus, bowel and urinary urgency and ease of use of the lubricants by clinicians upon performing a digital rectal examination. All patients between 18 and 80 years for whom a digital rectal examination was indicated, could understand the survey process and consented to participate were included in the study. Those who were too ill to communicate and/or consent, those with painful anal conditions such as thrombosed hemorrhoids, anal fissures, infiltrating anorectal cancers and anal strictures were excluded. Patients were recruited from 15th June to 19th August 2021.
Study setting
This study was conducted at the surgical, urological and emergency units of the Ho Teaching Hospital which is the foremost referral facility in the Volta Region and attends to an average of 170,000 patients annually.
Ethical considerations and trial registration
The trial was approved by the University of Health and Allied Sciences, Research Ethics Committee with protocol number UHAS-REC A. 2(4) 20 − 2. It has been registered with the Pan African Clinical Trials Registry on the 18/11/2020 with the unique identification number PACTR202011687956222 and the Food and Drugs Authority (FDA) Ghana Clinical Trials Registry with certificate number FDA/CT/217. The investigational product (shea lubricant) underwent physiochemical and microbiological analysis at the Ghana Standards Authority. The certificate of analysis (COA) of the control lubricant was similarly verified by FDA, Ghana. The trial was conducted according to the declaration of Helsinki and trial participants gave written informed consent before enrollment. The study protocol further outlines the rationale, design and methods of the trial[15].
Sampling
To estimate the sample size, we considered the standard deviations for pain perception after catheterization from a previous study done by Stav et al[11], a randomized controlled trial comparing pain perception of 2% lidocaine gel to liquid Paraffin oil. Table 1 summarizes findings from Stav et al [11]. We chose this study because it compared an oil-based lubricant to lidocaine gel, which is the intent of the present study. To determine the non-inferiority limit, we relied on a systematic review and meta-analysis by Hong et al [13] where the mean difference for pain was estimated at -0.96 (95% confidence interval, -1.43 to -0.49) after including sixteen randomized trials. Thus non-inferiority limit was set at -0.72 which is a 50% discount of the lower limit of the 95% confidence interval (-1.43) of the mean pain reduction effect of the control lubricant (2% lidocaine gel); as shown in literature [14]. An attempt to ensure that the shea lubricant preserved at least half the effect of 2% lidocaine gel. The trial was therefore designed to randomly allocate 153 patients with 90% certainty (power), assuming that the lower limit of the 95% confidence interval was within a prespecified boundary of -0.72 in mean pain perception difference using the visual analogue scale, with a 1:1 allocation ratio and \({\mu }_{1}-{\mu }_{2}\)= 0 for non-inferiority trials, as shown in literature [16][17]. Our trial participants were similar to participants in the randomized trial by Goldfisher et al [5] and Siderias et al [6] where the control lubricant (2% lidocaine gel) was investigated, except in the latter, women were excluded due to the perception that they experienced less pain on urethral catheterization. This is however inapplicable in the present study where the comparator is digital rectal examination.
Table 1
Visual Analogue Scores: comparison between 2% Lidocaine gel and Paraffin oil (extracted from Stav et al)
Lubricants
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Before procedure
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After catheterization
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30 minutes after procedure
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2% lidocaine gel
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0 ± 0
|
4.8 ± 1.5
|
0.6 ± 0.4
|
Paraffin oil
|
0 ± 0
|
3.5 ± 1.1
|
0.7 ± 0.6
|
Sampling procedure
Male and female patients, between ages 18 and 80 who presented to the Emergency, Urological and Surgical units for whom a digital rectal examination was indicated, and met our eligibility criteria and consented to participate were invited. There were two treatment arms, Shea Lubricant (A) and 2% lidocaine gel (B). A clinical trial randomization software (National Cancer Institute Clinical Trial Randomization tool) was employed to allocate patients to the two groups using a 1:1 allocation ratio. Patients assigned odd numbers were randomized to Group A and those assigned an even number, to Group B. The process continued till the required number of participants were obtained in the two groups. The examination procedure was explained after informed consent was sought from each patient. Participants were assured of their privacy, confidentiality and their rights to opt out of the trial at any point time without affecting access to quality care. Structured questionnaires were administered before, immediately and 30 minutes after the procedure to assess pain perception, peri-anal discomfort and pruritus, urinary and bowel urgency. The questionnaire also evaluated trial doctors’ assessment of ‘ease of use’ of the lubricants.
