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Neurobiology of Bulimia Nervosa

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ClinicalTrials.gov Identifier: NCT04225221
Recruitment Status : Recruiting
First Posted : January 13, 2020
Last Update Posted : September 24, 2020
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief Summary:
This pilot study experimentally manipulates ovarian hormones to examine the direct impact of estrogen (E2) and progesterone (P4) on binge eating symptom burden and the behavioral reward response in women with bulimia nervosa (n=15). This is completed by taking medications that change ovarian hormone levels. This line of research could lead to the development of pharmacological interventions developed to target specific areas of the brain, brain receptors, or pathways identified to be involved in the mechanism underlying ovarian hormone change and binge eating.

Condition or disease Intervention/treatment Phase
Bulimia Nervosa Drug: Estradiol Drug: Micronized progesterone Drug: Leuprolide Acetate Drug: Placebo Oral Capsule Phase 2

Detailed Description:

Eating disorders (EDs) affect 15 million women in the United States and have one of the highest mortality rates of any mental illness. Despite this, the underlying neurobiology remains poorly understood. EDs predominantly occur in women, and the frequency of certain symptoms change in a predictable pattern over the menstrual cycle; specifically, symptom changes appear to be triggered by normal fluctuations in the ovarian hormones estradiol (E2) and progesterone (P4).

The objective of this study is to examine the direct and mechanistic role of E2 and P4 on binge eating in women with bulimia nervosa (BN; n = 15). The experimental design parallels an established design developed to determine the hormonal triggers of premenstrual dysphoric disorder and depression: temporarily stopping the menstrual cycle using a Gonadotropin-releasing hormone (GnRH) agonist (Lupron) and addback E2 and P4 independently in a double-blind crossover design. The overarching hypothesis is that BN represents a hormone-sensitive phenotype, and this sensitivity is modulated by E2's effects on aspects of the reward response such that reward-motivated behaviors increase in the context of low E2. This line of research will provide direction for future research addressing neuroendocrine, neurobiological, and brain activity and function in BN. To date, there are no medications that have been developed specifically for the treatment of individuals with BN.

Our specific aims are to:

Aim 1: Quantify the direct effect of E2 and P4 on binge eating in women with BN.

Aim 2: Determine the effect of E2 on reward response in women with BN.

Aim 3: Examine the association between reward response and binge eating before and after E2 addback.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Ovarian Hormones, Reward Response, and Binge Eating in Bulimia Nervosa: An Experimental Design
Actual Study Start Date : February 24, 2020
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones

Arm Intervention/treatment
Experimental: Sequence A: estradiol followed by progesterone

Participants are randomly assigned to treatment Sequence A: after achieving hormone suppression using Lupron, participants begin the addback period and take study medications for 8 weeks. During the 8 week period, participants will take placebo or estradiol or progesterone. Participants will not know when or for how long they are on active medication (i.e., estradiol or progesterone) or inactive (i.e., placebo) medication. When active medication is administered, participants randomized to treatment sequence A will receive estradiol addback first, followed by progesterone.

Estradiol and progesterone are never given simultaneously. Participants are on active medication for a total of 4 weeks.

Drug: Estradiol
During estradiol administration, 2mg of estradiol is given twice daily via oral capsule.
Other Names:
  • E2
  • Estrace

Drug: Micronized progesterone
During progesterone administration, 200mg of progesterone is given twice daily via oral capsule.
Other Names:
  • P4
  • Prometrium

Drug: Leuprolide Acetate
Initial 3.75 mg intramuscular injection administered approximately Day 6 of menstrual cycle and then monthly thereafter for a total of 3 months.
Other Name: Lupron Depot

Drug: Placebo Oral Capsule
Placebo is administered during the addback phase when participants are not taking active medication. Placebo is given so that medication administration occurs throughout the entire 8-week addback period in order to blind participants to when and for how long they are on the active medication.
Other Name: Sugar pill

Experimental: Sequence B: progesterone followed by estradiol

Participants are randomly assigned to treatment Sequence B: after achieving hormone suppression using Lupron, participants begin the addback period and take study medications for 8 weeks. During the 8 week period, participants will take placebo or estradiol or progesterone. Participants will not know when or for how long they are on active medication (i.e., estradiol or progesterone) or inactive (i.e., placebo) medication. When active medication is administered, participants randomized to treatment sequence B will receive progesterone first followed by estradiol.

Estradiol and progesterone are never given simultaneously. Participants are on active medication for a total of 4 weeks.

Drug: Estradiol
During estradiol administration, 2mg of estradiol is given twice daily via oral capsule.
Other Names:
  • E2
  • Estrace

Drug: Micronized progesterone
During progesterone administration, 200mg of progesterone is given twice daily via oral capsule.
Other Names:
  • P4
  • Prometrium

Drug: Leuprolide Acetate
Initial 3.75 mg intramuscular injection administered approximately Day 6 of menstrual cycle and then monthly thereafter for a total of 3 months.
Other Name: Lupron Depot

Drug: Placebo Oral Capsule
Placebo is administered during the addback phase when participants are not taking active medication. Placebo is given so that medication administration occurs throughout the entire 8-week addback period in order to blind participants to when and for how long they are on the active medication.
Other Name: Sugar pill




Primary Outcome Measures :
  1. Change in weekly average binge-eating frequency with estradiol administration [ Time Frame: Lupron (Week 10), Estradiol (Week 12) ]
    Binge eating frequency is based on a daily diary of self-reported binge eating frequency. Average weekly frequency will be determined based on daily reported binge eating frequency.

  2. Change in weekly average binge-eating frequency with progesterone administration [ Time Frame: Lupron (Week 10), Progesterone (Week 16) ]
    Binge eating frequency is based on a daily diary of self-reported binge eating frequency. Average weekly frequency will be determined based on daily reported binge eating frequency.

  3. Change in binge eating sum score with estradiol administration [ Time Frame: Lupron (Week 10), Estradiol (Week 12) ]
    Binge eating will be measured using the 8-item binge eating subscale of the Eating Pathology Symptoms Inventory (EPSI), which measures features of binge eating (e.g., consumption of large quantities of food, mindless eating) on a 5-point Likert scale from "never" to "very often." The EPSI scale is designed to assess behavior over the past 28 days; however, to be sensitive to the timeframe of the present study, the instructions will be modified to ask participants to consider the past week. Items are summed for a scale score ranging from 0-32. Higher scores indicate more frequent experiences with binge eating behavior.

  4. Change in binge eating sum score with progesterone administration [ Time Frame: Lupron (Week 10), Progesterone (Week 16) ]
    Binge eating will be measured using the 8-item binge eating subscale of the Eating Pathology Symptoms Inventory (EPSI), which measures features of binge eating (e.g., consumption of large quantities of food, mindless eating) on a 5-point Likert scale from "never" to "very often." The EPSI scale is designed to assess behavior over the past 28 days; however, to be sensitive to the timeframe of the present study, the instructions will be modified to ask participants to consider the past week. Items are summed for a scale score ranging from 0-32. Higher scores indicate more frequent experiences with binge eating behavior.

  5. Change in response latency to reward during the Monetary Incentive Delay Task with estradiol manipulation [ Time Frame: Lupron (Week 10), Estradiol (Week 12) ]
    Time (ms) between stimulus and response will be measured during the Monetary Incentive Delay task during the win trials. During MID the task, participants need to select the correct response during "win" and "lose" conditions by pressing a button.

  6. Change in delay discounting parameter k using the Monetary Choice Questionnaire with estradiol manipulation [ Time Frame: Lupron (Week 10), Estradiol (Week 12) ]
    Participants will be asked to make a series of hypothetical choices between small, sooner (impulsive) vs. larger, later (self controlled) hypothetical monetary outcomes.

  7. Change in Behavioral Inhibition/Behavioral Activation with estradiol manipulation [ Time Frame: Lupron (Week 10), Estradiol (Week 12) ]
    This measures assesses individual disposition toward avoiding and engaging in activities. The BIS/BAS has three behavioural activation (BA) subscales, and only one subscale assesses behavioural inhibition (BI). The BA subscales used are Fun Seeking and Reward Responsiveness. Each subscale is summed to get the respective subscale scores. The minimum score on BA Drive is 4, maximum 16. Higher scores indicate greater drive to engage. The minimum score on the BA Reward Responsiveness subscale is 5, maximum 20. Higher scores indicate greater reward responsiveness.The minimum score on the BI subscale is 7, maximum 28. Greater scores indicate greater behavioural inhibition.

  8. Change in self-reported reward sensitivity subscale score with estradiol manipulation [ Time Frame: Lupron (Week 10), Estradiol (Week 12) [3 months] ]
    Sensitivity to Punishment/Sensitivity to Reward Questionnaire will be used to measure reward sensitivity. The reward sensitivity subscale will be used, which is rated on a true/false scale with scores ranging 0-24. Higher scores indicate more sensitivity to reward.

  9. Change in behavioral inhibition with estradiol administration as assessed through a behavioral task [ Time Frame: Lupron (Week 10), Estradiol (Week 12) ]
    Behavioral response inhibition will be examined during a go/no-go computerized task. Inhibitory control is defined by the response accuracy of the go no/go trials with fewer errors ("go" response on a "no/go" trial) indicating better inhibitory control.

  10. The correlation between change in reward response and change in binge eating before and after estradiol addback [ Time Frame: Lupron (Week 10), Estradiol (Week 12) ]
    Pearson correlations between change in reward response and change in binge eating between screening, baseline, and E2 addback will be examined



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Men will not be included in this study given the stated purpose of studying the impact of ovarian hormones.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Participants will be women aged 18-35 with a current DSM-5 bulimia nervosa (BN) diagnosis who meet the below criteria. Only participants capable of giving informed consent and understanding the risks associated with the study will be enrolled.

  • A regular menstrual cycle for at least three months (defined as having a menstrual period every 21-35 days, with no skipped periods in the past 3 months; menstrual cycle variability < 7 days)
  • BMI < 30; BMI > 18.5
  • Free of medication or medical condition that impacts ovarian hormones or is contraindicated for use with study interventions (including birth control pills)
  • Speaks English

Exclusion Criteria

Patients will not be permitted to enter this protocol if they have any of the following:

  • peanut allergy
  • bipolar or psychotic disorder;
  • current substance use disorder or frequent binge drinking behavior;
  • frequent diuretic or laxative use, ipecac use;
  • currently smoking > 10 cigarettes daily;
  • history of a suicide attempt or current suicidal ideation;
  • endometriosis;
  • abnormal genital/vaginal bleeding;
  • undiagnosed enlargement of the ovaries;
  • liver disease;
  • breast cancer;
  • personal history of blood clots (a history of blood clots in the legs or lungs; DVT)
  • history of seizures or epilepsy;
  • porphyria;
  • diabetes mellitus;
  • malignant melanoma;
  • gallbladder or pancreatic disease;
  • heart or kidney disease;
  • cerebrovascular disease (stroke);
  • history of osteoporosis or osteopenia;
  • recurrent migraine with aura;
  • pregnancy-related medical conditions such as hyperemesis gravidarum, pretoxemia and toxemia, deep vein thrombosis (DVT), bleeding diathesis, or seizures
  • first degree relative (immediate family) with premenopausal breast cancer or breast cancer presenting in both breasts or any woman who has multiple family members (greater than three relatives) with postmenopausal breast cancer will also be excluded from participating in this protocol;
  • Refusal to use non-hormonal contraception throughout study;
  • Pregnant women will be excluded from participation (patients will be warned not to become pregnant during the study and will be advised to employ barrier contraceptive methods), and women who become pregnant (although unlikely because of the hormone manipulation) will be withdrawn;
  • Any condition or symptoms considered by the study team to detrimentally impact subject safety.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04225221


Contacts
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Contact: Lauren Harper 984-215-5519 lauren_harper@med.unc.edu

Locations
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United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Lauren Harper, BS    984-215-5519    lauren_harper@med.unc.edu   
Principal Investigator: Jessica Baker, PhD         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Jessica Baker, PhD University of North Carolina, Chapel Hill
Publications:

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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT04225221    
Other Study ID Numbers: 19-2343
R21MH121726 ( U.S. NIH Grant/Contract )
First Posted: January 13, 2020    Key Record Dates
Last Update Posted: September 24, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Deidentified individual data that supports the results will be shared beginning 18 to 24 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
Supporting Materials: Statistical Analysis Plan (SAP)
Analytic Code
Time Frame: Deidentified individual data that supports the results will be shared beginning 18 to 24 months following publication.
Access Criteria: Approval from an IRB, IEC, or REB, as applicable and execution of a data use/sharing agreement with UNC.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of North Carolina, Chapel Hill:
bulimia nervosa
binge eating
eating disorder
estrogen
Additional relevant MeSH terms:
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Bulimia
Bulimia Nervosa
Hyperphagia
Signs and Symptoms, Digestive
Feeding and Eating Disorders
Mental Disorders
Leuprolide
Estradiol
Progesterone
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Reproductive Control Agents
Progestins
Fertility Agents, Female
Fertility Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents