INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive Disorder

Study Overview
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Brief Summary
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This is a randomised, double-blind, placebo-controlled clinical trial in which patients with major depressive disorder will receive augmentation through minocycline (MCO), celecoxib (CXB) or placebo.

Detailed Description
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This project aims to repurpose two established anti-inflammatory compounds as adjuvant therapy for immune-mediated depression, in line with state-of-the-art research of the last 10 years. Immune-mediated depression represents a subtype which accounts for approximately 30% of depressive disorders. Patients with this immunosubtype are more likely to have a higher severity of depression, a lower quality of life and more somatic symptoms. Furthermore it is accompanied by a high incidence of treatment resistance. While their mechanisms of action completely differ from those of existing antidepressant treatment options, immunomodulatory drugs celecoxib and minocycline have proven their merit as add-on treatment in depressive episodes. They have been on the Belgian market for years and come with a known pharmacological and safety profile. Patient stratification at baseline based on inflammatory status will reveal which inflammatory subpopulation benefits most from each of the two investigated anti-inflammatory compounds. Additionally, our distinctive study design allows head-to-head comparison of both add-on therapies and will as such provide the last stepping stones towards clinical implementation of individualised treatment strategies in depression.

Official Title
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INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive

Conditions
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Major Depressive Disorder, Inflammation

