Simvastatin Addition for Patients With Recent-onset Schizophrenia

Sponsor

Iris Sommer (Other)

Overall Status

Completed

CT.gov ID

NCT01999309

Collaborator

Stanley Medical Research Institute (Other)

121

Enrollment

Locations

Arms

74.6

Actual Duration (Months)

60.5

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Rationale: There is ample evidence that inflammatory processes play a role in the pathophysiology of schizophrenia. Although Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) have been shown to be able to reduce symptoms in these patients, these drugs either have unfavourable cardiovascular side effects or are otherwise not well tolerated. Moreover, patients with schizophrenia already tend to have an increased cardiovascular risk. The combination of well-established vascular protection and reduction of inflammation by simvastatin offers a highly attractive potential to further improve the treatment of schizophrenia and related disorders.

Hypotheses: Daily treatment with 40mg simvastatin in addition to antipsychotic treatment reduces psychotic symptoms, improves cognition, attenuates brain volume loss, and decreases the risk for metabolic syndrome as well as for movement disorders, when compared to placebo.

Objective: The primary objective of this trial is to investigate the proposed beneficial effect of simvastatin as compared to placebo when given for one year in addition to antipsychotic medication to patients with psychotic disorder. We expect lower symptom severity as measured with the PANSS (Positive and Negative Syndrome Scale) and less cognitive decline as measured with the BACS (Brief Assessment of Cognition in Schizophrenia).Secondary objectives are assessment of general functioning, presence and severity of metabolic syndrome and degree of movement disorders, and assessments of brain volume. Lastly, we examine various immunological parameters in serum and peripheral blood mononuclear cells and the experience of childhood trauma.

Study design: Randomized placebo-controlled double-blind trial.

Study population: 150 men and women, between 18 and 50 years of age, diagnosed with schizophrenia, schizoaffective or schizophreniform disorder (DSM-IV 295.*) or psychosis NOS (not otherwise specified) (298.9). Onset of first psychosis no longer than 3 years ago.

Intervention: Patients will be randomized 1:1 to either 40 mg simvastatin or placebo daily, in the form of identical tablets.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia Schizoaffective Disorder Schizophreniform Disorder Psychosis NOS	Drug: Simvastatin Drug: Placebo	Phase 3

Detailed Description

Rationale: Different lines of evidence now suggest that low grade inflammation in the central nervous system is involved in the pathogenesis of schizophrenia. These include the altered risk of schizophrenia patients and their relatives for specific auto-immune diseases, clinical similarities between the course of schizophrenia and auto-immune disease and decreased prevalence of schizophrenia in men who have used Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or glucocorticosteroids for somatic disorders. Furthermore, an infectious cause or trigger is suggested by the observed association between schizophrenia and pre- and perinatal infections, as well as by seroconversion to certain pathogens in patients with schizophrenia. On a cellular level, inflammation of the central nervous system is suggested by an increased number of activated microglia cells in the brains of patients with schizophrenia as visualized by positron electron tomography. In an activated state, microglia cells can produce free radicals, pro-inflammatory components and other neurotoxic substances, causing cell death in their proximity. The activation of microglia cells provides a possible route by which an increased pro-inflammatory state in the brain could cause increased gray matter loss and more severe negative and cognitive symptoms. Although Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) have been shown to be able to reduce symptoms in these patients, these drugs either have unfavourable cardiovascular side effects or are otherwise not well tolerated. Moreover, patients with schizophrenia already tend to have an increased cardiovascular risk. The combination of well-established vascular protection and reduction of inflammation by simvastatin offers a highly attractive potential to further improve the treatment of schizophrenia and related disorders.

Objective: The primary objective of this trial is to investigate the proposed beneficial effect of simvastatin as compared to placebo when given for one year in addition to antipsychotic medication to patients with psychotic disorder. We expect lower symptom severity as measured with the Positive And Negative Symptom Scale (PANSS) and less cognitive decline as measured with the Brief Assessment of Cognition in Schizophrenia (BACS).Secondary objectives are assessment of general functioning using the General Assessment of Functioning (GAF), presence and severity of metabolic syndrome, as defined by the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLB), presence and severity of movement disorders using validated scales, and assessments of brain volume through magnetic resonance imaging (MRI). Lastly, we examine various immunological parameters in serum and peripheral blood mononuclear cells and the experience of childhood trauma using the Childhood Trauma Questionnaire Short Form (CTQ-SF).

