Trial of Amitriptyline for Chronic Oral Food Refusal in Children 9 Months to 8 Years of Age

• Sponsor: Ann Davis, PhD, MPH, ABPP (Other)
• Overall Status: Completed
• CT.gov ID: NCT01206478
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 21
• Locations: 3
• Arms: 2
• Duration (Months): 52
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Gastrojejunal (G-J) feeding tubes are placed in infants and children who refuse to eat or are unable to eat enough to have normal growth. Although often intended as temporary short-term solutions to medical complications, feeding tubes can become a permanent method for eating.

While tube feeding routinely saves the lives of children who have long term food refusal, continuation of tube feeding can be hard for patients, caregivers, and families. At the current time there are few treatments for helping children move from tube to oral feeding. Some patients may be treated with the help of inpatient programs such as a combination of medical and behavioral techniques to train children to eat orally. These programs typically require hospital stays of 2-4 months.

By doing the current study the investigators hope to learn if the investigational drug amitriptyline is helpful in moving children from tube to oral feeding, and to look at whether or not the treatment of pain helps with this transition.

Condition or Disease	Intervention/Treatment	Phase
Chronic Oral Food Refusal	Drug: Amitriptyline; Drug: Placebo; Drug: Megestrol	Phase 2

Detailed Description

This research study involves a study drugs called amitriptyline and megestrol. Amitriptyline might help children who have feeding problems with pain and megestrol is known to increase appetite. Amitriptyline and megestrol are liquid syrups that are given by feeding tube daily.

Amitriptyline has not been approved by the United States Food and Drug Administration (FDA) for the treatment of child with feeding problems. Amitriptyline is an investigational drug that is being studied to find out what the side effects are, and whether or not the product works for child with feeding problems. Amitriptyline is approved by the FDA for the treatment of depression.

Megestrol has not been approved by the United States Food and Drug Administration (FDA) for the treatment of children with feeding problems. Megestrol is an investigational drug that is being studied to find out what the side effects are, and whether or not the product works for children with feeding problems. Megestrol has been approved by the FDA for the treatment of adults. Though megestrol is not FDA approved to treat children with feeding problems, it is often used for this purpose.

Megestrol and Amitriptyline both affect the nerve cells that carry pain sensations to and from the brain. Both drugs reduce the intensity of the pain signals going to the part of the brain that feels pain. Each drug attaches to the nerve cell but at separate spots on the nerve cell so pain can be better managed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II, Randomized-Controlled, Multicenter Trial of Amitriptyline for Chronic Oral Food Refusal in Children 9 Months to 8 Years of Age
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Amitriptyline plus Megestrol Amitriptyline once daily at bedtime plus megestrol starting at visit 2	Drug: Amitriptyline; Amitriptyline 1 mg/kg once daily at bedtime.; Drug: Megestrol; At Visit 2, after participating in the study for ten weeks, children will receive a prescription for the appetite stimulant megestrol. The dose each child will receive depends on their age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.
Active Comparator: Placebo plus Megestrol Matching placebo once daily at bedtime plus megestrol starting at visit 2	Drug: Placebo; Placebo (looks like study drug but has no active ingredients) once daily at bedtime.; Drug: Megestrol; At Visit 2, after participating in the study for ten weeks, children will receive a prescription for the appetite stimulant megestrol. The dose each child will receive depends on their age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.

Outcome Measures

Primary Outcome Measures

1. % Calories Taken Orally [baseline, 24 weeks]

   Percent Kilocalories (kcal) Obtained Orally. This measure was obtained using the 24 hour food recall, a standardized five-pass method developed by the US Department of Agriculture for use in national dietary surveillance. This measure has been widely used in several large trials and data suggest it is the most valid and reliable method of dietary assessment for children (20). The data were collected at week 0, week 10, and week 24 using standardized probes by highly trained research staff, and parents were presented with paper food models and measuring devices prior to interviews to reference during the recall. Recalls were analyzed with the Nutritional Data System for Research, version 2005; University of Minnesota, Minneapolis, MN.

Secondary Outcome Measures

1. Change in Non-communicating Children's Pain Checklist - Revised (NCCPC-R) Scores [baseline, 24 weeks]

   Non-communicating Children's Pain Checklist - Revised (NCCPC-R) used to measure outcome. The NCCPC-R is a 30 item measure intended to assess pain in children who are unable to speak because of cognitive or physical impairments. There are 7 sub-scales including vocal, social, facial, activity, body/limbs, physiological, and eating/sleeping. Each question has a potential score of 0 to 3. Scores are totaled for each sub-scale. Sub-scale scores are then added together for the Total Score. Total Scores can range from 0 to 90. The higher the score, the higher level of pain indicated by the child. This measure was completed by parents at week 0, week 10, and week 24.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 9 Months to 8 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria

Subjects must meet all of the following inclusion criteria:

1. Males or females 9 months to 8 years 0 months 0 days of age.

2. Able to obtain parental or legal guardian written informed consent from subjects as applicable by local laws and regulations.

3. Subjects must possess the oral motor skills necessary for eating according to Table 1 in the Appendix.

4. Subjects must possess behavioral skills necessary for mealtime according to Table 2 in the Appendix.

5. Subjects must have a history of chronic oral food refusal (3 months of refusing to eat more than 5% of their caloric intake orally) and be fed >95% of their caloric intake through a gastrostomy tube for 3 months or longer.

