Treatment Of Chronic Anal Fissure (TOCA)

Treatment Of Chronic Anal Fissure (TOCA): a Randomized Clinical Trial on Levorag® Emulgel Versus Diltiazem Gel 2%

The purpose of this study is to investigate the effect of Levorag Emulgel compared with diltiazem gel on the healing of chronic anal fissures.

Study Overview

• Status: Terminated
• Conditions: Chronic Anal Fissure
• Intervention / Treatment: Drug: Diltiazem; Other: Levorag Emulgel

Detailed Description

Anal fissure is an ulcer-like, longitudinal tear in the anal canal, most commonly located in the dorsal or ventral midline, and distal to the dentate line. Anal fissures constitute a common medical problem that affects sexes equally. The initiation of the fissure is most likely caused by the passage of hard stools that traumatizes the anal canal. Patients suffer from anal pain lasting up to several hours after defecation and rectal bleeding.3 Most acute anal fissures heal spontaneously, but a proportion progress into chronic fissures with symptoms beyond 8-12 weeks. There is no strict definition of a chronic anal fissure, but previously the presence of two of the following three symptoms has been used:

1. Pain after defecation lasting for more than three months;
2. presence of a sentinel anal tag; and
3. Exposure of the horizontal fibres of the internal anal sphincter. The severe pain may be caused by a hypertonic contraction of the internal anal sphincter leading to ischemia. Treatment strategies have therefore aimed to relieve this hypertonia by surgical and non-operative approaches. Primary therapy is initiated with ointments such as Diltiazem and glyceryltrinitrat gels.

A novel approach is the Levorag® Emulgel, an ointment classified as Medical Device class 1. According to the manufacturer (THD SpA, Italy) the effect of Levorag® Emulgel is mediated through the effects of myoxinol, a plant extract from the Hibiscus plant with a botox-like effects on the anal sphincter and carboxymethyl glucan, a natural yeast polysaccharide with immune stimulating properties. The effect of the widely used Diltiazem gel, is mediated through diltiazem hydrochloride, a calcium channel blocker that decreases the anal sphincter pressure.

This is an interventional, randomized clinical trial including adult patients with chronic anal fissures referred directly to the Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, or referred to a private surgical practice in Copenhagen. Patients are randomized to 1) Diltiazem gel 2%, one application twice daily for 8 weeks, or 2) Levorag® Emulgel, one application twice daily for 8 weeks. In addition to the allocated treatment, all patients will be kept on standard care for anal fissure, including high-fibre diet proper hydration and laxatives.

The primary endpoint is the rate of complete healing after 12 weeks. Secondary endpoints are complete healing after 8 weeks, incidence of adverse effects and efficacy on pain relief.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, DK8000
    • Department of Surgery P, Aarhus University Hospital
  • Copenhagen, Denmark, DK2400
    • Digestive disease center, Bispebjerg Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Danish citizens, age ≥ 18 years
2. Presence of a midline anal fissure, dorsal or ventral
3. Pain during and after defecation lasting for more than 8 weeks
4. Presence of a sentinel anal tag or hypertrophic papilla
5. Exposure of the horizontal fibres of the internal anal sphincter

1-3 has to be fulfilled for inclusion. Additionally 4 AND/OR 5 has to be present

Exclusion Criteria:

1. Inflammatory bowel disease, known venereal disease, immunodeficiency disease
2. Anal/perianal abscess
3. Anal or rectal surgery within 12 weeks
4. Pregnancy or breastfeeding females
5. History of migraine or chronic headache requiring treatment with analgetics
6. Any cardiovascular or cerebrovascular disease
7. Current use of calcium channel blockers in general or history of use of calcium channel blockers in the treatment of the fissure
8. Signs of other rectal diseases, fistula, infection including severe perianal eczema and tumours

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Diltiazem, calcium channel blocker; Diltiazem gel 2% applied twice daily for 8 weeks	Drug: Diltiazem
Experimental: Levorag, Hibiscus plant extract; Levorag Emulgel applied twice daily for 8 weeks	Other: Levorag Emulgel; Other Names: Myoxinol; Carboxymethyl glucan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete healing at week 12	Complete healing of the anal fissure after 12 weeks	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete healing at week 8	Complete healing of the anal fissure after 8 weeks	8 weeks
Defecation pain at day 3	Perianal pain at or after defecation at day 3	3 days
Defecation pain at day 7	Perianal pain at or after defecation at day 7	7 days
Adverse events	Any adverse events recorded during the study period	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incontinence	Cleveland Clinic incontinence score	8 and 12 weeks
Anal resting pressure	Anal resting and maximal pressure measured by anal manometry (Peritron)	8 and 12 weeks

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Collaborators: Sacomed
• Investigators: Study Chair: Peter-Martin Krarup, MD, Bispebjerg Hospital; Principal Investigator: Andreas Nordholm-Carstensen, MD, Bispebjerg Hospital

Publications and helpful links

General Publications

• Nordholm-Carstensen A, Perregaard H, Wahlstrom KL, Hagen KB, Hougaard HT, Krarup PM. Treatment of chronic anal fissure: a feasibility study on Levorag(R) Emulgel versus Diltiazem gel 2. Int J Colorectal Dis. 2020 Apr;35(4):615-621. doi: 10.1007/s00384-020-03515-z. Epub 2020 Jan 24.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): February 5, 2018
• Study Completion (Actual): February 5, 2018

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 5, 2014
• First Posted (Estimate): June 6, 2014

Study Record Updates

• Last Update Posted (Actual): January 14, 2020
• Last Update Submitted That Met QC Criteria: January 13, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Anus Diseases; Fissure in Ano; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Diltiazem
• Other Study ID Numbers: H-6-2014-020

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No