Enoxolone in Major Depression - Biomarker-outcome Relationship

• ClinicalTrials.gov Identifier: NCT05570110
• Recruitment Status: Recruiting
• First Posted: October 6, 2022
• Last Update Posted: October 6, 2022
• Sponsor: Philipps University Marburg Medical Center
• Collaborator: Slovak Academy of Sciences
• Information provided by (Responsible Party): Harald Murck, Philipps University Marburg Medical Center

Study Description

Brief Summary:

Many different forms of depression exist. It is difficult to predict to what treatment a given patient with depression responds. Studies demonstrate that biomarkers can help to distinguish different forms of depression. Simple markers, like aldosterone from the saliva, blood pressure and inflammation markers from the blood, have been identified as predictors of a more difficult to treat depression. Enoxolone is a molecule derived from the licorice plant and has demonstrated an effect on these biomarkers, which may indicate a better response. In a randomized placebo controlled trial this study is assessing whether the administration of enoxolone vs. placebo can change these markers and if patients benefit from these biomarker changes clinically. In addition, this study records the volume and structure of certain brain areas, which could be involved in this action.

Condition or disease	Intervention/treatment	Phase
Unipolar Depression	Drug: Enoxolone	Phase 1; Phase 2

Detailed Description:

The objective of the study is 1. to confirm patient characteristics, which are related to lesser responsivity to antidepressant treatment and 2. to explore the utility of the 11 beta hydroxysteroid-dehydrogenase type 2 (11betaHSD2) inhibitor enoxolone to reverse these markers of refractoriness and, potentially, improve clinical outcome. A broad spectrum of patients is recruited in order to provide the opportunity to compare those with relevant markers of refractoriness vs. those without.

The identified markers are related to the activity of aldosterone, which appears to affect specific CNS areas, which are involved in mood and autonomic regulation. One area of particular relevance is the pontine nucleus of the solitary tract (NTS). Potential primary triggers for an increased aldosterone release under stressful conditions are related to low blood pressure, electrolyte alterations and a dysfunction of the peripheral mineralocorticoid receptor (MR).

Enoxolone leads to an activation of the peripheral MR by reducing the activity of the 11betaHSD2, therefore allowing cortisol access to the MR and, as a consequence, suppress the release of renin, angiotensin and aldosterone. In addition, it can increase blood pressure slightly.

A set of markers is studied, which follow this mechanistic pathway, in detail:

1. The effects of enoxolone on salivary and plasma hormones, to establish molecular target engagement, in particular a reduction of aldosterone concentration.

2. The relationship between changes in hormone concentrations and markers of CNS activation of MR, i.e. functional target engagement. These are:

   1. Heart rate variability and heart rate
   2. Nocturnal blood pressure
   3. Total sleep- and slow wave sleep duration
   4. Salt taste sensitivity and -preference
   5. Inflammatory markers
   6. Optional: volumes of lateral ventricles, corpus callosum and choroid plexi.
   7. Optional: white matter integrity, as measured by diffusion tensor imaging
3. The correlation between the baseline levels of these markers of molecular and functional target engagement and clinical outcome are studied, as determined by the relative change of the Hamilton-Depression Rating Scale (HAMD-17) and other scales.
4. Exploration will be performed whether markers, which define an increased activity of brain MR activation at baseline, characterize a group of subjects with preferential differentiation between enoxolone vs. placebo treatment. This allows to further establish the subgroup of subjects, who may benefit from the administration of enoxolone best.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized parallel group design, first two subjects open label.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Active and Placebo Capsules of the same shape and size are utilized
• Primary Purpose: Diagnostic
• Official Title: Double-blind Randomized Placebo Controlled Study on the Effect of Enoxolone ( 11-beta Hydroxysteroid-dehydrogenase Type 2 Inhibitor) on the RAAS, Autonomic and Imaging Biomarkers and the Outcome of Depression
• Actual Study Start Date: September 23, 2022
• Estimated Primary Completion Date: March 2025
• Estimated Study Completion Date: March 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: enoxolone; 100 mg enoxolone in a capsule	Drug: Enoxolone; one capsule of active or placebo in the evening; Other Name: glycyrrhetinic acid
Placebo Comparator: placebo; Placebo in a capsule	Drug: Enoxolone; one capsule of active or placebo in the evening; Other Name: glycyrrhetinic acid

Outcome Measures

Primary Outcome Measures :

1. Saliva aldosterone/cortisol ratio [ Time Frame: week 2 (baseline as covariate) ]
   Ratio of saliva aldosterone concentration/saliva cortisol concentration
2. Urine aldosterone/cortisol ratio [ Time Frame: week 2 (baseline as covariate) ]
   Ratio of nocturnal urine aldosterone concentration/urine cortisol concentration
3. Nocturnal heart rate variability [ Time Frame: week 2 (baseline as covariate) ]
   Average nocturnal heart rate variability, expressed as stress level (Garmin, arbitrary unit)
4. Nocturnal blood pressure minimum [ Time Frame: week 2 (baseline as covariate) ]
   Minimum of continuously monitored systolic blood pressure (mmHg)
5. Total sleep duration [ Time Frame: week 2 (baseline as covariate) ]
   Total sleep duration, as determined by wearable device (Garmin) (minutes)
6. Salt taste preference [ Time Frame: week 2 (baseline as covariate) ]
   salt taste preference, as determined by tasting a 0.9% NaCl solution, 11 item Likert scale (Murck et al., 2018)
7. Inflammation: C-reactive protein [ Time Frame: week 2 (baseline as covariate) ]
   Plasma C-reactive protein concentration (mg/L)
8. Depression rating [ Time Frame: week 2 (baseline as covariate) ]
   Hamilton depression rating scale (HAMD) - 17 items; higher is worse
9. Depression self rating [ Time Frame: week 2 (baseline as covariate) ]
   Patient health questionnaire for depression (PHQ-9), higher is worse
10. Rating for symptoms of normal pressure hydrocephalus [ Time Frame: week 2 (baseline as covariate) ]
    Idiopathic normal pressure hydrocephalus grading scale (iNPHGS) (Kubo et al., 2008), higher is worse
11. Cerebral ventricular volume [ Time Frame: change from baseline to 4 weeks ]
    Volume of lateral ventricles (sum) (mL)
12. Corpus callosum volume [ Time Frame: change from baseline to 4 weeks ]
    Volume of corpus callosum (mL)
13. Choroid Plexus Volume [ Time Frame: change from baseline to 4 weeks ]
    Volume of Choroid Plexi (sum) (mL)

Secondary Outcome Measures :

1. Saliva aldosterone/cortisol ratio [ Time Frame: week 4 (baseline as covariate) ]
   Ratio of saliva aldosterone concentration/saliva cortisol concentration
2. Urine aldosterone/cortisol ratio [ Time Frame: week 4 (baseline as covariate) ]
   Ratio of nocturnal urine aldosterone concentration/urine cortisol concentration
3. Nocturnal heart rate variability [ Time Frame: week 4 (baseline as covariate) ]
   Average nocturnal heart rate variability, expressed as stress level (Garmin, arbitrary unit)
4. Nocturnal blood pressure minimum [ Time Frame: week 4 (baseline as covariate) ]
   Minimum of continuously monitored systolic blood pressure (mmHg)
5. Total sleep duration [ Time Frame: week 4 (baseline as covariate) ]
   Total sleep duration, as determined by wearable device (Garmin) (minutes)
6. Salt taste preference [ Time Frame: week 4 (baseline as covariate) ]
   salt taste preference, as determined by tasting a 0.9% NaCl solution, 11 item Likert scale (Murck et al., 2018)
7. Inflammation: C-reactive protein [ Time Frame: week 4 (baseline as covariate) ]
   Plasma C-reactive protein concentration (mg/L)
8. Depression rating [ Time Frame: week 4 (baseline as covariate) ]
   Hamilton depression rating scale (HAMD) - 17 items; higher is worse
9. Depression self rating [ Time Frame: week 4 (baseline as covariate) ]
   Patient health questionnaire for depression (PHQ-9), higher is worse
10. Rating for symptoms of normal pressure hydrocephalus [ Time Frame: week 4 (baseline as covariate) ]
    Idiopathic normal pressure hydrocephalus grading scale (iNPHGS) (Kubo et al., 2008), higher is worse

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Unipolar Depression
• in women: Contraceptive means