6. Subjects will be required to have a body mass index for age/gender of 25% or greater prior to beginning the protocol to ensure that subjects are sufficiently nourished.

Exclusion Criteria

Study enrollment will exclude potential subjects with any of the following conditions or taking any of the following medication:

1. Children on MAO inhibitors or who have thyroid problems will be excluded.

2. Children with diabetes or adrenal insufficiency will be excluded.

3. Children with known heart conduction abnormalities.

4. Children taking tricyclic medications.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
2	Children's Hospital of New Orleans	New Orleans	Louisiana	United States	70118
3	Nationwide Children's Hospital	Columbus	Ohio	United States	43205

Sponsors and Collaborators

• Ann Davis, PhD, MPH, ABPP
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Ann Davis, Ph.D., MPH, ABPP, University of Kansas Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ann Davis, PhD, MPH, ABPP, Professor, University of Kansas Medical Center
• ClinicalTrials.gov Identifier: NCT01206478
• Other Study ID Numbers: 12261; R21HD066629
• First Posted: Sep 21, 2010
• Last Update Posted: Aug 15, 2016
• Last Verified: May 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Megestrol; Amitriptyline

Study Results

Participant Flow

Arm/Group Title	Amitriptyline, Megestrol	Placebo, Megestrol
Arm/Group Description	Amitriptyline 1 mg/kg: Amitriptyline 1 mg/kg once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.	Placebo: Placebo (looks like study drug but has no active ingredients) once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.
Period Title: Overall Study
STARTED	9	12
COMPLETED	7	7
NOT COMPLETED	2	5

Baseline Characteristics

Arm/Group Title	Amitriptyline, Megestrol	Placebo, Megestrol	Total
Arm/Group Description	Amitriptyline 1 mg/kg: Amitriptyline 1 mg/kg once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.	Placebo: Placebo (looks like study drug but has no active ingredients) once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.	Total of all reporting groups
Overall Participants	9	12	21
Age (age (years)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [age (years)]	3.54 (2.25)	3.89 (1.84)	3.73 (1.99)
Sex: Female, Male (Count of Participants)
Female	4 44.4%	7 58.3%	11 52.4%
Male	5 55.6%	5 41.7%	10 47.6%
Region of Enrollment (participants) [Number]
United States	9 100%	12 100%	21 100%

Outcome Measures

1. Primary Outcome

Title	% Calories Taken Orally
Description	Percent Kilocalories (kcal) Obtained Orally. This measure was obtained using the 24 hour food recall, a standardized five-pass method developed by the US Department of Agriculture for use in national dietary surveillance. This measure has been widely used in several large trials and data suggest it is the most valid and reliable method of dietary assessment for children (20). The data were collected at week 0, week 10, and week 24 using standardized probes by highly trained research staff, and parents were presented with paper food models and measuring devices prior to interviews to reference during the recall. Recalls were analyzed with the Nutritional Data System for Research, version 2005; University of Minnesota, Minneapolis, MN.
Time Frame	baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amitriptyline, Megestrol	Placebo, Megestrol
Arm/Group Description	Amitriptyline 1 mg/kg: Amitriptyline 1 mg/kg once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.	Placebo: Placebo (looks like study drug but has no active ingredients) once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.
Measure Participants	7	7
Mean (Standard Deviation) [change in percent kcal obtained orally]	68.62 (17.29)	76.89 (15.68)

2. Secondary Outcome

Title	Change in Non-communicating Children's Pain Checklist - Revised (NCCPC-R) Scores
Description	Non-communicating Children's Pain Checklist - Revised (NCCPC-R) used to measure outcome. The NCCPC-R is a 30 item measure intended to assess pain in children who are unable to speak because of cognitive or physical impairments. There are 7 sub-scales including vocal, social, facial, activity, body/limbs, physiological, and eating/sleeping. Each question has a potential score of 0 to 3. Scores are totaled for each sub-scale. Sub-scale scores are then added together for the Total Score. Total Scores can range from 0 to 90. The higher the score, the higher level of pain indicated by the child. This measure was completed by parents at week 0, week 10, and week 24.
Time Frame	baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amitriptyline, Megestrol	Placebo, Megestrol
Arm/Group Description	Amitriptyline 1 mg/kg: Amitriptyline 1 mg/kg once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.	Placebo: Placebo (looks like study drug but has no active ingredients) once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.
Measure Participants	7	7
Mean (Standard Deviation) [units on a scale]	-2.5 (19.85)	-6.86 (8.65)

Adverse Events

Arm/Group Title	Amitriptyline, Megestrol		Placebo, Megestrol
Arm/Group Description	Amitriptyline 1 mg/kg: Amitriptyline 1 mg/kg once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.		Placebo: Placebo (looks like study drug but has no active ingredients) once daily at bedtime. At Visit 2, after participating in the study for ten weeks, children in both Groups 1 and 2 will receive a prescription for the appetite stimulant megestrol. The dose your child will receive depends on your child's age and weight. The dose of megestrol is 6 mg/kg divided into two doses per day.
All Cause Mortality
	Amitriptyline, Megestrol		Placebo, Megestrol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Amitriptyline, Megestrol		Placebo, Megestrol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Amitriptyline, Megestrol		Placebo, Megestrol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/12 (0%)

Limitations/Caveats

Major weakness was our small sample size, which was directly due to problems with recruitment, which occurred uniformly across sites. The primary reason for refusal was that parents did not want to be randomly assigned to the amitriptyline/placebo.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.