Clinical trial NCT02849743: Intranasal Oxytocin in Hypothalamic Obesity
Official title: Intranasal Oxytocin to Promote Weight Loss in Children, Adolescents, and Adults With Brain Tumors and Hypothalamic Obesity Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Craniopharyngioma
Hypothalamic Obesity
Keywords: oxytocin
hypothalamic obesity
craniopharyngioma
metabolism
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
First posted: 2016-07-29
Enrollment: 18
Sex: ALL
Minimum age (years): 10
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This research study will test if oxytocin, delivered by nasal spray, will promote weight loss in children, adolescents, and adults with Hypothalamic Obesity as compared to a placebo. The study is divided into two parts. During the first part, subjects will receive either oxytocin or placebo. In the second part, subjects will "cross-over" to receive the other treatment - either oxytocin or placebo. During study visits participants will do blood tests, physical exams, metabolic testing, a MRI scan, and some surveys and questionnaires.


Eligibility criteria: Inclusion Criteria:

1. Proficient in English.
2. Males or females age 10 to 35 years, inclusive.
3. Weight ≥ 51 kg.
4. Girls must have a negative urine/serum pregnancy test and post-menarchal girls must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.
5. Hypothalamic obesity, defined for the purposes of this protocol as:

   * previously diagnosed with a brain tumor\*
   * currently overweight or obese (BMI \> 85%ile for age/sex for \< 18 years, BMI \> 25 kg/m2 for 18 - 35 years)
   * has at least one other endocrinopathy, indicating hypothalamic damage
   * rate of annualized weight gain during any 6 month period (given variability in clinical course) preceding or after diagnosis and treatment greater than 2 standard deviations above population reference ranges for age and sex.
6. At least 6 months since completion of therapy with stable disease/lack of recurrence.
7. Stable for at least 2 months on any pituitary replacement (e.g., glucocorticoid, thyroid hormone, estrogen/progestin or testosterone, growth hormone, except for adjustments of less than or equal to 20%). (Desmopressin is not required to be stable for 2 months. Participants with DI taking desmopressin are required to have intact thirst and be well-controlled on their current dosing regimen.)
8. Stable for at least 2 months on any appetite-modulating medications (e.g., stimulants).
9. Be able to ambulate independently.
10. Parental/guardian permission (informed consent) and child assent.

Exclusion Criteria:

1. Diabetes insipidus without intact thirst mechanism (i.e., history that participant is not thirsty when hypernatremic and/or continues to be thirsty when hyponatremic, by participant/family and/or practitioner report and medical records) and/or "brittle" diabetes insipidus, defined as requiring \>1 admission in the past year and/or any admission within the previous 3 months.
2. Diabetes mellitus requiring insulin or insulin secretagogue. Laboratory values: HgbA1c ≥8%
3. Cardiovascular condition, as defined as any of the following: i) abnormal blood pressure, defined as \<3%ile or \>97%ile for age, sex and height; ii) history of cardiac arrhythmia or arrhythmia detected on screening ECG; iii) history of heart failure and/or cardiomyopathy; iv) prolonged QTc interval (QTc \> 460 msec), and/or long QT syndrome phenotype and/or positive genotype for long QT syndrome pathogenic mutations.
4. Concurrent use of medications known to prolong QTc interval and pose high risk for Torsades de Pointes (TdP) according to the current information available (www.crediblemeds.org). Concomitant medications will be assessed by IDS pharmacist, in collaboration with study cardiologist, if additional clarification is needed. In addition, we require that potential participants be on a stable dose for at least 2 months of any medication with the potential to alter cardiac rhythm to ensure the screening ECG reflects steady-state physiology.
5. History of liver disease, with screening laboratory studies:

   Laboratory values: ALT/SGPT \> 3.0X upper limit of normal or AST/SGOT \> 3.0X upper limit of normal
6. History of chronic kidney disease, with screening laboratory studies:

