Crohn's Disease, Inflammation
Conditions
Keywords
naltrexone, LDN, IBD, Inflammatory bowel disease
Brief summary
It is hypothesized that the opioid antagonist naltrexone will improve inflammation of the bowel and quality of life in subjects with active Crohn's disease compared to placebo. In order to test this hypothesis the following specific aims are proposed: 1. Evaluate the effects of low dose naltrexone compared to placebo on the activity of Crohn's disease by the following end points: Crohn's Disease Activity Index (CDAI), pain assessment, laboratory values (CRP and ESR), endoscopic appearance, histology, and quality of life surveys; 2. Examine the effects of naltrexone given over 3 months compared to 6 months for durability of response; 3. Determine the safety and toxicity of low dose naltrexone in subjects with active Crohn's disease, and 4. Study the mechanism by which naltrexone exerts its effect by measuring plasma enkephalin levels of subjects on therapy. Purpose statement: The purpose of this study is to evaluate the effects of low dose naltrexone in a blinded placebo controlled study to determine the safety and efficacy of this compound in those with active Crohn's disease.
Detailed description
Study design : The study is designed as a double-blind placebo controlled study for 3 months followed by a pseudo cross-over such that all subjects receiving placebo the first 3 months will receive active drug the second 3 months and all receiving naltrexone the first 3 months remain on the drug the last 3 months of this 6 month study.
Interventions
DRUGNaltrexone-HCl
naltrexone 4.5 mg
DRUGPlacebo
Placebo
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
The Broad Foundation
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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
* All subjects must give written informed consent * Male or female subjects, \> 18 years * Patients must have endoscopic, histologic, or radiographic confirmed Crohn's Disease. * Patients must have a Crohn's Disease Activity Index (CDAI) of at least 220 at Baseline * Stable doses of medications for Crohn's disease over proceeding 4 weeks (for aminosalicylates and steroids: prednisone of 10mg or less daily and Entocort 3 mg/ day are allowed), and 12 weeks for azathioprine or 6-mercaptopurine.)
Exclusion criteria
* Subjects with ostomies or ileorectal anastomosis from prior surgical colectomy. * Subjects who received infliximab (Remicade) within 8 weeks of study screening or humira for 4 weeks. * Subjects requiring steroids either intravenously or prednisone \>10mg /day or Entocort \> 3 mg daily. * Subjects with short-bowel syndrome. * Abnormal liver enzymes at screening visit or known hepatitis or cirrhosis * Hemoglobin less than 10. * Subjects with cancer (other than skin cancer) in past 5 years. * Women of childbearing potential unless surgically sterile or using adequate contraception (either IUD, oral or deport contraceptive, or barrier plus spermicide), and willing and able to continue contraception for 3 months after the completion of the study. * Women who are pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving a 70-point Decline in CDAI Scores (Crohn's Disease Activity Index) Scores; | 3 months | The CDAI score is a number which consists of information collected from a 7-day diary from the patient regarding symptoms. It also includes objective information from the physical exam, weight and hemotocrit. Remission is considered a score of 150 or less. Active disease is considered 220 or greater. A response to therapy is considered a decline in the CDAI score of 70-points from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline of Quality of Life IBDQ (Inflammatory Bowel Disease Quality of Life Survey) | Between baseline and 3 months | IBDQ (Inflammatory bowel Disease questionnaire) contains questions about health ranging from a score of poor (i.e., 32) to excellent (i.e., 224) an increase from baseline indicates improvement in quality of life. |
| Percentage of Patients With a 5 Point Drop in CDEIS Score by Endoscopy | 12 weeks | A secondary outcome was the appearance of the colonic mucosa on endoscopy using the Crohn's Disease Endoscopic Index of Severity (CDEIS) score described by Mary et al. Gut 1989;30:983-989.This score ranges from 0-44 based upon the extent and severity of inflammation and ulcers seen during endoscopy of the colon. A response is a drop of \> 5 points from baseline. Endoscopic remission is a score of \< 6 and Complete endoscopic remission is a score of \> 3. |
| Histology Inflammatory Score by Colon Biopsies | 12 weeks | Histology scores to assess microscopic inflammation and structural architecture were determined at baseline and after 12 weeks of either naltrexone therapy or placebo by mucosal biopsy samples obtained during colonoscopies.The pathology specimens were reviewed and scored by a Pathologist blinded to the treatment. The mean scores at baseline were the same between both groups.Differences between naltrexone and placebo treated subjects was assessed.The range in scores could be 0-25, with 0 representing no inflammation and 25 being maximum or severe inflammation.. |
Countries
United States
Participant flow
Recruitment details
This prospective, double blind, randomized placebo-controlled trial, undertaken between September 2006 and September 2009 at the Pennsylvania State University College of Medicine.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Daily Subjects will receive placebo for 3 months then be crossed over to active drug for an additional 3 months | 20 |
| Naltrexone 4.5 mg po Daily Group 2 will receive naltrexone 4.5 mg by mouth once a day for 6 months | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Daily | Naltrexone 4.5 mg po Daily | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 20 Participants | 39 Participants |
| Age, Continuous | 44.8 years STANDARD_DEVIATION 2.8 | 40.5 years STANDARD_DEVIATION 2.4 | 42.3 years STANDARD_DEVIATION 2.5 |
| Crohn's Disease Activity Index (CDAI) score | 327 CDAI score STANDARD_DEVIATION 19 | 365 CDAI score STANDARD_DEVIATION 16 | 346 CDAI score STANDARD_DEVIATION 17.5 |
| Region of Enrollment United States | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 20 | 5 / 40 |
| serious Total, serious adverse events | 0 / 20 | 0 / 40 |
Outcome results
Primary
Percentage of Subjects Achieving a 70-point Decline in CDAI Scores (Crohn's Disease Activity Index) Scores;
The CDAI score is a number which consists of information collected from a 7-day diary from the patient regarding symptoms. It also includes objective information from the physical exam, weight and hemotocrit. Remission is considered a score of 150 or less. Active disease is considered 220 or greater. A response to therapy is considered a decline in the CDAI score of 70-points from baseline.
