- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02124811
Minocycline Augmentation to Clozapine
August 29, 2018 updated by: Robert Cotes, Emory University
A Pilot Study of Minocycline Augmentation to Clozapine in Individuals With Treatment Resistant Schizophrenia
The proposed pilot study will compare minocycline augmentation with clozapine in individuals with high vs low inflammation as measured by CRP.
Investigators hypothesize that minocycline will be well tolerated and will result in an improvement in the symptoms of schizophrenia, cognition, as well as improve the quality of life for patients preferentially in patients with high CRPs.
Investigators plan to use a variety of different scales to measure improvement in the varying symptoms of schizophrenia as well as cognitive function, which will be administered to patients at three week intervals for a total study time of twelve weeks.
Investigators hypothesize that minocycline could prove to be an effective, well tolerated, and inexpensive medication for treatment resistant patients with schizophrenia whom have particular difficulties with social interactions, obtaining and maintaining employment, and overall quality of life.
Furthermore, investigators hypothesize that the data obtained in this study will contribute to the ongoing exploration of the role of inflammation in the brain of patients with schizophrenia and help understand and target the role of various inflammatory markers in the pathophysiology and treatment of treatment resistant schizophrenia.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Schizophrenia is a major mental illness characterized by a variety of different symptoms including hallucinations, paranoia, difficulties with formulating and expressing thoughts, feelings similar to depression, and problems with cognitive processes.
Individuals with schizophrenia are usually treated with a class of medications called anti-psychotics, which typically help alleviate some of the symptoms of the disorder.
In general, anti-psychotic medications do not completely cure the disorder, and many patients are left with some degree of ongoing symptoms.
Furthermore, it is estimated that 20-30% of individuals with schizophrenia are considered treatment refractory or resistant and do not respond to anti-psychotic medications.
The Food and Drug Administration has approved one antipsychotic medication for use in patients who are considered to have treatment resistant schizophrenia (TRS).
This medication, clozapine, has been shown to be beneficial for patients with TRS, though as many as 40-70% of patients fail to respond or are partially responsive to treatment with clozapine.
In an extensive search of the medical and psychiatric literature, the study team has been impressed by the potential of minocycline, a tetracycline antibiotic, as an adjunctive therapy in patients with schizophrenia based on its reported neuroprotective and anti-inflammatory effects.
It is a fairly inexpensive drug, well tolerated, and two randomized clinical trials have demonstrated favorable results in early-phase schizophrenia.
Only one case series with two patients has investigated minocycline in patients with schizophrenia on clozapine.
Minocycline is also an interesting medication for augmentation with clozapine, as investigators are interested in previous findings of increased inflammation in the brains of patients with schizophrenia and the potential role of inflammation in treatment resistant schizophrenia.
Though there are many markers of increased inflammation in the brain, for this current study, investigators are interested in a general marker of inflammation called C-Reactive Protein (CRP).
The study team hypothesizes that some patients may have increased levels of inflammation in the brain, as measured by the CRP level (drawn from peripheral blood), and that those patients with increased levels of CRP may respond better to augmentation with minocycline.
The proposed pilot study will compare minocycline augmentation with clozapine in individuals with high vs low inflammation as measured by CRP.
Investigators hypothesize that minocycline will be well tolerated and will result in an improvement in the symptoms of schizophrenia, cognition, as well as improve the quality of life for patients preferentially in patients with high CRPs.
Investigators plan to use a variety of different scales to measure improvement in the varying symptoms of schizophrenia as well as cognitive function, which will be administered to patients at three week intervals for a total study time of twelve weeks.
Investigators hypothesize that minocycline could prove to be an effective, well tolerated, and inexpensive medication for treatment resistant patients with schizophrenia whom have particular difficulties with social interactions, obtaining and maintaining employment, and overall quality of life.
