E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Anal fissure is a linear tear in the mucosa of the anal canal |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
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 |
The primary objective of the study is to assess the effect of Nifedipine, applied intra-anally through RDD drug delivery device in anal fissure patients that are being managed with conservative treatment. |
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E.2.2 | Secondary objectives of the trial |
These objectives are: i. Incidence of Rectal Bleeding ii. Reduction in maximal rectal pain. iii. Rate of healing of anal fissure. iv. Rate of recurrence of anal fissure during the follow up period. v. Effect on the quality of life.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The Effect of Intra-anal Nifedipine, Used As Add-on to Conservative Therapy, on Pain in Patients with Anal Fissure- Open Label Extension |
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E.3 | Principal inclusion criteria |
Subjects meeting the following criteria will be eligible to participate in the trial: 1. Single anal fissure; 2. Signed written informed consent; 3. Male or female subjects 18 to 65 years of age inclusive; 4. Has chronic anal fissure defined as history of rectal pain at least three days a week for at least 6 weeks - or more AND at least one of the following: a) Sentinel skin tag b) Hypertrophied anal papilla c) Exposure of the underlying internal anal sphincter d) Anal cicatrisation 5. Visual analogue scale of average 24 hours rectal pain (VAS) of > 40 mm in screening visit; 6. Capable of using the IVRS and able to adequately communicate comprehension of the IVRS questions to the investigator; 7. If female, is non-lactating, has a negative urine pregnancy test result, and does not plan on becoming pregnant during the study, or not of childbearing potential (hysterectomy or tubal ligation at least 6 months prior to entry to the study or post-menopausal for 1 year); if of childbearing potential (including peri-menopausal women who have had a menstrual period within one year) must practice or be willing to continue to practice acceptable birth control from screening and until 1 week after the study medication has been discontinued. Acceptable birth control includes : a) combined (estrogen and progestogen containing) hormonal contraception b) associated with inhibition of ovulation; oral OR intravaginal OR transdermal. c) progestogen-only hormonal contraception associated with inhibition of ovulation: oral OR injectable OR implantable. d) progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action e) intrauterine device (IUD) f) intrauterine hormone-releasing system ( IUS) g) bilateral tubal occlusion h) vasectomised partner i) sexual abstinence j) male or female condom with or without spermicide k) cap, diaphragm or sponge with spermicide
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E.4 | Principal exclusion criteria |
Subjects are excluded from participation in the study if any of the following criteria apply: 1. Known allergy to Nifedipine 2. Unwilling to stop all other concomitant topical preparations applied in and around the anus from screening through the end of the study 3. Subfissure injection of botulinum toxin in the 3 months prior to screening. 4. Fissure resulting from inflammatory bowel disease, venereal disease, perianal psoriasis, immunodeficiency syndrome 5. Atypical fissure (occurs off the midline) in which secondary causes were not excluded. 6. Deemed by the investigator as anal fissure for which surgery is indicated 7. Anal abscess; 8. Grade 4 hemorrhoids 9. Fixed anal stenosis 10. Active or past history of cardiovascular or cerebrovascular disease including but not limited to angina pectoris, myocardial infarction, transient ischemic attacks/stroke, arrhythmia or ecg changes that requires medical treatment or deemed by the investigator as clinically significant, moderate to severe congestive heart failure, or cardiac valve abnormalities; 11. Type 1 diabetes mellitus 12. Insulin treated type 2 diabetes mellitus 13. Renal failure defined as a serum creatinine > 1.5 mg/dL (133 µmol/L) at screening 14. Liver disease defined as Aspartate aminotransferase (AST) or alanine aminotransferase(ALT) >2 X upper limit of normal at screening 15. Malignant disease within 3 years of screening 16. Has uncontrolled hypertension (sitting blood pressure >160/95 mmHg at screening) 17. Has hypotension (blood pressure lower than 90/60 mm Hg at screening) 18. History of chronic gastrointestinal disease such as Crohn’s disease or ulcerative colitis 19. History of major rectal surgery 20. History of HIV, Hepatitis B, Hepatitis C 21. Has clinical laboratory test values (chemistry, hematology, or urinalysis) judged to be clinically significant by the investigator at screening; 22. Has used, in the last two weeks, drugs that may affect blood coagulation, such as Aspirin at a dose higher than 500 mg/day, Warfarin, Sintrom, Enoxaparin, Nadroparin, Heparin, Clopidogrel, Ticlopidine Rivaroxaban, Apixaban, Edoxaban 23. Is treated with drugs that may affect the anal sphincter: a. Calcium channel blockers such as Nifedipine, Diltiazem or Verapamil b. Nitroglycerin or nitrates 24. Has, upon physical examination, a rectal deformation or signs of rectal disease such as fistula, infection or space occupying lesion; 25. Participated in a clinical study in the last 30 days prior to screening. 26. Is an immediate family member of personnel directly affiliated with the study at the investigative site, or is personally directly affiliated with the study at the investigative site; or is employed or related to the Sponsor, CRO or investigator;
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is change in the 24-hour average anal fissure rectal pain as determined by 100 mm visual analogue scales (VAS) from baseline through week 8. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary efficacy parameters will include the following: 1. Proportion of subjects with at least 50% reduction in the 24-hour average rectal pain from baseline through week 8. 2. Time to reach a 50% reduction in the 24-hour average severity of rectal pain from baseline as determined by NRS score. 3. Change in the 24-hour average severity of rectal pain over a period of days not to exceed one week as determined by NRS score 4. Change in anal fissure rectal pain as determined by 100 mm visual analogue scales (VAS) from baseline through week 5. 5. Change in maximal anal fissure rectal pain with or following defecation as determined by 100 mm visual analogue scales (VAS) from baseline through week 8. 6. Change in maximal rectal pain as determined by 100 mm visual analogue scales (VAS) from baseline through week 8. 7. Proportion of subjects with at least 30% reduction in the 24-hour average rectal pain from baseline through week 8. 8. Time to reach a 30% reduction in the 24-hour average severity of rectal pain from baseline as determined by NRS score. 9. Change in the 24-hour average anal fissure rectal pain as determined by 100 mm visual analogue scales (VAS) during the Open Label period (i.e., second treatment cycle) . 10. The effect of Intra-anal Nifedipine on complete healing of anal fissure, defined as evidence of re-epithelialization without drainage or dressing requirements confirmed at two consecutive visits at least two weeks apart. 11. Recurrence during the 8-week follow up period, defined as: • rectal pain severity is greater than 4 in NRS 10-point and experience increase in rectal pain severity compared to week 8 and AND/OR • Recurrence of rectal bleeding. 12. Proportions of patients with resolution of rectal pain that was maintained for the treatment period. 13. Incidence of rectal bleeding episodes as assessed in the patient daily diary. 14. Changes in quality of life as assessed by EQ-5D-5L
In addition the following device associated endpoints will be collected: • Ease of use. • Device malfunction. • Patient discomfort during device use. • Success in delivery the capository to the anal canal. • Retention of capository after delivery.
This study also contains exploratory endpoints as outlined in the SAP and pharmacokinetic assessments of intra-analy applied Nifedipine.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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) | Yes |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Moldova, Republic of |
Poland |
Romania |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |