Diltiazem Hydrochloride Cream for Anal Fissure

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
S.L.A. Pharma AG
ClinicalTrials.gov Identifier:
NCT01217515
First received: October 6, 2010
Last updated: July 7, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Chronic Anal Fissure
Drug: Diltiazem hydrochloride 4% cream
Drug: Diltiazem hydrochloride 2% cream
Other: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomised,Double-Blind, Placebo-Controlled Trial of the Safety and Efficacy of Diltiazem Hydrochloride Cream in Subjects With Anal Fissure

Resource links provided by NLM:


Further study details as provided by S.L.A. Pharma AG:

Primary Outcome Measures:
  • Change From Baseline in Average of Worst Anal Pain Associated With or Following Defaecation for Week 4 (for the 7 Treatment Days Immediately Preceding the Week 4 Visit). [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change from baseline in average of worst anal pain associated with or following defaecation for Week 4 (for the 7 treatment days immediately preceding the Week 4 visit). Numerical Rating Scale, range 0-10 where 0 = no pain and 10 = worst pain imaginable.


Secondary Outcome Measures:
  • Patient's Global Impression of Improvement (PGI-I) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Compared to the way you felt prior to starting the study treatment, how would you now describe your problems related to the anal fissure?" Responses will be measured on a 7-point Likert scale where 1 = substantially worse, 2 = moderately worse, 3 = slightly worse, 4 = no change, 5 = slightly improved, 6 = moderately improved, and 7 = substantially improved. Percentage of subjects scoring 5,6 or 7 was assessed.

  • Assessment of Adverse Events, Clinical Laboratory Results, Vital Signs and Sensitivity Reactions [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    Number of subjects with adverse events, abnormal clinical laboratory results, vital signs and occurrence of any local sensitivity reactions. Data are presented where the incidence is greater than or equal to 5%.


Enrollment: 465
Study Start Date: October 2010
Study Completion Date: May 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Diltiazem hydrochloride 4% cream
2.5 cm Diltiazem hydrochloride 4% cream applied peri-anally three times daily for eight weeks.
Drug: Diltiazem hydrochloride 4% cream
3 times daily
Experimental: Diltiazem hydrochloride 2% cream
2.5 cm of Diltiazem hydrochloride 2% cream applied peri-anally three times daily for eight weeks.
Drug: Diltiazem hydrochloride 2% cream
3 times daily
Placebo Comparator: Placebo cream
2.5 cm placebo cream applied peri-anally three times daily for eight weeks.
Other: Placebo
3 times daily

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01217515

Locations
Bulgaria
Dr Kantcho Kostadinov
Sevileva, Sevilieva, Bulgaria, 5400
D Rusev
Sofia, Bulgaria, 1618
Military Medical Academy
Sofia, Bulgaria, 1606
Vth MHAT
Sofia, Bulgaria, 1233
MHAT Alexandrovska EAD
Sofia, Bulgaria, 1606
General Hospital for Active Treatment "Stefan Cherkezov"
Veliko Tarnovo, Bulgaria, 5000
Germany
Praxis
Blankenhain, Germany, 99444
Praxis
Fürth, Germany, 90762
End- und Dickdarm-Zentrum Mannheim
Mannheim, Germany, 68165
Gemeinschaftspraxis
Marl, Germany, 45770
Practice of Internal Medicine
Wiesbaden, Germany, 65185
Lithuania
Kaunas Medical University Clinics
Kaunas, Lithuania, 50009
Siauliai Hospital
Siauliai, Lithuania, 76231
UAB Baltic and American Medical and Surgical Clinic
Vilnius, Lithuania, 10103
Romania
Spitalul Clinic de Urgenta "Prof Dr O Fodor" Cluj
Cluj Nopoca, Romania, 400162
Spitalul Clinic de Urgenta "Prof. Dr O Fodor"
Cluj-Napoca, Romania, 400162
Spitalul Judetean de Urgenta Deva
Deva, Romania, 330084
Institutul de Gastroenterologie si Hepatologie lasi
Lasi, Romania, 700111
Spitalul Clinic Judetean de Urgente "Sf.Spiridon" lasi
Lasi, Romania, 700111
Cabinet Medical "Dr Lokos" Chirurgie Generala
Miercurea Ciuc, Romania, 530180
Spitalul Clinic Judetean Mures
Tg Mures, Romania, 540103
Spitalul Clinic Judetean de Urgenta Timisoara
Timisoara, Romania, 300723
Centrul Medical Tuculanu SRL
Timisoara, Romania, 300167
Salvo-San-Ciobanca SRL
Zalau, Romania, 450112
Spain
Hospital Clinico Universitario Lozano Blesa
Zaragoza, Spain, 50009
United Kingdom
Derby City General Hospital
Derby, Derbyshire, United Kingdom, DE22 3DT
Royal Sussex County Hospital
Brighton, United Kingdom, BN2 5BE
Sponsors and Collaborators
S.L.A. Pharma AG
Investigators
Study Director: Chris Jordan, PhD S.L.A. Pharma
  More Information

No publications provided

Responsible Party: S.L.A. Pharma AG
ClinicalTrials.gov Identifier: NCT01217515     History of Changes
Other Study ID Numbers: D-AF-09
Study First Received: October 6, 2010
Results First Received: November 7, 2013
Last Updated: July 7, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Fissure in Ano
Anus Diseases
Rectal Diseases
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Diltiazem
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Antihypertensive Agents
Vasodilator Agents

ClinicalTrials.gov processed this record on July 23, 2014