Clinical trial NCT02527109: The Effect of Intra-anal Nifedipine, Used As Add-on to Conservative Therapy, on Pain in Patients With Anal Fissure
Official title: The Effect of Intra-anal Nifedipine, Used As Add-on to Conservative Therapy, on Pain in Patients With Anal Fissure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Chronic Anal Fissure
Lead sponsor: RDD Pharma Ltd
Sponsor class: INDUSTRY
First posted: 2015-08-18
Enrollment: 339
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of the study is to examine the effect of Nifedipine, applied intra-anally through our drug delivery device, on rectal pain severity in anal fissure patients that are being managed with conservative treatment.

Detailed description: This is a randomized, double-blinded study. All patients in the study will be treated with the conservative standard of care for anal fissure. Study medication will be used as an add-on to conservative therapy, and will consist of 3 groups:

1. Treatment Group 1- 12 mg of Nifedipine to be self-administered twice daily.
2. Treatment Group 2- 12 mg of Nifedipine to be self-administered once daily in the morning hours and placebo to be self-administered in the evening.
3. Placebo Group - Placebo to be self-administered twice daily. Approximately 330 subjects will participate in this study. A screening visit will be used to determine subject suitability for inclusion in the trial. Within one week of the screening visit, subjects who meet all inclusion criteria and none of the exclusion criteria will receive either Nifedipine 12 mg X2 a day (BID) (24 mg/day total) or Nifedipine 12 mg X1/day to be administered in the morning hours and a matching placebo X1/day to be administered in the evening hours (12 mg/day total) or a matching placebo X2 a day (BID) (0 mg/day total) for a period of 8 weeks. During this period, 4 study visits (at 0, 2, 5, and 8 weeks) will take place. Study medication and placebo will be administered BID (in the morning and in the evening). In addition to receiving study medication, subjects will be maintained on a conservative standard treatment for Anal Fissure: sitz baths, high fiber diet, stool softeners and plenty of fluids.

Upon completion of the treatment cycle, patients will be contacted by phone (at weeks 10, 13 and 16) and will be questioned about recurrent symptoms e.g. pain or bleeding.

Patients that:

1. Were enrolled to one of the investigational groups ,and completed the 8 weeks treatment period or discontinued treatment because the investigator deemed them as healed AND
2. Experience symptoms of recurrence AND ARE
3. Willing to participate in an open label extension will receive Nifedipine 12 mg X2 a day (BID) for a period of 8 weeks. During this period, 4 study visits (at 0, 2, 5, and 8 weeks from the start of retreatment) will take place.

Eligibility criteria: 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:

   * Sentinel skin tag
   * Hypertrophied anal papilla
   * Exposure of the underlying internal anal sphincter
   * 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 :

* combined (estrogen and progestogen containing) hormonal contraception
* associated with inhibition of ovulation; oral OR intravaginal OR transdermal.
* progestogen-only hormonal contraception associated with inhibition of ovulation: oral OR injectable OR implantable.
* progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
* intrauterine device (IUD)
* intrauterine hormone-releasing system ( IUS)
* bilateral tubal occlusion
* vasectomised partner
* sexual abstinence
* male or female condom with or without spermicide
* cap, diaphragm or sponge with spermicide

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:

      1. Calcium channel blockers such as Nifedipine, Diltiazem or Verapamil
      2. 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;

Primary outcomes:
measure: Rectal pain and measured by VAS
timeFrame: measured at day 56
Secondary outcomes:
measure: Healing of anal fissure
timeFrame: day 56
Other outcomes:
Locations:
city: Plovdiv
country: Bulgaria
facility: UMHAT "Sveti Georgi", Internal Consulting Department
city: Sofia
country: Bulgaria
facility: "Multiprofile Hospital for Active Treatment - Doverie" AD, Clinic of Gastroenterology
city: Sofia
country: Bulgaria
facility: II MHAT, Internal Clinic, Department of Gastroenterology
city: Sofia
country: Bulgaria
facility: MC Health BG EOOD
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Lulin
city: Stara Zagora
country: Bulgaria
facility: MC "New rehabilitation centre'' EOOD
city: Veliko Tarnovo
country: Bulgaria
facility: "Multiprofile Regional Hospital for Active Treatment - Dr. St. Cherkezov" AD Department of Gastroenterology
city: Chisinau
country: Moldova, Republic of
facility: IMSP Spitalul Clinic Municipal Nr 1
city: Chisinau
country: Moldova, Republic of
facility: IMSP Spitalul Clinic Municipal Nr 3 "Sfanta Treime"
city: Chisinau
country: Moldova, Republic of
facility: IMSP Spitalul Clinic Republican
city: Lodz
country: Poland
facility: Med-Gastr Centrum Medyczne
city: Lublin
country: Poland
facility: Ambulatorium Medyczne Medical Hair & Esthetic
city: Piaseczno
country: Poland
facility: Centrum Innowacyjnych Terapii Sp. z o.o. Oddział w Piasecznie
city: Wolomin
country: Poland
facility: NZOZ Specjalistyczne Centrum Medyczne Flebo
city: Oradea
country: Romania
facility: Pelican Impex SRL
state: Jud. Bihor
city: Cluj Napoca
country: Romania
facility: IRGH
state: Jud. Cluj
city: Cluj Napoca
country: Romania
facility: Tvm Med Serv Srl
state: Jud. Cluj
city: Cluj-Napoca
country: Romania
facility: Institutul Regional de Gastroenterologie si Hepatologie "Prof. Dr. Octavian Fodor"
state: Jud. Cluj
city: Ploiesti
country: Romania
facility: SC Schnelbach Medical Care SRL
state: Jud. Prahova
city: Constanta
country: Romania
facility: Spit. Clinic Judetean de Urgenta "Sf. Apostol Andrei" Constanta
state: Judet Constanta
city: Ploiesti
country: Romania
facility: Dacmed SRL
state: Judetul Prahova
city: Brasov
country: Romania
facility: Centrul Medical de Diagnostic si Tratament Ambulator Neomed SRL
city: Bucharest
country: Romania
facility: Institutul Clinic Fundeni
city: Bucharest
country: Romania
facility: Centrul Medical Sfanta Vineri SRL
Study officials:
References: