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The Benefit of Minocycline on Negative Symptoms in Schizophrenia: Extent and Mechanisms (BeneMin)

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ClinicalTrials.gov Identifier: NCT02928965
Recruitment Status : Completed
First Posted : October 10, 2016
Last Update Posted : April 18, 2019
Sponsor:
Collaborators:
University of Edinburgh
University of Cambridge
University College, London
University of Birmingham
King's College London
Manchester Mental Health & Social Care Trust
Greater Manchester Mental Health NHS Foundation Trust
Salford Royal NHS Foundation Trust
Lancashire Care NHS Foundation Trust
Cambridgeshire and Peterborough NHS Foundation Trust
West London Mental Health NHS Trust
North East London Foundation Trust
Central and North West London NHS Foundation Trust
Camden and Islington NHS Foundation Trust
South London and Maudsley NHS Foundation Trust
NHS Lothian
NHS Fife
NHS Borders
University Hospital Birmingham NHS Foundation Trust
Information provided by (Responsible Party):
Bill Deakin, University of Manchester

Brief Summary:
The purpose of this study is to investigate if minocycline limits the development of negative symptoms in early psychosis and to test via what mechanism of action this change occurs.

Condition or disease Intervention/treatment Phase
Schizophrenia and Disorders With Psychotic Features Drug: Minocycline Drug: Placebo Phase 2

Detailed Description:

Background

Negative symptoms of psychosis do not respond to the traditional therapy with first- or second-generation antipsychotics and are among main causes of a decrease in quality of life observed in individuals suffering from the disorder. Minocycline, a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties has been suggested as a new potential therapy for negative symptoms. In the two previous clinical trials comparing minocycline and placebo, both added to the standard care, patients receiving minocycline showed increased reduction in negative symptoms. Three routes to neuroprotection by minocycline have been identified: neuroprotection against grey matter loss, anti-inflammatory action and stabilisation of glutamate receptors. However, it is not yet certain what the extent of the benefit of minocycline in psychosis is and what its mechanism is. This proposal is for a multi-centre double-blind randomised placebo-controlled clinical trial entitled The Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin).

Methods

After providing informed consent, 226 participants in the early phase of psychosis will be randomised to receive either 100 mg modified-release capsules of minocycline or similar capsules with placebo for 12 months in addition to standard care. The participants will be tested for outcome variables before and after the intervention period. The extent of benefit will be tested via clinical outcome measures, namely the Positive and Negative Syndrome Scale score, social and cognitive functioning scores, antipsychotic medication dose equivalent and level of weight gain. The mechanism of action of minocycline will be tested via blood screening for circulating cytokines and magnetic resonance imaging with three-dimensional T1-weighted rapid gradient-echo, proton density T2-weighted dual echo and T2*-weighted gradient echo planar imaging with N-back task and resting state. Eight research centres in the United Kingdom (UK) and 15 National Health Service Trusts and Health Boards will be involved in recruiting participants, performing the study and analysing the data.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 207 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: The Benefit of Minocycline on Negative Symptoms in Schizophrenia: Extent and Mechanisms
Study Start Date : February 2013
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Minocycline
Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.
Drug: Minocycline
Capsules containing 100mg minocycline (modified release), administered orally by the patient, two per day for the first two weeks and then three per day for the reminder of the 12 month treatment period in addition to standard therapy.
Other Name: Acnamino MR (modified release)

Placebo Comparator: Placebo
Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.
Drug: Placebo
Matching placebo with appearance of over - encapsulated minocycline




Primary Outcome Measures :
  1. Severity of negative symptoms of psychosis [ Time Frame: twelve months ]
    Measured by Negative symptoms scale in the Positive and Negative Syndrome Scale


Secondary Outcome Measures :
  1. Change in body weight [ Time Frame: Twelve months ]
    Measuring weight gain in kilograms, a side effect of standard anti-psychotic medication therapy

  2. Positive symptoms of psychosis [ Time Frame: twelve months ]
    Measured by the Positive symptoms scale in the Positive and Negative Syndrome Scales

  3. General social and psychological functioning [ Time Frame: twelve months ]
    Measured by Global Assessment of Functioning from DSM-IV

  4. Intelligence [ Time Frame: twelve months ]
    Measured by Wechsler Adult Intelligence Scale for patients with schizophrenia

  5. Anti-psychotic medication dose [ Time Frame: twelve months ]
    Measured in chlorpromazine equivalent units

  6. Verbal learning [ Time Frame: 12 months ]
    Auditory-Verbal Learning Task

  7. Social and Occupational functioning [ Time Frame: 12 months ]
    Score on Social Functioning Scale


Other Outcome Measures:
  1. Change in medial prefrontal grey matter volume (primary biomarker outcome) [ Time Frame: twelve months ]
    Change Measured by T1-weighted magnetic resonance imaging (MRI)

