Napoleon Trial: Optimal Treatment for Recurrent Haemorrhoidal Disease

Study Overview
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Brief Summary
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Rationale: There is level I evidence in literature that the first management step of HD is basic treatment, including laxatives and high fibre dieti, ii. The next treatment modality after basic treatment in case of persistent symptoms is rubber band ligation (RBL), which can be repeated if necessary. There is currently no consensus and a lack of evidence regarding the best treatment option for these patients having recurrent HD: continuing RBL or a surgical intervention. Furthermore, there is no estimate of costs and cost-effectiveness in this patient group. Objective: The primary objective of this RCT is to compare the effectiveness of RBL, sutured mucopexy and haemorrhoidectomy regarding recurrence and patient-reported symptoms for recurrent grade 2 and 3 HD after at least 2 previous RBL treatments. Secondary objectives are to compare RBL, sutured mucopexy and haemorrhoidectomy for recurrent grade 2 and 3 HD after previous RBL treatments in terms of early and late complications, impact of symptoms on daily activities, patient satisfaction with treatment, health-related quality of life, costs and cost-effectiveness, and budget impact. Study design: Dutch prospective multicentre randomized controlled trial. Study population: Patients ≥18 who have recurrent grade 2 or 3 haemorrhoidal disease and who had at least 2 rubber band ligation treatments. In total, 558 patients will be included. Intervention: Rubber band ligation versus sutured mucopexy versus haemorrhoidectomy. All three interventions are part of Dutch usual care, and serve as each other's control. Main study parameters/endpoints: Primary outcomes are (1) recurrence and (2) patient-reported symptoms assessed after 12 months. Secondary outcome variables are early and late complications, impact of symptoms on daily activities, patient satisfaction with treatment, health-related quality of life, costs, cost-effectiveness and budget-impact.

Detailed Description
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Haemorrhoidal disease (HD) is the most common type of anorectal complaint in the Netherlands, with an annual prevalence of 10% in general practice. There is level I evidence in literature that the first management step of HD is basic treatment,including laxatives and high fibre diet. The general practitioner usually offers basic treatment. If basic treatment fails patients are referred to the hospital. About 50.000 patients are referred to a hospital for HD in the Netherlands annually. The next treatment modality after basic treatment in case of persistent symptoms is rubber band ligation (RBL), which can be repeated if necessary. RBL is an easy, cheap and outpatient-based procedure. Thirty per cent of the patients, approximately 15.000 patients a year, develop recurrent symptoms after basic treatment and repeat RBL. There is currently no consensus and a lack of evidence regarding the best treatment option for these patients having recurrent HD: continuing RBL or a surgical intervention. Literature indicates that haemorrhoidectomy is the surgical treatment of choice based on outcomes like recurrencerate. The major drawback of this technique is that it is very painful and more costly compared to RBL. A relatively novel, but regular surgical alternative is the sutured mucopexy. Although hospital costs of sutured mucopexy are comparable to haemorrhoidectomy, the operation is less painful and requires less recuperation time. The recurrence rate of sutured mucopexy is ranked between that of RBL and haemorrhoidectomy. A Dutch national survey conducted by our research group evaluating the management practices of HD demonstrated considerable variation in the best (surgical) treatment option regarding recurrent HD, resulting in potentially undesirable practice variation. The treatment of recurrent grade 2 or 3 HD currently depends on the preference and the experience of the surgeon and of the patient, without high level evidence substantiating this practice variation. This implies a need for a high quality study regarding the treatment of recurrent grade 2 or 3 HD. Diminishing this practice variation will endorse cost-effectiveness in healthcare settings.To our knowledge, this will be the first RCT worldwide comparing RBL, sutured mucopexy and haemorrhoidectomy in recurrent grade 2 or 3 HD and generating high-level evidence of the (cost-) effectiveness. The investigators consider combining 2 trials in one with a direct comparison between these three interventions to be an efficient research approach. Up till now, trials were mostly powered on traditional outcomes like recurrence, a definition that differs widely between studies.To improve transparency between studies and facilitate the ability to compare and combine (future) studies, our research group developed a European Society of Coloproctology (ESCP) Core Outcome Set (COS) for HD. This international COS for HD selected 'patient-reported symptoms' as primary outcome. Additionally, the investigators recently developed a patient reported symptom score for HD: the PROM-HISS. This PROM is based on most cited symptoms in literature and patient interviews. The patient advisory board (PAB) of this project underlines the clinical relevance of this PROM. As the PROM-HISS has not yet been used in other studies and has to be validated, the investigators will additionally use patient-reported symptoms assessed by the PROM-HISS, next to recurrence, as primary outcome in this trial.

