Anorexia Nervosa
Conditions
Keywords
Anorexia Nervosa, Leptin, Metreleptin, Weight gain, Depression
Brief summary
The treatment of anorexia nervosa often proves to be difficult. There are no drugs that work specifically for the treatment of anorexia nervosa. Experimental administration of metreleptin (synthetically produced leptin) to patients with anorexia nervosa has produced positive results. This study tests the effect of metreleptin in comparison with placebo, which could potentially make treatment easier. The aim of the study is to investigate whether treatment with metreleptin can help to reduce the symptoms of anorexia nervosa and improve mood and weight.
Detailed description
Anorexia nervosa (AN) mainly affects young people, especially young women. AN is one of the most lethal psychiatric disorders. Treatment often proves to be very difficult, and the course of AN is frequently chronic. Specific pharmacological therapies for AN are lacking. Recent studies have shown that metabolic alterations play a major role in the etiology and pathogenesis of AN. An important metabolic alteration involved in the etiology and pathogenesis of AN is the hormone leptin. Patients with AN show hypoleptinemia. The role of hypoleptinemia in the neuroendocrine adaptation to starvation seems to induce emotional, cognitive, and behavioral symptoms of AN. From a theoretical point of view, pharmacotherapy aimed at increasing leptin levels in patients with AN has great therapeutic potential. Recently, positive effects following the experimental administration of subcutaneous metreleptin have been observed in small number of young patients with severe AN. Importantly, no side effects have been observed. For all these reasons, the present study will investigate, using a double-blind design, the therapeutic effect of metreleptin in patients with AN. Metreleptin will be administrated to 50 inpatients with AN: 25 patients will receive verum and 25 will receive placebo for 14 days. The primary objectives of this study are the amelioration of mood and weight. Secondary objectives are the investigation of functional brain connectivity, AN symptoms, as well as hematological, blood chemistry and neuroendocrinological parameters.
Interventions
DRUGMetreleptin
Metreleptin 3 mg is packaged in 3 ml Type I glass vials with chlorobutyl rubber stoppers, and aluminum seals with plastic flip-off caps. The vials are stored in refrigerator (2 - 8°C) and protected from light. Metreleptin for injection is a sterile, white, solid lyophilised cake. Prior to patient use, the content of a vial is reconstituted with 0.6 ml of water for injection for a final formulation of 10 millimolar (mM) glutamic acid, 2% glycine, 1% sucrose, 0.01% polysorbate 20, potential hydrogen (pH) 4.25. The resulting solution is administered by subcutaneous injection.
DRUGSodium chloride
The placebo will consist of sterile 0.9% saline (Sodium chloride), drawn up from a 10 ml i.v. vials. The placebo will be administered as an subcutaneous injection in an identical procedure as the metreleptin verum.
Sponsors
Gabriella Milos
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Placebo-controlled, double-blind, randomized trial. The efficacy of metreleptin in Anorexia Nervosa patients will be tested against an inactive placebo.
Eligibility
Sex/Gender
ALL
Age
17 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Main key inclusion criteria: * Current diagnosis of AN according to fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) confirmed with Structured Clinical Interview for DSM-5 (SCID-5) * BMI \> 13 kg/m2; BMI ≤ 18 kg/m2; body weight ≥ 35 kg * Hospitalisation in the Eating Disorders Unit, Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital of Zurich * Ability to understand German language * Age range: 17 - 65 years * Depressive symptoms: HAMD-17 ≥ 8 * Negative urine pregnancy test, non-lactating and double birth control * Informed Consent as documented by signature Main key
Exclusion criteria
* Illicit drug intake within last month; current alcohol use disorder * Severe psychiatric and/or severe somatic comorbidities; f. e. lifetime diagnosis of schizophrenia, bipolar disorder, inflammatory bowel disorders, diabetes mellitus, autoimmune disorders, pancreatitis, neurological disorders, cancer including lymphoma * Acute suicidality or current serious non-suicidal self-injury
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinician-rated depression on the 17 point Hamilton Depression Scale (HAMD-17) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | HAMD-17 is a semi-structured interview and consists of 17 items assessing symptoms of depression from the perspective of the clinician. Possible scores range from 0 (no depressive symptom) to 4 (strong depressive symptom). The higher the total score, the more severe the depressive symptoms. |
| Body weight status in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | Body weight status will be indicated by weight in kilograms (kg). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjective depression by the Beck Depression Inventory-II (BDI-II) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | The Beck Depression Inventory-II is a self-report rating inventory that measures characteristic attitudes and symptoms of depression with 21 items, ranging from 0 (no depressive symptoms) to 3 (strong depressive symptoms). The higher the total score, the more severe the depressive symptoms. |
| Functional brain connectivity in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | For assessment of intrinsic functional connectivity in the brain, functional MRI images will be acquired for each patient. A region-of-interest analysis and calculating correlations between any pair of two brain regions, obtaining a connectivity matrix, will be done. |
