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

A Phase 3B, Randomized, Double-Blind, Placebo-Controlled, Parallel-Treatment Group, Multicenter Efficacy and Safety Study of Topical Diltiazem Hydrochloride 2% Cream in Subjects With Anal Fissure

The purpose of this study is to determine if the study drug, VEN307 (diltiazem hydrochloride cream) is safe and to see if it will help with treatment of pain associated with 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:

1. Males or females, aged ≥ 18 to ≤ 75 years.
2. Subjects with evidence of a circumscribed fissure, with induration at the edges.
3. 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).
4. 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).
5. 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.
6. 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).
7. 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.
8. Able to communicate adequately with the investigator and to comply with the requirements for the entire study.
9. Capable of using the IVRS and able to adequately communicate comprehension of the IVRS questions to the investigator.
10. Capable of and freely willing to provide written informed consent prior to participating in the study.

Exclusion Criteria:

1. Unwilling to have visual or medical examination of the AF.

2. More than 1 AF.

3. 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.

4. Unwilling to stop all other concomitant topical preparations applied in and around the anus from signing of ICF through Day 29 of the study.

5. Use of glyceryl trinitrate (GTN) ointment for 7 days (continuous or not) in the 28 days prior to signing the ICF.

6. 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.

7. Unwilling to discontinue use of anesthetics from signing the ICF to end of study.

8. Subfissure injection of botulinum toxin in the 3 months prior to signing the ICF.

9. Known sensitivity to investigational product(s) or calcium channel blockers.

10. Previous treatment with diltiazem hydrochloride cream or any other topical calcium channel blockers.

11. Active treatment with anti-viral therapies for HIV (e.g. indinavir, nelfinivir, ritonavir).

12. 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

13. 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.

14. History of radiation therapy to the pelvis.

15. Fixed anal stenosis/fibrosis.

16. Major organ transplant.

17. Any clinically significant laboratory abnormalities during screening per investigator judgment.

18. Body Mass Index (BMI) > 40 kg/m2

19. Malignancy within 5 years prior to randomization (with the exception of treated basal cell/squamous cell carcinoma of the skin).

20. Any disease or prior/planned surgery that may interfere with the subject successfully completing the study.

21. Currently using narcotic(s).

22. Breast-feeding females.

23. Employees, family members, or students of the investigator or clinical site.