Study design: Randomized placebo-controlled double-blind trial.

Study population: 150 men and women, between 18 and 50 years of age, diagnosed with schizophrenia, schizoaffective or schizophreniform disorder (DSM-IV 295.*) or psychosis NOS (not otherwise specified) (298.9). Duration of disease should be no more than three years.

Intervention: Patients will be randomized 1:1 to either 40 mg simvastatin or placebo daily, in the form of identical tablets.

Main study parameters/endpoints: Primary outcome is change in total symptom severity (PANSS score) from baseline to end of treatment. Secondary outcomes will be the changes in GAF scores, cognitive functioning, presence and severity of metabolic syndrome and movement disorders and assessment of brain volume change, in addition to the measurement of various immunological biomarkers, childhood trauma. and depression symptoms.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Use of simvastatin implies that there is a risk of side effects, as all lipid-lowering drugs carry the risk of negative effects. The number of patient visits will be limited and mainly requires time investment for a few physical examinations, questionnaires and two cognitive testing sessions (around 10 hours per year in total).

Blood will be drawn at four occasions with negligible and known risks (e.g. irritation). The burden and risks are acceptable while the benefits are expected to be considerable.

Study Design

Study Type:

Interventional

Actual Enrollment :

121 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Simvastatin Addition for Patients With Recent-onset Schizophrenia

Actual Study Start Date :

Oct 1, 2013

Actual Primary Completion Date :

Dec 19, 2019

Actual Study Completion Date :

Dec 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Simvastatin The lipid-lowering drug simvastatin is added to normal antipsychotic treatment. One 40 mg simvastatin tablet daily for the treatment period of one year.	Drug: Simvastatin The lipid-lowering drug simvastatin is added to normal antipsychotic treatment. One 40 mg simvastatin tablet daily for the treatment period of one year. Other Names: Zocor
Placebo Comparator: Placebo Placebo is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year.	Drug: Placebo Placebo is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year.

Arm

Intervention/Treatment

Experimental: Simvastatin

The lipid-lowering drug simvastatin is added to normal antipsychotic treatment. One 40 mg simvastatin tablet daily for the treatment period of one year.

Drug: Simvastatin

The lipid-lowering drug simvastatin is added to normal antipsychotic treatment. One 40 mg simvastatin tablet daily for the treatment period of one year.

Other Names:

Zocor

Placebo Comparator: Placebo

Placebo is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year.

Drug: Placebo

Placebo is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year.

Outcome Measures

Primary Outcome Measures

Total symptom severity [0, 1, 3, 6, 9 and 12 months]
Change in Positive And Negative Syndrome Scale (PANSS) total score

Secondary Outcome Measures

Change in positive, negative and general symptom severity [0, 1, 3, 6, 9 and 12 months]
Change in PANSS positive, negative and general psychopathology scale scores
Global functioning [0, 1, 3, 6, 9, and 12 months]
Change in Global Assessment of functioning scale (GAF) score
Change in cognitive functioning [0 and 12 months]
Total score of the Brief Assessment of Cognition in Schizophrenia (BACS)
Presence and severity of metabolic syndrome [0, 1, 6 and 12 months]
As defined by the American Heart Association/National Heart, Lung and Blood Institute. The definitions and reference ranges for metabolic syndrome are: Abdominal obesity (waist circumference) men ≥ 102 cm, women ≥ 88 cm Triglycerides ≥ 150 mg/dL High density lipoprotein (HDL-C) men < 40 mg/dL, women < 50 mg/dL Blood pressure systolic ≥ 130 or diastolic ≥ 85 mmHg Fasting glucose ≥ 100 mg/dL
Change in presence and severity of movement disorders [0, 6 and 12 months]
Using SHRS and BARS (validated scales)
Change in brain volume [0 and 12 months]
As measured with Magnetic Resonance Imaging (MRI)

