Diltiazem Hydrochloride Cream for Anal Fissure
Condition: Chronic Anal Fissure
MeSH terms: Fissure in Ano
Intervention: Diltiazem hydrochloride 4% cream; Diltiazem hydrochloride 2% cream; Placebo
Intervention description: 3 times daily; 3 times daily; 3 times daily
Intervention MeSH terms: Diltiazem
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 465.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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.