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Endocannabinoid Control of Microglia Activation as a New Therapeutic Target in the Treatment of Schizophrenia (CANGLIA)

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ClinicalTrials.gov Identifier: NCT02932605
Recruitment Status : Completed
First Posted : October 13, 2016
Last Update Posted : March 27, 2020
Sponsor:
Information provided by (Responsible Party):
M.G. Bossong, UMC Utrecht

Tracking Information
First Submitted Date  ICMJE September 21, 2016
First Posted Date  ICMJE October 13, 2016
Last Update Posted Date March 27, 2020
Actual Study Start Date  ICMJE November 3, 2017
Actual Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 8, 2018)
the concentration of prefrontal metabolites as measured with 1H-MRS [ Time Frame: 4 weeks ]
the concentration of prefrontal metabolites as measured with 1H-MRS, with the level of myo-inositol being regarded as a marker of glia function
Original Primary Outcome Measures  ICMJE
 (submitted: October 10, 2016)
[11C]-R-PK11195 Binding Potential [ Time Frame: 4 weeks ]
The main study parameter is the [11C]-R-PK11195 BPP, which is the binding potential relative to total plasma concentration after correction for radioactive metabolites. This is an assessment of microglia activation.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2018)
  • Tolerability associated with CBD treatment [ Time Frame: 4 weeks ]
    Number of treatment-related adverse events as assessed by the study physician
  • Psychotic symptoms [ Time Frame: 4 weeks ]
    Measured with the Positive and Negative Syndrome Scale (PANSS)
  • Depressive symptoms [ Time Frame: 4 weeks ]
    Measured with the Hamilton Depression Rating Scale (HAM-D)
  • Anxiety [ Time Frame: 4 weeks ]
    Measured with the State-Trait Anxiety Inventory (STAI)
  • Clinical impression [ Time Frame: 4 weeks ]
    Measured with the Clinical Global Impressions Scale (CGI)
  • Psychosocial functioning [ Time Frame: 4 weeks ]
    Measured with the Global Assessment of Functioning scale (GAF)
  • Social and Occupational functioning [ Time Frame: 4 weeks ]
    Measured with the Social and Occupational Functional Assessment Scale (SOFAS)
  • Role functioning [ Time Frame: 4 weeks ]
    Measured with the Global Functioning Role (GF:R) scale
  • Social functioning [ Time Frame: 4 weeks ]
    Measured with the Global Functioning Social (GF:S) scale
  • Cognitive function [ Time Frame: 4 weeks ]
    Measured with the Brief Assessment of Cognition in Schizophrenia (BACS)
  • CBD plasma concentrations [ Time Frame: 4 weeks ]
  • Blood cytokine concentrations [ Time Frame: 4 weeks ]
    Examples of cytokines that could be assessed in the current study include but are not restricted to interferon-γ, interleukin (IL)-1α, IL-1RA, IL-6, IL-10, IL-12, IL-15, tumour necrosis factor-α, and S100B
  • Haematological blood parameters [ Time Frame: 4 weeks ]
    Platelet activation and platelet aggregate formation are measured
  • MRI measures [ Time Frame: 4 weeks ]
    Brain structure and function
Original Secondary Outcome Measures  ICMJE
 (submitted: October 10, 2016)
  • Tolerability associated with CBD treatment [ Time Frame: 4 weeks ]
    Number of treatment-related adverse events as assessed by the study physician
  • Psychotic symptoms [ Time Frame: 4 weeks ]
    Measured with the Positive and Negative Syndrome Scale (PANSS)
  • Depressive symptoms [ Time Frame: 4 weeks ]
    Measured with the Hamilton Depression Rating Scale (HAM-D)
  • Anxiety [ Time Frame: 4 weeks ]
    Measured with the State-Trait Anxiety Inventory (STAI)
  • Clinical impression [ Time Frame: 4 weeks ]
    Measured with the Clinical Global Impressions Scale (CGI)
  • Psychosocial functioning [ Time Frame: 4 weeks ]
    Measured with the Global Assessment of Functioning scale (GAF)
  • Social and Occupational functioning [ Time Frame: 4 weeks ]
    Measured with the Social and Occupational Functional Assessment Scale (SOFAS)
  • Role functioning [ Time Frame: 4 weeks ]
    Measured with the Global Functioning Role (GF:R) scale
  • Social functioning [ Time Frame: 4 weeks ]
    Measured with the Global Functioning Social (GF:S) scale
  • Cognitive function [ Time Frame: 4 weeks ]
    Measured with the Brief Assessment of Cognition in Schizophrenia (BACS)
  • CBD plasma concentrations [ Time Frame: 4 weeks ]
  • Blood cytokine concentrations [ Time Frame: 4 weeks ]
    Examples of cytokines that could be assessed in the current study include but are not restricted to interferon-γ, interleukin (IL)-1α, IL-1RA, IL-6, IL-10, IL-12, IL-15, tumour necrosis factor-α, and S100B
  • RNA expression [ Time Frame: 4 weeks ]
    RNA expression of immune-related genes is measured
  • Haematological blood parameters [ Time Frame: 4 weeks ]
    Platelet activation and platelet aggregate formation are measured
  • MRI measures [ Time Frame: 4 weeks ]
    Brain structure and hippocampal glutamate and myoinositol levels are measured
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Endocannabinoid Control of Microglia Activation as a New Therapeutic Target in the Treatment of Schizophrenia
Official Title  ICMJE Endocannabinoid Control of Microglia Activation as a New Therapeutic Target in the Treatment of Schizophrenia
Brief Summary The main objective of this study is to compare microglia activation as measured with proton Magnetic Resonance Spectroscopy (1H-MRS) between recent-onset schizophrenia patients who are randomised to CBD and those randomised to placebo.
Detailed Description