   Laboratory values: eGFR \< 60 mL/min/1.73m2, as defined by the Schwartz formula
7. Clinically significant anemia, with screening laboratory studies:

   Laboratory values: Hemoglobin \< 10 g/dL
8. Seizure in the past 12 months.
9. History of gastrectomy, gastric bypass, small or large bowel resection.
10. History of active substance abuse.
11. Current psychotic disorder and/or suicidality.
12. Supra-physiologic (\>15 mg/m2/day) prescribed doses of hydrocortisone equivalent.
13. Anticipated clinical plan to initiate or modify pituitary hormone replacement and/or appetite-modulating drugs during the course of the study.
14. Any investigational drug use within 30 days prior to enrollment.
15. Pregnant or lactating females.
16. Individuals with a known sensitivity to either oxytocin or the components of its formulation.
17. Inability to take an intranasal medication (e.g., recent injury).
18. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

Primary outcomes:
measure: Weight Loss
timeFrame: Assessed at the beginning and end of each Intervention Period (Intervention 1: Visit 1 to Visit 4 = 8 Weeks, Intervention 2: Visit 5 to Visit 8 = 8 Weeks)
Secondary outcomes:
measure: Peripheral Oxytocin Area Under the Curve (AUC)
timeFrame: Assessed during each treatment block: at either initial lower dose at baseline (week 0 & week 12) or increased dose at 2 weeks (week 2 & week 15); 50% of participants at each set.
Other outcomes:
measure: Cognitive Restraint at Test Meal Attributable to Oxytocin vs Placebo
timeFrame: Intervention 1: Week 2 (Low Dose) or Week 4 (High Dose) and Intervention 2: Week 14 (Low Dose) or Week 16 (High Dose)
measure: Within Participant Difference in Calories Consumed Attributable to Oxytocin vs Placebo Dose 1 (Week 0 & Week 12), as a % of kcal Offered.
timeFrame: Assessed during Intervention 1: Week 0 (Dose 1) and Intervention 2: Week 12 (Dose 1)
measure: Within Participant Difference in Calories Consumed Attributable to Oxytocin vs Placebo Dose 2 (Week 2 & Week 14), as a % of kcal Offered.
timeFrame: Assessed during Intervention 1: Week 2 (Dose 2) and Intervention 2: Week 14 (Dose 2).
measure: Within Participant Difference After Oxytocin vs After Placebo in Resting Energy Expenditure (kcal/kg Lean Body Mass/Day)
timeFrame: Assessed at the end of each treatment block: Week 8 & Week 20.
measure: Respiratory Quotient (VCO2/VO2)
timeFrame: Assessed at the end of each treatment block: week 8 & week 20.
measure: Within Participant Difference After Oxytocin vs Placebo in % Body Fat
timeFrame: Assessed at the end of each treatment block: week 8 & week 20.
measure: Skeletal Muscle Oxidative Phosphorylation (OXPHOS) Capacity
timeFrame: Assessed at the end of each treatment block.
measure: Within Participant Change in Hyperphagia (Total Score) Attributable to Oxytocin vs Placebo
timeFrame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20).
measure: Within Participant Change in Disinhibition of Eating Attributable to Oxytocin vs Placebo
timeFrame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20).
measure: Within Participant Change in Mental and Emotional Health Related Quality of Life Attributable to Oxytocin vs Placebo
timeFrame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20)
measure: Within Participant Change in Family Assessment Device-General Function Scale (FAD-GFS) Attributable to Oxytocin vs Placebo
timeFrame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20).
measure: Within Participant Change in Voluntary Physical Activity Attributable to Oxytocin vs Placebo
timeFrame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20)
measure: Eye-Tracking Task
timeFrame: Assessed at the end of each treatment block.
measure: EEG Task
timeFrame: Assessed at the end of each treatment block.
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Shana E McCormack, MD
role: PRINCIPAL_INVESTIGATOR
References: