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

NCT ID: NCT05644301

Last Updated: 2024-10-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-09-21
• Study Completion Date: 2026-09-30

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.

Conditions

Major Depressive Disorder; Inflammation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Minocyclin + Treatment As Usual (TAU)

Group Type: ACTIVE_COMPARATOR

Minocyclin

Intervention Type: DRUG

Oral capsule, 100 mg, twice daily, for 12 weeks

High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Celecoxib + Treatment As Usual (TAU)

Group Type: ACTIVE_COMPARATOR

Celecoxib

Intervention Type: DRUG

Oral capsule, 200 mg, twice daily, for 12 weeks

High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Placebo + Treatment As Usual (TAU)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral capsule, no active substance, twice daily, for 12 weeks

High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Minocyclin + Treatment As Usual (TAU)

Group Type: ACTIVE_COMPARATOR

Minocyclin

Intervention Type: DRUG

Oral capsule, 100 mg, twice daily, for 12 weeks

High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Celecoxib + Treatment As Usual (TAU)

Group Type: ACTIVE_COMPARATOR

Celecoxib

Intervention Type: DRUG

Oral capsule, 200 mg, twice daily, for 12 weeks

High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Placebo + Treatment As Usual (TAU)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral capsule, no active substance, twice daily, for 12 weeks

Interventions

Celecoxib

Oral capsule, 200 mg, twice daily, for 12 weeks

Intervention Type: DRUG

Minocyclin

Oral capsule, 100 mg, twice daily, for 12 weeks

Intervention Type: DRUG

Placebo

Oral capsule, no active substance, twice daily, for 12 weeks

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Research Foundation Flanders

OTHER

Sponsor Role: collaborator

KU Leuven

OTHER

Sponsor Role: collaborator

Vrije Universiteit Brussel

OTHER

Sponsor Role: collaborator

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: collaborator

Universiteit Antwerpen

OTHER

Sponsor Role: lead

Responsible Party

Manuel Morrens

Professor Doctor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Manuel Morrens, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Professor

Locations

UPC Duffel

Duffel, Antwerpen, Belgium

Site Status: RECRUITING

UZ Brussel

Brussels, , Belgium

Site Status: RECRUITING

Katholiek Universiteit Leuven Campus Kortenberg

Leuven, , Belgium

Site Status: RECRUITING

Countries

Belgium

Central Contacts

Jonas Janssens, MD

Role: CONTACT

jonas.janssens@emmaus.be

015304643

Celine Wessa, MD

Role: CONTACT

Celine.wessa@emmaus.be

Facility Contacts

Manuel Morrens

Role: primary

manuel.morrens@uantwerpen.be

Chris Baeken, PhD MD

Role: primary

Elfi Vergaelen, MD PhD

Role: primary

References

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.

Reference Type: BACKGROUND

PMID: 31258105 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34729541 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23200297 (View on PubMed)

Wessa C, Janssens J, Coppens V, El Abdellati K, Vergaelen E, van den Ameele S, Baeken C, Zeeuws D, Milaneschi Y, Lamers F, Penninx B, Claes S, Morrens M, De Picker L. Efficacy of inflammation-based stratification for add-on celecoxib or minocycline in major depressive disorder: Protocol of the INSTA-MD double-blind placebo-controlled randomised clinical trial. Brain Behav Immun Health. 2024 Sep 19;41:100871. doi: 10.1016/j.bbih.2024.100871. eCollection 2024 Nov.

Reference Type: DERIVED

PMID: 39350954 (View on PubMed)

Other Identifiers

T001222N

Identifier Type: -

Identifier Source: org_study_id