Randomised, Double-blind, Placebo-controlled to Assess the Efficacy and Safety of the Food Supplement Microsmin® Plus

Randomised, Double-blind, Placebo-controlled to Assess the Efficacy and Safety of the Food Supplement Microsmin® Plus

Randomised, Double-blind, Placebo-controlled, Parallel-group, Multicentre, Interventional Clinical Trial to Assess the Efficacy and Safety of the Food Supplement Microsmin® Plus in the Symptomatic Treatment of Haemorrhoids

Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus . The classical position of haemorrhoids corresponds to three positions which are the right anterior, right posterior and the left lateral areas of the anal canal. Haemorrhoids may be external or internal. External haemorrhoids are covered with skin and internal haemorrhoids are covered with anal mucous membranes. The grading system used by Banov to classify internal haemorrhoids is one of the most common grading systems used by clinicians and is used to guide therapeutic practice. Internal haemorrhoids can be divided into four categories depending on the degree of prolapse (the protrusion of the haemorrhoid through the anus). The most widely accepted classification is the Goligher classification: Bleeding but no prolapse (grade I). Hemorrhoidal piles prolapse through the anus during straining, but they reduce spontaneously (grade II). Hemorrhoidal piles prolapse through the anus during straining and require manual reduction (grade III). The prolapse is irreducible (grade IV). Most symptoms and signs which patients present with arise from internal haemorrhoids, derive from structural changes of the normal anatomic padding (enlarged internal haemorrhoids) and are generally associated with chronic straining either due to constipation, diarrhoea or prolonged periods trying to defecate. They are also common during pregnancy and childbirth.

Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus . The classical position of haemorrhoids corresponds to three positions which are the right anterior, right posterior and the left lateral areas of the anal canal. Haemorrhoids may be external or internal. External haemorrhoids are covered with skin and internal haemorrhoids are covered with anal mucous membranes. The grading system used by Banov to classify internal haemorrhoids is one of the most common grading systems used by clinicians and is used to guide therapeutic practice. Internal haemorrhoids can be divided into four categories depending on the degree of prolapse (the protrusion of the haemorrhoid through the anus). The most widely accepted classification is the Goligher classification : Bleeding but no prolapse (grade I). Hemorrhoidal piles prolapse through the anus during straining, but they reduce spontaneously (grade II). Hemorrhoidal piles prolapse through the anus during straining and require manual reduction (grade III). The prolapse is irreducible (grade IV). Most symptoms and signs which patients present with arise from internal haemorrhoids, derive from structural changes of the normal anatomic padding (enlarged internal haemorrhoids) and are generally associated with chronic straining either due to constipation, diarrhoea or prolonged periods trying to defecate. They are also common during pregnancy and childbirth. The acute clinical manifestation of the hemorrhoidal disease (commonly known as "hemorrhoidal crisis") is characterized by symptoms and signs, also common in chronic pathologies, such as rectal bleeding, prolapse, pruritus (itching), pain, oedema, often thrombosis, and less frequently soiling or mucoid discharge. Rectal bleeding (the most common presenting sign) is classically bright red as there is a high blood oxygen content within the arteriovenous anastomosis. This bleeding is usually described as bright red spotting on the toilet tissue or dripping in the toilet bowl and normally occurs at the end of defecation, separately from the stool. External haemorrhoids may be asymptomatic or associated with discomfort or with acute extreme pain in the event of a local thrombosis (formation of a clot). Phlebotonics are a heterogenous class of drugs consisting of plant extracts (i.e., flavonoids) and synthetic compounds. Although their precise mechanism of action has not been fully established, they are known to strengthen blood vessel walls, improve venous tone, stabilise capillary permeability and increase lymphatic drainage. They have been used to treat a variety of conditions including chronic venous insufficiency, lymphoedema and haemorrhoids. In particular, numerous trials assessing the effect of phlebotonics in treating the symptoms and signs of haemorrhoidal disease (they are generally used in the less severe stages of haemorrhoids, first and second-grade haemorrhoids and during the thrombosis episodes) suggest that there is a potential benefit. Moreover, 2 reviews and 1 systematic review evaluated the micronized purified flavonoid fraction (MPFF) activities and performance in haemorrhoids. Based on the available clinical evidence, current national guidelines and extensive clinical experience in treating patients affected by the haemorrhoidal disease, MPFF can be administered as a first-line treatment, in combination with diet (increased fibre and fluid intake) and lifestyle modifications, for acute grade I/II HD. A new micronized formulation of diosmin was incorporated in a new dietary supplement called Microsmin® Plus to increase plasma concentrations due to the property manufacturing process able to improve intestinal absorption following oral intake. This product has evidenced a better bioavailability compared with micronized diosmin in rats (4-fold increased) and in healthy volunteers (19) (9.4 greater with higher plasmatic concentrations). Moreover, a randomized, double-blind, placebo-controlled trial carried out in patients with chronic venous disease (CVD) showed that the administration of a low dose of Microsmin® Plus is safe and effective in relieving symptoms and improving QoL in patients with CVD after 8 weeks of treatment. This study aims to investigate the efficacy and safety of phlebotonics (dietary supplement containing micronized diosmin, i.e., Microsmin® Plus) in alleviating the signs, symptoms and severity of haemorrhoidal disease in a set of standard clinical practices where the administration of phlebotonics is integrated with lifestyle counselling. Therefore, the Research Question of the present trial is the following: in a population of adult patients, men and women, suffering from symptomatic haemorrhoids, will the administration of the dietary supplement Microsmin® Plus (diosmin and micronized flavonoids) for 63 days (7-days acute treatment phase + 55-days maintenance phase), integrated with lifestyle counselling, improve the symptomatology (clinical signs and symptoms) in comparison with patients receiving placebo, results observed after 4, 7 and 63 days after the beginning of the treatment?

DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP OF THE FOOD SUPPLEMENT MICROSMIN® PLUS (DIOSMIN AND MICRONIZED FLAVONOIDS)

Investigational food supplement placebo will be administered according to the same schedule provided for the active product: From day 1 to day 4: 1 tablet three times a day, before meals (breakfast, lunch and dinner) From day 5 to day 7: 1 tablet twice a day, before breakfast and dinner From day 8 to day 62: 1 tablet once a day, before breakfast

The dosage will be the following: From day 1 to day 4: 1 tablet three times a day, before meals (breakfast, lunch and dinner) From day 5 to day 7: 1 tablet twice a day, before breakfast and dinner From day 8 to day 62: 1 tablet once a day, before breakfast

Evaluate the efficacy of the tested food supplement Microsmin® Plus (diosmin and micronized flavonoids) in comparison with placebo in the symptomatic treatment of haemorrhoids in adult patients affected by Grade I-II (Goligher classification) haemorrhoids as assessed by the patient at the end of the treatment period.

To evaluate the safety of the tested food supplement through adverse events and serious adverse events incidence assessed by Investigators and reported according to the current legislation

To evaluate the safety of the tested food supplement through AE and SAE incidence assessed by Investigators and reported according to the current legislation.

To evaluate the early efficacy of the tested food supplement in comparison with placebo in the symptomatic treatment of haemorrhoids as assessed by the patient after 4 and 7 days of treatment

To evaluate the early efficacy of the tested food supplement in comparison with placebo in the symptomatic treatment of haemorrhoids as assessed by the patient after 4 and 7 days of treatment.

To evaluate the efficacy of the tested food supplement in comparison with placebo in the clinical improvement of haemorrhoids as assessed by the Investigator at each visit (day 7 and 63)

To evaluate the efficacy of the tested food supplement in comparison with placebo in the clinical improvement of haemorrhoids as assessed by the Investigator at each visit (days 7 and 63).

To evaluate analgesic consumption in patients treated with the tested food supplement in comparison with placebo as reported by the patient in the diary

To evaluate analgesic consumption in patients treated with the tested food supplement in comparison with placebo as reported by the patient in the diary.

To assess the overall satisfaction with the tested food supplement in comparison with placebo according to patient's judgement, at the end of the treatment period (day 63)

To assess the overall satisfaction with the tested food supplement in comparison with placebo according to patient's judgement, at the end of the treatment period (day 63).

To assess the improvement in the quality of life by means of the Short Heath Scale for Hemorrhoidal Disease (SHSHD) score; assessed by patients after 7 and 63 days of treatment

To assess the improvement in the quality of life by means of the Short Heath Scale for Hemorrhoidal Disease (SHSHD) score; assessed by patients after 7 and 63 days of treatment.

Inclusion Criteria: Men or women aged ≥ 18 and ≤ 60 years. The sex will be balanced by randomized stratification. Patients diagnosed with Grade I - II symptomatic haemorrhoids (according to Goligher classification) confirmed by clinical and anoscopic or proctoscopic examination performed within 3 months before baseline. Ultrasound examination at baseline is recommended, but not mandatory. Patient free from the following treatments for haemorrhoids from at least 4 weeks: laser treatments for haemorrhoids, steroidal or non-steroidal anti-inflammatory drugs, analgesics (other than the rescue medicine indicated in the protocol), any anti-hemorrhoidal treatment (included phlebotonic compounds both drugs and dietary supplements), anticoagulants, and antiplatelet agents. Able to communicate adequately with the Investigator and to comply with the requirements for the entire study. Capable of and freely willing to provide written informed consent prior to participating in the study. Exclusion Criteria: Inflammatory and infectious disease of the digestive tract (e.g., IBD - Inflammatory Bowel Diseases). Acute haemorrhoids or complicated haemorrhoids with bleeding requiring admission, such as strangulated internal haemorrhoids, thrombosed internal or external haemorrhoids. Previous haemorrhoidectomy or previous laser treatment. Moderate to severe hypertension, cardiovascular diseases, renal failure, cirrhosis, colorectal cancer, anal fissure or fistula. Use of laser treatments for haemorrhoids, steroidal or non-steroidal anti-inflammatory drugs, analgesics (other than the rescue medicine indicated in the protocol), any anti-hemorrhoidal treatment (included phlebotonic compounds both drugs and dietary supplements), anticoagulants, and antiplatelet agents in the 4 weeks prior to inclusion and during the whole study. Alcohol or drug abuse. Patients considered smokers (≥10 cigarettes/day). Energy-restricted diet for weight loss. Pregnant woman, lactating woman, and woman of childbearing potential who is planning a pregnancy or is unwilling to use appropriate methods of contraception* during the study. *Methods of contraception: hormonal contraceptive, intrauterine device or intrauterine system, double barrier method (condom with spermicide/diaphragm or cervical cap with spermicide), surgical sterilization (vasectomy, tubal ligation, etc.). Hypersensitivity to active principle (diosmin) or to any other ingredient contained in the tested food supplement. History of anaphylaxis or severe complicated allergy symptoms. Patients unlikely to cooperate. Patients with any other medical condition that, in the opinion of the Investigator, would compromise participation or be likely to lead to hospitalisation during the study. Participation in an interventional clinical study or administration of any investigational agents in the previous 30 days.

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