  2. Circulating interleukin (IL-6) concentration (primary biomarker outcome) [ Time Frame: twelve months ]
    Measured by blood cytokine screen test

  3. Dorsolateral-prefrontal cortex blood oxygen level dependent response during working memory task (primary biomarker outcome) [ Time Frame: twelve months ]
    Measured by functional magnetic resonance imaging during N-back task

  4. Pattern of total and regional grey matter volumes (secondary biomarker outcome) [ Time Frame: twelve months ]
    Measured by T1-weighted magnetic resonance imaging

  5. Multivariate pattern of circulating cytokine concentrations (secondary biomarker outcome) [ Time Frame: twelve months ]
    Measured by blood cytokine screen test

  6. Distribution of Hurst exponent (brain functional connectivity measure; secondary biomarker outcome) [ Time Frame: twelve months ]
    Measured by functional magnetic resonance imaging during resting state

  7. Verbal fluency [ Time Frame: 12 months ]
    Verbal fluency, words per minute beginning with F, A and S

  8. Working memory [ Time Frame: 12 months ]
    Performance on the N-back task during scanning



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meeting DSM-IV criteria for schizophrenia, schizophreniform or schizo-affective psychosis as assessed by the research team
  • In an episode as defined by the presence of positive symptoms measured by Positive and Negative Syndrome Scale with a score higher than two in items 1,2,3 or 6 in the Positive scale
  • In contact with early intervention community or in-patient service
  • Within 5 years of first diagnosis
  • Intelligence quotient (IQ) greater than 70
  • Participants and their partners must be willing to use effective birth control throughout the study and seven days after stopping trial medication. Females should have a negative pregnancy test
  • Able to understand and willing to give written informed consent
  • Fluent in English

Exclusion Criteria:

  • Current substance misuse diagnosis that in the opinion of the investigator may interfere with the study
  • Patients who, in the investigator's judgement pose a current serious suicidal or violence risk
  • Use of tetracycline antibiotics within 2 months of the randomisation visit or history of sensitivity or intolerance for this type of antibiotics
  • History of Systemic Lupus Erythematosis (SLE) or a history of SLE in a first-degree relative
  • Use of any investigational drug within a month of randomisation visit
  • Relevant current or past hematologic, hepatic, renal, neurological or other medical disorder in the opinion of the principal investigator (PI) or the responsible medical officer (RMO) may interfere with the trial
  • Taking medical treatments that could seriously interact with minocycline as described in the summary of product characteristics (SPC) and judged by the PI or the RMO
  • Clinically significant deviation from the reference range in clinical laboratory test results as judged by the investigator
  • Previous randomisation in the present study
  • Pregnant or breastfeeding
  • Meeting MRI exclusion criteria as defined by local scanning centres

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02928965


Sponsors and Collaborators
University of Manchester
University of Edinburgh
University of Cambridge
University College, London
University of Birmingham
King's College London
Manchester Mental Health & Social Care Trust
Greater Manchester Mental Health NHS Foundation Trust
Salford Royal NHS Foundation Trust
Lancashire Care NHS Foundation Trust
Cambridgeshire and Peterborough NHS Foundation Trust
West London Mental Health NHS Trust
North East London Foundation Trust
Central and North West London NHS Foundation Trust
Camden and Islington NHS Foundation Trust
South London and Maudsley NHS Foundation Trust
NHS Lothian
NHS Fife
NHS Borders
University Hospital Birmingham NHS Foundation Trust
Investigators
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Principal Investigator: Bill Deakin, Professor University of Manchester
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Responsible Party: Bill Deakin, Professor of Psychiatry and Director of Neuroscience Research in the Division of Psychiatry, University of Manchester
ClinicalTrials.gov Identifier: NCT02928965    
Other Study ID Numbers: EME-09/100/23
2010-022463-35 ( EudraCT Number )
10411 ( Other Identifier: United Kingdom Clinical Research Network )
First Posted: October 10, 2016    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Fully anonymised database will be made available in 2018. Basic demographics, Primary clinical and mechanistic outcome measures. Treatment allocation code
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Analytic Code
Time Frame: January 2019
Access Criteria: Academic researcher, clear analysis plan, publication plan Agreement of Chief investigator
Keywords provided by Bill Deakin, University of Manchester:
psychosis
schizophrenia
negative symptoms
minocycline
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Minocycline
Anti-Bacterial Agents
Anti-Infective Agents