Fissure in Ano, Pain
Conditions
Keywords
Pain associated with chronic anal fissure
Brief summary
Anal fissure is a solitary ulcer in the squamous epithelium of the anus causing intense anal pain especially during defecation and for 1 or 2 hours afterwards. There are no approved drugs in the United States (US) for this condition and surgery is often the treatment choice. Strakan is conducting this confirmatory study so the product can be submitted for regulatory approval in the US. Strakan currently markets this product throughout Europe. The objective of this study is to determine the effect of nitroglycerin ointment 0.4% (Cellegesic) versus placebo on average pain intensity over every 24 hour period for up to 21 days of treatment in 250 patients.
Interventions
DRUGCellegesic
Cellegesic was supplied as an ointment containing 0.4% w/w nitroglycerin.
DRUGPlacebo
Placebo was supplied as an ointment identical to Cellegesic ointment except that it contained no nitroglycerin.
Sponsors
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Consenting patients of either sex. * Between 18 and 75 years of age. * With a single, chronic, posterior midline anal fissure. * Defined as having anal pain for the 6 weeks prior to Screening.
Exclusion criteria
* More than one anal fissure. * A fistula-in-ano or anal abscess. * Inflammatory bowel disease. * Fibrotic anal stenosis. * Anal fissure secondary to an underlying condition. * Any anal surgery. * Concomitant medication that may interfere with study evaluation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pain Intensity at Days 14-18 | Baseline to Day 18 | Participants rated the pain associated with their chronic anal fissure over the preceding 24 hours on a 100 mm visual analog scale at Baseline and on Days 14 through 18. The average pain rating on Days 14 through 18 was calculated and used to determine the change from Baseline. The left-end of the visual analog scale was labelled least possible pain and the right-end of the visual analog scale was labelled worst possible pain. The pain rating ranged from 0 to 100, with a higher score indicating more pain. A negative change score indicated improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to an Improvement in Pain Intensity | Baseline to Day 21 | Participants rated the pain associated with their chronic anal fissure over the preceding 24 hours on a 100 mm visual analog scale (VAS) at Baseline and on each of the 21 treatment days of the study. The left-end of the visual analog scale was labelled least possible pain and the right-end of the visual analog scale was labelled worst possible pain. The pain rating ranged from 0 to 100, with a higher score indicating more pain. Improvement was defined as either a ≥ 50% decrease or a ≥ 10 mm decrease from Baseline in rated pain intensity. |
| Percentage of Responders | Baseline to Day 18 | Participants rated the pain associated with their chronic anal fissure over the preceding 24 hours on a 100 mm visual analog scale at Baseline and on Days 14 through 18. The average pain rating on Days 14 through 18 was calculated. The left-end of the visual analog scale was labelled least possible pain and the right-end of the visual analog scale was labelled worst possible pain. The pain rating ranged from 0 to 100, with a higher score indicating more pain. A responder was defined as a participant with either a ≥ 50% decrease or a ≥ 10 mm decrease from Baseline in the 24 hour average pain intensity averaged over Days 14 to 18. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cellegesic (Nitroglycerin 0.4%) Participants applied Cellegesic 375 mg ointment containing approximately 1.5 mg of nitroglycerin anally twice daily for 21 days. In addition, participants took acetaminophen 650 mg orally twice daily for 21 days. | 123 |
| Placebo Participants applied placebo 375 mg ointment anally twice daily for 21 days. In addition, participants took acetaminophen 650 mg orally twice daily for 21 days. | 124 |
| Total | 247 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 3 |
| Overall Study | Did not receive treatment | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Voluntary withdrawal | 5 | 4 |
Baseline characteristics
| Characteristic | Cellegesic (Nitroglycerin 0.4%) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 7 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 114 Participants | 117 Participants | 231 Participants |
| Age, Continuous | 46.5 years STANDARD_DEVIATION 12.61 | 43.4 years STANDARD_DEVIATION 13.22 | 45.0 years STANDARD_DEVIATION 12.99 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 31 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 100 Participants | 93 Participants | 193 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 16 Participants | 37 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) White | 99 Participants | 96 Participants | 195 Participants |
| Sex: Female, Male Female | 58 Participants | 58 Participants | 116 Participants |
| Sex: Female, Male Male | 65 Participants | 66 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 123 | 67 / 124 |
| serious Total, serious adverse events | 2 / 123 | 1 / 124 |
Outcome results
Primary
Change From Baseline in Pain Intensity at Days 14-18
Participants rated the pain associated with their chronic anal fissure over the preceding 24 hours on a 100 mm visual analog scale at Baseline and on Days 14 through 18. The average pain rating on Days 14 through 18 was calculated and used to determine the change from Baseline. The left-end of the visual analog scale was labelled least possible pain and the right-end of the visual analog scale was labelled worst possible pain. The pain rating ranged from 0 to 100, with a higher score indicating more pain. A negative change score indicated improvement.