Furthermore, investigators hypothesize that the data obtained in this study will contribute to the ongoing exploration of the role of inflammation in the brain of patients with schizophrenia and help understand and target the role of various inflammatory markers in the pathophysiology and treatment of treatment resistant schizophrenia.
Study Type
Interventional
Enrollment (Actual)
10
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Georgia
-
Atlanta, Georgia, United States, 30303
- Grady Memorial Hospital
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
16 years to 63 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Mini International Neuropsychiatric Interview 6.0 diagnosis of schizophrenia or schizoaffective disorder
- Persistent symptoms of schizophrenia as measured by one of the following PANSS items: Total score ≥60, negative subscale ≥ 15, positive subscale ≥ 15, general psychopathology subscale ≥ 30
- Currently taking clozapine and the dose has been adjusted within 100 mg of study enrollment
- Currently taking clozapine for 3 months and documented clozapine level ≥ 350 ng/ml prior to study start
- No other psychotropic medication changes for one month prior to study enrollment
- No new psychosocial interventions for one month prior to study enrollment
- No prior experience on minocycline for greater than 1 week
- May be taking any other psychotropic, dermatologic, or gastrointestinal drugs
Exclusion Criteria:
- History of organic brain disease
- Diagnostic and Statistical Manual of Mental Disorders (DSM) IV-TR diagnosis of Mental Retardation or Dementia
- DSM-IV-TR diagnosis of Alcohol or Substance Dependence within the last six months (except nicotine)
- Pregnancy or lactation
- Known hypersensitivity to tetracyclines
- Current known infection
- Any known neurological disease or medical condition that could impact the measurement of the constructs being assessed
- Inpatient psychiatric hospitalization for worsening of psychiatric symptoms, OR worsening of symptoms requiring a new level of outpatient support, OR started on a new anti-inflammatory medication for greater than one week duration, OR addition of a new psychotropic medication for psychiatric symptom control
- A change in > 15% in PANSS score from the "Lead-In Visit" to the "M0 visit"
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: High CRP
Subjects with a High Baseline CRP will receive Minocycline.
During the first week, subjects will receive one 100 mg capsule daily.
On weeks 2-12, the subject will receive two 100 mg capsules at bedtime.
The blinded psychiatrist (blinded to CRP status) will be allowed to reduce the dose if the subject complains of any side effect.
Pending tolerability, the subject will have 200 mg per day.
|
|
Experimental: Low CRP
Subjects with a Low Baseline CRP will receive Minocycline.
During the first week, subjects will receive one 100 mg capsule daily.
On weeks 2-12, the subject will receive two 100 mg capsules at bedtime.
The blinded psychiatrist (blinded to CRP status) will be allowed to reduce the dose if the subject complains of any side effect.
Pending tolerability, the subject will have 200 mg per day.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Positive Subscale Score of the Positive and Negative Syndrome Scale (PANSS)
Time Frame: Baseline, Week 12
|
Positive symptoms (representing unusual thought content) of schizophrenia/schizoaffective disorder were measured with the positive subscale of the Positive and Negative Syndrome Scale (PANSS).
The PANSS is scored by the clinician-researcher after an interview with the patient and it is the most commonly used measure for assessing the symptoms of schizophrenia.
Seven items measure the positive symptoms of delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility.
The items are scored on a scale of 1 to 7 where 1 means the symptom is absent and 7 means the symptom is extreme.
The total summed score for the positive subscale ranges between 7 and 49 where higher scores indicate more severe symptoms.
A reduction in the score indicates an improvement in symptom severity.
|
Baseline, Week 12
|
Negative Subscale Score of the Positive and Negative Syndrome Scale (PANSS)
Time Frame: Baseline, Week 12
|
Negative symptoms (representing a loss of normal functions) of schizophrenia/schizoaffective disorder were measured with the negative subscale of the Positive and Negative Syndrome Scale (PANSS).
The PANSS is scored by the clinician-researcher after an interview with the patient and it is the most commonly used measure for assessing the symptoms of schizophrenia.
