Aim of the study
The primary aim of the study is to prove that in routine clinical practice, treating patients without a tamponade dressing after hemorrhoidectomy results in a lower pain burden, and is non-inferior to the use of tamponade in terms of the incidence of severe postoperative bleeding requiring surgical revision.
Secondary aims are to assess all patients in the group without primary tamponade dressing after surgery who needed emergency tamponade, and to compare differences between the study groups in preoperative and postoperative hemoglobin values and the use of pain medications. Quality of life and patient satisfaction will also be compared between the two treatment groups.
The safety analysis aims to compare the number of adverse events (AE) and serious adverse events (SAE) in the two study groups in order to make a statement on the potential risk to patients without a tamponade dressing after hemorrhoidectomy.
Design
The NoTamp study is designed as a German national, multicenter, randomized controlled clinical non-inferiority trial. Participants are randomly allocated in a 1:1 ratio to each treatment group. Randomization will be stratified per study site. Allocation to treatment groups will be performed using a centralized web-based tool. Randomization is recommended to be performed at the earliest 12 h before the start of surgery. The patient will not be informed about the result of randomization before surgery. The duration of the clinical trial for each randomized patient is 7 days. There will be no blinding of participants, physicians, nurses or outcome assessors. No interim analysis is planned.
Setting
This multicenter study will be conducted in hospital departments with a special focus on colonic and rectal surgery. Participating study sites are general and visceral surgery departments with at least one expert who has passed the German examination for specialization in proctology. The study is mainly performed within but not limited to the Helios clinic group. The majority of the participating study sites are hospitals for basic and standard care. Two study sites are maximum care hospitals. The Helios clinic group ensures uniform quality management and standardized documentation in the clinical file. For trial sites outside Helios, suitability for participation will be assessed before inclusion in the study. Study sites are located all over Germany. The number of study sites may be adjusted according to the frequency of patient recruitment.
In order to ensure the best possible transferability of the study results into the clinical routine, local clinical standards are applied, evaluated with regard to their influence on the results, and fully reported. Patients are provided with the best clinical standard.
Participants
The target population of this clinical study includes patients with symptomatic hemorrhoids, who require wound treatment after Milligan-Morgan or Parks hemorrhoidectomy.
All adult patients (age ≥ 18 years) suffering from symptomatic hemorrhoids of grade III or IV and scheduled for hemorrhoidectomy by the Milligan-Morgan or Parks procedure are eligible for the NoTamp study. Study participants must be fully legally competent and need to provide written informed consent before randomization, inclusion in the trial, and any trial-related procedure.
Patients with inflammatory anal diseases such as abscesses, fistulas, or gangrene, and pregnant women (according to the patient’s self-report) will be excluded from participation in this clinical study. Patients who are in a dependency and/or employment relationship with the study leader or any of the study staff are not allowed to be included in the trial.
Any inability of the patient to respond to requests, to adequately assess risk, or to comply with the requirements of the course of study, both in the inpatient and outpatient therapy episode, must be considered as non-compliance. If, in the estimation of the clinical investigator, a patient is non-compliant at the time of inclusion or is expected to be non-compliant during the course of the trial, this patient may not be included. Patients participating in other clinical trials that are expected to affect the outcome of the NoTamp-study will not be included.
Figure 1 provides a full overview of the inclusion and exclusion criteria. Reasons for non-enrolment or non-eligibility will be documented for all patients who fulfil the inclusion criteria but who are not included in the trial.
Intervention and comparison
In the intervention group, no tamponade dressing will be placed in the rectum of the patient after achieving complete hemostasis. The rectum and anus will be cleaned and a pad with high-absorbence capacity will be placed on the aperture to absorb potential blood loss. The pad will be fixed with mesh pants.
In the control group a tamponade dressing is to be placed in the patient’s anal canal and lower rectum after complete hemostasis. The intraoperatively inserted tamponade remains in the rectum of the patient at least until first defecation and possible spontaneous removal, but usually for a maximum of 24 h. Tamponade dressings may be used according to clinical routine. The type of tamponade used for the study participants will be recorded in the case report forms (CRF).
Previous and concomitant medication and therapy
The NoTamp study focuses on the evaluation of post-surgical wound treatment. The surgical procedure takes place followed by postoperative care. The surgical procedures allowed in this study include Milligan Morgan’s open hemorrhoidectomy and Park’s submucosal hemorrhoidectomy. Both surgical procedures remove the excessive hemorrhoidal tissue and result in an open wound that needs further treatment.
Thrombosis prophylaxis with low-molecular-weight heparin is mandatory for all patients. Rectal cleansing (preoperative), urinary catheters, analgesics, stool control, and topical applications (ointments) are optional. Discharge management and postoperative controls are usually customized to the individual patient. Pain therapy and prophylaxis include local anesthetics, opioids, non-steroidal anti-inflammatory drugs, muscle relaxants, and other medications such as diosmin and/or sucralfate. During the postoperative period in the recovery room, the patient may receive intravenous or oral pain medication as needed. Subsequently, patients in both treatment groups may receive analgesics as needed until a correspondingly low level of pain (numeric rating scale (NRS) ≤ 3) or freedom from pain is achieved.
After hospital discharge, patients are asked to record their pain medication with type, frequency and amount of intake and to provide this information for documentation in the CRF at the study visit after 7 days. An appropriate supporting documentation template will be provided for the patient.
All previous and concomitant medication will be administered as per clinical routine and according to the patient’s needs and demands. All drugs and other treatments administered will be recorded in the CRF. Since this study represents an evaluation of clinical routine, no treatment guidelines are given.
Primary and secondary outcomes
Primary outcomes of the NoTamp study are maximum postoperative pain, as measured by a numerical rating scale (NRS) at four time points within 48 h after the surgical procedure, and the occurrence of postoperative bleeding with the need for surgical revision within 7 days after hemorrhoidectomy. Postoperative pain is measured at rest within routine care at 6, 12, 24, and 48 h after the surgical procedure. The most severe pain within 48 h of the surgical procedure will be compared between the treatment groups.
As a secondary outcome, the postoperative pain at each predetermined evaluation time point (6, 12, 24, and 48 h and 7 days after surgery) will be compared between treatment groups. Additionally, the change in pain intensity from 6 h after the surgical procedure to 12, 24, and 48 h and day 7 after the procedure and the development of pain between 24 and 48 h will be compared between the intervention and control group. The number of patients in the group without primary tamponade who require tamponade dressings will also be documented.
Further secondary endpoints that will be compared between the treatment groups are the use of analgesics; the lowest hemoglobin documented in clinical routine within 7 days; quality of life using EuroQuol 5 dimensions (EQ. 5D) at screening, on discharge and on day 7 and patient satisfaction on day 7. Patient satisfaction will be measured using the key figures “subjective treatment errors”; “subjective treatment success”; the satisfaction index and the expectation fulfillment scale of the Cologne Patient Satisfaction Questionnaire of Pfaff et al. [26].
For safety analysis all expected and unexpected AEs and SAEs occurring in temporal relation to the clinical trial will be documented and compared between the treatment groups. Documentation includes the causal relationship with the therapy to be investigated and/or with the previous surgical treatment. The nature of the event and the onset, end, and severity (mild, moderate, severe) of each AE will be documented. A full overview of the visit plan and the schedule of enrollment, interventions, and assessments are provided in Figs. 2 and 3.
Statistical analysis and power calculation
The analysis of the primary and secondary endpoints will be performed according to an adapted intention-to-treat (ITT) principle. There will be no interim analysis. The ITT analysis population will include all randomized participants who have undergone the surgical procedure (hemorrhoidectomy). The ITT analysis population will comprise participants assigned to the treatment group based on the randomization schedule, regardless of the treatment actually received. Randomization will be performed up to 12 h prior to the surgical intervention. However, without the surgical intervention there will be no postoperative wound that requires further treatment and thus there will be no data collected and analysis will not be possible. The study participant will therefore be excluded from the clinical trial if the scheduled surgery is not performed. Patients who are excluded from the trial after randomization and before the start of the observation period (postoperative wound care with or without tamponade) are replaced by another study participant in order to achieve the required number of cases. The randomization sequence will be continued. The next patient does not receive the randomized allocation of the excluded patient. The study will be continued until the required number of evaluable patients has been reached. Due to complications it may not be possible to comply with the randomly assigned treatment regimen in a very small number of patients. These patients will not be excluded from the study. Study participants will also be excluded from the clinical trial if a surgical procedure other than Milligan-Morgan or Parks is performed, which does not result in an open wound.
Details of participants’ baseline characteristics including preoperative pain and hemoglobin levels will be provided, but the data will not be compared statistically (by calculating the p value) because any differences between groups at this point must arise by chance (if randomized properly).
As a secondary approach, a per-protocol (PP) analysis will be performed excluding patients with any serious protocol deviations, if applicable. The safety analysis will be performed based on the as-treated (AS) population.
In order to address the primary aim of the study to prove that treating patients without a tamponade dressing after hemorrhoidectomy results in a lower pain burden while the incidence of bleeding requiring surgical revision is no greater than in the patients treated with tamponade (non-inferiority), the primary outcome variables will be examined in terms of an a priori ordered hypothesis at a level of significance of 0.05. Pain values will be described by the mean (SD) and median (IQR). The last observation carried forward (LOCF) method will be used to replace missing values for pain, but only if at least one documentation of postoperative pain is available. Differences in pain will be analyzed using the non-parametric U test (two-sided; alpha = 0.05). If significantly lower pain levels are detected in the treatment arm without tamponade, non-inferiority in the bleeding rate will be also be analyzed at the 5% significance level. Alpha error correction is not required [27]. The incidence of postoperative bleeding needing revision (bleeding rate) will be determined in both treatment arms and will be tested for non-inferiority by calculating the 90% confidence interval (CI) (one-sided hypothesis), with a rate of bleeding two times higher considered acceptable, whereas a bleeding rate three times higher will no longer be considered non-inferior. This rate difference (together with the 90% CI margins) will be considered in relation to the observed revision rate in the control arm. This gives the estimator for the relative increase together with the confidence margins. If the upper limit of this relative increase exceeds 3, then a threefold increase is still possible and non-inferiority is rejected. If the upper limit of this relative increase is < 3, non-inferiority is assumed (with an error rate of 5%). In the unexpected case that the revision rate in the control group is rather low (< 2%) or even 0%, the relative increase will not be calculated. In this case, only the revision rates in the treatment groups are reported (with the 95% CI). The number of patients requiring tamponade in the postoperative course in the group that did not receive primary tamponade after surgery will be presented with the 95% CI.
Pain values at all predetermined survey times and the development of pain between selected time points will be compared in the two treatment groups using the U test. The lowest hemoglobin values in the postoperative period up to day 7 will be compared in the two treatment groups using the two-sided t test. The amount and type of postoperative pain medication will be described by percent values for each treatment group. For the safety analysis the incidence of AEs and SAEs by category (severity) will be compared in the two treatment groups using Fisher’s exact test.
There will be no a priori planned subgroup analysis, but a multivariate analysis of all study patients (ITT population) will be performed investigating the occurrence of severe postoperative bleeding (dependent variable). In this logistic regression, the following variables are considered as possible predictors (independent variables): age, gender, surgical method used (Milligan-Morgan or Parks), severity of hemorrhoids (grade III/IV), use of tamponade (yes/no), type of tamponade used, type of anesthesia used, occurrence of intraoperative complications, preoperative hemoglobin levels, type and amount of pain therapy (in particular the performance of a pudendal block), and type and amount of anticoagulation therapy. If this multivariate analysis shows that there is a significant predictor of bleeding that is not evenly distributed within the two study groups (significance in demonstrating the comparability of the two groups), a subgroup analysis of this variable will be performed. In this case, primary and secondary endpoints will be analyzed as described previously, in the subgroups of the unequally distributed variable.
Mental illness in the study participants, preoperative pain levels, the use and type of concomitant pain therapy, and the type of tamponade used represent factors possibly influencing pain, quality of life, and patient satisfaction. The influence of these factors on the aforementioned outcomes will be examined.
Based on the results of the single-center pilot study that demonstrated significant pain reduction (first primary outcome) without tamponade, it can be assumed with great probability that an advantage can also be demonstrated in this much larger multicenter study (first hypothesis). For the second primary outcome based on the results of the pilot study and the international literature it is predicted that 4% of the patients will need surgical revision with tamponade due to severe postoperative bleeding in the treatment group (96% estimated success rate in the control group).
In the intervention group without tamponade a slightly higher rate of bleeding needing surgical revision of ca. 8% is expected. The bleeding rate was 10% in 52 cases included in the pilot study. Therefore, the clinically acceptable and justified limit for non-inferiority is set at 12%, or 8% higher than in the control group with tamponade (8% non-inferiority limit).
Based on these assumptions, the sample size is 433 per group, or 866 patients in total. For study enrollment, assuming a maximum 10% rate of loss to follow up, 953 patients are required. The power was set at 80% in all calculations. Detailed procedures for executing the statistical analysis of the primary and secondary variables and other data will be provided in a statistical analysis plan.