Intranasal Oxytocin in Hypothalamic Obesity

Sponsor

Shana McCormack, MD (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02849743

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

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

Anticipated Enrollment :

30 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 :

Oct 1, 2016

Actual Primary Completion Date :

Apr 1, 2021

Anticipated Study Completion Date :

Apr 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Syntocinon (= Oxytocin), then Placebo 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) 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) 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) 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.

Arm

Intervention/Treatment

Experimental: Syntocinon (= Oxytocin), then Placebo

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) 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)

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) 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

Weight loss [8 weeks]
The primary objective of this study is to determine whether treatment with 8 weeks of inhaled 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 21 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

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [Assessed during each treatment block: at weeks 0 & 12, 0.3 & 12.3, 2 & 14, 2.3 & 14.3, 6 & 18, 8 & 20 and any unscheduled visits]
All subjects receiving at least one dose of OXT and/or placebo will be included in the safety analysis. The frequencies of AEs by type, body system, severity and relationship to study drug will be summarized. SAEs (if any) will be described in detail. In particular, the proportion of study subjects who were able to achieve the full dosing amount and the proportion of those receiving synthetic vasopressin requiring modification to their usual synthetic vasopressin regimen will also be noted. The incidence of hyponatremia will be reported. Participants will be screened for adverse events using a safety monitoring uniform report form (SMURF).
Peripheral oxytocin area under the curve (AUC) [Assessed during each treatment block: at either initial 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).

Other Outcome Measures

Cognitive restraint at test meal [Assessed during each treatment block: at either initial dose at baseline (week 0 & week 12) or increased dose at 2 weeks (week 2 & week 15); 50% of participants at each set]
Measured using stop-signal task
Calories consumed at test meal [Assessed during each treatment block: at either initial dose at baseline (week 0 & week 12) or increased dose at 2 weeks (week 2 & week 15); 50% of participants at each set]
Measured using standardized meal
Resting energy expenditure (kcal/kg lean body mass/day) [Assessed at the end of each treatment block: week 8 & week 20]
Measured using indirect calorimetry
Respiratory quotient (VCO2/VO2) [Assessed at the end of each treatment block: week 8 & week 20]
Measured using indirect calorimetry
% body fat [Assessed at the end of each treatment block: week 8 & week 20]
Measured using dual energy x-ray absorptiometry
Skeletal muscle oxidative phosphorylation capacity [Assessed at the end of each treatment block: week 8 &week 20]
Measured using MRI-based post-exercise Creatine Chemical Exchange Saturation Transfer (CrCEST) decline exponential time constant
Hyperphagia [Assessed during each treatment block: at screening, week 2 & week 14 (dose escalation), week 4 & week 16 (interim visit), and week 8 & week 20 (final visit)]
Measured using the Hyperphagia Questionnaire
Disinhibition of eating [Assessed during each treatment block: at screening, week 2 & week 14 (dose escalation), week 4 & week 16 (interim visit), and week 8 & week 20 (final visit)]
Measured using the Eating Inventory questionnaire
Mental and emotional health related quality of life [Assessed during each treatment block: at screening, week 2 & week 14 (dose escalation), week 4 & week 16 (interim visit), and week 8 & week 20 (final visit)]
Measured using the National Institute of Neurological Disorders and Stroke (NINDS) quality of life in neurological disorders (Neuro-QoL) scale
Family function [Assessed during each treatment block: at screening, week 2 & week 14 (dose escalation), week 4 & week 16 (interim visit), and week 8 & week 20 (final visit)]
Measured using the Family Assessment Device-General Function Scale (FAD-GRS)
Voluntary physical activity [Assessed during each treatment block: at screening, week 2 & week 14 (dose escalation), week 4 & week 16 (interim visit), and week 8 & week 20 (final visit)]
Measured using the Bone Mineral Density in Childhood Study (BMDCS) physical activity questionnaire
Eye-tracking task [Assessed at the end of each treatment block: week 8 & week 20]
Amount of time spent viewing socially relevant versus socially irrelevant stimuli during eye-tracking
EEG task [Assessed at the end of each treatment block: week 8 & week 20]
N170 EEG signal during eye-tracking

Eligibility Criteria

Criteria

Ages Eligible for Study:

10 Years to 35 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Proficient in English.
Males or females age 10 to 35 years, inclusive.
Weight ≥ 51 kg.
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.
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 - 21 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.

At least 6 months since completion of therapy with stable disease/lack of recurrence.
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.)
Stable for at least 2 months on any appetite-modulating medications (e.g., stimulants).
Be able to ambulate independently.
Parental/guardian permission (informed consent) and child assent.

Exclusion Criteria:

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.
Diabetes mellitus requiring insulin or insulin secretagogue. Laboratory values: HgbA1c ≥8%
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.
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.
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

History of chronic kidney disease, with screening laboratory studies:

Laboratory values: eGFR < 60 mL/min/1.73m2, as defined by the Schwartz formula

Clinically significant anemia, with screening laboratory studies:

Laboratory values: Hemoglobin < 10 g/dL

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