Trial Design: This trial is designed as a 1:1:1 randomized, controlled, parallel design.
The primary endpoints are change in pain score and wound healing from baseline to 1 week
from the study start date; secondary endpoints are change in pain score and wound healing
at 6 and 10 weeks from the study start date, defecation strain score & the patient's
global impression of improvement at 10 weeks.
Assessments & Visits: The patient will be assessed for pain, wound healing, strain during
defecation, impression of improvement, & adverse events at weeks 1, 6 & 10 after the
study start date. Trained resident or research assistant (RA) will administer the
questionnaires on pain score, strain during defecation, & patient's global impression of
improvement. During the follow-up visits, the average score for each of the pain &
defecation strain scores will be taken for the 3 most recent days that the patient has
defecated. The patient will be given a paper diary to record the pain score & strain
score during defecation 3 days prior to the follow-up clinic visit.
Sample Size: The investigators will design this superiority trial as three-arm trials,
where one arm is Diltiazem, second is MEBO, & last is a combination of both. Assuming
that the pain score difference between both treatments will be 0.5 points with a 1-point
standard deviation on the numeric rating scale (5 for DTZ & 3 for combination arm DTZ &
MEBO), & using an alpha of 0.05 & a power of 80%, a sample size of 47 patients in each
arm is needed. After accounting for a 30% loss to follow up, 61 patients will need to be
recruited in each arm. The total number of patients to be recruited in the three arms is
183 patients.
Recruitment: At the American University of Beirut Medical Center, patients with acute
anal fissure are treated at the outpatient center (private & outpatient clinics) of the
hospital by all the general surgeons. The patients will be introduced to the study by
their attending physician. If the patient agrees to participate, the RA (part of the
research team) will approach & screen the patient according to the defined inclusion &
exclusion criteria. If the patient is found eligible for the study, the RA will discuss
the study & obtain his/her informed consent. The expected recruitment rate is 4
patients/week. The first 2 visits of the patient to the clinic at weeks 1 &6 from the
start date of the study are part of clinical care & the patient will not be reimbursed
for these visits. The last visit to the clinic that will take place at week 10 will be
for follow-up as part of the research, so the patient and physician will be reimbursed
for transportation and professional fees, respectively, by the research grant.
ASSIGNMENT OF INTERVENTIONS
Sequence Generation: Participants will be randomly assigned to their treatment in a 1:1:1
ratio, according to a computer-generated schedule, stratified by type of treatment (MEBO
or DTZ), using permuted blocks of variable sizes.
Allocation Concealment Mechanism: Random sequence generation will be selected by CRI
biostatistician using computer software. The CRI person will hold details of the blocking
& block sizes in a separate document unavailable to those involved in the study so ensure
allocation concealment. The CRI person will not share the treatment intervention with
study personnel until baseline characteristics are collected, & the patient is recruited
into the trial. The physician will contact the CRI biostatistician & receive treatment
allocation, so he/she can prescribe the ointment to which the patient is randomized to.
Implementation: The CRI biostatistician, who is not involved in this study, will generate
the randomization sequence & keep hold of it. The patient will be recruited & consented
without any knowledge about their allocation arm. The allocation will be revealed only to
the physician to administer the treatment.
Blinding: The physician & the patient will not be blinded to the allocation, but the rest
of the study team will be blinded. It is difficult to blind the physician or patient
because of the characteristic smell of MEBO that is easily recognizable. Also blinded to
allocation is the physician who will assess for outcomes, the RA who are collecting the
data, & data analyst.
DATA COLLECTION, MANAGEMENT, & ANALYSIS
Data Collection Methods: Data on basic demographics of the study subjects, relevant risk
factors, confounders, & indication for the type of treatment will be collected at
baseline using protocol-specific standardized case report forms (CRF). The CRF will be
completed by the RA directly from patients, following informed consent & prior to the
administration of treatment. The different sections of that data will be collected at the
different points in time of the study by questionnaires administered by the study RA to
the patient. Evaluators are requested to fill immediately a case report form each time an
outcome evaluation on a study subject is performed. These forms will be handed in the
same setting to the RA who will take care of storing them. To improve retention &
compliance to the study, the investigators will contact the patient ahead of time, & help
schedule their clinic visits on time to collect the outcomes. When a patient fails to
comply with the follow-up exams, the investigators will collect applicable data on the
phone (Appendix C). For those who drop from the study, the investigators will analyze
their basic demographic & disease data to determine whether or not those are similar to
those who stayed on the study.