Schizophrenia is a chronic and severe mental disorder with an urgent need for new and more effective treatments. A promising novel pharmacological target in this respect is the endocannabinoid system. In particular the cannabinoid compound cannabidiol (CBD) displays a highly favourable profile for development as a new antipsychotic agent. Increasing evidence indicates a significant role for neuroinflammation in the pathophysiology of schizophrenia, especially for activation of resident macrophages of the brain: microglia. Interestingly, converging preclinical evidence suggests that microglia activation is under control of the endocannabinoid system. However, how manipulation of the endocannabinoid system affects microglia activation in humans has not been established, but it is presumably related to clinical improvement of schizophrenia patients.

In this project, we propose to study endocannabinoid control of microglia activation as a new therapeutic target in the treatment of schizophrenia. Using a placebo-controlled, randomised, double-blind design, we will investigate this in a group of 36 recent-onset schizophrenia patients after four weeks of daily CBD treatment, in addition to their regular antipsychotic medication. First, we will examine if CBD treatment attenuates microglia activation and levels of peripheral inflammatory markers. In vivo microglia activation is assessed before and after treatment using 1H-MRS, with the level of myo-inositol being regarded as a marker of glia function. Second, we will determine if reduced microglia activation and levels of inflammatory markers relate to improvement of symptomatology and cognitive function. Third, we will assess how microglia activation and levels of inflammatory markers before treatment predict the clinical response to CBD.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE Schizophrenia
Intervention  ICMJE
  • Drug: Placebo
    Placebo
  • Drug: Cannabidiol
    Cannabidiol
Study Arms  ICMJE
  • Experimental: Cannabidiol
    Patients will be treated with 600mg CBD daily for 4 weeks (28 days)
    Intervention: Drug: Cannabidiol
  • Placebo Comparator: Placebo
    Patients will be treated with placebo daily for 4 weeks (28 days)
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 26, 2020)
32
Original Estimated Enrollment  ICMJE
 (submitted: October 10, 2016)
50
Actual Study Completion Date  ICMJE January 31, 2020
Actual Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • A DSM-IV diagnosis of 295.x (schizophrenia, schizophreniform disorder or schizoaffective disorder) or 298.9 (psychosis NOS). Diagnosis must be confirmed in writing by the treating psychiatrist.
  • Age 16 - 40
  • Onset of first psychosis no longer than five years ago
  • Written informed consent of the subject

Exclusion Criteria:

  • Any clinically significant medical condition that may influence the results of the trial or affect the ability to take part in a trial
  • Routine laboratory screening values considered an impediment for participation by a medical doctor (see Appendix 1)
  • Positive urine test on any drug of abuse, except cannabis
  • Treatment with more than one antipsychotic agent or with an unstable dose of one type of antipsychotic medication in the month prior to study inclusion
  • Use of glucocorticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) within two weeks prior to study inclusion
  • Use of co-medication other than antipsychotics that has a clinically relevant interaction with the cytochrome P450 (CYP) 2C19 or CYP3A classes of liver enzymes within two weeks prior to study inclusion (because CBD may be an inhibitor of these classes of liver enzymes; see paragraph 6.3)
  • Intake of investigational drug within one month prior to study inclusion
  • Daily use of alcohol or drugs of abuse (including cannabis) in the three months prior to study inclusion
  • Any current or previous neurological disorder, including epilepsy
  • History of head injury resulting in unconsciousness lasting at least 1 hour
  • IQ < 70, as measured with Dutch version of the National Adult Reading Test (DART)
  • Breastfeeding, pregnancy or attempting to conceive
  • MRI contraindications, e.g. claustrophobia or metal objects in or around the body
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02932605
Other Study ID Numbers  ICMJE ABR58805
2016-003529-41 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party M.G. Bossong, UMC Utrecht
Study Sponsor  ICMJE UMC Utrecht
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Matthijs Bossong, PhD UMC Utrecht
PRS Account UMC Utrecht
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP