INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive Disorder (INSTA-MD)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Inflammation; Major Depressive Disorder
• Intervention / Treatment: Drug: Minocyclin; Drug: Celecoxib; Drug: 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.

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jonas Janssens, MD; Phone Number: 015304643; Email: jonas.janssens@emmaus.be
• Study Contact Backup: Name: Celine Wessa, MD; Email: Celine.wessa@emmaus.be

Study Locations

• Belgium
  • Brussels, Belgium
    • Recruiting
    • UZ Brussel
    • Contact: Chris Baeken, PhD MD
  • Leuven, Belgium
    • Recruiting
    • Katholiek Universiteit Leuven Campus Kortenberg
    • Contact: Elfi Vergaelen, MD PhD
    • Sub-Investigator: Emma Saillart
  • Antwerpen
    • Duffel, Antwerpen, Belgium, 2570
      • Recruiting
      • UPC Duffel
      • Contact: Manuel Morrens; Email: manuel.morrens@uantwerpen.be
      • Sub-Investigator: Tim Rietberg
      • Sub-Investigator: Céline Wessa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune markers	Cytokines: interleukin-6, interleukin-1β, tumor necrosis factor α, interferon γ, Interleukin-1 receptor, interleukin-7	T0 -> T6 (12 weeks)
Alternate immune markers	Peripheral blood monocytes (PBMCs)	T0 -> T6 (12 weeks)
Tryptophan pathway metabolites	Kynurenine (KYN), Kynurenic Acid (KYNA), Quinolinic Acid (QA), 3-Hydroxykynurenine (3-HK)	T0 -> T6 (12 weeks)
Vascular and (neuro)trophic factors	Vascular endothelial growth factor (VEGF), Brain-derived neurotrophic factor (BDNF)	T0 -> T6 (12 weeks)

Collaborators and Investigators

• Sponsor: Universiteit Antwerpen
• Collaborators: KU Leuven; Amsterdam UMC, location VUmc; Vrije Universiteit Brussel; Research Foundation Flanders
• Investigators: Principal Investigator: Manuel Morrens, MD PhD, PROFESSOR

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2023
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: November 24, 2022
• First Submitted That Met QC Criteria: December 8, 2022
• First Posted (Actual): December 9, 2022

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 9, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; Celecoxib; Immunopsychiatry; Minocyclin; Randomised Controlled Clinical Trial
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Depression; Depressive Disorder; Inflammation; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Anti-Bacterial Agents; Cyclooxygenase 2 Inhibitors; Celecoxib; Minocycline
• Other Study ID Numbers: T001222N

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No