Metreleptin in Anorexia Nervosa (METRAN)

Metreleptin in Anorexia Nervosa, Randomized Controlled Trial; Effects on Depressive Symptoms and Concomitant Changes in Brain Connectivity

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Anorexia Nervosa
• Intervention / Treatment: Drug: Sodium chloride; Drug: Metreleptin

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 AN course is frequently chronic. Specific pharmacological therapies for AN are lacking. Recent studies have shown that metabolic alterations play a great role in the etiology and pathogenesis of AN. An important metabolic alteration playing a role 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 augmenting leptin levels in patients with AN have a great therapeutic potential. Recently, positive effects with experimental administration of subcutaneous metreleptin in few young patients with severe AN have been observed. Importantly, no side effects have been observed. For all these reasons, the present study will investigate - with a double blind design - the therapeutic effect of metreleptin in patients with AN. Metreleptin will be administrated to 50 AN-inpatients: 25 patients will receive verum and 25 will receive placebo during 14 days. 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 hematologic, blood chemistry and neuroendocrinological hormones.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gabriella Milos, Prof. Dr. med.; Phone Number: 0041 44 255 52 80; Email: Gabriella.Milos@usz.ch
• Study Contact Backup: Name: Lisa Guth, MSc Psychology; Phone Number: 0041 44 255 97 17; Email: Lisa.Guth@usz.ch

Study Locations

• Switzerland
  • Zurich, Switzerland, 8091
    • Clinic of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich
    • Contact: Florian Remund, MSc. Business Administration
    • Principal Investigator: Gabriella Milos, Prof. Dr. med.
    • Sub-Investigator: Lisa Guth, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Current diagnosis of AN according to fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnosed with Structured Clinical Interview for DSM-5 (SCID-5)
• BMI > 13 kg/m2; BMI ≤ 17.5 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: 18 - 40 years
• Depressive symptoms: HAMD-17 ≥ 8
• Negative pregnancy test, non-lactating and double birth control
• Informed Consent as documented by signature

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

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
Experimental: Metreleptin; 25 patients will receive a daily subcutaneous injection of metreleptin for 14 days. The dose starts with 0.4 ml daily, and gradually increases until 1.8 ml; until 1.2 ml in male patients daily.	Drug: Metreleptin; 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.; Other Names: Myalept®
Placebo Comparator: Placebo; 25 patients will receive a daily subcutaneous injection of inactive substance (placebo) for 14 days. To ensure blinding, the dosing scheme of placebo will have the identical volume to the dosing scheme of metreleptin (verum).	Drug: Sodium 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinician-rated depression on the 17 point Hamilton Depression Scale (HAMD-17) in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	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.	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Body weight status in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Body weight status will be indicated by weight in kilograms (kg).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective depression by the Beck Depression Inventory-II (BDI-II) in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	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.	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Functional brain connectivity in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	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.	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Anorexia Nervosa psychopathology assessed by the Eating Disorders Examination Questionnaire (EDE-Q) in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	The Eating Disorders Examination Questionnaire (EDE-28) is the self-report version of the Eating Disorder Examination (EDE). The EDE-Q assesses the specific eating disorder psychopathology on the four subscales of restraint, eating concern, weight concern, and shape concern. The 22 items with subscale assignment 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.	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
External rated hyperkinesia assessed by the Structured Inventory for Anorexic and Bulimic Eating Disorders (SIAB, item 42) in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	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).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Subjective hyperkinesia assessed by the Exercise and Eating Disorders Questionnaire (EED) in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	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.	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Autism symptoms assessed by the Autism-Spectrum Quotient-short version (AQ-k) in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	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.	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
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 treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	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.	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Visual Analog Scale (VAS) about key Anorexia Nervosa and depression symptoms in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	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).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Hematology in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with hemoglobin grams per liter (g/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with Sodium millimoles per liter (mmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with thyroid-stimulating hormon (TSH) milliunits per liter (mU/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Hematology in the Metreleptin treatment group compared to placebo group between	Measured with hematocrit liter per liter (l/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Hematology in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with erythrocytes Tera per liter (T/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Hematology in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with thrombocytes Giga per liter (G/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Hematology in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with leucocytes Giga per liter (G/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with potassium millimoles per liter (mmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with phosphate millimoles per liter (mmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with creatinine micromoles per liter (µmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with creatinine kinase Units per liter (U/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with bilirubin total micromoles per liter (µmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with pancreatic amylase Units per liter (U/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with lipase Units per liter (U/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with free thyroxin (fT3) picomole per liter (pmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with free thyroxin (fT4) picomole per liter (pmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with follicle stimulating hormone (FSH) international units per liter (IE/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with luteinizing hormone (LH) international units per liter (IE/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with morning cortisol level nanomoles per liter (nmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with fasting insulin millimoles per liter (mmol/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with leptin nanogram per milliliter (ng/ml).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with ghrelin picogram per milliliter (pg/ml).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with cytokine (IL-6) picogram per milliliter (pg/ml).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with cytokine (IL-7) picogram per milliliter (pg/ml).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with estimated Glomerular Filtration Rate (eGFR) milliliters per minute (ml/min).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with alanine aminotransferase Units per liter (U/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with gamma-glutamyltranspeptidase Units per liter (U/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with alkaline phosphatase Units per liter (U/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Blood chemistry in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with C-reactive protein (CRP) milligrams per liter (mg/l).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)
Neuroendocrinological blood parameters in the Metreleptin treatment group compared to placebo group between Baseline, Post Treatment and 5 weeks Follow Up	Measured with brain derived neurotrophic factor (BDNF) picogram per milliliter (pg/ml).	Baseline (day -1), Post Treatment (day 14) and after 5 weeks Follow Up (day 49)

Collaborators and Investigators

• Sponsor: Gabriella Milos

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: February 6, 2024
• First Submitted That Met QC Criteria: March 7, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Depression; Leptin; Anorexia Nervosa; Weight gain; Metreleptin
• Additional Relevant MeSH Terms: Mental Disorders; Signs and Symptoms, Digestive; Feeding and Eating Disorders; Anorexia; Anorexia Nervosa
• Other Study ID Numbers: BASEC 2022-01328

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No