E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002153 |
E.1.2 | Term | Anal fissure |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether topical application of diltiazem cream is superior to placebo in relieving pain associated with anal fissure.
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E.2.2 | Secondary objectives of the trial |
1. To determine the optimum concentration of diltiazem cream, applied topically, to provide relief from pain associated with chronic anal fissure.
2. To determine the impact of topical diltiazem on the healing of chronic anal fissure.
3. To evaluate the safety and tolerability of topical diltiazem cream in the treatment of chronic anal fissure.
4. To evaluate the population kinetics after topical administration of diltiazem cream.
5. To determine the impact of topical diltiazem on Quality of Life in patients with chronic anal fissure.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For inclusion in the study, subjects must satisfy all of the following criteria:
1. Male or female subjects aged ≥ 18 years who have given written, informed consent.
2. Symptomatic, chronic anal fissure (pain on or following defecation) present for ≥4 weeks and presenting with notable fissure-related pain.
3. Evidence of circumscribed fissure, with induration at the edges, with or without a sentinel tag.
4. Female subjects of childbearing potential must have negative urine pregnancy test on entry and be using adequate contraception.
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E.4 | Principal exclusion criteria |
Subjects for whom any of the following criteria apply are not eligible for inclusion in the study:
1. Subject with acute fissure (symptoms of duration <4 weeks, no induration at edges).
2. Previous surgical treatment for anal fissure.
3. Other previous surgery involving the anal canal or perianal region.
4. Score of ≤30mm at baseline on the Visual Analogue Scale (VAS) for anal pain on defecation and a score of ≤2 on the Numeric Rating Scale for anal pain on defecation (baseline pain score is the average anal pain on defecation for the 3 defecations prior to randomisation).
5. Medical treatment of anal fissure during the past 4 weeks with gyceryl trinitrate cream (GTN cream, Rectogesic) or topical steroid containing creams (e.g. Xyloproct cream, Anusol HC etc.).
6. Subjects who have previously failed to respond to topical diltiazem therapy.
7. Subjects currently using any drugs which, in the opinion of the investigator, may influence anal sphincter tone or blood supply (e.g. α- or β-adrenoceptor agonists [other than inhaled β-agonists] or antagonists, sympathomimetics, anti-hypertensive agents, medical treatments for irritable bowel syndrome, PDE V inhibitors).
8. Subjects on antibiotic therapy.
9. Subjects with a history of inflammatory bowel disease.
10. Subjects with anal fissure associated with other conditions such as HIV infection, fistula-in-ano, perianal sepsis, malignancy or as a result of traumatic childbirth.
11. History or evidence on examination of pre-existing cardiac disease, including severe bradycardia, arrhythmias and conduction abnormalities.
12. Coexisting gastrointestinal disease or previous gut resection.
13. Known hypersensitivity to diltiazem.
14. Any mental or other impairment which, in the investigator’s opinion would render them unlikely to be able to comply with the requirements of the study.
15. Participation in a clinical trial within the past 3 months.
16. Previous participation in the D-CAF-06 trial.
17. Concomitant medication acting on the central nervous, cardiovascular (other than low-dose aspirin for prophylaxis) or gastrointestinal system. Xyloproct use is not permitted. Analgesics use is also not permitted during the study, although limited paracetamol use will be permitted.
18. Women who are pregnant or breast-feeding.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy will be based on pain on defecation experienced each day and will be recorded on a visual analogue scale (VAS) pain score (0-100mm) in the subject diary.
The primary measure of efficacy will be response to treatment assessed as the percentage change in the Week 4 average pain on defecation score compared to baseline i.e.
[Sum of pain on defecation, for each defecation, from Day 22 to Day 28 inclusive] divided by [Number of defecations]
Response is defined as a ≥ 30% decrease in Week 4 average pain score from baseline.
The average pain on defecation will be calculated for each treatment week; Week 4 will be considered primary.
Baseline pain score will be average pain on defecation for the 3 defecations prior to randomisation.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 25 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |