Estrogen Replacement in Anorexia Nervosa (HOSAN)

Prospective, Randomized, Double-blind, Placebo-controlled Clinical Trial on the Effects of an Estrogen-progestin Combination as add-on to Inpatient Psychotherapy in Adult Female Patients Suffering From Anorexia Nervosa

The present study is a placebo-controlled randomised study on the effects of estrogen replacement upon AN-associated psychopathology, several neurocognitive domains and appetite-regulating circuits in female patients with AN.

The investigators aim at assessing peripheral concentrations of neuroendocrinological components of the Hypothalamus-Pituitary-Gonadal (HPG) and Hypothalamus-Pituitary-Adrenal (HPA) axis, as well as appetite-regulating hormones in AN and to examine associations with AN-associated psychopathology and neurocognitive performances before (baseline), during and after inpatient psychotherapy of female patients receiving concomitant treatment with estrogens (vs. placebo).

Study Overview

• Status: Terminated
• Conditions: Anorexia Nervosa
• Intervention / Treatment: Drug: Placebo oral capsule; Drug: ethinyl estradiol 0.03mg and dienogest 2 mg (combination)

Detailed Description

While there is broad knowledge on the disruption of appetite regulation, neurocognitive deficits in AN patients, the impact of cortisol on neurocognitive performances in patients with AN and the effects of estrogen on neurocognitive features in healthy subjects, up to now, no study has implemented estrogen replacement in AN patients, in order to examine ist effects upon AN-associated psychopathology, neurocognition and peptides regulating appetite. Thus, this is the first study of its kind.

Primary target: Assessment of the impact of sexual hormone replacement using an estrogen-progestin-combination as add-on to psychotherapy upon neurocognitive performance in patients suffering from anorexia nervosa by means of a neuropsychological test battery consisting of a test of verbal intelligence, the Trail making test A and B, a Go/No-go paradigm and the Wisconsin Card Sorting Test.

Secondary targets:

• Examination of safety and tolerability of sexual hormone replacement using an estrogen-progestin-combination in patients with anorexia nervosa.
• Assessment of the impact of the sexual hormone replacement upon psychopathology in patients with anorexia nervosa by means of the Eating Disorder Examination Questionnaire (EDE-Q) and the Eating Disorder Inventory-2 (EDI-2).
• Assessment of the impact of substitution upon anxiety (STAI)
• Assessment of the impact on cortisol levels
• Assessment of the impact on appetite-regulating plasma peptides
• Assessment of the impact on the prescription of antidepressants

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Department of Psychosomatic Medicine and Psychotherapy, University Hospital Erlangen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• anorexia nervosa according to the Diagnostic and Statistical Manual of Mental Disorders (DSM V) or subsyndromal anorexia nervosa (lack of a diagnostic symptom according to DSM V)
• BMI ≥ 13 kg/m2 and ≤ 18.5 kg/m2
• able to provide written informed consent

Exclusion Criteria:

• a known hypersensitivity to the active compound or to other components of the study drug
• one or more contraindications for the use of hormonal contraception: Smoking over 20 cigarettes/day; Acute venous thromboembolic disease or increased risk; Known hereditary or acquired predisposition for venous thrombosis, e.g. activated protein C (APC)-resistance (including factor V Leiden Mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency; Risk for arterial thromboembolism (diabetes mellitus with vascular sequelae, severe hypertonus, severe dyslipoproteinemia); Known hereditary or acquired predisposition for arterial thrombosis, e.g. hyperhomocysteinemia and anti-phospholipid antibodies (anticardiolipin antibodies, Lupus anticoagulants); Cerebrovascular disease (past cerebral infarction or prodromal states such as transitory ischemia attacks); Past migraine with focal neurological symptoms; Liver disease or pancreatitis; Dubin-Johnson syndrome and Rotor syndrome; Known porphyria; Known or suspected sexual hormone sensitive tumors; Unresolved vaginal bleeding
• a present severe depressive episode (major depression) according to the DSM V
• past or present alcohol or drug abuse
• severe psychiatric disorders (axis I) according to the DSM V (such as bipolar affective disorder or schizophrenia) in addition to anorexia nervosa
• suicidality
• known diabetes mellitus
• severe somatic comorbidity or organ dysfunction that is not compatible with intake of the study drug
• use of hormonal depot compounds (injectable drugs, implants), or hormonal intrauterine pessaries during the last four weeks before the screening visit (V1)
• pregnancy
• breastfeeding during the last 6 months before V1

