Clinical trial NCT05644301: INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive Disorder
Official title: INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Major Depressive Disorder
Inflammation
Keywords: Immunopsychiatry
Celecoxib
Minocyclin
Inflammation
Randomised Controlled Clinical Trial
Lead sponsor: Universiteit Antwerpen
Sponsor class: OTHER
Collaborators: name: Research Foundation Flanders
name: KU Leuven
name: Vrije Universiteit Brussel
name: Amsterdam UMC, location VUmc
First posted: 2022-12-09
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in depressive symptom severity (HDRS-17)
timeFrame: T0 -> T6 (12 weeks)
measure: Remission rate of depression (HDRS-17)
timeFrame: T0 -> T6 (12 weeks)
Secondary outcomes:
measure: Change in depressive symptom severity (IDS-30SR)
timeFrame: T0 -> T6 (12 weeks)
measure: Response rate of depressive symptoms (HDRS-17)
timeFrame: T0 -> T6 (12 weeks)
measure: Change in night-time sleep (PSQI)
timeFrame: T0 -> T6 (12 weeks)
measure: Change in anxiety (STAI)
timeFrame: T0 -> T6 (12 weeks)
measure: Change in core assessment of psychomotor change (CORE)
timeFrame: T0 -> T6 (12 weeks)
measure: Depressive symptom profiles (IDS-SR)
timeFrame: T0 -> T6 (12 weeks)
measure: Therapy compliance (MARS)
timeFrame: T0 -> T6 (12 weeks)
measure: Adverse effects
timeFrame: T0 -> T6 (12 weeks)
measure: Metabolic blood markers
timeFrame: T0 -> T6 (12 weeks)
measure: Other metabolic measures
timeFrame: T0 -> T6 (12 weeks)
measure: Other metabolic measures
timeFrame: T0 -> T6 (12 weeks)
Other outcomes:
measure: Immune markers
timeFrame: T0 -> T6 (12 weeks)
measure: Alternate immune markers
timeFrame: T0 -> T6 (12 weeks)
measure: Tryptophan pathway metabolites
timeFrame: T0 -> T6 (12 weeks)
measure: Vascular and (neuro)trophic factors
timeFrame: T0 -> T6 (12 weeks)
Locations:
city: Duffel
country: Belgium
facility: UPC Duffel
state: Antwerpen
city: Brussels
country: Belgium
facility: UZ Brussel
city: Leuven
country: Belgium
facility: Katholiek Universiteit Leuven Campus Kortenberg
Study officials:
affiliation: Professor
name: Manuel Morrens, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med. 2019 Sep;49(12):1958-1970. doi: 10.1017/S0033291719001454. Epub 2019 Jul 1.
citation: Foley EM, Parkinson JT, Kappelmann N, Khandaker GM. Clinical phenotypes of depressed patients with evidence of inflammation and somatic symptoms. Compr Psychoneuroendocrinol. 2021 Aug 5;8:100079. doi: 10.1016/j.cpnec.2021.100079. eCollection 2021 Nov.
citation: Carvalho LA, Torre JP, Papadopoulos AS, Poon L, Juruena MF, Markopoulou K, Cleare AJ, Pariante CM. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord. 2013 May 15;148(1):136-40. doi: 10.1016/j.jad.2012.10.036. Epub 2012 Nov 27.