Efficacy and Safety Study With Diltiazem Hydrochloride Cream to Treat Anal Fissures

Primary Objective:

To evaluate the efficacy of diltiazem hydrochloride cream on reduction of worst anal fissure (AF)-related pain associated with or following defecation when administered three times a day (TID) for 28 days.

Inclusion criteria

• Males or females, aged ≥ 18 to ≤ 75 years.
• Subjects with evidence of a circumscribed fissure, with induration at the edges.
• Subjects with AF-related pain associated with or following defecation occurring at least 2 times a week for at least 28 days prior to signing the informed consent form (ICF).
• AF-related pain associated with or following defecation of at least 5 on an 11-point numerical rating score scale (NRS) at the last defecation prior to signing the ICF (0 being no pain; 10 being the worst possible pain).
• Average AF-related pain associated with or following defecation of at least 5 on an 11-point NRS during the last 3 days in which subject had a defecation during the 7 days prior to randomization.
• Any female of non-childbearing potential, including any female who: a) has had a hysterectomy, b) has had a bilateral oophorectomy, c) has had a bilateral tubal ligation or d) is post menopausal (demonstration of total cessation of menses for ≥ 1 year from the date of screening visit).
• Females of child bearing potential who agree to use at least one form of contraception (may be a barrier method), during the full duration of the study.
• Able to communicate adequately with the investigator and to comply with the requirements for the entire study.
• Capable of using the IVRS and able to adequately communicate comprehension of the IVRS questions to the investigator.
• Capable of and freely willing to provide written informed consent prior to participating in the study.

Exclusion criteria

• Unwilling to have visual or medical examination of the AF.
• More than 1 AF.
• Subjects with AF associated with or caused by other conditions, including but not limited to: drug-induced, trauma, HIV infection, fistula-in-ano, inflammatory bowel disease, perianal sepsis or malignancy.
• Unwilling to stop all other concomitant topical preparations applied in and around the anus from signing of ICF through Day 29 of the study.
• Use of glyceryl trinitrate (GTN) ointment for 7 days (continuous or not) in the 28 days prior to signing the ICF.
• Unwilling to discontinue use of sitz baths for up to 4 hours after each application of investigational product from signing of ICF to end of study.
• Unwilling to discontinue use of anesthetics from signing the ICF to end of study.
• Subfissure injection of botulinum toxin in the 3 months prior to signing the ICF.
• Known sensitivity to investigational product(s) or calcium channel blockers.
• Previous treatment with diltiazem hydrochloride cream or any other topical calcium channel blockers.
• Active treatment with anti-viral therapies for HIV (e.g. indinavir, nelfinivir, ritonavir).
• Treatment with any of the following medications within 14 days prior to signing the ICF:

• Amitriptyline
• Benzodiazepines
• β-adrenoceptor antagonists (Beta-Blockers)
• Buspirone
• Calcium channel blockers
• Carbamazepine
• Cimetidine
• Cyclosporin
• Digoxin
• Investigational agents
• Lovastatin
• Opioids
• Pregabalin
• Quinidine
• Rifampin
• Following concomitant disease state:

• Sick sinus syndrome except in the presence of a functioning ventricular pacemaker.
• Second-or third-degree AV block except in the presence of a functioning ventricular pacemaker.
• Hypotension (less than 90 mm Hg systolic).
• Acute myocardial infarction and pulmonary congestion documented by x-ray.
• History of bipolar disorder, psychosis, schizophrenia, mania, suicide attempt or suicidal ideation, or any other significant psychiatric illness (with the exception of intermittent anxiety) per investigator judgment.
• History of clinically significant renal disease per investigator judgment.
• History of clinically significant Alzheimer's or Parkinson's disease per investigator judgment.
• History of clinically significant hepatic disease per investigator judgment.
• Current infection treated with a macrolide antibiotic.
• Clinical evidence or history of fecal incontinence.
• Clinical evidence or history of anal fistula.
• Clinical evidence or history of anal abscess.
• History of inflammatory bowel disease (e.g. Crohn's disease, Ulcerative Colitis).
• History of any prior anal or rectal surgery including but not limited to: lateral sphincterotomy and anal stretch (with the exception of hemorrhoidal banding and laser surgery).
• Grade 4 hemorrhoids.
• Chronic constipation.
• History of radiation therapy to the pelvis.
• Fixed anal stenosis/fibrosis.
• Major organ transplant.
• Any clinically significant laboratory abnormalities during screening per investigator judgment.
• Body Mass Index (BMI) > 40 kg/m2
• Malignancy within 5 years prior to randomization (with the exception of treated basal cell/squamous cell carcinoma of the skin).
• Any disease or prior/planned surgery that may interfere with the subject successfully completing the study.
• Currently using narcotic(s).
• Breast-feeding females.
• Employees, family members, or students of the investigator or clinical site.