- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01999309
Simvastatin Addition for Patients With Recent-onset Schizophrenia
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.
Study Overview
Status
Intervention / Treatment
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.
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 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 Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
-
Groningen, Netherlands, 9700 RB
- University Medical Center Groningen
-
Utrecht, Netherlands, 3584 CX
- University Medical Center Utrecht
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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):
- Ferrous objects in or around the body (e.g. braces, glasses, pacemaker, metal fragments)
- Claustrophobia
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / 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.
|
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:
|
Placebo Comparator: Placebo
Placebo is added to normal antipsychotic treatment.
One identical looking placebo tablet daily for the treatment period of one year.
|
Placebo is added to normal antipsychotic treatment.
One identical looking placebo tablet daily for the treatment period of one year.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Total symptom severity
Time Frame: 0, 1, 3, 6, 9 and 12 months
|
Change in Positive And Negative Syndrome Scale (PANSS) total score
|
0, 1, 3, 6, 9 and 12 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in positive, negative and general symptom severity
Time Frame: 0, 1, 3, 6, 9 and 12 months
|
Change in PANSS positive, negative and general psychopathology scale scores
|
0, 1, 3, 6, 9 and 12 months
|
Global functioning
Time Frame: 0, 1, 3, 6, 9, and 12 months
|
Change in Global Assessment of functioning scale (GAF) score
|
0, 1, 3, 6, 9, and 12 months
|
Change in cognitive functioning
Time Frame: 0 and 12 months
|
Total score of the Brief Assessment of Cognition in Schizophrenia (BACS)
|
0 and 12 months
|
Presence and severity of metabolic syndrome
Time Frame: 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:
|
0, 1, 6 and 12 months
|
Change in presence and severity of movement disorders
Time Frame: 0, 6 and 12 months
|
Using SHRS and BARS (validated scales)
|
0, 6 and 12 months
|
Change in brain volume
Time Frame: 0 and 12 months
|
As measured with Magnetic Resonance Imaging (MRI)
|
0 and 12 months
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in immunological parameters
Time Frame: 0, 1 and 12 months
|
|
0, 1 and 12 months
|
Change in depressive symptoms
Time Frame: 0, 6 and 12 months
|
Assessed with the Calgary Depression Scale for Schizophrenia (CDSS) total score
|
0, 6 and 12 months
|
Number of participants with Adverse Events as a measure of safety and tolerability
Time Frame: 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.
|
0 and 12 months
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Iris EC Sommer, Prof. dr., University Medical Center Groningen
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Schizophrenia Spectrum and Other Psychotic Disorders
- Schizophrenia
- Disease
- Psychotic Disorders
- Mental Disorders
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Simvastatin
Other Study ID Numbers
- 43806
Plan for Individual participant data (IPD)
Study Data/Documents
-
Study Protocol
Information comments: Simvastatin augmentation for recent-onset psychotic disorder: A study protocol (open access)
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.
Clinical Trials on Schizophrenia
-
Organon and CoCompletedSchizophrenia, Paranoid | Schizophrenia, Disorganized | Schizophrenia, Undifferentiated
-
Organon and CoCompletedSchizophrenia, Paranoid | Schizophrenia, Disorganized | Schizophrenia, Undifferentiated
-
Bradley LegaRecruiting
-
Central Institute of Mental Health, MannheimNot yet recruitingSchizophrenia | Treatment Resistant SchizophreniaGermany
-
All India Institute of Medical Sciences, BhubaneswarRecruitingTreatment Resistant SchizophreniaIndia
-
King's College LondonSouth London and Maudsley NHS Foundation TrustRecruitingTreatment-resistant Schizophrenia | Healthy Controls | Treatment-responsive SchizophreniaUnited Kingdom
-
University of Sao PauloUnknownRefractory Schizophrenia | Super Refractory SchizophreniaBrazil
-
Peking UniversityNot yet recruitingTreatment-resistant Schizophrenia
-
Rakitzi, StavroulaActive, not recruiting
Clinical Trials on Simvastatin
-
University of CopenhagenCompletedCardiovascular Disease | Diabetes MellitusDenmark
-
Organon and CoCompletedMyocardial Infarction | Hypercholesterolemia
-
dr.Frank L.J. VisserenMerck Sharp & Dohme LLCCompletedThe PostprAndial eNdothelial Function After Combination of Ezetimibe and simvAstatin Study (PANACEA)Metabolic SyndromeNetherlands, Spain
-
University of Sao PauloCompletedCoronary Heart Disease
-
University of Maryland, BaltimoreMerck Sharp & Dohme LLCCompletedMetabolic SyndromeUnited States
-
Peking Union Medical College HospitalUnknownAtherosclerosisChina
-
Hue University of Medicine and PharmacyUniversità degli Studi di SassariUnknownChronic Kidney Diseases | HypercholesterolemiaVietnam
-
Organon and CoCompletedHypercholesterolemia
-
Federal State Budgetary Scientific Institution,...Completed
-
Organon and CoSchering-PloughCompletedCoronary Disease | Hypercholesterolemia