Clinical trial NCT05570110: Enoxolone in Major Depression - Biomarker-outcome Relationship
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Unipolar Depression
Keywords: Atypical depression;
Lead sponsor: Philipps University Marburg
Sponsor class: OTHER
Collaborators: name: Slovak Academy of Sciences
First posted: 2022-10-06
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized parallel group design, first two subjects open label.
Primary purpose: DIAGNOSTIC

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/cortisol in body fluids, blood pressure and inflammation markers , have been identified as predictors of therapy resistance in depression. Enoxolone is a molecule derived from the licorice plant and has demonstrated an effect on these biomarkers, which may imply an improved response. The current randomized placebo controlled study is assessing whether the presence of markers of therapy resistance can predict a preferential effect of enoxolone vs. placebo on clinical outcome. Secondarily, it is tested whether these markers change differentially in the treatment groups. Finally, the relationship between the change of the markers and clinical change will be assessed.

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). The resultant aldosterone release evokes activity at the NTS, which may lead to depression and anxiety.

Enoxolone leads to an activation primarily 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.

1. A set of potentially predictive markers for therapy response of enoxolone vs. placebo will be studied, based on this mechanistic pathway, in detail:

   For the primary analysis subjects are grouped into those with higher vs. lower systolic blood pressure values, as determined by the median systolic blood pressure value at baseline.

   For the secondary analysis the ratio of urine aldosterone/cortisol, as collected over night will be used as a differentiating parameter. Split at the median defines the groups.

   Exploratory parameters for a split are the following:
   1. sleep duration
   2. heart rate variability
   3. salt taste sensitivity and salt preference
   4. inflammation markers, in particular C-reactive protein in plasma.
   5. Optional: volumes of lateral ventricles, corpus callosum and choroid plexi.
   6. Optional: white matter integrity, as measured by diffusion tensor imaging
2. Markers of target engagement:

   1. Effect of enoxolone vs. placebo on systolic blood pressure.
   2. Effect of enoxolone vs. placebo on urine aldosterone/cortisol concentration.
   3. Effect of enoxolone vs. placebo on plasma sodium/potassium concentration ratio.
3. The relationship between changes in hormone concentrations and markers of CNS activation of MR, i.e. functional CNS target engagement. These are:

   1. Heart rate variability and heart rate
   2. Systolic blood pressure at rest and nocturnal blood pressure dip
   3. Total sleep time
   4. Salt taste preference and sensitivity
   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

Eligibility 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.

Primary outcomes:
measure: Systolic blood pressure
timeFrame: Baseline, as predictor for differentiation of treatment groups clinical response
measure: Urine aldosterone/cortisol ratio
timeFrame: Baseline, as predictor for differentiation of treatment groups clinical resposne
measure: Depression rating
timeFrame: change from baseline to week 4, with systolic blood pressure as covariate
measure: Depression self rating
timeFrame: change from baseline to week 4, with systolic blood pressure as covariate
Secondary outcomes:
measure: Systolic blood pressure
timeFrame: change from baseline to week 4
measure: Urine aldosterone/cortisol ratio
timeFrame: change from baseline to week 4
measure: Plasma ratio of sodium/potassium
timeFrame: change from baseline to week 4
measure: Nocturnal heart rate variability
timeFrame: change from baseline to week 4
measure: Nocturnal blood pressure dip (difference between pre-sleep and minimal nocturnal blood pressure
timeFrame: change from baseline to week 4
measure: Total sleep duration
timeFrame: change from baseline to week 4
measure: Salt taste preference and sensitivity
timeFrame: change from baseline to week 4
measure: Inflammation: C-reactive protein
timeFrame: change from baseline to week 4
measure: Rating for symptoms of normal pressure hydrocephalus
timeFrame: change from baseline to week 4
Other outcomes:
measure: Lateral cerebral ventricular volume
timeFrame: change from baseline to 4 weeks
measure: Corpus callosum volume
timeFrame: change from baseline to 4 weeks
measure: Choroid Plexus Volume
timeFrame: change from baseline to 4 weeks
measure: Saliva aldosterone/cortisol ratio
timeFrame: change from baseline to 4 weeks
Locations:
city: Marburg
country: Germany
facility: Clinic for Psychiatry and Psychotherapy
state: Hessen
Study officials:
affiliation: Philipps University Marburg
name: Harald Murck, MD PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.