| Anorexia Nervosa psychopathology assessed by the Eating Disorders Examination Questionnaire (EDE-Q) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | The Eating Disorders Examination Questionnaire (EDE-Q) is the self-report version of the Eating Disorder Examination (EDE). The 22 items on the four subscales of restraint, eating concern, weight concern, and shape concern are used to assess eating disorder-specific characteristics in their current manifestations during the last 28 days. 7-point rating scales are used to assess frequencies from 0 (characteristic was not present) to 6 (characteristic was present every day or to an extreme degree). Six further, non-scale-forming items also measure the frequency of diagnostically relevant core behaviors over the last 28 days. The EDE-Q is evaluated by calculating subscale mean values for the Restraint, Eating Concern, Weight Concern and Shape Concern subscales and a total score. At Baseline, Post Treatment and intermediate measurements, the instruction of EDE-Q will be modified to refer to a shortened shortened observation time (last week). |
| External rated hyperkinesia assessed by the Structured Inventory for Anorexic and Bulimic Eating Disorders (SIAB, item 42) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | Hyperkinesia will be assessed with only one item (item 42) from the Structured Inventory for Anorexic and Bulimic Eating Disorders (SIAB). This Inventory is used to record the entire spectrum of eating disorder symptoms. Item 42 assesses excessive physical exercise ranging from 0 (no physical exercise) to 4 (very frequent physical exercise). |
| Subjective hyperkinesia assessed by the Exercise and Eating Disorders Questionnaire (EED) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | The Exercise and Eating Disorders Questionnaire (EED) is a clinically derived, self-report questionnaire. 19 items are used to assess compulsive exercise among eating disorder patients. The 6-point rating scale is used to assess the frequencies (never, rare, sometimes, often, mostly, always) during the last 4 weeks. A higher total score indicates a stronger manifestation of compulsive exercises. |
| Autism symptoms assessed by the Autism-Spectrum Quotient-short version (AQ-k) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | The Autism-Spectrum Quotient-short version (AQ-k) is a self-assessment tool for screening for autistic disorder. The 10 items represent autistic symptoms and a 4-point response scale is used to assess the agreement (complete agreement, agree more, rather disagree, complete disagreement) to those. |
| Patient's quality of life by items 1, 2, 5, 6, 7, 10, 17, 19, 20, and 22 from the WHO Quality of Life Questionnaire (WHOQOL-BREF) in the metreleptin-assisted therapy group compared to placebo-therapy between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | The WHO Quality of Life Questionnaire (WHOQOL-BREF) with 26 items is a short form of the WHOQOL-100 and is an instrument for recording subjective quality of life. Items 1, 2, 5, 6, 7, 10, 17, 19, 20, and 22 will be used, ranging from 1 (very dissatisfied/ no agreement) to 5 (very satisfied/fully agreement). A higher total score indicates a increased quality of life. |
| Visual Analog Scale (VAS) about key Anorexia Nervosa and depression symptoms in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | 10 items assessing hunger, repetitive thought of food, fear of weight gain, drive for activity, inner tension, feeling full, nausea, feeling fat, depressed mood and feeling tired on a 10-point response scale ranging from 1 (not pronounced symptom) to 10 (strongly pronounced symptom). |
| Social interaction by the Liebowitz Social Anxiety Scale (LSAS) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | The Liebowitz Social Anxiety Scale is a clinician-administered assessment that measures the fear and avoidance associated with social anxiety. Item 2,3,4,5,8,10,11,12,15 and 19 will be rated on the response scale for avoidance behavior from 1 (never) to 4 (almost always). Higher scores indicating greater severity of social anxiety. |
| Anhedonia by the Snaith-Hamilton Pleasure Scale (SHAPS-D) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | Anhedonia will be assessed with the german version of the Snaith-Hamilton Pleasure Scale (SHAPS-D) that assesses self-reported anhedonia in psychiatric patients. The respective degree of consent regarding the 14 items on the questionnaire will be rated on a bipolar four-point response scale. For the evaluation, each disagree response ('disagree' or 'strongly disagree') is given 1 point and each agree response is given 0 points. By adding up the points, a higher value indicates a greater degree of anhedonia. |
| Hematology in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | Measured with hemoglobin grams per liter (g/l). |
| Blood chemistry in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | Measured with Sodium millimoles per liter (mmol/l). |
| Neuroendocrinological blood parameters in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | Measured with thyroid-stimulating hormon (TSH) milliunits per liter (mU/l). |
| Heart Frequency Variation (HFV) in the metreleptin-assisted therapy group compared to placebo-therapy group between Baseline, Post Treatment and 5 weeks Follow Up | Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49) | Assessed with ECG and will be analysed with the software HRVTool in Matlab. |
Countries
Switzerland
Contacts
CONTACTGabriella Milos, Prof. Dr. med.
CONTACTLisa Guth, MSc Psychology
Outcome results
None listed