Intranasal Oxytocin in Hypothalamic Obesity

• ClinicalTrials.gov Identifier: NCT02849743
• Recruitment Status: Completed
• First Posted: July 29, 2016
• Results First Posted: October 5, 2022
• Last Update Posted: October 5, 2022
• Sponsor: Shana McCormack, MD
• Information provided by (Responsible Party): Shana McCormack, MD, Children's Hospital of Philadelphia

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Craniopharyngioma; Hypothalamic Obesity	Drug: Syntocinon; Drug: Placebo (for Syntocinon)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Intranasal Oxytocin to Promote Weight Loss in Children, Adolescents, and Adults With Brain Tumors and Hypothalamic Obesity Syndrome
• Study Start Date: October 2016
• Actual Primary Completion Date: April 2021
• Actual Study Completion Date: May 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Syntocinon (= Oxytocin), then Placebo; Week 0 to Week 7: Intranasal oxytocin, administered 3 times per day (at mealtimes) for 8 weeks (dosage based on weight: 16 IU to 24 IU; dose escalation, if appropriate, occurs at 2 weeks) Week 8 to Week 11: Washout Week 12 to Week 20: Intranasal placebo, administered 3 times per day (at mealtimes) for 8 weeks (dosage based on weight: 16 IU to 24 IU; dose escalation, if appropriate, occurs at 2 weeks) *Dose Escalation, as appropriate, at 2 Weeks	Drug: Syntocinon; The active substance of Syntocinon is a synthetic nonapeptide identical to the posterior pituitary hormone oxytocin.; Drug: Placebo (for Syntocinon); The placebo is identical to the Syntocinon formulation with the exception of the active compound, i.e., without oxytocin.
Experimental: Placebo, then Syntocinon (= Oxytocin); Week 0 to Week 7: Intranasal placebo, administered 3 times per day (at mealtimes) for 8 weeks (dosage based on weight: 16 IU to 24 IU; dose escalation, if appropriate, occurs at 2 weeks) Week 8 to Week 11: Washout Week 12 to Week 20: Intranasal oxytocin, administered 3 times per day (at mealtimes) for 8 weeks (dosage based on weight: 16 IU to 24 IU; dose escalation, if appropriate, occurs at 2 weeks)	Drug: Syntocinon; The active substance of Syntocinon is a synthetic nonapeptide identical to the posterior pituitary hormone oxytocin.; Drug: Placebo (for Syntocinon); The placebo is identical to the Syntocinon formulation with the exception of the active compound, i.e., without oxytocin.

Outcome Measures

Primary Outcome Measures :

1. Weight Loss [ Time Frame: 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) ]
   The primary objective of this study is to determine whether treatment with 8 weeks of intranasal OXT (relative to 8 weeks of placebo) will promote weight loss in children and adolescents with brain tumors and hypothalamic obesity syndrome ages 10 to 35 years. Specifically, the primary outcome will be: the difference of the post-treatment weight between the two periods (treatment vs. placebo); the statistical model will include the difference of the baseline weight between the two periods and the sequence (OXT-PBO versus PBO-OXT).

Secondary Outcome Measures :

1. Peripheral Oxytocin Area Under the Curve (AUC) [ Time Frame: 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. ]

   We will determine the immediate peripheral pharmacokinetics of intranasal oxytocin (versus placebo/endogenous oxytocin). In order to minimize participant burden, each participant had the assessment at one time point with either the low or high dose of oxytocin. And at one point during the placebo block.

   For this exploratory outcome, visits representing lower dose and higher dose oxytocin were Combined versus lower and higher dose placebo.

Other Outcome Measures:

1. Cognitive Restraint at Test Meal Attributable to Oxytocin vs Placebo [ Time Frame: Intervention 1: Week 2 (Low Dose) or Week 4 (High Dose) and Intervention 2: Week 14 (Low Dose) or Week 16 (High Dose) ]

   Cognitive Restraint at Test Meal Attributable to Oxytocin vs Placebo measured using stop-signal task, stop signal reaction time (SSRT).

   For this exploratory outcome, in order to minimize participant burden, each participant had the assessment at one time point with either the low or high dose of oxytocin. And at one point during the placebo block for comparison.

2. Within Participant Difference in Calories Consumed Attributable to Oxytocin vs Placebo Dose 1 (Week 0 & Week 12), as a % of kcal Offered. [ Time Frame: Assessed during Intervention 1: Week 0 (Dose 1) and Intervention 2: Week 12 (Dose 1) ]
   Within Participant Difference in Calories Consumed Attributable to Oxytocin vs Placebo Dose 1 (Week 0 & Week 12). Total number of calories consumed during the standardized test meal.
3. Within Participant Difference in Calories Consumed Attributable to Oxytocin vs Placebo Dose 2 (Week 2 & Week 14), as a % of kcal Offered. [ Time Frame: Assessed during Intervention 1: Week 2 (Dose 2) and Intervention 2: Week 14 (Dose 2). ]
   Within Participant Difference in Calories Consumed Attributable to Oxytocin vs Placebo Dose 2 (Week 2 & Week 14). Total number of calories consumed during the standardized test meal.
4. Within Participant Difference After Oxytocin vs After Placebo in Resting Energy Expenditure (kcal/kg Lean Body Mass/Day) [ Time Frame: Assessed at the end of each treatment block: Week 8 & Week 20. ]
   Within Participant Difference After Oxytocin vs After Placebo in Resting Energy Expenditure (kcal/kg lean body mass/day). Resting Energy Expenditure (REE) with output of kcal/kg lean body mass/day measured using indirect calorimetry.
5. Respiratory Quotient (VCO2/VO2) [ Time Frame: Assessed at the end of each treatment block: week 8 & week 20. ]
   Within Participant Difference After Oxytocin vs Placebo in Respiratory Quotient (RQ) measured using indirect calorimetry.
6. Within Participant Difference After Oxytocin vs Placebo in % Body Fat [ Time Frame: Assessed at the end of each treatment block: week 8 & week 20. ]
   Total % Body Fat measured using dual energy x-ray absorptiometry (DXA).
7. Skeletal Muscle Oxidative Phosphorylation (OXPHOS) Capacity [ Time Frame: Assessed at the end of each treatment block. ]
   Measured using MRI-based post-exercise Creatine Chemical Exchange Saturation Transfer (CrCEST) decline exponential time constant.
8. Within Participant Change in Hyperphagia (Total Score) Attributable to Oxytocin vs Placebo [ Time Frame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20). ]

   Measured using the Dykens Hyperphagia Questionnaire.

   The Dykens Hyperphagia Questionnaire is a 11-item questionnaire with responses on a scale of 1 to 5. 1 = Not a Problem, 5 = Severe or Frequent Problem. The scale includes three domains: hyperphagic behavior, hyperphagic drive, and hyperphagic severity. There is also a total or overall score which is calculated by combining the scores from each domain. Maximum Possible Score: 55, Minimum Possible Score: 11. Higher scores indicated more severe and/or frequent Hyperphagia.

9. Within Participant Change in Disinhibition of Eating Attributable to Oxytocin vs Placebo [ Time Frame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20). ]

   Within Participant Change in Disinhibition of Eating Attributable to Oxytocin vs Placebo. Measured using the Eating Inventory questionnaire.

   The Eating Inventory consists of 36 statements where participants respond true or false, 14 questions where participants select a response from 1 (least severe: rarely or not at all) to 4 (most severe: always or very much), one final question askes participants to rate their level of restraint in eating from 1 (no restraint) to 6 (constantly limiting food). The scores are assessed in 3 dimensions: Dietary Restraint (Max Score: 21), Disinhibition (Max Score: 16), and Hunger (Max Score: 14).

   Within Participant Change in Scores from the Disinhibition of Eating dimension are reported.

10. Within Participant Change in Mental and Emotional Health Related Quality of Life Attributable to Oxytocin vs Placebo [ Time Frame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20) ]

    The National Institute of Neurological Disorders and Stroke (NINDS) quality of life in neurological disorders (Neuro-QoL) scale is a set of self-reported measures to assess health-related quality of life of adults and children.

    Individuals rate domains on a scale from 1 (Never/Not at all) to 5 (Always/Very Often). Each response is assigned a value. Values are combined for a total raw score, then converted to a T-Scores (cohort-specific mean 50, SD 10). Higher scores on the sub-scale domains indicate more of the entity. Adult and child scores were combined in analyses.

11. Within Participant Change in Family Assessment Device-General Function Scale (FAD-GFS) Attributable to Oxytocin vs Placebo [ Time Frame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20). ]

    Within Participant Change in Family Assessment Device-General Function Scale (FAD-GFS) Attributable to Oxytocin vs Placebo.

    The Family Assessment Device (FAD-GFS) includes 12 statements where individuals select from a scale of 4 responses ranging from Strongly Agree (SA) to Strongly Disagree (SD). Each response has a score ranging from 1 to 4, some of the items are reverse scored (i.e. 1 = 4, 2 = 3, 3 = 2, 4 = 1). Minimum Total Score: 12, Maximum Total Score: 48. The scores for each question are added and then divided by the total number of questions. The Minimum Overall Score: 1, Maximum Overall Score: 4. A score of 2 or above is considered dysfunction.

12. Within Participant Change in Voluntary Physical Activity Attributable to Oxytocin vs Placebo [ Time Frame: Assessed using data from Intervention 1: Screening and Visit 4 (Week 8) and Intervention 2: Visit 5 (Week 12) and Visit 8 (Week 20) ]

    Measured using the Bone Mineral Density in Childhood Study (BMDCS) physical activity questionnaire.

    The Bone Mineral Density in Childhood Study (BMDCS) questionnaire captures the amount of time spent in physical activity. The assessment asks participants to record the number of hours spent in different categories of physical activity (Min: 0 hours per week, Max: 11+ hours per week).

13. Eye-Tracking Task [ Time Frame: Assessed at the end of each treatment block. ]
    Amount of time spent viewing socially relevant versus socially irrelevant stimuli during eye-tracking.
14. EEG Task [ Time Frame: Assessed at the end of each treatment block. ]
    N170 EEG signal during eye-tracking

Eligibility Criteria

• Ages Eligible for Study: 10 Years to 35 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

Shana McCormack, MD

Investigators

• Principal Investigator: Shana E McCormack, MD; Children's Hospital of Philadelphia

  Study Documents (Full-Text)

Documents provided by Shana McCormack, MD, Children's Hospital of Philadelphia:

Study Protocol  [PDF] August 20, 2019

Statistical Analysis Plan  [PDF] June 30, 2021

Informed Consent Form  [PDF] October 21, 2020

More Information

• Responsible Party: Shana McCormack, MD, Attending Physician, Children's Hospital of Philadelphia
• ClinicalTrials.gov Identifier: NCT02849743
• Other Study ID Numbers: 16-012730
• First Posted: July 29, 2016
• Results First Posted: October 5, 2022
• Last Update Posted: October 5, 2022
• Last Verified: September 2022

Keywords provided by Shana McCormack, MD, Children's Hospital of Philadelphia:

oxytocin; hypothalamic obesity; craniopharyngioma; metabolism

Additional relevant MeSH terms:

Craniopharyngioma; Adamantinoma; Obesity; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Bone Neoplasms; Neoplasms by Site; Bone Diseases; Musculoskeletal Diseases; Oxytocin; Oxytocics; Reproductive Control Agents; Physiological Effects of Drugs