Exclusion Criteria:

• Schizophrenic and delusional disorders
• Neurological diseases in which central nervous system involvement is known, such as epilepsies, storage diseases; severe mental retardation
• Internistic diseases of moderate or higher severity, which may make participation in the study risky from a clinical point of view. In particular, multiple systolic blood pressure (measured after at least 5 min supine position) of > 145 mm Hg as well as hypokalemia (< 3.5 mmol/l) and clinically relevant ECG changes
• Poorly controlled diabetes mellitus (HbA1c > 10)
• Pregnancy or active desire for pregnancy for the duration of the study
• Non-consent or inability to consent to the study
• Treatment with the following substances: spironolactone or eplerenone; systemic glucocorticoids
• Treatment with ketamine or electroconvulsive therapy in the last 3 months before randomization
• Acute suicidality
• Intolerance to licorice preparations or licorice contents.

Contacts and Locations

Contacts

Contact: Ulrich Schu, MD; +49 6421 5865200; schu@uni-marburg.de

Locations

Germany

Clinic for Psychiatry and Psychotherapy; Recruiting

Marburg, Hessen, Germany, 35039

Contact: Ulrich Schu, MD +49 6421 5865200 schu@uni-marburg.de

Sponsors and Collaborators

Philipps University Marburg Medical Center

Slovak Academy of Sciences

Investigators

• Study Director: Harald Murck, MD PhD; Philipps University Marburg Medical Center

More Information

Publications:

Murck H, Luerweg B, Hahn J, Braunisch M, Jezova D, Zavorotnyy M, Konrad C, Jansen A, Kircher T. Ventricular volume, white matter alterations and outcome of major depression and their relationship to endocrine parameters - A pilot study. World J Biol Psychiatry. 2021 Feb;22(2):104-118. doi: 10.1080/15622975.2020.1757754. Epub 2020 May 15.

Murck H, Lehr L, Hahn J, Braunisch MC, Jezova D, Zavorotnyy M. Adjunct Therapy With Glycyrrhiza Glabra Rapidly Improves Outcome in Depression-A Pilot Study to Support 11-Beta-Hydroxysteroid Dehydrogenase Type 2 Inhibition as a New Target. Front Psychiatry. 2020 Dec 10;11:605949. doi: 10.3389/fpsyt.2020.605949. eCollection 2020.

Engelmann J, Murck H, Wagner S, Zillich L, Streit F, Herzog DP, Braus DF, Tadic A, Lieb K, Muller MB. Routinely accessible parameters of mineralocorticoid receptor function, depression subtypes and response prediction: a post-hoc analysis from the early medication change trial in major depressive disorder. World J Biol Psychiatry. 2022 Oct;23(8):631-642. doi: 10.1080/15622975.2021.2020334. Epub 2022 Jan 25.

Murck H, Braunisch MC, Konrad C, Jezova D, Kircher T. Markers of mineralocorticoid receptor function: changes over time and relationship to response in patients with major depression. Int Clin Psychopharmacol. 2019 Jan;34(1):18-26. doi: 10.1097/YIC.0000000000000239.

Kubo Y, Kazui H, Yoshida T, Kito Y, Kimura N, Tokunaga H, Ogino A, Miyake H, Ishikawa M, Takeda M. Validation of grading scale for evaluating symptoms of idiopathic normal-pressure hydrocephalus. Dement Geriatr Cogn Disord. 2008;25(1):37-45. doi: 10.1159/000111149. Epub 2007 Nov 20.

• Responsible Party: Harald Murck, Apl. Professor, Philipps University Marburg Medical Center
• ClinicalTrials.gov Identifier: NCT05570110
• Other Study ID Numbers: MNS_02.1
• First Posted: October 6, 2022
• Last Update Posted: October 6, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Plan to share study data in concordance with local regulations
• Supporting Materials: Study Protocol
• Time Frame: available after study completion
• Access Criteria: CDA or other agreements

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Harald Murck, Philipps University Marburg Medical Center:

Atypical depression

Additional relevant MeSH terms:

Depression; Depressive Disorder; Behavioral Symptoms; Mood Disorders; Mental Disorders; Glycyrrhetinic Acid; Anti-Inflammatory Agents