Data Management: The RA will enter the data from the CRFs on the study data excel sheet
within 1 week of its collection. The data will be manually entered twice & independently
by the RA & another member of the study team. Data will be entered as the actual numeric
values or categorical variables, initially. In the end, the statistician will code all
the data in preparation for analysis. The principal investigator (PI) will perform spot
checks on the data & will review weekly all the CRF & assessment collection sheets
performed within each week. At AUBMC, data will be stored on the AUB intranet server on
the PI's computer. All research members will have access to the data. The Case Report
Forms will be stored in a locked cabinet in the PI office 3 years following the
publication of study results. The investigators will provide an SOP detailing data
management procedure to ensure consistency in case of a change in the study members.
Audits will be performed monthly on 20% of the charts.
Statistical Methods: the investigators will compare the three arms for the primary,
secondary, & exploratory outcomes. The investigators will use the chi-square or Fischer
exact test if the expected count of any of the outcomes is less than 5 per cell for
analysis of the incidence of categorical outcomes (like wound healing). The investigators
will use the independent t-test for analysis of the continuous outcomes (like pain score,
defecation strain score, Patient's Global Impression of Improvement). The investigators
will calculate relative risk with corresponding 95% confidence intervals to compare the
incidence of the categorical outcomes while reporting a difference in means for the
continuous outcomes. SPSS version 20 will be used to conduct the analysis. A 2 sided
p-value will be set at 5%. The univariate analysis will be performed separately for the
two primary outcomes & the three secondary outcomes at weeks 1, 6 & 10. Multivariate
analysis for change in pain score & wound healing will be performed using linear
regression and logistic regression respectively, controlling for age, gender, duration of
the anal fissure since presentation, analgesic medications intake (only with pain score),
defecation strain score. The investigators will perform both ITT & PP analysis for all
outcome measures. The ITT analysis will include all patients randomized per arm. In case
of failure of treatment in one of the arms, those who will switch to another arm will be
still analyzed as part of the arm initially randomized to. Multiple imputation methods
will be used to handle missing data. To assess the effect of missing data on the
analysis, sensitivity analyses will be performed. The study biostatistician will perform
the best case scenario, worst-case scenario, & group averages. The investigators will
assess the baseline characteristics of those who will be lost to follow up, which would
help understand what were the potential outcomes.
DATA MONITORING
Data Monitoring Committee: The DMC will be independent of the PI & funders of the trial &
composed of a surgeon, an internist, a nurse, a biostatistician, & a representative from
the patient advocacy office at AUBMC. The internist will have a clinical research
background. The nurse is chosen from the inpatient floors, to make sure that there is no
interaction with study subjects. All members should not have any conflict of interest
related to the study. The DMC will be chaired by the internist, who has to keep a record
of the meetings & recommendations for future reference. Since this is an
investigator-initiated trial, the PI will appoint the DMC members. The DMC will meet
every other month, at times of scheduled interim analysis, & upon conclusion of the
study. The primary role of the DMC is to review accumulating data & alert the steering
committee if there are alarming rates of side effects (SE) in any arm of the trial. This
committee doesn't have executive power to stop the trial or modify treatment. The
committee will report results to the PI. In addition, the DMC will keep track of the
accrual rate.
Interim Analysis: The interim analysis will be done 3 times throughout the study; upon
recruiting quarter, two-quarters, & three-quarters of the study population. The study
biostatistician who is blind to the treatment allocations will conduct the interim
analysis & will use the O'Brien Fleming stopping rules. The study biostatistician will
report the results of the interim analysis to the DMC confidentially. At each
interim-analysis interpretation, the DMC will alert the PI if one arm is found to be
beyond doubt either more beneficial or more harmful than the other arm. The PI will take
into consideration the results of the interim analysis, opinion of the DMC, & various
important factors to decide upon the fate of the trial. The chairperson of the DMC will
monitor the ClinicalTrials.gov website for registration of new trials & for newly
reported results from trials addressing the similar questions as this trial.
Harms: The adverse effects can be part of the outcome measures detailed earlier in the
protocol or other not specified SEs. Either way, any SE will be reported & the subject
will be managed according to the standard of care or the preference of the treating
physician. In case any adverse effects arise outside scheduled follow-up time, the
patient will be seen by the treating physician in an extra add-on visit. Those who fail
(meaning those who do not report any pain improvement after two weeks of treatment) from
either the MEBO or the Diltiazem arm will be switched to the combination arm. If these
patients also fail to improve after 2 weeks on the combination arm, then the patient will
be offered surgery. If the patient refuses to switch to the combination arm & wishes to
proceed to surgery immediately, then the patient will be directed to surgery. In case of
failure of the treatment, which is after 6 weeks of treatment, the patient will undergo
surgery. The patient may also undergo surgery in case he/she decides to stop medical
therapy during the treatment period & proceed to surgery. There is no standard for the
risk of failure of topical therapy to necessitate surgery. Hence, the risk of failure
cannot be evaluated with the use of MEBO.
The primary physician who is treating the patient will be responsible for the management
of the SEs.