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects Achieving a 70-point Decline in CDAI Scores (Crohn's Disease Activity Index) Scores; | 40 percentage of pts |
| Naltrexone 4.5 mg po Daily | Percentage of Subjects Achieving a 70-point Decline in CDAI Scores (Crohn's Disease Activity Index) Scores; | 88 percentage of pts |
Comparison: The proportion of those achieving a response with a 70-point decline in CDAI score was compared between naltrexone and placebo treated subjects using the Fisher's exact test. Analysis was performed with the intent-to-treat criteria. Clinical significance was accepted if the difference met 95% confidence (p\<0.05).p-value: 0.009Fisher Exact
Secondary
Histology Inflammatory Score by Colon Biopsies
Histology scores to assess microscopic inflammation and structural architecture were determined at baseline and after 12 weeks of either naltrexone therapy or placebo by mucosal biopsy samples obtained during colonoscopies.The pathology specimens were reviewed and scored by a Pathologist blinded to the treatment. The mean scores at baseline were the same between both groups.Differences between naltrexone and placebo treated subjects was assessed.The range in scores could be 0-25, with 0 representing no inflammation and 25 being maximum or severe inflammation..
Time frame: 12 weeks
Population: Tissue was removed by biopsy in those undergoing colonoscopy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Histology Inflammatory Score by Colon Biopsies | 17.5 units on a scale | Standard Error 4.5 |
| Naltrexone 4.5 mg po Daily | Histology Inflammatory Score by Colon Biopsies | 5.2 units on a scale | Standard Error 2.3 |
p-value: 0.048t-test, 1 sided
Secondary
Percentage Change From Baseline of Quality of Life IBDQ (Inflammatory Bowel Disease Quality of Life Survey)
IBDQ (Inflammatory bowel Disease questionnaire) contains questions about health ranging from a score of poor (i.e., 32) to excellent (i.e., 224) an increase from baseline indicates improvement in quality of life.
Time frame: Between baseline and 3 months
Population: Same as sample size calculation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline of Quality of Life IBDQ (Inflammatory Bowel Disease Quality of Life Survey) | 18 percentage of change | Standard Error 4 |
| Naltrexone 4.5 mg po Daily | Percentage Change From Baseline of Quality of Life IBDQ (Inflammatory Bowel Disease Quality of Life Survey) | 28 percentage of change | Standard Error 5 |
Secondary
Percentage of Patients With a 5 Point Drop in CDEIS Score by Endoscopy
A secondary outcome was the appearance of the colonic mucosa on endoscopy using the Crohn's Disease Endoscopic Index of Severity (CDEIS) score described by Mary et al. Gut 1989;30:983-989.This score ranges from 0-44 based upon the extent and severity of inflammation and ulcers seen during endoscopy of the colon. A response is a drop of \> 5 points from baseline. Endoscopic remission is a score of \< 6 and Complete endoscopic remission is a score of \> 3.
Time frame: 12 weeks
Population: Sample size was calculated under the assumption that at least 60% of the naltrexone-treated patients, and no more than 10% of the placebo-treated patients, would respond with at least a 70-point decline in CDAI scores. With a 10% withdrawal rate, 40 subjects yields an 86% power using a two-sided, 0.05-significance level Fisher's exact test.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Patients With a 5 Point Drop in CDEIS Score by Endoscopy | 28 percentage of patients | — |
| Naltrexone 4.5 mg po Daily | Percentage of Patients With a 5 Point Drop in CDEIS Score by Endoscopy | 78 percentage of patients | 0.05 |
Comparison: Percentage of patients having a 5-point decline in the endoscopic inflammation scorep-value: 0.008Fisher Exact