Trial process
In all, two trial nurses independent of the study and eight (8) trial doctors were recruited. To ensure quality control, reliability and reproducibility, the trial recruits were trained in data collection, trial protocols and procedures, seeking informed consent and safe disposal of waste. The investigational products were stored at the hospital’s pharmacy under ambient conditions. The lubricants were prepared by the independent trial nurses, and delivered in marked 5ml –syringes, labelled A and B to trial doctors. The control lubricant (Optilube active gel) has similar constituents to the reference lubricant used in previous trials [6][7].
All DRE examinations were done in the presence of a chaperone due to the sensitivity of the procedure. After explaining the procedure and seeking consent, participants were asked to undress including undergarments in privacy. A gown was used to preserve modesty till procedure was performed. Patients were made to lie on a couch in the left lateral position facing away from the examiner with the legs drawn up towards the chest. The examiner puts on sterile gloves and the examination starts with inspection of the natal clefts (the groove between the buttocks), the anus and the perianal skin for lesions. Any lesion that constitute a contraindication (refer to inclusion/exclusion criteria) led to an abandonment of the procedure. The patient is then asked to bear down; observing for lesions. The examiner lubricates the examining finger with 5 mls of the selected lubricant. At this stage, the examiner alerts the patient about the commencement of the procedure. The examiner gently pats the buttocks and applies gentle pressure at the anal margin to enter the anus and the rectum. The anal tone is determined by asking the patients to “squeeze” on the examining finger and release. The finger is then directed posteriorly following the curve of the sacrum observing for any lesions, tenderness, tightness and mobility of the rectal mucosa. The finger is then swept anteriorly in a clockwise direction to examine the prostate in men and pouch of douglas in women. The examination is completed by inspecting the examining finger for the nature of faecal matter, streaks of blood or any discharge.
Outcomes
A systematic review and meta-analysis[13] of sixteen randomized trials involving 1904 patients on pain reduction effects of lidocaine gel as compared to Plain gel established a mean pain difference of -0.96 (95% CI, -1.43 to 0.49) in favour of lidocaine gel. In this trial we aimed to determine the mean pain difference between 2% lidocaine gel and shea lubricant with a non-inferiority limit set at -0.72 as the primary outcome measure. Secondary outcome parameters included differences in the perception of discomfort, peri-anal pruritus, bowel and urinary urgency during the procedure using Likert scales and an assessment of the ease of use of the lubricants by trial doctors.
Stopping rules
Our stopping criteria were based on three ethical principles- safety, benefit or futility of the trial. Development of serious adverse events such as anaphylactic shock, urticaria, wheezing attacks or any other form of serious adverse drug reaction will trigger a discontinuation. Our patients have been reviewed over the period and no adverse reaction has been observed. Any indication of futility or supremacy of the shea lubricant will trigger trial discontinuation.
Methods of randomization and data collection
A total of 153 participants were involved in the study. A clinical trial randomization tool allocated patients to the two groups in a 1:1 allocation ratio. The allocation sequence was concealed from trial doctors and nurses, and only revealed to the trial nurse upon the recruitment of a participant while keeping the trial doctor in oblivion. The sequence was generated by an investigator assigned for that purpose whilst the trial nurses enrolled, assigned participants to an intervention and also assessed outcomes. Study participants were blinded to the interventions. However, since the consistency of the products were distinguishable the trial doctors could not be blinded. The study used a quantitative data collection approach. A structured questionnaire consisted of three sections 1) socio-demographic characteristics 2) patients’ perception 3) ease of use of the lubricants. Patients’ perception of anal pain was evaluated with a Visual analogue scale which rated pain from the most excruciating (10) to no pain (0). Peri-anal discomfort, pruritus, bowel and urinary urgency were assessed using 4-dimension Likert scales to each of the questions. Similarly, a 5-dimension Likert scale determined the ease of use of lubricants by clinicians. Questionnaires were administered through face-to-face interviews after written informed consent had been obtained with the privacy, confidentiality and security of patients’ data assured. Data collated was entered into Excel 2013 and exported to SPSS 25 and R 4.1.2 for analysis. Quality control measures instituted prior to data collection include 1. Training of research assistants, trial doctors and nurses on data collection and informed consent 2. Error correction 3. Appropriate storage of investigational products. The data collected was entered daily and validated. The authors vouch for the accuracy of data and the fidelity of the study to the protocol.
Data analysis
A detailed summary of the analyses of patients’ perception undertaken in the study is provided in Table 2 below.
Table 2
Summary of analyses of patients’ perception
Perception
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Tool
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Estimation approach
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Anal pain
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Visual analogue scale (V.A.S)
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A V.A.S tool assessed the perception of pain felt by patients during digital rectal examination. The scale rated pain from 0 (no pain) to 10 (worst imaginable pain). The mean score was determined by summing up the score in each group and dividing by the number of participants in that group. The mean difference in pain scores was deduced and compared to the non-inferiority limit of -0.72 to ascertain inferiority or otherwise of the shea lubricant.
|
Peri-anal discomfort and pruritus
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Likert scale
|
To estimate these variables, a 4-dimension Likert scale was adopted (i.e., [1] Nil, [2] Mild, [3] Moderate [4] Severe) in relation to the level of peri-anal discomfort and pruritus perceived by patients in the two arms. Mean scores in both groups were compared to determine if there was a difference in perception.
|
Urinary and bowel urgency
|
Likert scale
|
The urinary and bowel urgency score was obtained from responses to 4-dimension Likert scales (i.e., [1] Nil, [2] Mild, [3] Moderate [4] Severe) in relation to the perceptions of urinary and bowel urgency experienced by participants.
|
Ease of use of Lubricants and Lubricity
|
Likert scale
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Trial doctors assessed the ease of use of lubricants and lubricity using a 5-dimension Likert scale (i.e. [1] Effortless, [2] Easy, [3] Fair, [4] Difficult and [5] Very difficult). The scores achieved for each option are expressed as mean scores and in percentage terms. The proportions obtained for each dimension in the two groups are then compared.
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Statistical analysis
The collated data was entered into Excel 2013 and exported to SPSS 25 and R 4.1.2 for analysis. Friedman test was used to compare the mean ranks before, during and after the procedure, whilst Wilcoxon signed-rank test was used to compare two dependent groups. Mann Whitney test was used to compare two independent groups. Categorical variables were reported using frequency tables and charts while continuous variables reported using means and standard deviations. The primary end point was the mean difference in pain intensity experienced in the two groups, ascertained using the Visual analogue scale whilst the secondary end points, that is, differences in discomfort, peri-anal pruritus, bowel and urinary urgency were determined using a 4 point-rated Likert scale. The study end points were analyzed for the per-protocol population. A sensitivity analysis was then conducted for the intention-to-treat population. For the primary end point analysis, a 95% confidence interval with a two-sided 5% level of significance approach was employed. To establish non-inferiority of shea lubricant to 2% lidocaine gel, the lower limit of the 95% confidence interval should be above the non-inferiority limit set at -0.72. The non-inferiority test was performed for only the primary end point, the secondary end points were analyzed for superiority. All missing values were excluded in the analysis.