LDN-Ped: The Efficacy of Low Dose Naltrexone Therapy in Children With Crohn's Disease

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00715117
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 25
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Crohn's Disease	Drug: Naltrexone; Other: Placebo, sugar pill	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Efficacy of Low Dose Naltrexone Therapy in Children With Crohn's Disease
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Sugar pill Subjects will receive placebo for for the first 8 weeks administered orally one time daily. After 8 weeks placebo treated subjects are then crossed over to active drug naltrexone 0.1 mg/kg not to exceed 4.5 mg PO once daily for an additional 8 weeks.	Other: Placebo, sugar pill; Placebo -Sugar pill or liquid identical to active drug in appearance and taste given by mouth at bedtime once daily; Other Names: sugar pill
Experimental: Naltrexone Naltrexone 0.1 mg/kg (not to exceed 4.5mg) once a day orally either in capsules or liquid blinded for 8 weeks followed by open-labeled naltrexone for an additional 8 weeks. Safety and toxicity will be compared to placebo. Also change in Crohn's activity index scores of naltrexone to placebo are compared.	Drug: Naltrexone; Naltrexone 0.1 mg/kg (not to exceed 4.5mg) once a day orally for 16 weeks; Other Names: Revia, Vivitrol

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Penn State University hershey Medical center	Hershey	Pennsylvania	United States	17033

Sponsors and Collaborators

• Milton S. Hershey Medical Center

Investigators

• Principal Investigator: Jill P Smith, MD, Pennsylvania State University College of Medicine

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Penn State College of Medicine- Clinical Trials Office Site

Publications

• Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, Zagon IS. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn's disease: a randomized placebo-controlled trial. Dig Dis Sci. 2011 Jul;56(7):2088-97. doi: 10.1007/s10620-011-1653-7. Epub 2011 Mar 8.
• Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Low-dose naltrexone therapy improves active Crohn's disease. Am J Gastroenterol. 2007 Apr;102(4):820-8. Epub 2007 Jan 11.

• Responsible Party: Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00715117
• Other Study ID Numbers: PSU-IRB-27793
• First Posted: Jul 15, 2008
• Last Update Posted: Sep 6, 2018
• Last Verified: May 1, 2013

• Keywords provided by Milton S. Hershey Medical Center: children; pediatric; Crohn's Disease; naltrexone; LDN; IBD; Inflammatory bowel disease
• Additional relevant MeSH terms: Crohn Disease; Naltrexone

Study Results

Participant Flow

Recruitment Details	14 subjects were enrolled in this pilot trial and 2 were screen failures and not randomized or treated
Pre-assignment Detail	The 2 subjects who were screen failures had PCDAI scores less than 30.

Arm/Group Title	A: Placebo Then Naltrexone	B: Naltrexone Then Naltrexone
Arm/Group Description	Subjects will receive placebo for for the first 8weeks then be crossed over to active drug naltrexone for the last 8 weeks	Naltrexone 0.1 mg/kg (not to exceed 4.5mg) once a day for 8 weeks followed by the same treatment for an additional 8 weeks
Period Title: Overall Study
STARTED	6	6
Completion fo 8 Week Study	6	6
COMPLETED	6	5
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	A: Placebo Control Group	B: Naltrexone, Active Drug Group	Total
Arm/Group Description	Subjects will receive placebo for for the first 8weeks then be crossed over to active drug for the last 8 weeks	Naltrexone 0.1 mg/kg (not to exceed 4.5mg) once a day for 16 weeks	Total of all reporting groups
Overall Participants	6	6	12
Age (Count of Participants)
<=18 years	6 100%	6 100%	12 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.2 (3.31)	13 (3.22)	12.5 (3.2)
Sex: Female, Male (Count of Participants)
Female	2 33.3%	5 83.3%	7 58.3%
Male	4 66.7%	1 16.7%	5 41.7%
Sex: Female, Male (Count of Participants)
Female	2 33.3%	5 83.3%	7 58.3%
Male	4 66.7%	1 16.7%	5 41.7%
Region of Enrollment (participants) [Number]
United States	6 100%	6 100%	12 100%
Pediatric Crohn's Disease Activity Index (PCDAI) score (score) [Mean (Full Range) ]
Mean (Full Range) [score]	45	38.3	41.7