Other Outcome Measures

Change in immunological parameters [0, 1 and 12 months]
Multiplex immunoassay (including key cytokines, chemokines, metabolic markers, hormones, growth factors, acute phase reactants known to be associated with schizophrenia) will be measured at baseline. Infectious disease profiling: (serology and the presence of specific infectious agents will be measured, including herpes simplex virus type-1 and -2, cytomegalovirus, Chlamydophila pneumonia, Chlamydophila psittaci and Toxoplasma Gondii) at baseline. Flow cytometry (alterations in the number and functional responses of distinct sub-populations of blood cells will be analysed). Selective reaction monitoring (a technique called SRM will be applied to investigate potential candidate biomarkers of drug response identified by proteome profiling [LC-MSE]) Gene expression and MicroRNA profiling (RNA expression of a set of 43 immune-related genes and miRNA-146a will be measured in total blood and monocytes isolated from PBMCs using Q-PCR).
Change in depressive symptoms [0, 6 and 12 months]
Assessed with the Calgary Depression Scale for Schizophrenia (CDSS) total score
Number of participants with Adverse Events as a measure of safety and tolerability [0 and 12 months]
Incidences (number and % of subjects with at least one occurrence) of key Serious Adverse Events (SAEs) and Adverse Events (AEs) will be presented per group.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

A DSM-IV-R diagnosis of: 295.x (schizophrenia, schizophreniform disorder, or schizoaffective disorder) or 298.9 (psychosis NOS)
Onset of first psychosis no longer than 3 years ago.
Age between 18 and 50 years
Written informed consent is obtained
Female patients of childbearing potential need to utilize a proper method of contraception (the pill, vaginal ring, hormonal patch, intrauterine device, cervical cape, condom, contraceptive injection, diaphragm) in case of sexual intercourse during the study.

Exclusion Criteria:

Fulfilment of criteria for statin prescription; according to the Dutch Heart Foundation, statin treatment is indicated when the total cholesterol level is > 8 mmol/l (www.hartstichting.nl)
Presence of any of the contra-indications or warnings for the use of simvastatin as reported in the SPC (Summary of Product Characteristics)
Chronic use of glucocorticosteroids (temporary use is permitted, if stopped at least 1 month before start of treatment trial)
Chronic use of non-steroidal anti-inflammatory drugs (temporary use is permitted, if stopped at least 1 month before start of treatment trial)
Current use of statins or other lipid-lowering drugs
Pregnancy or breast-feeding
Active liver, kidney or muscle disease as defined by alanine aminotransferase (ALAT), creatinine or creatine kinase (CK) levels more than two times the upper boundary of normal levels
In case of familial risk for muscular disorders or previously experienced muscle toxicity when taking medication similar to simvastatin, creatine kinase (CK) levels will also be checked (as recommended by the Dutch Farmacotherapeutisch Kompas, www.farmacotherapeutischkompas.nl/). In addition, levels of aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gammaglutamyltranspeptidase (γ-GT) and creatinine will be checked when a history of alcohol abuse, liver or kidney disorders is reported.
Use of comedication that either inhibits or induces the live enzyme CYP3A4 which is responsible for the degradation of simvastatin. Inhibitors of CYP3A4 include itraconazole, ketoconazole, posaconazole, fluconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, telaprevir, boceprevir, imatinib, ticagrelor, voriconazole; inducers of CYP3A4 include carbamazepin, efavirenz, nevirapine, etravirine (can be washed out before start of trial)
Use of comedication that may increase the risk for myalgia, rhabdomyolysis and myopathy, including colchicine, bosentan, phenobarbital, phenytoin, hypericum, rifabutin, rifampicin, fibrates (e.g. gemfibrozil), fusidic acid, carbamazepin (can be washed out before start of trial)

For patients, the MRI scan requires addition exclusion criteria to be eligible to participate in this part of the study (if these additional criteria are not met, patients can participate in the study but not in the MRI component):