Seven items measure the negative symptoms of blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity & flow of conversation, and stereotyped thinking.
The items are scored on a scale of 1 to 7 where 1 means the symptom is absent and 7 means the symptom is extreme.
The total summed score for the negative subscale ranges between 7 and 49 where higher scores indicate more severe symptoms.
A reduction in the score indicates an improvement in symptom severity.
|
Baseline, Week 12
|
Brief Assessment of Cognition in Schizophrenia (BACS) Score
Time Frame: Baseline, Week 12
|
The Brief Assessment of Cognition in Schizophrenia (BACS) is an instrument that assesses the aspects of cognition found to be most impaired and most strongly correlated with outcomes in patients with schizophrenia (verbal memory, working memory, motor speed, verbal fluency, attention and processing speed, and executive function).
BACS takes less than 35 minutes to complete and was administered on an electronic tablet for this study.
The composite score is a T-score that averages the standardized scale scores of each of the six tests.
The composite T-score has a mean of 50 and a standard deviation of 10.
Scores below 50 indicate lower than average cognition while scores above 50 indicate higher than average cognition.
A prior study found that the BACS mean composite score for schizophrenia patients was 25.96 while healthy controls had a mean score of 47.00.
|
Baseline, Week 12
|
General Psychopathology Score of the Positive and Negative Syndrome Scale (PANSS)
Time Frame: Baseline, Week 12
|
General symptoms of schizophrenia/schizoaffective disorder were measured using the general psychopathology subscale of the Positive and Negative Syndrome Scale (PANSS).
The PANSS is scored by the clinician-researcher after an interview with the patient and it is the most commonly used measure for assessing the symptoms of schizophrenia.
Sixteen items measure general psychopathology symptoms of somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance.
Items are scored on a scale of 1 to 7 where 1 means the symptom is absent and 7 means the symptom is extreme.
Total scores for this subscale can range from 16 to 112 where higher scores indicate more severe symptoms.
A reduction in the score indicates an improvement in symptom severity.
|
Baseline, Week 12
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) Score
Time Frame: Baseline, Week 12
|
Perceived quality of life and general well being was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF).
The Q-LES-Q-SF is a 16-item questionnaire asking participants to rate how satisfied they have been with heath related qualities on a 5-point scale where 1 = very poor and 5 = very good.
Raw scores of the Q-LES-Q-SF range from 14 to 70 and higher scores indicate higher life enjoyment and satisfaction.
|
Baseline, Week 12
|
Global Assessment of Functioning (GAF) Score
Time Frame: Baseline, Week 12
|
Social, occupational, and psychological functioning was to be assessed using the Global Assessment of Functioning (GAF) in the initial study protocol.
|
Baseline, Week 12
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Principal Investigator: Robert O Cotes, MD, Emory University
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin B. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012 Sep;26(9):1185-93. doi: 10.1177/0269881112444941. Epub 2012 Apr 23.
- Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, Fennig S, Treves I, Kron S. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010 Feb;71(2):138-49. doi: 10.4088/JCP.08m04666yel. Epub 2009 Nov 3.
- Kelly DL, Vyas G, Richardson CM, Koola M, McMahon RP, Buchanan RW, Wehring HJ. Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms. Schizophr Res. 2011 Dec;133(1-3):257-8. doi: 10.1016/j.schres.2011.08.005. Epub 2011 Aug 26. No abstract available.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
February 1, 2015
Primary Completion (Actual)
November 1, 2016
Study Completion (Actual)
November 1, 2016
Study Registration Dates
First Submitted
April 25, 2014
First Submitted That Met QC Criteria
April 25, 2014
First Posted (Estimate)
April 28, 2014
Study Record Updates
Last Update Posted (Actual)
September 26, 2018
Last Update Submitted That Met QC Criteria
August 29, 2018
Last Verified
August 1, 2018
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- IRB00071195
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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