Back to resultsINflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive Disorder (INSTA-MD)
Primary Purpose
Major Depressive Disorder, Inflammation
Status
Not yet recruiting
Phase
Phase 3
Locations
Belgium
Study Type
Interventional
Intervention
Celecoxib
Minocyclin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Major Depressive Disorder focused on measuring Immunopsychiatry, Celecoxib, Minocyclin, Inflammation, Randomised Controlled Clinical Trial
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.
Sites / Locations
- UPC Duffel
- UZ Brussel
- Katholiek Universiteit Leuven Campus Kortenberg
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Active Comparator
Active Comparator
Placebo Comparator
Active Comparator
Active Comparator
Placebo Comparator
Arm Label
High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Minocyclin + Treatment As Usual (TAU)
High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Celecoxib + Treatment As Usual (TAU)
High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Placebo + Treatment As Usual (TAU)
High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Minocyclin + Treatment As Usual (TAU)
High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Celecoxib + Treatment As Usual (TAU)
High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Placebo + Treatment As Usual (TAU)
Arm Description
Outcomes
Primary Outcome Measures
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
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
Secondary Outcome Measures
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)
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.
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)
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)
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)
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)
Therapy compliance (MARS)
Therapy compliance measured on the Medication Adherence Scale (MARS; score is ranging from 0-10, higher scores indicate better medication adherence)
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
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)
Other metabolic measures
Waist circumference (cm), height (cm) will be measured to calculate the BMI (kg/m^2)
Other metabolic measures
Weight (kg) will be measured to calculate the BMI (kg/m^2)
Full Information
NCT ID
NCT05644301
First Posted
November 24, 2022
Last Updated
December 8, 2022
Sponsor
Universiteit Antwerpen
Collaborators
Research Foundation Flanders, KU Leuven, Vrije Universiteit Brussel, Amsterdam UMC, location VUmc
1. Study Identification
Unique Protocol Identification Number
NCT05644301
Brief Title
INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive Disorder
Acronym
INSTA-MD
Official Title
INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
January 2023 (Anticipated)
Primary Completion Date
September 2026 (Anticipated)
Study Completion Date
September 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Universiteit Antwerpen
Collaborators
Research Foundation Flanders, KU Leuven, Vrije Universiteit Brussel, Amsterdam UMC, location VUmc
4. Oversight
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
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder, Inflammation
Keywords
Immunopsychiatry, Celecoxib, Minocyclin, Inflammation, Randomised Controlled Clinical Trial
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
240 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Minocyclin + Treatment As Usual (TAU)
Arm Type
Active Comparator
Arm Title
High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Celecoxib + Treatment As Usual (TAU)
Arm Type
Active Comparator
Arm Title
High Sensitive C-reactive Protein (hs-CRP) < 3mg/L: Placebo + Treatment As Usual (TAU)
Arm Type
Placebo Comparator
Arm Title
High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Minocyclin + Treatment As Usual (TAU)
Arm Type
Active Comparator
Arm Title
High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Celecoxib + Treatment As Usual (TAU)
Arm Type
Active Comparator
Arm Title
High Sensitive C-reactive Protein (hs-CRP) > 3mg/L: Placebo + Treatment As Usual (TAU)
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Celecoxib
Intervention Description
Oral capsule, 200 mg, twice daily, for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Minocyclin
Intervention Description
Oral capsule, 100 mg, twice daily, for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Oral capsule, no active substance, twice daily, for 12 weeks
Primary Outcome Measure Information:
Title
Change in depressive symptom severity (HDRS-17)
Description
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
Time Frame
T0 -> T6 (12 weeks)
Title
Remission rate of depression (HDRS-17)
Description
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
Time Frame
T0 -> T6 (12 weeks)
Secondary Outcome Measure Information:
Title
Change in depressive symptom severity (IDS-30SR)
Description
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)
Time Frame
T0 -> T6 (12 weeks)
Title
Response rate of depressive symptoms (HDRS-17)
Description
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.
Time Frame
T0 -> T6 (12 weeks)
Title
Change in night-time sleep (PSQI)
Description
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)
Time Frame
T0 -> T6 (12 weeks)
Title
Change in anxiety (STAI)
Description
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)
Time Frame
T0 -> T6 (12 weeks)
Title
Change in core assessment of psychomotor change (CORE)
Description
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)
Time Frame
T0 -> T6 (12 weeks)
Title
Depressive symptom profiles (IDS-SR)
Description
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)
Time Frame
T0 -> T6 (12 weeks)
Title
Therapy compliance (MARS)
Description
Therapy compliance measured on the Medication Adherence Scale (MARS; score is ranging from 0-10, higher scores indicate better medication adherence)
Time Frame
T0 -> T6 (12 weeks)
Title
Adverse effects
Description
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
Time Frame
T0 -> T6 (12 weeks)
Title
Metabolic blood markers
Description
Cholesterol (mg/dl), High Density Lipoprotein (HDL) (mg/dl), Low Density Lipoprotein (LDL) (mg/dl), fasting glucose (mg/dl), triglycerides (mg/dl)
Time Frame
T0 -> T6 (12 weeks)
Title
Other metabolic measures
Description
Waist circumference (cm), height (cm) will be measured to calculate the BMI (kg/m^2)
Time Frame
T0 -> T6 (12 weeks)
Title
Other metabolic measures
Description
Weight (kg) will be measured to calculate the BMI (kg/m^2)
Time Frame
T0 -> T6 (12 weeks)
Other Pre-specified Outcome Measures:
Title
Immune markers
Description
Cytokines: interleukin-6, interleukin-1β, tumor necrosis factor α, interferon γ, Interleukin-1 receptor, interleukin-7
Time Frame
T0 -> T6 (12 weeks)
Title
Alternate immune markers
Description
Peripheral blood monocytes (PBMCs)
Time Frame
T0 -> T6 (12 weeks)
Title
Tryptophan pathway metabolites
Description
Kynurenine (KYN), Kynurenic Acid (KYNA), Quinolinic Acid (QA), 3-Hydroxykynurenine (3-HK)
Time Frame
T0 -> T6 (12 weeks)
Title
Vascular and (neuro)trophic factors
Description
Vascular endothelial growth factor (VEGF), Brain-derived neurotrophic factor (BDNF)
Time Frame
T0 -> T6 (12 weeks)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jonas Janssens, MD
Phone
015304643
Email
jonas.janssens@emmaus.be
First Name & Middle Initial & Last Name or Official Title & Degree
Celine Wessa, MD
Email
Celine.wessa@emmaus.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Manuel Morrens, MD PhD
Organizational Affiliation
Professor
Official's Role
Principal Investigator
Facility Information:
Facility Name
UPC Duffel
City
Duffel
State/Province
Antwerpen
ZIP/Postal Code
2570
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jonas Janssens
Phone
015304643
Email
jonas.janssens@emmaus.be
Facility Name
UZ Brussel
City
Brussels
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Seline Van den Ameele, PhD MD
Facility Name
Katholiek Universiteit Leuven Campus Kortenberg
City
Leuven
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elfi Vergaelen, MD PhD
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
31258105
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.
Results Reference
background
PubMed Identifier
34729541
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.
Results Reference
background
PubMed Identifier
23200297
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.
Results Reference
background
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INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive Disorder
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