Estrogen Replacement in Anorexia Nervosa

Study Overview
=================
Brief Summary
-----------------
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).

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

Official Title
-----------------
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

Conditions
-----------------
Anorexia Nervosa

Intervention / Treatment
-----------------
* Drug: ethinyl estradiol 0.03mg and dienogest 2 mg (combination)
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, placebo-controlled Phase IIa clinical trial in patients with anorexia nervosa
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: verum group<br>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)<br>* approved oral contraceptive (Germany): Maxim<br>|
| Placebo Comparator: placebo group<br>placebo | Drug: Placebo oral capsule<br>* placebo<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
anorexia nervosa, estrogen, psychotherapy, cortisol, appetite regulation, neurocognitive performance, eating disorder, sexual hormone