Diltiazem Hydrochloride Cream for Anal Fissure

NCT ID: NCT01217515

Last Updated: 2014-07-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 465 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-10-31
• Study Completion Date: 2012-05-31

Brief Summary

A Phase III, multicentre, randomised, double blind, placebo-controlled study in subjects having anal fissure (AF) with AF-related pain. Subjects will undertake a 1-week screening period to provide baseline data and for assessment of eligibility. At the Baseline visit (Week 0), eligible subjects (having an average Numerical Rating Scale (NRS) score of >4 for worst pain associated with or following defaecation) will be randomised on a 1:1:1 basis to one of the three treatment groups. Subjects will receive diltiazem hydrochloride 2% cream or diltiazem hydrochloride 4% cream or placebo cream. Study treatment will be applied in and around the anus, three times daily, for up to 8 weeks. Following the Week 0 Visit, subjects will be contacted by telephone during Week 1 to ensure adequate compliance with study treatment, to ensure that study drug is being tolerated and that any concomitant medications are used at a level consistent with that prior to randomisation. Subjects will return to the clinic for safety and efficacy assessments at Weeks 2, 4, and 8 and receive a follow-up telephone call at Week 12, following cessation of therapy.

Concomitant laxatives and stool softeners will be permitted, as needed, during the entire study period (screening and treatment) to ensure that constipation or passage of hard stools does not confound evaluation or improvement of the condition. Fibre supplements will be allowed but should be continued at the baseline level.

Instructions on the use of the Interactive Voice Response System (IVRS) diary will be issued to subjects to record fissure-related pain (NRS) and bowel symptoms daily during the 1-week screening period, to confirm eligibility and post-randomisation to record worst anal pain associated with or following defaecation (NRS) and daily overall AF-related pain (NRS). A record of the number of times the subject has defaecated, laxative and analgesic usage will also be made as well as the number of applications of study treatment, any changes to concurrent medications and any Adverse Events (AEs).

In addition, at some or all study visits, subjects will record the Patient's Global Impression of Improvement (PGI-I) on a 7 point Likert scale, complete a Short Form 36 (SF-36) quality of life questionnaire and will undergo examination of their AF. Routine blood samples will be taken and the Skin Irritation Score (SIS) recorded for safety evaluations.

Subjects may receive permitted medications for pain per Entry Criteria, but these should remain stable, where possible, up to the Week 8 Visit. Introduction of any new medication for AF will not be permitted unless the Investigator deems "rescue" intervention necessary. A subject will be deemed a treatment failure if rescue intervention is required and will have to be withdrawn from the study.

Any subject leaving the study following randomisation for any reason will be asked to complete the Early Withdrawal Visit. This includes subjects who withdraw due to the development of AEs or intolerance, as well as subjects who require rescue intervention. These subjects will return for safety follow-up visits at their previously scheduled follow-up assessment appointments. If complete healing has occurred at the 2 or 4 Week visits, (i.e. prior to the end of the 8-week treatment period), subjects will be asked to continue applying the medication for the full 8 week course, up to the final assessment.

Following the Week 8 visit (or Early Withdrawal Visit), subjects will be followed up for a further 4 weeks (following cessation of study medication) to note any AEs.

All routine blood analyses (haematology and biochemistry) and plasma levels of diltiazem and of its principal metabolites will be analysed by central laboratories.

Conditions

Chronic Anal Fissure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Diltiazem hydrochloride 4% cream

2.5 cm Diltiazem hydrochloride 4% cream applied peri-anally three times daily for eight weeks.

Group Type: EXPERIMENTAL

Diltiazem hydrochloride 4% cream

Intervention Type: DRUG

3 times daily

Diltiazem hydrochloride 2% cream

2.5 cm of Diltiazem hydrochloride 2% cream applied peri-anally three times daily for eight weeks.

Group Type: EXPERIMENTAL

Diltiazem hydrochloride 2% cream

Intervention Type: DRUG

3 times daily

Placebo cream

2.5 cm placebo cream applied peri-anally three times daily for eight weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

3 times daily

Interventions

Diltiazem hydrochloride 4% cream

3 times daily

Intervention Type: DRUG

Diltiazem hydrochloride 2% cream

3 times daily

Intervention Type: DRUG

Placebo

3 times daily

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• • Must give written informed consent.

• Male or female subjects, from 18 years of age.
• Subjects with at least a 4 week history of painful AF, prior to screening, where AF-related pain associated with, or following, defaecation is experienced at least twice a week for the 4 weeks prior to Screening with an average of ≥ 3 on an 11-point NRS (Numerical Rating Scale, range 0-10 where 0 = no pain and 10 = worst pain imaginable).
• Subjects with an average of ≥4 on an 11-point NRS during the screening phase for worst anal pain associated with, or following, defaecation for the most recent 3 days on which the subject has defaecated.
• Subjects with evidence of a circumscribed fissure, with induration at the edges.
• Willing to stop all other concomitant topical preparations applied perianally prior to commencing study treatment, and throughout the study.
• Willingness and ability to use the IVRS diary.

Exclusion Criteria

• Subjects unwilling to have examination of AF.
• Subjects with "acute" AF (i.e. duration of symptoms less than 4 weeks prior to screening, and/or no induration of fissure edges).
• More than 1 AF.
• Subjects who have had lateral sphincterotomy or anal stretch or other previous surgery involving the anal canal or perianal region.
• Subjects who have had sub-fissure injection of botulinum toxin in the 3 months prior to screening, or have used glyceryl trinitrate (GTN) ointment for >1 week in the 4 weeks prior to the screening visit.
• Subjects with AF associated with other conditions (drug-induced [e.g. nicorandil], trauma, HIV infection, fistula-in-ano, inflammatory bowel disease, perianal sepsis or malignancy).
• Subjects with cardiovascular disease (including those diagnosed by the screening ECG): history of reduced left ventricular function, bradycardia, 1st degree atrioventricular (AV) block or prolonged P-R interval (>0.2 seconds/ >200 milliseconds).
• Subjects with known hypersensitivity to diltiazem.
• Subjects who have previously received therapy with diltiazem hydrochloride cream or other topical calcium channel blockers.
• Subjects taking medications prohibited by the protocol.
• Subjects who have taken experimental agents must have been discontinued at least 8 weeks prior to screening, or for a period equivalent to 5 half-lives (t1/2) of the agent (whichever is longer);
• Subjects who have or have undergone the following gastrointestinal disorders or procedures:
• Inflammatory bowel disease.
• Chronic faecal incontinence.
• History of chronic constipation or constipation in the 4 weeks prior to the screening phase (defined as 2 or less defaecations per week; associated with straining/passage of hard stools).
• Anal abscess.
• A history of radiation therapy to the pelvis.
• Fixed anal stenosis/fibrosis.
• Subjects with a history of neoplastic disease within 5 years (except for basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin).
• Subjects with a clinically significant history of renal, hepatic, neurological, dermatological, immunological, major psychiatric (including drug or alcohol abusers), or haematological illness.
• Subjects with any laboratory tests considered clinically significant at screening.
• Subjects with planned elective or other treatment requiring hospitalisation, during the study, booked before entry into the study
• Subjects who will be unavailable for the duration of the trial, likely to be noncompliant with the protocol, or who are felt to be unsuitable by the Investigator for any other reason;
• Women of childbearing potential unless surgically sterile or using adequate contraception (IUD, oral or depot contraceptive, or barrier plus spermicide). Women using oral contraception must have started using it at least 2 months prior to enrolment.
• Women who are pregnant or breastfeeding.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

S.L.A. Pharma AG

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Chris Jordan, PhD

Role: STUDY_DIRECTOR

S.L.A. Pharma

Locations

Dr Kantcho Kostadinov

Sevileva, Sevilieva, Bulgaria

Vth MHAT

Sofia, , Bulgaria

MHAT Alexandrovska EAD

Sofia, , Bulgaria

Military Medical Academy

Sofia, , Bulgaria

D Rusev

Sofia, , Bulgaria

General Hospital for Active Treatment "Stefan Cherkezov"

Veliko Tarnovo, , Bulgaria

Praxis

Blankenhain, , Germany

Praxis

Fürth, , Germany

End- und Dickdarm-Zentrum Mannheim

Mannheim, , Germany

Gemeinschaftspraxis

Marl, , Germany

Practice of Internal Medicine

Wiesbaden, , Germany

Kaunas Medical University Clinics

Kaunas, , Lithuania

Siauliai Hospital

Šiauliai, , Lithuania

UAB Baltic and American Medical and Surgical Clinic

Vilnius, , Lithuania

Spitalul Clinic de Urgenta "Prof Dr O Fodor" Cluj

Cluj Nopoca, , Romania

Spitalul Clinic de Urgenta "Prof. Dr O Fodor"

Cluj-Napoca, , Romania

Spitalul Judetean de Urgenta Deva

Deva, , Romania

Institutul de Gastroenterologie si Hepatologie lasi

Lasi, , Romania

Spitalul Clinic Judetean de Urgente "Sf.Spiridon" lasi

Lasi, , Romania

Cabinet Medical "Dr Lokos" Chirurgie Generala

Miercurea-Ciuc, , Romania

Spitalul Clinic Judetean Mures

Tg Mures, , Romania

Centrul Medical Tuculanu SRL

Timișoara, , Romania

Spitalul Clinic Judetean de Urgenta Timisoara

Timișoara, , Romania

Salvo-San-Ciobanca SRL

Zalău, , Romania

Hospital Clinico Universitario Lozano Blesa

Zaragoza, , Spain

Derby City General Hospital

Derby, Derbyshire, United Kingdom

Royal Sussex County Hospital

Brighton, , United Kingdom

Countries

Bulgaria; Germany; Lithuania; Romania; Spain; United Kingdom

Other Identifiers

D-AF-09

Identifier Type: -

Identifier Source: org_study_id