Clinical trial NCT04091763: Polidocanol Foam Versus Rubber Band Ligation in the Treatment of Hemorrhoidal Disease
Official title: Sclerotherapy With Polidocanol Foam Versus Rubber Band Ligation in the Treatment of First, Second and Third-Grade Hemorrhoidal Disease: a Randomized, Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hemorrhoids, Internal
Keywords: Sclerotherapy
Rubber band ligation
Polidocanol foam
Hemorrhoidal disease
Lead sponsor: Universidade do Porto
Sponsor class: OTHER
First posted: 2019-09-17
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomly assigned to either rubber band ligation or sclerotherapy with polidocanol foam, stratified by grade of hemorrhoidal disease
Primary purpose: TREATMENT

Brief summary: Background: Hemorrhoidal disease is a common benign condition seen frequently in clinical settings. Rubber band ligation and sclerotherapy have proven to be the office-based procedures of choice in hemorrhoidal disease, with various studies reporting rubber band ligation as being more effective but also more painful and bleeding prone than sclerotherapy with liquid polidocanol. However, there are no studies comparing rubber band ligation and sclerotherapy with polidocanol foam, a new type of sclerosant agent that has already proved to be more effective and safer than liquid polidocanol in grade I hemorrhoidal disease.

The present study was designed to establish the clinical effectiveness and safety of sclerotherapy with polidocanol foam compared with rubber band ligation.

Methods: This randomized controlled trial includes patients with symptomatic hemorrhoidal disease grades I to III. The participants were randomly assigned (in a 1:1 ratio) to either rubber band ligation or sclerotherapy with polidocanol foam, stratified by grade of hemorrhoidal disease. During the intervention period the patients are submitted to one of the office-based procedures and, afterwards, in the follow-up period, evaluated every three months for a total period of one year.

The efficacy outcomes include symptom resolution, number of treatment sessions needed to achieve therapeutic success and evolution of hemorrhoidal disease grade in the intervention period and, during follow-up, recurrence incidence. Primary safety outcomes include the occurrence of any complication related to the office-based procedures.

Detailed description: INTRODUCTION Hemorrhoids are normal vascular structures in the anal canal, arising from a cushion of dilated arteriovenous channels and connective tissues, that drains into the superior and inferior hemorrhoidal veins. Their main function is to maintain anal continence, serve as a protection for the anal sphincters during the act of defecation and have a sensory function, allowing to differentiate liquids, solids or gases and to signal defecation.

The hemorrhoidal disease develops when the supporting tissues of hemorrhoidal cushions deteriorate due to various processes: abnormal venous dilation, vascular thrombosis, degenerative processes of collagen and fibroelastic tissue, distortion and rupture of anal subepithelial muscle, hyperperfusion of the hemorrhoidal plexus, inflammatory phenomena and hormonal changes (typical of pregnancy).

Hemorrhoidal disease occurs frequently in the adult population and a considerable number of patients are asymptomatic. Both sexes are similarly affected. The peak incidence occurs between 45-65 years, being rare before the age of 20.

Classification of hemorrhoidal disease corresponds to its position relative to the dentate line. External hemorrhoids are located below the dentate line and are covered by modified squamous epithelium, being richly innervated and therefore painful when there is associated thrombosis. On the contrary, internal hemorrhoids lie above the dentate line. Internal hemorrhoids are further classified based on their appearance and degree of prolapse according to the Goligher classification: grade I, without prolapse (they have the potential to bleed but are not visualized without the aid of an anoscope); grade II, prolapsed with defecation, but reduced spontaneously; grade III, prolapse with defecation requiring manual reduction and grade IV, prolapsed and non-reducible.

Since hemorrhoidal disease is a benign pathology, its treatment should be guided by the symptoms and the impact of the disease on quality of life. A prospective study by Pucher et al. developed and validated the Sodergren scale, which is based on a set of symptoms to assess the severity of hemorrhoidal disease. This scale can be used to assess the efficacy of treatment of haemorrhoids and the comparison of trials, consequently it is helpful in the choice of the best therapeutic option.

Treatment of hemorrhoidal disease can be divided into conservative measures, office-based procedures and surgical treatments.

First line therapy should be conservative and includes a set of lifestyle changes, dietary changes, laxative medication and phlebotonic and/or topical anti-inflammatory drugs. These measures produce beneficial effects and should be implemented in every grades of hemorrhoidal disease or in patients undergoing instrumental or surgical treatment.

The instrumental office-based treatment is usually indicated for hemorrhoidal disease grade I and II, thought it can also be used in grade III hemorrhoidal disease. It is aimed at decreasing hemorrhoidal vascularization, reducing redundant tissue and increasing hemorrhoidal rectal wall fixation to minimize prolapse. It includes rubber band ligation, sclerotherapy (liquid and foam agents), infrared photocoagulation, cryotherapy and radiofrequency ablation.

Rubber band ligation is the most commonly performed procedure in the office and is indicated for grade II and III internal hemorrhoids and works by causing hemorrhoid tissue necrosis and its fixation to the rectal mucosa. Complications associated with rubber band ligation include bleeding (ranging from mild to severe), pain, urinary symptoms, priapism, vagal symptoms, hemorrhoidal thrombosis, sepsis, fistulation or even death. Hemorrhage and pain are among the most frequent. Cumulatively, a success rate of 80% is observed with rubber band ligation.

Hemorrhoidal sclerosis is a procedure commonly used to treat grade I and II hemorrhoidal disease. It has also been used in internal grade III hemorrhoids, although in these cases there is little scientific evidence supporting its efficacy. In this technique a needle is introduced through an endoscope or anoscope and the sclerosing agent is injected into the hemorrhoid above the dentated line - Blanchard technique.

There are a variety of sclerosing agents such as 5% phenol in vegetable oil, quinine, tetradecyl sodium sulfate, sodium morphate or potassium aluminum sulfate and tannic acid (ALTA). More recently, a new sclerosing substance, polidocanol, a non-ionic detergent consisting of two components, a polar hydrophilic chain and a non-polar hydrophobic, started to be employed in the treatment of hemorrhoidal disease. The experience of its use in sclerotherapy comes mainly from the treatment of varicose veins and it can be used in its liquid or foam form. Several studies reported the efficacy of the use of sclerotherapy with liquid polidocanol in hemorrhoidal disease; it is considered a sclerosing agent with anesthetic properties, well tolerated, with low necrotic potential and a very promising agent for the treatment of grade I hemorrhoidal disease. The foam formation is based on the Tessari technique which uses a device that combines two syringes and a three-way tap in which the polidocanol is mixed with air under mechanical force ("Tourbillon technique"). This formulation allows for greater efficacy and use of lower doses of sclerosing agent since the volume will be greatly increased and hence also the area of contact with the vascular endothelium where the drug will exert its sclerosing action. The use of polidocanol foam in the treatment of varicose veins is safe and effective and has been shown to be superior to the use of liquid polidocanol. Its use is not indicated in cases of acute thromboembolism and allergy to polidocanol.

There is only one study showing the superiority of polidocanol foam compared to its liquid formulation in the treatment of grade I hemorrhoidal disease. In a recently published non-controlled study, 2000 patients with hemorrhoidal disease grades I to IV were treated with polidocanol foam and the authors concluded that this therapy was very successful, with 98% of the patients reporting satisfaction regarding bleeding control and prolapse reduction. Complications were rare and usually minor. There's a lack of studies comparing it with other ablative techniques.

The most common complications of sclerotherapy include mild anal discomfort and bleeding. However, the bleeding risk is lower compared to that observed with rubber band ligation. Rare complications include erectile dysfunction, mucosal ulceration, necrosis, prostatic abscess, retroperitoneal sepsis and transient bacteremia. Sclerotherapy is a valid alternative for the treatment of patients whose hemorrhage is the main symptom and where conservative therapy has not been effective, as well as for patients on anticoagulant medication, and for cirrhotic or immunocompromised patients.

There have been no comparative studies between polidocanol foam sclerotherapy and rubber band ligation.

With the present study, the investigators aim to fill a gap in the literature by evaluating the safety and efficacy in the treatment of hemorrhoidal disease with the seemingly most effective non-surgical office-based methods (rubber band ligation and sclerotherapy with polidocanol foam).

METHODS PARTICIPANTS AND ETHICAL ASPECTS Are included patients referred to proctologic consultation of Centro Hospitalar Universitário do Porto (CHUP) older than 18 years with symptomatic hemorrhoidal disease grade I, II and III (Goligher's classification) refractory to conservative management (dietary modification, intestinal transit modifiers, topical and phlebotonic medications) for a period of no less than 4 weeks. All participants must have prior endoscopic study, at least recto-sigmoidoscopy, or complete colonoscopy if they are older than 50 years or younger with family history of colorectal cancer, colon adenomas, or suspected inflammatory bowel disease.

The study was approved by the ethics committee of CHUP. All the participants enrolled sign an informed consent.

STATISTICAL ANALYSIS Sample size was determined considering a power of 80% (type II error ß of 20%) and significance level α of 5% (type I error). The required number in each treatment was 44 patients. In order to safeguard against potential drop-outs, a sample size of 120 (60+60) patients was considered.

It was generated a 1:1 randomization sequence, stratified by for the degree of hemorrhoidal disease (Goligher's classification), to assign participants to each one of the therapeutic arms either sclerotherapy with polidocanol foam or rubber band ligation.

Since the two office-based therapies under study have completely different techniques and procedures, it is not possible to blind either the patient or the clinician who apply the treatment. Therefore, an open label study is being conducted.

VISITS AND DATA COLLECTION Demographic data such as age, sex, body mass index (BMI) are collected. In the first visit informed consent and an information brochure explaining the study and adequate dietary and behavioral care is provided.

For purposes of evaluating efficacy and safety, two distinct periods were considered: intervention and follow-up.

During the intervention period, when office-based treatments are performed, patients are observed at 3-week intervals (minimum of 3 weeks and maximum of 9 weeks depending on the number of instrumental treatments performed) and, during follow-up period, every 3 months, 3 weeks after the last session of treatment to evaluate recurrence of hemorrhoidal disease (maximum 1 year; 4 visits).

At all visits, a proctologic examination with anoscopy is performed and clinical evaluation is carried out by filling the Sodergren's scale of symptoms. The severity of bleeding is also evaluated.

INTERVENTION PERIOD AND TECHNICAL ASPECTS The required number of sessions of any of the office-based treatments (maximum of 3 sessions) is determined by clinical and anoscopy response i.e., if 3 weeks after the previous treatment the participant scores zero points in the Sodergren scale and has bleeding grade ≤1 or the anoscopy doesn't reveal significant hemorrhoidal disease, there is no place for additional instrumental therapy and the patient starts the follow-up period.

If there is therapeutic failure (participants that, at the end of three sessions of instrumental treatment, aggravate or maintain the initial Sodergren score and bleeding grade) or if there is a significant complication (moderate or severe) the patient's participation in the study ends and he is referred for treatment with other type of office-based procedure or surgery.

Eligibility criteria: Inclusion Criteria:

* Patients referred to proctologic consultation of Centro Hospitalar Universitário do Porto (CHUP) older than 18 years;
* Clinical diagnosis of hemorrhoidal disease grade I, II and III (Goligher's classification);
* Refractory to conservative management (dietary modification, intestinal transit modifiers, topical and phlebotonic medications) for a period of no less than 4 weeks.

Exclusion Criteria:

* Hepatic cirrhosis;
* Pregnant or breast-feeding women;
* Known allergy to polidocanol
* Another perianal disease that can cause symptoms similar to hemorrhoidal disease;
* Concomitant presence of external hemorrhoidal disease and/or hemorrhoidal thrombosis;
* Office-based or surgical treatment for hemorrhoids within 6 months prior to inclusion;
* Antiplatelet or hypocoagulant medication;
* Inherited bleeding disorders;
* Immunosuppressive states ;
* Inflammatory bowel disease.

Primary outcomes:
measure: Efficacy outcome (therapeutic success)
timeFrame: Three to nine weeks (depending on the number of instrumental treatments performed)
measure: Efficacy outcome (recurrence)
timeFrame: One year (after the last office-based procedure)
measure: Safety outcome
timeFrame: Three to nine weeks (depending on the number of instrumental treatments performed)
Secondary outcomes:
measure: Efficacy outcome (number of sessions)
timeFrame: Three to nine weeks (depending on the number of instrumental treatments performed)
measure: Efficacy outcome (Goligher grade)
timeFrame: Three to nine weeks (depending on the number of instrumental treatments performed)
Other outcomes:
Locations:
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário do Porto
Study officials:
affiliation: Gastrenterologist
name: Paulo Salgueiro, MD
role: PRINCIPAL_INVESTIGATOR
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