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo group; placebo	Drug: Placebo oral capsule; placebo
Active Comparator: verum group; approved oral contraceptive: ethinyl estradiol 0.03mg and dienogest 2mg (combination drug) daily intake over 10 weeks	Drug: ethinyl estradiol 0.03mg and dienogest 2 mg (combination); approved oral contraceptive (Germany): Maxim

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in neurocognitive performance	Performance based on a neurocognitive test battery	10 weeks of hormonal substitution with an estrogen-progestin-combination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse Events (AE) (safety/tolerability)	Number of adverse events (including AE, AR, severe AE, SAR and SUSAR)	10 weeks of hormonal substitution with an estrogen-progestin-combination
Changes in psychopathology (EDE-Q)	Changes in sum scores in the EDE-Q	10 weeks of hormonal substitution with an estrogen-progestin-combination
Changes in psychopathology (EDI-2)	Changes in sum scores in the EDI-2	10 weeks of hormonal substitution with an estrogen-progestin-combination
Changes in psychopathology (STAI)	Changes in sum scores in the STAI	10 weeks of hormonal substitution with an estrogen-progestin-combination
Changes in psychopathology (Patient Health Questionnaire-9, PHQ-9)	Changes in sum scores in the PHQ-9	10 weeks of hormonal substitution with an estrogen-progestin-combination
Changes in psychopathology (Eating Disorder Quality of Life, EDQoL)	Changes in sum scores in the EDQoL	10 weeks of hormonal substitution with an estrogen-progestin-combination
Neuroendocrinological changes (cortisol)	Changes in plasma cortisol levels during a dexamethasone suppression test	10 weeks of hormonal substitution with an estrogen-progestin-combination
Neuroendocrinological changes (glucose)	Changes in plasma concentrations of glucose	10 weeks of hormonal substitution with an estrogen-progestin-combination
Neuroendocrinological changes (insulin)	Changes in plasma concentrations of insulin	10 weeks of hormonal substitution with an estrogen-progestin-combination
Neuroendocrinological changes (ghrelin)	Changes in plasma concentrations of the appetite-regulating peptide ghrelin	10 weeks of hormonal substitution with an estrogen-progestin-combination
Neuroendocrinological changes (leptin)	Changes in plasma concentrations of the appetite-regulating peptide leptin	10 weeks of hormonal substitution with an estrogen-progestin-combination
Changes in antidepressant medication	Changes in antidepressants´ use	10 weeks of hormonal substitution with an estrogen-progestin-combination

Collaborators and Investigators

• Sponsor: University of Erlangen-Nürnberg Medical School

Publications and helpful links

General Publications

• Paslakis G, Maas S, Gebhardt B, Mayr A, Rauh M, Erim Y. Prospective, randomized, double-blind, placebo-controlled phase IIa clinical trial on the effects of an estrogen-progestin combination as add-on to inpatient psychotherapy in adult female patients suffering from anorexia nervosa. BMC Psychiatry. 2018 Apr 10;18(1):93. doi: 10.1186/s12888-018-1683-1.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2016
• Primary Completion (Actual): January 15, 2019
• Study Completion (Actual): January 15, 2019

Study Registration Dates

• First Submitted: May 22, 2017
• First Submitted That Met QC Criteria: May 29, 2017
• First Posted (Actual): June 1, 2017

Study Record Updates

• Last Update Posted (Actual): January 30, 2019
• Last Update Submitted That Met QC Criteria: January 28, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: estrogen; psychotherapy; cortisol; anorexia nervosa; appetite regulation; eating disorder; neurocognitive performance; sexual hormone
• Additional Relevant MeSH Terms: Mental Disorders; Signs and Symptoms, Digestive; Feeding and Eating Disorders; Anorexia; Anorexia Nervosa; Physiological Effects of Drugs; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Estrogens; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Hormonal; Contraceptive Agents, Male; Estradiol; Ethinyl Estradiol; Dienogest
• Other Study ID Numbers: UKER-AN-HS-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No