Official Title
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Cost-effectiveness and Effectiveness of Rubber Band Ligation Versus Sutured Mucopexy Versus Haemorrhoidectomy in Patients With Recurrent Haemorrhoidal Disease: a Multicentre,Randomized Controlled Trial

Conditions
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Hemorrhoids

Intervention / Treatment
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* Procedure: RBL versus sutured mucopexy versus haemorrhoidectomy.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 years or older Recurrent grade 2 or 3 HD Patients underwent at least 2 RBL treatments in the last 3 years based on hospital electronic patient file (EPD) Eligible for e-mail questionnaires Sufficient understanding of the Dutch written language (reading and writing) Obtained written informed consent Exclusion Criteria: Previous rectal or anal surgery with the exception of rubber band ligation Patients that have had previous surgery treatment for HD (at any time) Previous rectal radiation Pre-existing sphincter injury Pathologies of the colon and rectum Medically unfit for surgery or for completion of the trial (ASA>III) Pregnancy Patients with hypercoagulability disorders Patients using Warfarin or Clopidogrel or oral anticoagulance therapy Patients that are unable to give full informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective multicentre randomized controlled trial.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Rubber Band Ligation (RBL)<br>RBL is generallya simple, inexpensive procedure. It entails a ligation of haemorrhoids using rubber bands. In RBL, a disposable suction device applies a rubber band at least 2 cm proximal to the dentate line at the base of each haemorrhoidal cushion by using an anoscope. The banding process causes necrosis of the banded tissue and slough. The resultant inflammatory reaction causes refixation of the mucosa to the underlying tissue, helping to eliminate haemorrhoidal prolapse.The end result is a return of the haemorrhoidal cushions to a more normal size and configuration, with resolution of haemorrhoidal symptoms. | Procedure: RBL versus sutured mucopexy versus haemorrhoidectomy.<br>* All 3 interventions are part of Dutch usual care, and serve as each other's control.<br>|
| Other: Sutured mucopexy<br>A sutured mucopexy is an operation performed under general anaesthesia. At 4 cm proximal of the dentate line, a Z- shaped stitch through the rectal wall is placed and then at the upper level of the haemorrhoidal tissue, pulling up the prolapsing haemorrhoid high into the anal canal. | Procedure: RBL versus sutured mucopexy versus haemorrhoidectomy.<br>* All 3 interventions are part of Dutch usual care, and serve as each other's control.<br>|
| Other: Haemorrhoidectomy<br>Haemorrhoidectomy involves excision of the haemorrhoidal tissue. An elliptical incision is made in the external haemorrhoidal tissue extending proximally through the dentate line to the upper limit of the haemorrhoids. The base of the haemorrhoidal complex is ligated and the haemorrhoid is excised. | Procedure: RBL versus sutured mucopexy versus haemorrhoidectomy.<br>* All 3 interventions are part of Dutch usual care, and serve as each other's control.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence | The definition of recurrent HD is: unchanged or worse symptoms of HD compared with before starting treatment. | Assessed after 12 months post-intervention. | 
| Patient-reported symptoms measured with the PROM-HISS | The Patient-Reported Outcome Measure-Haemorrhoidal Impact and Satisfaction Score (PROM-HISS) is a newly developed questionnaire assessing the symptoms of haemorrhoidal disease over time. These are blood loss, pain, prolapse, soiling and itching. These 5 items are graded using a 5-point Likert scale, ranging from (1) 'not at all', (2) 'a little', (3) 'reasonable', (4)'a lot' and (5) 'very much'. This results in a symptom score correlating with the severity of experienced HD symptoms. The PROM-HISS will be completed by e-mail. The PROM-HISS will assess a change of the symptoms over time. ThePROM-HISS is not validated yet, but an international validation study is being developed. Hence, the scale ranges are not clear yet. | The PROM-HISS will be completed by e-mail at four moments during follow-up: (1) at baseline; (2) 7 days; (3) 6 weeks; and (4) 12 months post-procedure. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early complication(s) - Abscess | Abscess will be assessed 7 days post-procedure. Abscess will be assessed by physical examination. | This outcome measure will be assessed within 7 days post-procedure. | 