Outcome Measures

1. Secondary Outcome

Title	Pediatric Crohn's Disease Activity Index Score (PCDAI)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	All Participants Pretreament	Placebo	Naltrexone
Arm/Group Description	All participants prior to receiving placebo or naltrexone at week 0	Patients were treated with a placebo (sugar pill)for 8 weeks.	Includes all Naltrexone treated participants 8 weeks of treatment.
Measure Participants	12	6	12
Mean (Standard Error) [units on a scale]	34.2 (3.3)	30 (4.9)	21.7 (3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Naltrexone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Naltrexone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Change in Quality of Life Scores From Baseline to After 8 Weeks of Naltrexone Therapy
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Baseline	Week 16
Arm/Group Description	Quality of life values in all subjects at baseline before receiving placebo or naltrexone.	Quality of life survey values in all subjects determined at week 16 after all 12 participants had received naltrexone for either 8 or 16 weeks.
Measure Participants	12	12
Bowel symptoms	20 (2.1)	23 (1.9)
Social well-being	40 (0.9)	45 (0.8)
Emotional Well-being	20 (1.6)	24 (1.5)
Systemic symtoms	9.8 (0.2)	10.1 (0.2)
Body image	10.2 (0.2)	10.3 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Bowel symptoms
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Social well-being
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Emotional well-being
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments	Systemic symptoms
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Body Image
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Number of Patients Reporting Side Effects
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Naltrexone
Arm/Group Description	These subjects received placebo for 8 weeks by mouth daily.	These subjects were treated with naltrexone at a dose 0.1 mg/kg not to exceed 4.5 mg po daily for either 8 or 16 weeks.
Measure Participants	6	12
Sleep disturbance	2 33.3%	2 33.3%
Unusal Dreams	0 0%	2 33.3%
Twitching	1 16.7%	1 16.7%
Headaches	1 16.7%	0 0%
Decreased appetite	1 16.7%	0 0%
Nausea	0 0%	1 16.7%
Hair loss	1 16.7%	0 0%
Fatigue	1 16.7%	0 0%
Flushed ears	0 0%	1 16.7%
Papules, rash	1 16.7%	0 0%
Double vision	0 0%	1 16.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Sleep disturbance
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Unusual dreams
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Twitching
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Headaches
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Decreased appetite
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Nausea
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Hair loss
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Fatigue
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Flushed ears
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Papules, rash
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	All Participants Pretreament, Placebo
	Comments	Double vision
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Arm/Group Title	A: Placebo Control Group		B: Naltrexone, Active Drug Group
Arm/Group Description	Subjects will receive placebo for 8weeks		Naltrexone 0.1 mg/kg (not to exceed 4.5mg) once a day for 8 or 16 weeks
All Cause Mortality
	A: Placebo Control Group		B: Naltrexone, Active Drug Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	A: Placebo Control Group		B: Naltrexone, Active Drug Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	A: Placebo Control Group		B: Naltrexone, Active Drug Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		4/12 (33.3%)
Eye disorders
Double vision	0/6 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Nausea	0/6 (0%)		1/12 (8.3%)
General disorders
Fatigue	1/6 (16.7%)		0/12 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/6 (16.7%)		0/12 (0%)
Nervous system disorders
Twitching	1/6 (16.7%)		1/12 (8.3%)
Headaches	1/6 (16.7%)		0/12 (0%)
Psychiatric disorders
Sleep disturbance	2/6 (33.3%)		2/12 (16.7%)
Unusual dreams	0/6 (0%)		2/12 (16.7%)
Skin and subcutaneous tissue disorders
Hair loss	1/6 (16.7%)		0/12 (0%)
Papules, rash	1/6 (16.7%)		0/12 (0%)
Vascular disorders
Flushed ears	0/6 (0%)		1/12 (8.3%)

Limitations/Caveats

This was a pseudo-crossover trial where 6 subjects received placebo for 8 wks then were crossed over to active drug for 8 wks to increase the N treated with active drug. A smaller cohort of subjects on placebo were for safety & toxicity comparison.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

No restrictions by the sponsor. The PI may disclose results after the manuscript has been published.