Anorexia Nervosa
Conditions
Keywords
anorexia nervosa, eating disorders, refeeding, adolescent medicine, nutritional rehabilitation
Brief summary
The purpose of this study is to compare the efficacy, safety, and cost-effectiveness of lower calorie refeeding versus higher calorie refeeding in hospitalized adolescents with anorexia nervosa.
Interventions
OTHERHigher Calorie Refeeding
OTHERLower Calorie Refeeding
Sponsors
Stanford University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 24 Years
Healthy volunteers
No
Inclusion criteria
* diagnosis of AN * atypical AN * no hospital admissions for the previous six months * meet hospitalization criteria: daytime heart rate (HR) \< 50 bpm or night time HR \< 45 bpm, blood pressure (BP) \<90/45 mmHg, temperature \< 35.6° C, or symptomatic orthostasis defined by increase in HR \> 35 bpm or decrease in systolic BP \> 20 mmHg or decrease in diastolic BP \> 10 mmHg from lying to standing
Exclusion criteria
* diagnosis of bulimia nervosa \[DSM-5\] * currently in remission (as defined by weight and EDE-Q score) * admission for food refusal without malnutrition * current pregnancy * chronic disease (e.g. immune/endocrine disorders, pulmonary, cardiac, or renal disease) * current suicidality or psychosis * \< 60% mBMI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Remission at Different Time Points of Assessment | up to 12 months | Clinical remission was defined as the combination of percentage mBMI and EDE-Q score at 1, 3, 6, and 12 months. This is a dichotomous variable 1/0. If participants achieve both weight recovery (defined as =\>95% of median BMI for sex and age), AND psychological recovery (defined as within 1SD of community norms for EDE-Q) then they are assigned a 1 for achieving clinical remission. If both parameters not met then 0 for not remitted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Achieve Medical Stability in Hospital | Inpatient hospitalization from day of admission to day of discharge, average of 10 days | Medical stability was adjudicated by a 6-point clinical index: (1) 24-hour heart rate of 45 beats/min or more, (2) systolic blood pressure of 90 mm Hg or more, (3) temperature of 35.6 °C or more, (4) orthostatic increase in heart rate of 35 beats/min or less, (5) orthostatic decrease in systolic blood pressure of 20 mm Hg or less, and (6) 75% or more of mBMI for age and sex. Criteria were assessed daily; for vital signs with multiple daily measures, the most deviant value was recorded (eg, lowest heart rate). Each criterion was scored as 1 if met, 0 if unmet, and missing (not scored) if not measured. Medical stability was considered restored when all measured criteria were stable for 24 hours, allowing a maximum of 2 missing values. Additional efficacy outcomes were time to restore heart rate to 45 beats/min or more (among those with bradycardia at baseline) and weight gain (change in percentage mBMI). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cost-effectiveness Per Adolescent Recovered | up to 12 months | defined as total cost (direct and indirect costs) |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled from February 8, 2016, to March 7, 2019 at 2 clinical sites, large tertiary care children's hospitals with eating disorder inpatient programs attended by interdisciplinary adolescent medicine care teams at the University of California San Francisco and Stanford University. Written informed consent was obtained from young adults and parents of minors, who provided written assent.
Pre-assignment details
Although 120 participants were randomized,116 started on the study. Of the 4 individuals who were randomized but did not receive treatment, 3 were found ineligible and 1 did not complete the consent, leaving 56 individuals in the LCR arm. Of those 56 individuals, an additional 5 individuals withdrew prior to receiving treatment, ultimately resulting in 51 participants in the LCR arm.
Participants by arm
| Arm | Count |
|---|---|
| Higher Calorie Refeeding (HCR) Protocol Meal-based refeeding in hospital: starting 2000 kcal/d and increasing 200 kcal/d to goal | 60 |
| Lower Calorie Refeeding (LCR) Protocol Meal-based refeeding in hospital: starting 1400 kcal/d and increasing 200 kcal every other day to goal | 56 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 12-month Follow-Up | Lost to Follow-up | 4 | 7 |
| Treatment in Hospital | Withdrawal by Subject | 0 | 5 |
Baseline characteristics
| Characteristic | Higher Calorie Refeeding (HCR) Protocol | Total | Lower Calorie Refeeding (LCR) Protocol |
|---|---|---|---|
| Admission percentage of median body mass index (%mBMI) | 83.3 % of mBMI STANDARD_DEVIATION 11.1 | 84.6 % of mBMI STANDARD_DEVIATION 11.9 | 86.6 % of mBMI STANDARD_DEVIATION 12.2 |
| Age, Continuous | 16.6 years STANDARD_DEVIATION 2.5 | 16.4 years STANDARD_DEVIATION 2.5 | 16.2 years STANDARD_DEVIATION 2.4 |
| Atypical anorexia nervosa (No., %) | 21 Participants | 48 Participants | 27 Participants |
| Global Eating Disorder Examination Questionnaire score (mean, SD) | 3.32 Score on a scale STANDARD_DEVIATION 1.68 | 3.34 Score on a scale STANDARD_DEVIATION 1.7 | 3.45 Score on a scale STANDARD_DEVIATION 1.71 |
| Lowest 24-hr heart rate, beats/min | 41.5 beats per minute STANDARD_DEVIATION 6.9 | 41.3 beats per minute STANDARD_DEVIATION 6.1 | 40.7 beats per minute STANDARD_DEVIATION 5.9 |
| Lowest Systolic Blood Pressure (mm Hg) | 94.2 mm Hg STANDARD_DEVIATION 8 | 93.7 mm Hg STANDARD_DEVIATION 8.1 | 93.3 mm Hg STANDARD_DEVIATION 8.3 |
| Race/Ethnicity, Customized Race/ethnicity Asian | 7 Participants | 14 Participants | 7 Participants |
| Race/Ethnicity, Customized Race/ethnicity Hispanic or Latino | 15 Participants | 24 Participants | 9 Participants |
| Race/Ethnicity, Customized Race/ethnicity Non-Hispanic White | 36 Participants | 69 Participants | 33 Participants |
| Race/Ethnicity, Customized Race/ethnicity Other or >1 race/ethnicity reported | 2 Participants | 9 Participants | 7 Participants |
| Region of Enrollment United States | 60 Participants | 116 Participants | 56 Participants |
| Sex: Female, Male Female | 53 Participants | 105 Participants | 52 Participants |
| Sex: Female, Male Male | 7 Participants | 11 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 51 |
| other Total, other adverse events | 14 / 60 | 21 / 51 |
| serious Total, serious adverse events | 14 / 60 | 10 / 51 |
Outcome results
Primary
Number of Participants With Clinical Remission at Different Time Points of Assessment
Clinical remission was defined as the combination of percentage mBMI and EDE-Q score at 1, 3, 6, and 12 months. This is a dichotomous variable 1/0. If participants achieve both weight recovery (defined as =\>95% of median BMI for sex and age), AND psychological recovery (defined as within 1SD of community norms for EDE-Q) then they are assigned a 1 for achieving clinical remission. If both parameters not met then 0 for not remitted.
