Unable to enroll adequate participants

The purpose of this study is to examine the effect of standard dosing of cyproheptadine for both cycled and continuous administration, as compared to no medication, on appetite stimulation and growth in the pediatric gastroenterology feeding team patient population. The secondary aim is to evaluate the effect, if any, of the suspected tachyphylaxis that is commonly associated with cyproheptadine use. The third aim will be to examine the type and duration of side effects of cyproheptadine in this population. The ultimate goal will be to create a standardized protocol for cyproheptadine therapy in children with feeding disorders and suboptimal growth.

BACKGROUND, SIGNIFICANCE, AND RATIONALE Failure to thrive or inadequate weight gain is a frequent complaint amongst patients seen by general pediatricians and pediatric gastroenterologists. The reasons behind this diagnosis vary widely including, but not limited to feeding disorders of diverse etiologies, poor environmental structure and inadequate intake, medication side effects, swallowing disorders, and a variety of underlying organic diseases. For most feeding disorders, behavioral feeding techniques and strategies to increase caloric intake is utilized to correct the suboptimal growth. However, feeding disorders are sometimes so imprinted that behavioral interventions may be insufficient to promote ideal growth or, if sufficient for growth, are inadequate in helping children avoid or graduate from nutritional support such as enteral tubes. For this reason, medications that promote and stimulate appetite and weight gain are frequently used in children with feeding disorders.

In pediatric gastroenterology practice, cyproheptadine is the most commonly used drug for appetite stimulation, weight gain, and feeding intolerance in younger children with feeding disorders. A first generation histamine and serotonin antagonist, cyproheptadine is thought to promote appetite stimulation and weight gain by increasing insulin-like growth factor-1 (IGF-1) concentration. It may also interact with receptors in the ventromedial hypothalamus and exert hormonal effects. While the exact mechanism of action is still being investigated, several studies have evaluated the benefits of cyproheptadine in select patient groups, including patients with cystic fibrosis, cancer, undernourished children, and children with feeding disorders. These studies have all reported that cyproheptadine promotes weight gain and stimulates appetite. Reported side effects of cyproheptadine in these studies are primarily related to drowsiness which tends to significantly improve or resolve within two weeks of use. Another undesired effect is the development of drug tolerance, i.e. tachyphylaxis. To avoid this, it is common clinical practice to cycle on and off the medication a few weeks each month.

While a few studies report outcomes of the use of cyproheptadine in children with feeding disorders or failure to thrive, these studies have enrolled only small patient cohorts and there are no randomized trials in children enrolled in a feeding team program. Two recent studies examined the role of cyproheptadine in patients who are undernourished or followed in pediatric feeding programs. However, a randomized study examining the effects of continuous cyproheptadine versus a fixed cycled medication dosing versus abstaining from medication has not been performed in the pediatric gastroenterology population.

OUTCOME MEASURES:

Number of Participants in Study: The total number of patients required for this study is 75 (25 in each group). The groups consist of three treatment arms:

1. continuous use of cyproheptadine
2. cycled cyproheptadine or
3. no drug intervention

This number was derived from looking at past statistical data from other studies and using similar power, alpha error, and beta error. Investigators used Analysis of Variance (ANOVA) analysis for multiple groups looking at repeat measures within factors. Alpha error was 0.05, Power 0.95.

Data Collection: The following categories of data will be collected (see subsections list below): medical record number (MRN), demographics, feeding behavior, side effects experience from use cyproheptadine, 24 hour diet recalls, medical history, and anthropometrics.

Demographic Information: Data will be collected as part of the demographics questionnaire. This includes participant's age, sex, ethnicity, identification of primary caretaker, caretaker's relation to participant, caretaker education level, and caretaker marital status.

Feeding Behavior Questionnaire: Patients/parents will complete the Mealtime Behavior Questionnaire (MBQ). Participants' guardians will complete the Mealtime Behavior Questionnaire (MBQ). This is a validated, 31-item, parent-report questionnaire assessing the mealtime behavior structure in young children above 2 years.

The questionnaire measures variables including:

1. food refusals/avoidance
2. food manipulation
3. mealtime aggression and
4. choking/gagging/vomiting related to meals.

Each behavior is assigned a frequency scale with 1 corresponding to "never" and 5 corresponding to "always." The MBQ then consist of a total score and four subcategory scores (listed above).

24 Hour Diet Recall: Guardians of participants will be questioned weekly regarding oral intake (type of food consumed and amount) over the past 24 hrs. Caloric intake will be calculated based on these recalls and compared across duration of study.

Cyproheptadine Side Effect Questionnaire: Guardians will undergo weekly questionnaire looking at common side effects of cyproheptadine. A list of side effects will be read to the participant's guardians with positive (yes) or negative (no) replies if the participant has experienced individual side effects since the last survey.

Medical Information: Data collected will include anthropometrics at initial and final visit (weight, height, BMI, mid-arm circumference, upper arm skin fold), current and past medical diagnoses and surgeries, current medications, current gastrointestinal symptoms, dependence on tube feeds

RISK CATEGORY:

Research not involving greater than minimal risk to the children.

KNOWN SIDE EFFECTS OF CYPROHEPTADINE:

Cyproheptadine has both antihistamine and antiserotonergic and has side effects related to these mechanisms. These side effects include drowsiness or sleepiness, confusion, excitement, fatigue, insomnia, hallucinations, blurred vision, tinnitus, dizziness, tachycardia, increase perspiration, appetite stimulation, weight gain, constipation, diarrhea, changes in frequency of urination, thickening of secretions, and dry mucus membranes. Over-dosage can results in atropine-like effects as well as central nervous depression, convulsions.

SECURITY OF DATA COLLECTED:

All investigators have received Health Insurance Portability and Accountability Act (HIPAA) training and a certificate of completion for the Collaborative Institutional Training Initiative (CITI) training course on the protection of human research subjects before starting the review. Information derived from questionnaires, data collection will be compiled on one central data collection form. These forms will be coded (have a special identifier number that is linked to patient's MRN). The central database used for data collection will be password protected. A separate secure (password protected) database will link the coding number to the patient's MRN. Only the principal investigator (PI), co-investigators and the members of the study team will be gathering the data and have access to the study database. Paper records will be locked in file cabinets within the Gastroenterology office area and electronic records will be stored in password-protected computers. Each subject's identifying number and related electronic data will be kept on a secured, password-protected database that provides access only to the PI and research staff. Only authorized research personnel will have access to the databases and paper records.

PROVISION FOR THE PROTECTION OF PRIVACY OF SUBJECTS (confidentiality, health and financial risks) AND TO MAINTAIN THE CONFIDENTIALITY OF DATA:

Data will be stored on Medical College of Wisconsin secured shared drives.

PROVISIONS FOR MONITORING DATA TO ENSURE THE SAFETY OF SUBJECTS; AND ADDITIONAL SAFEGUARDS TO PROTECT THE RIGHTS AND WELFARE OF SUBJECTS WHO ARE LIKELY TO BE VULNERABLE:

The PI will monitor the health of all patients in the study per standard clinical practice. Primary and Co-investigators will monitor protocol adherence and supervise data collection, entry, and analysis.

ANTICIPATED BENEFITS ASSOCIATED WITH THE PROTOCOL (value or desired outcome / advantage) TO HUMAN RESEARCH PARTICIPANTS AND SOCIETY (medical, psychosocial, altruistic) Anticipated direct benefits of this study include the improvement in appetite/behavior and growth amongst the patients receiving cyproheptadine. These benefits may also be present in group abstaining from cyproheptadine due to standard education that is given to all groups. However, the investigators anticipate these benefits to be significantly lower in this group as compared to patients who are on cyproheptadine. Long-term benefits include the creation and utilization of a protocol outlining the use of cyproheptadine in feeding team patients. The results of this study will also address the side effect profile of cyproheptadine in this population. It may also further investigators' knowledge of the treatment approaches that are most successful, allowing physicians to develop standardized care to better serve these patients and their families.

STOPPING POINTS THAT WOULD NOT ALLOW THE STUDY TO CONTINUE AS PROPOSED:

Stopping points for the study include achieving adequate information on enough of the goal subjects, inability to obtain enough data, or patients/caregivers electing to discontinue the study.

DESCRIBE HOW THE CONSENT (AND ASSENT, IF APPLICABLE) PROCESS WILL TAKE PLACE. INCLUDE A LIST OF APPROPRIATELY TRAINED PERSONNEL WHO WILL BE INVOLVED.

Written informed consent for participation will be obtained from guardians for their child's participation. Consent will be obtained by study personnel at the participant's appointment in the GI Clinic. Participants' consent will allow for accessing information collected for program evaluation/clinical purposes. Participants' guardians will have the option of having the consent document read aloud to them to facilitate understanding. Copies of signed consent documents will be given to participants' guardians. Consent will be obtained by the study's principal investigator, co-investigators, or members of the research team. As additional research staff or team members are added, their names will be submitted to the International Review Board (IRB) as a protocol amendment to allow them to obtain consent.

PROCEDURES TO BE EMPLOYED IN ANALYZING DATA (including a power analysis) AND THE ANTICIPATED SIGNIFICANCE OF THE PROPOSED STUDY Analyses will be conducted with Statistical Package for the Social Sciences (SPSS) and Statistical Analysis System (SAS) software programs. Probability levels of < .05 will be used as cut offs for statistical significance. Descriptive analyses will examine distribution normality and the extent to which parametric test assumptions are met. Descriptive analyses will also provide summary information about participant characteristics. Pearson correlations will be used to examine relationships between continuous variables, while chi square analyses will examine associations between categorical variables.

The key significance of this study is the analysis of the effect that cyproheptadine has on stimulating weight gain and improving behaviors associated with feeding. In addition, it will help give clear comparison between the use of continuous versus cycled cyproheptadine. Cyproheptadine has been suspected to have tachyphylaxis after a couple weeks and many practitioners implement cycling of medication without clear evidence supporting this practice. Investigators expect after this study to be able to design a protocol regarding use of cyproheptadine in feeding team patients.

FINANCIAL RELATIONSHIPS:

There are no financial relationships or interests to disclose.

ADVERTISEMENTS / FLIERS (how will they be used / distributed):

None will be used

Inclusion Criteria:

• All children aged 1-10 years, presenting to initial intake appointment with the Pediatric Gastroenterology Feeding Team Clinic at the Children's Hospital of Wisconsin (CHW), with BMI Z score of < or equal to 0 (normal WHO BMI defined as Z score of -1 to 1), who have a parent willing to participate, will qualify for inclusion in the study. Children with vomiting due to presumed volume intolerance may be included in the study.

Exclusion Criteria:

• Untreated organic disease Anatomical barrier to swallowing or known swallowing disorder Diagnosis of severe developmental delay or mental retardation Significant brain pathology or seizure disorder that may affect oropharyngeal motor skills On medication with known effects on appetite or interactions with cyproheptadine

We had trouble recruiting patients for this study

8 weeks

Fatigue, Headache, Diarrhea, Vomiting, Constipation, Dry mouth, Nausea, sleepiness, Restlessness

Early termination leading to small numbers of subjects analyzed;