Crohn's Disease
Conditions
Keywords
children, pediatric, Crohn's Disease, naltrexone, LDN, IBD, Inflammatory bowel disease
Brief summary
It is hypothesized that oral naltrexone will improve inflammation of the bowel by increasing endogenous enkephalin levels in subjects with active Crohn's disease. This is especially important in children who often are suffering from nutritional deprivation which retards their growth. The key objectives are to: 1. Evaluate the effects of low dose naltrexone in children with Crohn's Disease by using the Pediatric Crohn's Disease Activity Index (PCDAI), plasma inflammatory markers, weight, and pediatric quality of life survey. 2. To determine the safety and toxicity of low dose naltrexone in pediatric subjects with active Crohn's Disease. 3. Assess the potential mechanism by which naltrexone exerts its action by measuring plasma opioid (enkephalin and endorphin levels) and proinflammatory cytokines.
Detailed description
The present proposal is designed as double-blinded placebo controlled study involving 30 children between 6-17 years of age with active Crohn's disease. Children will be treated with either naltrexone or placebo for the first 8 weeks then all subjects will receive active naltrexone drug the last 8 weeks. A one month follow-up appointment will be scheduled 4-weeks after completion of the active drug for safety and to assess Crohn's activity. Low dose naltrexone (LDN) will be dispensed in either capsules at a dose of 4.5 mg for those ages 10 years or older and in liquid form at 0.1 mg/kg for those under age of 10 or less than 45 kg. Half of the subjects in the first 8 weeks will be randomized to placebo which will be either capsules filled with avicel (see section 6.0) or diluent (flavored water) if in liquid form. Children are eligible who are not of child-bearing potential or are using two means of effective birth control, have a Pediatric Crohn's Disease Activity Index (PCDAI) of at least 31 points, and have the confirmed diagnosis of Crohn's disease by either endoscopic or radiographic tests.
Interventions
DRUGNaltrexone
Naltrexone 0.1 mg/kg (not to exceed 4.5mg) once a day orally for 16 weeks
OTHERPlacebo, sugar pill
Placebo -Sugar pill or liquid identical to active drug in appearance and taste given by mouth at bedtime once daily
Sponsors
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
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* All subjects must give written informed consent by parent or guardian * Male or female subjects, \> 6 - 17 years * Patients must have endoscopic or radiographic confirmed Crohn's Disease. * Patients must have a Pediatric Crohn's Disease Activity Index (PCDAI) of at least 31.
Exclusion criteria
* Adolescent women of childbearing potential and / or sexually active 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. * Adolescent women who are pregnant or breastfeeding * Subjects with an ostomy or ileocolic anastomosis from surgery as these operations interfere with the PCDAI assessment * Subjects taking tacrolimus, cyclosporin, mycophenolate, or anti-TNF-α therapy must be discontinued 4 weeks prior to study initiation. * Patients with abnormal liver function tests * Prednisone greater than 10 mg or \> 0.2 mg/kg orally
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Reporting Side Effects | 8 weeks or 16 weeks | Using adverse events and laboratory values Safety & toxicity were evaluated between those on placebo for 8 weeks and those on naltrexone for either 8 or 16 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pediatric Crohn's Disease Activity Index Score (PCDAI) | Pretreatment and 8 weeks | Secondary outcome was efficacy on clinical activity. Mean pretreatment PCDAI scores in patients had moderate to severe disease activity at baseline were compared between those who received placebo for 8 weeks and those who received active experimental drug, naltrexone. The PCDAI score is a number unit that is calculated from symptoms scores by the subject over a 7-day period prior to the visit, laboratory values, height & weight, and physical exam findings. A score of 10 and under denotes remission. Mild disease (score of 11-30); moderate disease (score of 31-45), a severe disease (scores greater than 45. A decline of 10 points or more is considered response to therapy. The score can range from 0 to \>60 Patient must have a PCDAI score of equal or greater than 30 to qualify for this study (i.e., moderate to severe disease). |
| Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | 16 weeks | IMPACT III was a pediatric Crohn's specific quality of life survey used in this study. It examines five major categories influencing the quality of life in children with Crohn's disease including bowel symptoms, systemic symptoms, emotional well-being, social well-being, and body image perception. The IMPACT-III uses 5-point Likert scale ranging from 1 to 5 for all answers. The outcome score ranges from 35 to 175, with higher scores suggesting better quality of life. So an increase in score denotes improved Quality of life. |
Countries
United States
Participant flow
Recruitment details
14 subjects were enrolled in this pilot trial and 2 were screen failures and not randomized or treated
Pre-assignment details
The 2 subjects who were screen failures had PCDAI scores less than 30.
Participants by arm
| Arm | Count |
|---|---|
| A: Placebo Control Group Subjects will receive placebo for for the first 8weeks then be crossed over to active drug for the last 8 weeks | 6 |
| B: Naltrexone, Active Drug Group Naltrexone 0.1 mg/kg (not to exceed 4.5mg) once a day for 16 weeks | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Crohn's flare and rescue with steroids | 0 | 1 |
Baseline characteristics
| Characteristic | A: Placebo Control Group | B: Naltrexone, Active Drug Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 12.2 years STANDARD_DEVIATION 3.31 | 13 years STANDARD_DEVIATION 3.22 | 12.5 years STANDARD_DEVIATION 3.2 |
| Pediatric Crohn's Disease Activity Index (PCDAI) score | 45 score | 38.3 score | 41.7 score |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 6 | 4 / 12 |
| serious Total, serious adverse events | 0 / 6 | 0 / 12 |
Outcome results
Primary
Number of Patients Reporting Side Effects
Using adverse events and laboratory values Safety & toxicity were evaluated between those on placebo for 8 weeks and those on naltrexone for either 8 or 16 weeks.
