The primary objective of this trial is to investigate the proposed beneficial effect of simvastatin on total symptom severity (PANSS) ascompared to placebo when given in addition to antipsychotic medication, and the effects on neurocognitive…
ID
Source
Brief title
Condition
- Metabolism disorders NEC
- Schizophrenia and other psychotic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main study parameter is symptom severity as measured with the Positive and
Negative Syndrome Scale (PANSS) (Kay et al. 1987). We
will compare the effect of simvastatin versus placebo, both given in addition
to antipsychotic medication, with regards to change in symptom
severity expressed as overall PANSS score after 12 months of treatment. In
addition, we will examine neurocognitive functioning as measured
with the Brief Assessment of Cognition in Schizophrenia (BACS; Keefe et al.
2004).
Secondary outcome
Our secondary study parameters are the PANSS subscales: the positive scale,
negative scale and general psychopathology scale. Furthermore, general
assessment of functioning will be evaluated using the Global Assessment of
Functioning scale (GAF; Jones et al. 1995), presence and severity of metabolic
syndrome as defined by the American Heart Association/National Heart, Lung and
Blood Institute (AHA/NHLB; Grundy et al. 2005), and presence and severity of
movement disorders using validated scales. MRI will be used to investigate
changes in the structural properties of the brain. These parameters will be
compared after 12 months of treatment, between patients treated with
simvastatin versus placebo. Other parameters are severity of depression as
assessed with the Calgary Depression Scale for Schizophrenia (CDSS; Addington
et al. 1993) and experience of childhood trauma will be evaluated with the
Childhood Trauma Questionnaire Short Form (CTQ-SF). In addition, in order to
investigate immunological and metabolic biomarkers that predict treatment
response to simvastatin therapy, serum, peripheral blood mononuclear cells
(PBMC) and RNA of all patients will be analyzed.
Background summary
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
(reviewed by Sommer et al. 2012), these drugs either have unfavourable
cardiovascular side effects or are otherwise not well tolerated (Solomon et al.
2005). Moreover, patients with schizophrenia already tend to have an increased
cardiovascular risk (Hennekens et al. 2005). The combination of
well-established vascular protection and reduction of inflammation by
simvastatin (Orr et al. 2008) offers a highly attractive potential to further
improve the treatment of schizophrenia and related disorders.
Study objective
The primary objective of this trial is to investigate the proposed beneficial
effect of simvastatin on total symptom severity (PANSS) as
compared to placebo when given in addition to antipsychotic medication, and the
effects on neurocognitive functioning as measured with the Brief Assessment of
Cognition in Schizophrenia (BACS).Secondary objectives concern assessment of
positive and negative
symptoms as well as general psychopathology (PANSS subscales), in addition to
general functioning using the GAF (Global Assessment of
Functioning), presence and severity of metabolic syndrome as defined by the
American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLB),
changes in the brain using MRI, and presence and severity of movement disorders
using validated scales. Various immunological and metabolic parameters will be
assessed in blood samples to examine whether these parameters predict treatment
response to simvastatin augmentation, as well as an assessment of childhood
trauma (Childhood Trauma Questionnaire-Short Form; CTQ-SF). In addition,
severity of depression will be assessed using the Calgary Depression Scale for
Schizophrenia (CDSS; Addington et al. 1993). Finally, safety data will be
evaluated by comparing incidences (number and % of subjects with at least one
occurrence) of key SAEs and SUSARs between both groups, e.g. hospitalisations.
Study design
Randomized multi-centre placebo-controlled double-blind trial.
Intervention
Patients will be randomized 1:1 to either 40 mg simvastatin or placebo daily,
in the form of identical tablets.
Study burden and risks
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 16
hours in total during the treatment period of 1 year and the follow-up visit 24
months post baseline). Blood will be drawn at six occasions with negligible and
known risks (e.g. irritation). The two magnetic resonance imaging (MRI) scan
sessions are not associated with any known risks. The burden and risks are
acceptable while the benefits are expected to be considerable.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
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 (Hartstichting), 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;
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 (temporary use is permitted, if stopped at least 1 month before start of treatment trial);
Pregnancy or breast-feeding (urine pregnancy test will be performed for sexually active females with child bearing potential);
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 (ASAT), alanine aminotransferase (ALAT), gamma-glutamyltranspeptidase (gamma-GT) and creatinine will be checked when a history of alcohol abuse, liver or kidney disorders is reported based as recommended by the Dutch Farmacotherapeutisch Kompas, www.farmacotherapeutischkompas.nl/);
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 carbamazepine, efavirenz, nevirapin, etravirin (can be washed out before start of trial);
Use of comedication that may increase the risk for myalgia, rhabdomyolyse and myopathy, including colchicine, bosentan, fenobarbital, fenytoin, hypericum, rifabutin, rifampicin, fibrates (e.g. gemfibrozil), fusidic acid, carbamazepine (can be washed out before start of trial). The MRI scan requires additional exclusion criteria to be eligible to participate in this part of the study (if these additional criteria are 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | ClinicalTrials.gov identifier: NCT01999309 |
| EudraCT | EUCTR2013-000834-36-NL |
| CCMO | NL43806.041.13 |