Time frame: Baseline to Day 18
Population: Intent-to-treat population: All randomized participants who had applied the study medication at least once.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cellegesic (Nitroglycerin 0.4%) | Change From Baseline in Pain Intensity at Days 14-18 | -40.4 Units on a scale | Standard Error 3.12 |
| Placebo | Change From Baseline in Pain Intensity at Days 14-18 | -34.9 Units on a scale | Standard Error 3.04 |
Secondary
Percentage of Responders
Participants rated the pain associated with their chronic anal fissure over the preceding 24 hours on a 100 mm visual analog scale at Baseline and on Days 14 through 18. The average pain rating on Days 14 through 18 was calculated. The left-end of the visual analog scale was labelled least possible pain and the right-end of the visual analog scale was labelled worst possible pain. The pain rating ranged from 0 to 100, with a higher score indicating more pain. A responder was defined as a participant with either a ≥ 50% decrease or a ≥ 10 mm decrease from Baseline in the 24 hour average pain intensity averaged over Days 14 to 18.
Time frame: Baseline to Day 18
Population: Intent-to-treat population: All randomized participants who had applied the study medication at least once.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cellegesic (Nitroglycerin 0.4%) | Percentage of Responders | ≥ 50% decrease | 72.4 Percentage of responders |
| Cellegesic (Nitroglycerin 0.4%) | Percentage of Responders | ≥ 10 mm decrease | 88.6 Percentage of responders |
| Placebo | Percentage of Responders | ≥ 50% decrease | 64.5 Percentage of responders |
| Placebo | Percentage of Responders | ≥ 10 mm decrease | 85.5 Percentage of responders |
Secondary
Time to an Improvement in Pain Intensity
Participants rated the pain associated with their chronic anal fissure over the preceding 24 hours on a 100 mm visual analog scale (VAS) at Baseline and on each of the 21 treatment days of the study. The left-end of the visual analog scale was labelled least possible pain and the right-end of the visual analog scale was labelled worst possible pain. The pain rating ranged from 0 to 100, with a higher score indicating more pain. Improvement was defined as either a ≥ 50% decrease or a ≥ 10 mm decrease from Baseline in rated pain intensity.
Time frame: Baseline to Day 21
Population: Intent-to-treat population: All randomized participants who had applied the study medication at least once. Only participants with an improvement in pain intensity were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cellegesic (Nitroglycerin 0.4%) | Time to an Improvement in Pain Intensity | ≥ 50% decrease | 10.7 Days | Standard Error 0.6 |
| Cellegesic (Nitroglycerin 0.4%) | Time to an Improvement in Pain Intensity | ≥ 10 mm decrease | 6.1 Days | Standard Error 0.5 |
| Placebo | Time to an Improvement in Pain Intensity | ≥ 50% decrease | 13.2 Days | Standard Error 0.7 |
| Placebo | Time to an Improvement in Pain Intensity | ≥ 10 mm decrease | 7.2 Days | Standard Error 0.6 |