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

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia and Disorders With Psychotic Features
• Intervention / Treatment: Drug: Minocycline; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 207
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 35 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of negative symptoms of psychosis	Measured by Negative symptoms scale in the Positive and Negative Syndrome Scale	twelve months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in body weight	Measuring weight gain in kilograms, a side effect of standard anti-psychotic medication therapy	Twelve months
Positive symptoms of psychosis	Measured by the Positive symptoms scale in the Positive and Negative Syndrome Scales	twelve months
General social and psychological functioning	Measured by Global Assessment of Functioning from DSM-IV	twelve months
Intelligence	Measured by Wechsler Adult Intelligence Scale for patients with schizophrenia	twelve months
Anti-psychotic medication dose	Measured in chlorpromazine equivalent units	twelve months
Verbal learning	Auditory-Verbal Learning Task	12 months
Social and Occupational functioning	Score on Social Functioning Scale	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in medial prefrontal grey matter volume (primary biomarker outcome)	Change Measured by T1-weighted magnetic resonance imaging (MRI)	twelve months
Circulating interleukin (IL-6) concentration (primary biomarker outcome)	Measured by blood cytokine screen test	twelve months
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
Pattern of total and regional grey matter volumes (secondary biomarker outcome)	Measured by T1-weighted magnetic resonance imaging	twelve months
Multivariate pattern of circulating cytokine concentrations (secondary biomarker outcome)	Measured by blood cytokine screen test	twelve months
Distribution of Hurst exponent (brain functional connectivity measure; secondary biomarker outcome)	Measured by functional magnetic resonance imaging during resting state	twelve months
Verbal fluency	Verbal fluency, words per minute beginning with F, A and S	12 months
Working memory	Performance on the N-back task during scanning	12 months

Collaborators and Investigators

• Sponsor: University of Manchester
• Collaborators: King's College London; Northern Care Alliance NHS Foundation Trust; University College, London; University Hospital Birmingham NHS Foundation Trust; University of Edinburgh; NHS Lothian; University of Cambridge; University of Birmingham; Lancashire Care NHS Foundation Trust; South London and Maudsley NHS Foundation Trust; NHS Fife; Cambridgeshire and Peterborough NHS Foundation Trust; Greater Manchester Mental Health NHS Foundation Trust; Central and North West London NHS Foundation Trust; Manchester Mental Health & Social Care Trust; West London Mental Health NHS Trust; North East London Foundation Trust; Camden and Islington NHS Foundation Trust; NHS Borders
• Investigators: Principal Investigator: Bill Deakin, Professor, University of Manchester

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (ACTUAL): May 1, 2016
• Study Completion (ACTUAL): May 1, 2016

Study Registration Dates

• First Submitted: September 23, 2016
• First Submitted That Met QC Criteria: October 6, 2016
• First Posted (ESTIMATE): October 10, 2016

Study Record Updates

• Last Update Posted (ACTUAL): April 18, 2019
• Last Update Submitted That Met QC Criteria: April 15, 2019
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: schizophrenia; psychosis; minocycline; negative symptoms
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia; Schizophrenia Spectrum and Other Psychotic Disorders; Anti-Infective Agents; Anti-Bacterial Agents; Minocycline
• Other Study ID Numbers: EME-09/100/23; 10411 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); 2010-022463-35 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Fully anonymised database will be made available in 2018. Basic demographics, Primary clinical and mechanistic outcome measures. Treatment allocation code
• IPD Sharing Time Frame: January 2019
• IPD Sharing Access Criteria: Academic researcher, clear analysis plan, publication plan Agreement of Chief investigator
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE