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

Schizophrenia and Disorders With Psychotic Features Clinical Trial

— BeneMin  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02928965
• Other study ID #: EME-09/100/23
• Secondary ID: 2010-022463-3510
• Status: Completed
• Phase: Phase 2
• Start date: February 2013
• Est. completion date: May 2016

Study information

• Verified date: October 2017
• Source: University of Manchester
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 207
• Est. completion date: May 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 35 Years

Eligibility

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

Related Conditions & MeSH terms

• Schizophrenia
• Schizophrenia and Disorders With Psychotic Features
• Schizophrenia Spectrum and Other Psychotic Disorders

Intervention

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.
• Placebo
Matching placebo with appearance of over - encapsulated minocycline

Locations

Country	Name	City	State
n/a

Sponsors (20)

Lead Sponsor

Collaborator

University of Manchester

Cambridge and Peterborough NHS Foundation Trust, Camden and Islington NHS Foundation Trust, Central and North West London NHS Foundation Trust, Greater Manchester Mental Health NHS Foundation Trust, King's College London, Lancashire Care NHS Foundation Trust, Manchester Mental Health & Social Care Trust, NHS Borders, NHS Fife, NHS Lothian, North East London Foundation Trust, Salford Royal NHS Foundation Trust, South London and Maudsley NHS Foundation Trust, University College, London, University Hospital Birmingham NHS Foundation Trust, University of Birmingham, University of Cambridge, University of Edinburgh, West London Mental Health NHS Trust

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in medial prefrontal grey matter volume (primary biomarker outcome)	Change Measured by T1-weighted magnetic resonance imaging (MRI)	twelve months
Other	Circulating interleukin (IL-6) concentration (primary biomarker outcome)	Measured by blood cytokine screen test	twelve months
Other	Dorsolateral-prefrontal cortex blood oxygen level dependent response during working memory task (primary biomarker outcome)	Measured by functional magnetic resonance imaging during N-back task	twelve months
Other	Pattern of total and regional grey matter volumes (secondary biomarker outcome)	Measured by T1-weighted magnetic resonance imaging	twelve months
Other	Multivariate pattern of circulating cytokine concentrations (secondary biomarker outcome)	Measured by blood cytokine screen test	twelve months
Other	Distribution of Hurst exponent (brain functional connectivity measure; secondary biomarker outcome)	Measured by functional magnetic resonance imaging during resting state	twelve months
Other	Verbal fluency	Verbal fluency, words per minute beginning with F, A and S	12 months
Other	Working memory	Performance on the N-back task during scanning	12 months
Primary	Severity of negative symptoms of psychosis	Measured by Negative symptoms scale in the Positive and Negative Syndrome Scale	twelve months
Secondary	Change in body weight	Measuring weight gain in kilograms, a side effect of standard anti-psychotic medication therapy	Twelve months
Secondary	Positive symptoms of psychosis	Measured by the Positive symptoms scale in the Positive and Negative Syndrome Scales	twelve months
Secondary	General social and psychological functioning	Measured by Global Assessment of Functioning from DSM-IV	twelve months
Secondary	Intelligence	Measured by Wechsler Adult Intelligence Scale for patients with schizophrenia	twelve months
Secondary	Anti-psychotic medication dose	Measured in chlorpromazine equivalent units	twelve months
Secondary	Verbal learning	Auditory-Verbal Learning Task	12 months
Secondary	Social and Occupational functioning	Score on Social Functioning Scale	12 months