| Impact of symptoms on daily life and patient satisfaction with treatment | Assessed with the second part of the Patient-Reported Outcome Measure-Haemorrhoidal Impact and Satisfaction Score (PROM-HISS), which are each scored on a numeric rating scale from 0 to 10. Regarding impact of symptoms, 0 correlates with 'no impact at all' and 10 with 'highly impacted on daily life'. For patient satisfaction with treatment, this ranges between 0 'not satisfied' and 10 'very satisfied'. The PROM-HISS is not validated yet, but an international validation study is being developed. Hence, the scale ranges are not clear yet. | The PROM-HISS will be completed by e-mail at four moments during follow-up: (1) at baseline; (2) 7 days; (3) 6 weeks; and (4) 12 months post-procedure. | 
| Health Related Quality of Life | Measured by the EQ-5D-5L questionnaire and EQ-Visual Analogue Scale. These index scores are combined with length of life to calculate the QALY. | The PROM-HISS will be completed by e-mail at four moments during follow-up: (1) at baseline; (2) 7 days; (3) 6 weeks; and (4) 12 months post-procedure. | 
| Early complication(s) - Urinary retention | Urinary retention will be assessed 7 days post-procedure. It will be assessed by ultrasonography. | This outcome measure will be assessed within 7 days post-procedure. | 
| Late complication(s) - Incontinence | The Wexner Fecal Incontinence Score will be used to assess incontinence. | Incontinence will be assessed at 52 weeks (1 year) post-procedure. | 
| Late complication(s) - Anal stenosis | Anal stenosis will be assessed by physical examination. | Anal stenosis will be assessed at 52 weeks (1 year) post-procedure. | 
| Late complication(s) - Fistula | Fistula will be assessed by physical examination, in case this is inconclusive, MR imaging will be performed. | Fistula will be assessed at 52 weeks (1 year) post-procedure. | 
| Costs | Total costs over the course of 12 months will be calculated by multiplying resource use with the costs per unit. Resource use(e.g. treatment, control visits, visits to the GP, other diagnostic/medical procedures, medication) will be obtained from the CRFand from recall cost-questionnaires (e.g. over the-counter medication, and lost work days). Sources for valuation of the costs will be cost prices of the Dutch costing manual and cost prices from thePharmaco therapeutic compass. If necessary, local hospital cost prices or otherwise NZa tariffs will be used, which are largely based on integral cost prices from the Dutch hospitals. Absence of work will be calculated by using the friction cost method,which is recommended by the Dutch manual for costing (Zorginstituut Nederland, 2015). | The questionnaires will be filled out at baseline, 6 weeks and 12 months follow-up. | 
| Cost-effectiveness | The cost-effectiveness analysis from the healthcare perspective will be based on the cumulative proportion of patients whopresent with a recurrence up to 12 months follow-up. The cost-effectiveness analysis from the societal perspective (QALYs as outcome) will be based on the EQ-5D-5L. | The EQ-5D-5L will be administered at baseline, 1 week, 6 weeks and at 12 months follow-up. | 
| Budget Impact Analysis | A budget impact analysis (BIA) will be performed in accordance with the Dutch guidelines for economic evaluations and the ISPOR guidelines. The BIA will be performed from different perspectives (e.g. societal, healthcare) with a time horizon of 5 years. As input for the BIA, we will use the results that will become available from the clinical and cost-effectiveness study.The BIA will be performed using a simple decision analytic model. Different scenarios will be compared to investigate various levels of implementation or full substitution of any of the 3 interventions, as well as the swiftness of implementation (1-5 years). In order to test the robustness of the results, sensitivity analyses will be performed on data input and assumptions. No discounting will be performed. The target population in the BIA will be similar to the study population. | Time horizon of 5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemorrhoids, haemorrhoidal disease, recurrence, rubber band ligation, haemorrhoidectomy