Time frame: 8 weeks or 16 weeks
Population: The Fisher Exact Test was used to evaluate the number of side effects reported between placebo and naltrexone groups. The Student T-test was used to evaluate the differences between the mena values of laboratory tests.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants Pretreament | Number of Patients Reporting Side Effects | Papules, rash | 1 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Double vision | 0 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Sleep disturbance | 2 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Unusal Dreams | 0 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Twitching | 1 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Headaches | 1 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Decreased appetite | 1 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Nausea | 0 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Hair loss | 1 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Fatigue | 1 participants |
| All Participants Pretreament | Number of Patients Reporting Side Effects | Flushed ears | 0 participants |
| Placebo | Number of Patients Reporting Side Effects | Flushed ears | 1 participants |
| Placebo | Number of Patients Reporting Side Effects | Decreased appetite | 0 participants |
| Placebo | Number of Patients Reporting Side Effects | Double vision | 1 participants |
| Placebo | Number of Patients Reporting Side Effects | Fatigue | 0 participants |
| Placebo | Number of Patients Reporting Side Effects | Sleep disturbance | 2 participants |
| Placebo | Number of Patients Reporting Side Effects | Nausea | 1 participants |
| Placebo | Number of Patients Reporting Side Effects | Unusal Dreams | 2 participants |
| Placebo | Number of Patients Reporting Side Effects | Papules, rash | 0 participants |
| Placebo | Number of Patients Reporting Side Effects | Twitching | 1 participants |
| Placebo | Number of Patients Reporting Side Effects | Hair loss | 0 participants |
| Placebo | Number of Patients Reporting Side Effects | Headaches | 0 participants |
Comparison: Sleep disturbancep-value: 1Fisher Exact
Comparison: Unusual dreamsp-value: 0.45Fisher Exact
Comparison: Twitchingp-value: 1Fisher Exact
Comparison: Headachesp-value: 1Fisher Exact
Comparison: Decreased appetitep-value: 1Fisher Exact
Comparison: Nauseap-value: 1Fisher Exact
Comparison: Hair lossp-value: 1Fisher Exact
Comparison: Fatiguep-value: 1Fisher Exact
Comparison: Flushed earsp-value: 1Fisher Exact
Comparison: Papules, rashp-value: 1Fisher Exact
Comparison: Double visionp-value: 1Fisher Exact
Secondary
Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy
IMPACT III was a pediatric Crohn's specific quality of life survey used in this study. It examines five major categories influencing the quality of life in children with Crohn's disease including bowel symptoms, systemic symptoms, emotional well-being, social well-being, and body image perception. The IMPACT-III uses 5-point Likert scale ranging from 1 to 5 for all answers. The outcome score ranges from 35 to 175, with higher scores suggesting better quality of life. So an increase in score denotes improved Quality of life.
Time frame: 16 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants Pretreament | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Social well-being | 40 units on a scale | Standard Error 0.9 |
| All Participants Pretreament | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Systemic symtoms | 9.8 units on a scale | Standard Error 0.2 |
| All Participants Pretreament | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Emotional Well-being | 20 units on a scale | Standard Error 1.6 |
| All Participants Pretreament | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Body image | 10.2 units on a scale | Standard Error 0.2 |
| All Participants Pretreament | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Bowel symptoms | 20 units on a scale | Standard Error 2.1 |
| Placebo | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Body image | 10.3 units on a scale | Standard Error 0.2 |
| Placebo | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Bowel symptoms | 23 units on a scale | Standard Error 1.9 |
| Placebo | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Social well-being | 45 units on a scale | Standard Error 0.8 |
| Placebo | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Emotional Well-being | 24 units on a scale | Standard Error 1.5 |
| Placebo | Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy | Systemic symtoms | 10.1 units on a scale | Standard Error 0.2 |
Comparison: Bowel symptomsp-value: >0.05t-test, 2 sided
Comparison: Social well-beingp-value: 0.035t-test, 2 sided
Comparison: Emotional well-beingp-value: >0.05t-test, 2 sided
p-value: 0.035t-test, 2 sided
Comparison: Body Imagep-value: >0.05t-test, 2 sided
Secondary
Pediatric Crohn's Disease Activity Index Score (PCDAI)
Secondary outcome was efficacy on clinical activity. Mean pretreatment PCDAI scores in patients had moderate to severe disease activity at baseline were compared between those who received placebo for 8 weeks and those who received active experimental drug, naltrexone. The PCDAI score is a number unit that is calculated from symptoms scores by the subject over a 7-day period prior to the visit, laboratory values, height & weight, and physical exam findings. A score of 10 and under denotes remission. Mild disease (score of 11-30); moderate disease (score of 31-45), a severe disease (scores greater than 45. A decline of 10 points or more is considered response to therapy. The score can range from 0 to \>60 Patient must have a PCDAI score of equal or greater than 30 to qualify for this study (i.e., moderate to severe disease).
Time frame: Pretreatment and 8 weeks
Population: The power calculations were performed using STPLAN version 4.1. The current investigation was designed as a pseudo-cross over study to increase the number of participants. In the proposed study, it was assumed that 80% would respond to naltrexone and that no more than 25% of the placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants Pretreament | Pediatric Crohn's Disease Activity Index Score (PCDAI) | 34.2 units on a scale | Standard Error 3.3 |
| Placebo | Pediatric Crohn's Disease Activity Index Score (PCDAI) | 30 units on a scale | Standard Error 4.9 |
| Naltrexone | Pediatric Crohn's Disease Activity Index Score (PCDAI) | 21.7 units on a scale | Standard Error 3.9 |
p-value: 0.005t-test, 2 sided
p-value: >0.05t-test, 2 sided