Intervention / Treatment
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* Drug: Celecoxib
* Drug: Minocyclin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18-65 years inclusive. Able and willing to give informed consent and take oral medication. Physically healthy. Diagnosis of Major Depressive Disorder by DSM-5 criteria, confirmed by the Mini International Neuropsychiatric Interview (MINI). The current episode of depression has failed to remit to the current antidepressant treatment at the adequate dose (as defined in the Maudsley Prescribing guidelines). Relapse while taking an antidepressant is also considered a treatment failure. Tolerant to the current antidepressant and having no planned changes in their current therapy for the duration of the study. Stable on current treatment for a minimum of 4 weeks (6 weeks for fluoxetine) prior to baseline. If female and of childbearing age, willing to use adequate contraceptive precautions and willing to take a pregnancy test at baseline. Exclusion Criteria: Primary diagnosis of a bipolar disorder, psychotic spectrum disorder, obsessive-compulsive disorder, eating disorder, post-traumatic stress disorder, or alcohol and/or substance use disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (< 4 weeks before screening, excl. nicotine and caffeine). Use of immunosuppressant or immunostimulant drugs within 21 days of screening (e.g., glucocorticoid treatment, methotrexate, etc.). History of peptic ulcer disease or gastrointestinal (GI) bleeding. Having an acute infection or inflammatory bowel disorder. Current severe cardiovascular disease, congestive heart failure (NYHA-class II-IV), ischemic or thrombotic events or unstable coronary artery (incl. coronary artery bypass graft (CABG) surgery), Liver impairment (alanine aminotransferase > 2x upper limit, serum albumin < 25 g/l or Child-Pugh Score ≥ 10) Renal impairment (creatinine clearance < 30 mL/min). Having received >14 days of tetracycline or non-steroidal anti-inflammatory medication within the previous 2 months, or having a history of sensitivity or intolerance to these classes of drugs. Chronic severe hypertension (systolic BP > 170 mmHg). Serology positive for hepatitis-B surface antigen, hepatitis-C antibodies or HIV antibodies. Received electroconvulsive therapy < 2 months prior to screening. Blood donation in 30 days prior to screening. Pregnancy or breastfeeding. Currently enrolled in an intervention study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Minocyclin + Treatment As Usual (TAU)<br> | Drug: Minocyclin<br>* Oral capsule, 100 mg, twice daily, for 12 weeks<br>|
| Active Comparator: High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Celecoxib + Treatment As Usual (TAU)<br> | Drug: Celecoxib<br>* Oral capsule, 200 mg, twice daily, for 12 weeks<br>|
| Placebo Comparator: High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Placebo + Treatment As Usual (TAU)<br> | Drug: Placebo<br>* Oral capsule, no active substance, twice daily, for 12 weeks<br>|
| Active Comparator: High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Minocyclin + Treatment As Usual (TAU)<br> | Drug: Minocyclin<br>* Oral capsule, 100 mg, twice daily, for 12 weeks<br>|
| Active Comparator: High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Celecoxib + Treatment As Usual (TAU)<br> | Drug: Celecoxib<br>* Oral capsule, 200 mg, twice daily, for 12 weeks<br>|
| Placebo Comparator: High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Placebo + Treatment As Usual (TAU)<br> | Drug: Placebo<br>* Oral capsule, no active substance, twice daily, for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in depressive symptom severity (HDRS-17) | Change in severity of depression measured as the change in the 17-point scale of the Hamilton Depression Rating Scale (HDRS-17; score is ranging from 0 to 52, higher scores indicate higher severity of depressive symptoms) between baseline and endpoint | T0 -> T6 (12 weeks) | 
| Remission rate of depression (HDRS-17) | Rates of remission measured as a score of ≤7 on the 17-point scale of the Hamilton Depression Rating Scale (HDRS-17; score is ranging from 0 to 52, higher scores indicate higher severity of depressive symptoms and scores 0-7 are considered as being normal) at endpoint | T0 -> T6 (12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in depressive symptom severity (IDS-30SR) | Change in severity of depression measured as the change in the Inventory of Depressive Symptomatology - Self Report (IDS-SR; score is ranging from 0 to 84, higher scores indicate higher severity of depressive symptoms) | T0 -> T6 (12 weeks) | 
| Response rate of depressive symptoms (HDRS-17) | Response rates of the depressive symptoms measured on the 17-point scale of the Hamilton Depression Rating Scale (HDRS-17; score is ranging from 0 to 52, higher scores indicate higher severity of depressive symptoms), with response being defined as a 50% reduction in HDRS-17-score from baseline and partial response as a 25% reduction. | T0 -> T6 (12 weeks) | 
| Change in night-time sleep (PSQI) | Change in night-time sleep quality and/or quantity measured on the Pittsburgh Sleep Quality Index (PSQI; score is ranging from 0 to 21, higher scores indicate more sleep disturbances) | T0 -> T6 (12 weeks) | 
| Change in anxiety (STAI) | Change in anxiety measured on the Stait Trait Anxiety Inventory-Self Report (STAI; score is ranging from 20 tot 80, higher scores indicate higher levels of anxiety intensity) | T0 -> T6 (12 weeks) | 
| Change in core assessment of psychomotor change (CORE) | Change in the degree of psychomotor disturbance (which is as an integral component of melancholia) measured on the Core Assessment Of Psychomotor Change (CORE; score is ranging from 0-54, higher scores indicate higher levels of psychomotor disturbances) | T0 -> T6 (12 weeks) | 
| Depressive symptom profiles (IDS-SR) | Profile of the depression measured on the Inventory of Depressive Symptomatology - Self Report (IDS-SR; score is ranging from 0 to 84, higher scores indicate higher severity of depressive symptoms) | T0 -> T6 (12 weeks) | 
| Therapy compliance (MARS) | Therapy compliance measured on the Medication Adherence Scale (MARS; score is ranging from 0-10, higher scores indicate better medication adherence) | T0 -> T6 (12 weeks) | 
| Adverse effects | Side effects measured with a questionnaire based on the list as used in the Antidepressant Side-Effect Checklist (ASEC-21) and the known side effects of Minocycline and Celecoxib | T0 -> T6 (12 weeks) | 
| Metabolic blood markers | Cholesterol (mg/dl), High Density Lipoprotein (HDL) (mg/dl), Low Density Lipoprotein (LDL) (mg/dl), fasting glucose (mg/dl), triglycerides (mg/dl) | T0 -> T6 (12 weeks) | 
| Other metabolic measures | Waist circumference (cm), height (cm) will be measured to calculate the BMI (kg/m^2) | T0 -> T6 (12 weeks) | 
| Other metabolic measures | Weight (kg) will be measured to calculate the BMI (kg/m^2) | T0 -> T6 (12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunopsychiatry, Celecoxib, Minocyclin, Inflammation, Randomised Controlled Clinical Trial