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Drug supply withdrawn (dec 2019)
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| Name | Class |
|---|---|
| Rigshospitalet, Denmark | OTHER |
| University of Copenhagen | OTHER |
| ACADIA Pharmaceuticals Inc. | INDUSTRY |
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Schizophrenia is a severe, often chronic mental disorder, characterized by positive and negative symptoms and cognitive deficits. The serotonin hypothesis of schizophrenia was proposed in the 1950s, but only recently, pimavanserin, the first antipsychotic medication with selective affinity for the serotonin 2A receptor was approved.
The aim of this translational proposal is to test the clinical validity of the serotonin hypothesis of schizophrenia and to guide development of operational, objective criteria for stratification of first-episode schizophrenia spectrum patients before antipsychotic treatment.
Our previous data have strongly suggested, that a subgroup of antipsychotic-naïve patients will respond to serotonin 2A receptor (2AR) blockade. This treatment will cause minimal side-effects compared with conventional dopamine D2/3 receptor blockade.
In this Danish, investigator-initiated trial, we will establish a cohort of 40 antipsychotic-free, first-episode schizophrenia spectrum patients and enrol them in a 6-week open label, one-armed trial with selective serotonin 2AR blockade (pimavanserin).
Before initiation of pimavanserin patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR binding potential using the radioligand [¹¹C]Cimbi-36; magnetic resonance spectroscopy (MRS) of cerebral glutamate levels; structural Magnetic Resonance imaging (MRI), including Diffusion Tensor Imaging (DTI); cognitive and psychopathological examinations; Electrocardiography (ECG), and blood sampling for genetic- and metabolic analyses.
Matched healthy controls will undergo parallel examinations, but not medical treatment and PET .
ACADIA Pharmaceuticals Inc. provides the study medication (pimavanserin). ACADIA had no influence on study design and will not take part in data processing or publication of the results of the study.
(More information will follow on study approval).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients | Experimental | 40 antipsychotic-free, first-episode schizophrenia spectrum patients will receive 6 weeks of treatment with a selective serotonin 2A Receptor (2AR) blockade. Before initiation of treatment patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR binding potential using the radioligand [¹¹C]Cimbi-36; magnetic resonance spectroscopy (MRS) of cerebral glutamate levels; structural Magnetic Resonance Imaging (MRI), including diffusion tensor imaging (DTI); cognitive and psychopathological examinations; Electrocardiography (ECG), and blood sampling for genetic- and metabolic analyses. (Full description will be updated on approval). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pimavanserin 34 milligrams (MG) [Nuplazid] | Drug | Daily treatment with 34 mg per os for 6 weeks. Followed by a wash-out period up to 14 days, do to the theoretical risk of corrected QT interval (QTc) prolongation. Conventional anti-psychotic treatment will be initiated only upon normal ECG. |
| Measure | Description | Time Frame |
|---|---|---|
| Reduction in positive symptoms - Clinical response in patients after 6 weeks of treatment | Reduction in the Positive and Negative Syndrome Scale (PANSS) positive subscale score [PANSS positive baseline - PANSS positive week 6]. To assess a patient using PANSS, an approximately 45-minute clinical interview is conducted. The patient is rated from 1 to 7 on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers.[4] Positive scale 7 Items, (minimum score = 7, maximum score = 49) Negative scale 7 Items, (minimum score = 7, maximum score = 49) General Psychopathology scale 16 Items, (minimum score = 16, maximum score = 112) For the primary outcome only the chance in PANSS positive scores will be reported. | 6 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Reduction in positive symptoms after week 2 and 4 - Secondary clinical endpoints | Include reduction in PANSS positive subscale score compared to baseline by week 2 and 4, respectively. See description of PANSS score under primary outcome. | 6 weeks |
| Reduction in negative symptoms after 6 weeks of treatment, measured with the Brief Negative Symptom Scale (BNSS). |
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Patients - Inclusion Criteria:
Patients - Exclusion Criteria:
Healthy controls - Inclusion Criteria:
Healthy controls - Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bjørn H Ebdrup, MD, PhD | University of Copenhagen | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32425802 | Derived | Baltzersen OB, Meltzer HY, Frokjaer VG, Raghava JM, Baandrup L, Fagerlund B, Larsson HBW, Fibiger HC, Glenthoj BY, Knudsen GM, Ebdrup BH. Identification of a Serotonin 2A Receptor Subtype of Schizophrenia Spectrum Disorders With Pimavanserin: The Sub-Sero Proof-of-Concept Trial Protocol. Front Pharmacol. 2020 Apr 30;11:591. doi: 10.3389/fphar.2020.00591. eCollection 2020. |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| D011618 | Psychotic Disorders |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C510793 | pimavanserin |
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Proof-of-principle study, investigator initiated, open label study
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Secondary clinical endpoints, negative symptoms Negative symptoms will be assessed by Brief Negative Symptom Scale (BNSS). Measures 5 domains: blunted affect, alogia, asociality, anhedonia, and avolition. The BNSS includes a manual, score sheet, and workbook, and has 13 items organized into 6 subscales. The manual defines the terms used in the scale, provides anchors for each item, and gives instructions for a semistructured interview, including suggested questions. The workbook extracts the suggested questions and the anchors and is designed for the rater's reference during administration. All the items in the BNSS are rated on a 7-point (0-6) scale, with anchor points generally ranging from the symptom's being absent (0) to severe (6). |
| 6 weeks |
| Reduction in obsessive symptoms after 6 weeks of treatment, measured with The Brief Obsessive Compulsive Scale (BOCS). | Secondary clinical endpoints, obsessive symptoms Measured by The Brief Obsessive Compulsive Scale (BOCS). The BOCS consists of a 15-item Symptom Checklist including three items (hoarding, dysmorphophobia and self-harm) related to the The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) category "Obsessive-compulsive related disorders", accompanied by a single six-item Severity Scale for obsessions and compulsions combined. Total severity scale (questions 1-6) score range from: 0-24. Endorsement of 2 or more items in the checklist or a mean score of 1.5 or above on the severity scale suggests an Obsessive-compulsive disorder (OCD). Higher mean scores on the severity scale (questions 1-6) starting on page 4 indicate higher severity. | 6 weeks |
| The proportion of patients achieving symptomatic remission (using the Andreasen criteria) at week 6. | Secondary clinical endpoints, patients in remission Andreasen criteria: Positive and Negative Syndrome Scale (PANSS) Items for use in Symptoms of Remission, patients must score less than or equal to 3 (mild) on these eight items. Name; Item nr: Delusions; P1 Unusual thought content; G9 Hallucinatory behavior; P3 Conceptual disorganization; P2 Mannerisms/Posturing; G5 Blunted affect; N1 Passive social withdrawal; N4 Lack of spontaneity/Flow of Conversation; N6 | 6 weeks |
| The serotonin 2AR binding potential in relation to treatment response | Secondary neuropsychiatric endpoints; positron emission tomography (PET) In-depth characterization pre-treatment measurements of patients, who respond to serotonergic 2AR blockade. Analysis of PET scans regarding serotonin 2AR binding potential compared with treatment response as well as characterization of differences in sub-regions. | 6 weeks |
| Characterization of response in Magnetic Resonance Imaging parameters after 6 weeks of treatment. | Secondary neuropsychiatric endpoints; MR In-depth characterization pre-treatment measurements of patients, who respond to serotonergic 2AR blockade. Analysis of structural MR, spectroscopy of glutamate levels and diffusion tensor imaging (DTI). | 6 weeks |
| Response in cognitive functioning using CANTAB after 6 weeks of treatment. | Secondary neuropsychiatric endpoints In-depth characterization pre-treatment measurements of patients, who respond to serotonergic 2AR blockade. Neuropsychology: test of cognition using CANTAB and selected paper and pencil tests. | 6 weeks |
| Characterization of para-clinical parameters in patients using both genetic high-density-snip-arrays and clinical blood markers. | To exclude other clinical diseases than schizophrenia and as a safety-measure, blood-samples are taken for somatic screening including haemoglobin, hematocrit, ferritin, white blood cells, platelet count, sodium, potassium, creatinine, carbamide, albumin, C-reactive protein (CRP), HbA1c and fasting glucose, fasting lipids, thyroid stimulating hormone, alanine and aspartate amino transferase, bilirubin, lactate dehydrogenase and alkaline phosphatase. The genetic-blood samples will be analysed with an array designed for population based genetic studies. We will use a high-density-snip-array of approximately 1 million snips (SNP/snip: single nucleotide polymorphism). The array will be applied to the genome in full, but genome sequencing will not be performed neither of individual genes nor the full genome. The genetic data will be used to identify a genetic risk score compared to the background population. | 6 weeks |