Time frame: up to 12 months
Population: Clinical remission defined as the combination of %mBMI and EDE-Q score. Instead of assuming missing data at random in the generalized linear mixed-effects regression model, clinical remission was modeled as a nominal multinomial outcome (yes, no, or missing), with time (1, 3, 6, or 12 months after discharge), treatment group, and time\*treatment group interaction as fixed effects. Longitudinal analysis included only participants with both %mBMI and EDE-Q scores.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Higher Calorie Refeeding (HCR) Protocol | Number of Participants With Clinical Remission at Different Time Points of Assessment | 1 month | 12 Participants |
| Higher Calorie Refeeding (HCR) Protocol | Number of Participants With Clinical Remission at Different Time Points of Assessment | 3 months | 10 Participants |
| Higher Calorie Refeeding (HCR) Protocol | Number of Participants With Clinical Remission at Different Time Points of Assessment | 6 months | 16 Participants |
| Higher Calorie Refeeding (HCR) Protocol | Number of Participants With Clinical Remission at Different Time Points of Assessment | 12 months | 18 Participants |
| Lower Calorie Refeeding (LCR) Protocol | Number of Participants With Clinical Remission at Different Time Points of Assessment | 12 months | 13 Participants |
| Lower Calorie Refeeding (LCR) Protocol | Number of Participants With Clinical Remission at Different Time Points of Assessment | 1 month | 8 Participants |
| Lower Calorie Refeeding (LCR) Protocol | Number of Participants With Clinical Remission at Different Time Points of Assessment | 6 months | 10 Participants |
| Lower Calorie Refeeding (LCR) Protocol | Number of Participants With Clinical Remission at Different Time Points of Assessment | 3 months | 13 Participants |
Comparison: The study was powered to detect a difference in 12-months clinical remission rates between groups. N = 60 per arm with 85% retention would provide 80% power on a 2-sided 0.05-level test to detect a 20% difference between groups in 12-months clinical remission rates. A generalized linear mixed-effects regression model was used to compare study arms with respect to achievement and maintenance of clinical remission.p-value: 0.42Regression, Linear
Secondary
Time to Achieve Medical Stability in Hospital
Medical stability was adjudicated by a 6-point clinical index: (1) 24-hour heart rate of 45 beats/min or more, (2) systolic blood pressure of 90 mm Hg or more, (3) temperature of 35.6 °C or more, (4) orthostatic increase in heart rate of 35 beats/min or less, (5) orthostatic decrease in systolic blood pressure of 20 mm Hg or less, and (6) 75% or more of mBMI for age and sex. Criteria were assessed daily; for vital signs with multiple daily measures, the most deviant value was recorded (eg, lowest heart rate). Each criterion was scored as 1 if met, 0 if unmet, and missing (not scored) if not measured. Medical stability was considered restored when all measured criteria were stable for 24 hours, allowing a maximum of 2 missing values. Additional efficacy outcomes were time to restore heart rate to 45 beats/min or more (among those with bradycardia at baseline) and weight gain (change in percentage mBMI).
Time frame: Inpatient hospitalization from day of admission to day of discharge, average of 10 days
Population: Modified intention to treat analysis (mITT) included all participants who received at least one day of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Calorie Refeeding (HCR) Protocol | Time to Achieve Medical Stability in Hospital | 7.0 Days | Standard Deviation 7 |
| Lower Calorie Refeeding (LCR) Protocol | Time to Achieve Medical Stability in Hospital | 10.0 Days | Standard Deviation 8 |
Comparison: This trial was powered at 0.80 to detect a 12% to 20% difference in restored medical stability at 0.05 type I error and correlation between time points from 0.1 to 1.p-value: 0.0195% CI: [1.1, 2.53]Survival analysis with log rank test
Other Pre-specified
Cost-effectiveness Per Adolescent Recovered
defined as total cost (direct and indirect costs)
Time frame: up to 12 months
Population: The analysis was a modified intent-to-treat (mITT) approach including all randomized participants who received treatment for at least one day. A total of 9 participants were excluded: 3 were found to be ineligible after randomization and 6 withdrew prior to receiving treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Higher Calorie Refeeding (HCR) Protocol | Cost-effectiveness Per Adolescent Recovered | 38,112 USD |
| Lower Calorie Refeeding (LCR) Protocol | Cost-effectiveness Per Adolescent Recovered | 57,168 USD |
Comparison: Cost outcomes of group differences and 95% confidence intervals were estimated.p-value: 0.002Wilcoxon (Mann-Whitney)