Pharmacokinetic,Safety and Exploratory Efficacy of RECTIV® in Adolescents With Chronic Anal Fissure

A Phase 4, Multiple-dose, Pharmacokinetic, Safety, and Exploratory Efficacy Study of Nitroglycerin Ointment 0.4% (RECTIV®) in Adolescents (Age ≥12 to <17 Years) With Moderate to Severe Pain Due to Chronic Anal Fissure

RECTIV® is an ointment containing 0.4% nitroglycerin (NTG) for the treatment of moderate to severe pain associated with chronic anal fissure approved in June 2011 by the US Food and Drug Administration (FDA) for adults. The purpose of this study is to assess the safety, pharmacokinetics, and exploratory efficacy of RECTIV® in adolescents

Study Overview

• Status: Withdrawn
• Conditions: Anal Fissure
• Intervention / Treatment: Drug: Nitroglycerin Ointment 0.4%

Detailed Description

This is an open-label, multicenter study conducted in up to 10 sites in the United States. A total of 13 pediatric male or female patients age ≥12 to <17 years will be enrolled. The patients will administer a dose of Rectiv® twice daily to characterize the safety, pharmacokinetics , and exploratory efficacy of Nitroglycerin Ointment 0.4% (RECTIV® )over 5 days

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital
  • Florida
    • Miami, Florida, United States, 33135
      • Advanced Medical Research Center
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital for Children
  • Louisiana
    • Shreveport, Louisiana, United States, 71118
      • Willis-Knighton Pediatric GI Specialist
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Texas
    • Sealy, Texas, United States, 77474
      • Sealy Urgent Care Center and Medical Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Male or female ≥12 and <17 years of age
• At least 1 anal fissure for a minimum of 3 weeks in duration
• Anal fissure pain experienced over the last 24 hours at Screening and before enrollment
• Patient (and parent or caregiver as appropriate) has provided written informed consent

Key Exclusion Criteria:

• Current diagnosis of hemorrhoids
• Hypersensitivity, allergy, or contraindication to nitroglycerin
• History of hypertension and/or cardiovascular disease
• History or current diagnosis of inflammatory bowel disease
• History or current diagnosis of fistula(e)-in-ano or an anal abscess
• Fibrotic anal stenosis
• Previous anal surgery
• Diagnosis of cancer
• History of migraine or chronic headaches requiring treatment with analgesics
• Pregnant or lactating female patients
• Weight <36 kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rectiv	Drug: Nitroglycerin Ointment 0.4%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Noncompartmental pharmacokinetic (PK) analyses will be performed on the full pharmacokinetic curves for NTG and its metabolites (1,2 glyceryl dinitrate and 1,3 glyceryl dinitrate) on Day 5	The following PK parameters will be calculated as data permit: Maximum observed concentration (Cmax); Time of the maximum observed plasma concentration (Tmax); Area under the concentration time curve from dosing up to the last quantifiable concentration (AUC0-last).; Area under the concentration time curve from dosing up to 480 minutes (AUC0-480); The extrapolated area under the concentration time curve from dosing up to 12 hours (AUC0-12h) also will be calculated if quantifiable concentrations are observed during the entire dose interval.; Terminal elimination half-life (t1/2) On the basis of the results of the study, additional noncompartmental PK parameters may be calculated and reported. In addition, a population PK model for NTG will be developed based on the PK data from Day 5. By using this model, the following additional PK parameters may be reported: Apparent volume of distribution (V/F); Apparent clearance (CL/F)	Day 5

Secondary Outcome Measures

Outcome Measure	Time Frame
• Absolute change from baseline in 24-hour average anal fissure pain scores assessed by the Wong-Baker FACES® and the Numerical Rating Scale for pain after each evening dose over days 1 through 4	Day 5

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the safety of Rectiv® in adolescents (age ≥12 to <17 years)	Safety and tolerability are assessed through adverse events (AEs), clinical laboratory test results (hematology, serum biochemistry, and urinalysis), vital sign measurements (heart rate, supine and orthostatic blood pressure, oral temperature, and respiratory rate), 12-lead ECG results, anal area assessment, physical examination findings (including body weight), and concomitant medications (including the use of rescue acetaminophen for headaches).	Screening through the completion of study participation

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Investigators: Principal Investigator: Paul Hyman, MD, Children's Hospital New Orleans, LA; Study Director: Taryn Weissman, MD

Publications and helpful links

General Publications

• Demirbag S, Tander B, Atabek C, Surer I, Ozturk H, Cetinkursun S. Long-term results of topical glyceryl trinitrate ointment in children with anal fissure. Ann Trop Paediatr. 2005 Jun;25(2):135-7. doi: 10.1179/146532805X45737.
• Kenny SE, Irvine T, Driver CP, Nunn AT, Losty PD, Jones MO, Turnock RR, Lamont GL, Lloyd DA. Double blind randomised controlled trial of topical glyceryl trinitrate in anal fissure. Arch Dis Child. 2001 Nov;85(5):404-7. doi: 10.1136/adc.85.5.404.
• Schiano di Visconte M, Di Bella R, Munegato G. Randomized, prospective trial comparing 0.25 percent glycerin trinitrate ointment and anal cryothermal dilators only with 0.25 percent glycerin trinitrate ointment and only with anal cryothermal dilators in the treatment of chronic anal fissure: a two-year follow-up. Dis Colon Rectum. 2006 Dec;49(12):1822-30. doi: 10.1007/s10350-006-0731-y.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: August 7, 2013
• First Submitted That Met QC Criteria: August 7, 2013
• First Posted (Estimate): August 9, 2013

Study Record Updates

• Last Update Posted (Estimate): May 4, 2015
• Last Update Submitted That Met QC Criteria: May 1, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Pediatrics; Nitroglycerin; Anal Fissure; RECTIV®; Pediatric Research Equity Act
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Anus Diseases; Fissure in Ano; Vasodilator Agents; Nitroglycerin
• Other Study ID Numbers: APT-NIT_S-PRO-M_PEDKPK1_E