SchizophreniaPhase 2NCT03994965
The Sub-Sero Study
A Phase 2 study testing Pimavanserin 34 milligrams (MG) [Nuplazid] in people with Schizophrenia and Psychosis, run by Bjorn H. Ebdrup.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 45 years
- Conditions the study is for
- Schizophrenia, Psychosis
- What is being tested?
- Pimavanserin 34 milligrams (MG) [Nuplazid]
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 1 Dec 2024to 4 Dec 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- No healthy volunteers
- Adult
Patients - Inclusion Criteria:
- Antipsychotic-free (as defined under Exclusion Criteria below)
- Fulfilling the diagnostic criteria of schizophrenia, persistent delusional disorder, acute and transient psychotic disorders, schizoaffective disorder, other non-organic psychotic disorders and unspecified non-organic disorders (ICD-10: F20.x; F22.x; F23.x; F24.x; F25.x; F28; F29); verified by The Schedules for Clinical Assessment in Neuropsychiatry (SCAN) 2.0 interview (Wing et al. 1990)
- Age: 18-45 years
- Legally competent (In Danish: 'myndige og habile i retslig forstand')
Patients - Exclusion Criteria:
- Prior use of antipsychotic medication longer than an episode of two weeks in the previous year and/or 6 weeks lifetime, and/or antipsychotic treatment within 30 days prior to inclusion.
- Current substance abuse ICD-10 (F1x.2) or substance abuse in any period up to 3 months prior to referral (exception: tobacco/nicotine, F17.2)
- Head injury with more than 5 minutes of unconsciousness
- Any coercive measure
- Metal implanted by operation
- Pacemaker
- Pregnancy (assessed by urine human chorionic gonadotropin (HCG))
- Female patients: Unwillingness to use safe contraception (Intra Uterine Device/System or hormonal contraceptives) during the study period including the wash out period.
- Severe physical illness
- Known QT prolongation or congenital prolongation of the QT interval
- Medical history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia
- Current treatment with drugs known to prolong QT interval including: Class 1A antiarrhythmics (e.g., quinidine, procainamide); Class 3 antiarrhythmics (e.g., amiodarone, sotalol); certain antibiotics (e.g., gatifloxacin, moxifloxacin).
- Allergies to any of the inactive ingredients and film coat components: pregelatinized starch, magnesium stearate, microcrystalline cellulose, hypromellose, talc, titanium dioxide, polyethylene glycol, and saccharin sodium.
Healthy controls - Inclusion Criteria:
- Matched with patients on age (+/- 2 years), sex and parental socioeconomic status
- Age 18-45 years
- Legally competent (In Danish: 'myndige og habile i retslig forstand')
- Recruitment: through online advertisement (www.forsøgsperson.dk)
Healthy controls - Exclusion Criteria:
- Any psychiatric illness any first-degree relatives with known psychiatric diagnoses or physical disease
- Substance abuse during the past 3 months or positive urine-screening of illegal drugs
- Head injury with more than 5 minutes of unconsciousness
- Components of metal implanted by operation
- Pacemaker
- Pregnancy (assessed by urine HCG)
- Severe physical illness
About this study
Official title: Identification of a Serotonin 2A Receptor Subtype of Schizophrenia Spectrum Disorders With Pimavanserin: The Sub-Sero Proof-of-principle Study
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.
Read more
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.
Read the detailed description
(More information will follow on study approval).
- Conditions
- Schizophrenia, Psychosis
- Being tested
- Pimavanserin 34 milligrams (MG) [Nuplazid]
- Keywords
- Pimavanserin, serotonin 2AR, MR, PET
- Medical subject headings
- Schizophrenia, Psychotic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: Drug: Pimavanserin 34 milligrams (MG) [Nuplazid] |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 6 weeks
Secondary outcomes (8)
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.
Measured: 6 weeks
Reduction in negative symptoms after 6 weeks of treatment, measured with the Brief Negative Symptom Scale (BNSS).
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).
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jun 2019
- Study start1 Dec 2024
- Primary completion2 Dec 2024
- Study completion4 Dec 2024
Why it stopped: Drug supply withdrawn (dec 2019)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Proof-of-principle study, investigator initiated, open label study
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bjorn H. Ebdrup
- Sponsor type
- University, hospital or other
- Collaborators
- Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, ACADIA Pharmaceuticals Inc.
- Responsible party
- Sponsor-investigator, Bjorn H. Ebdrup, University of Copenhagen
- Investigators
- Bjørn H Ebdrup, MD, PhD, Principal investigator, University of Copenhagen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03994965
- Sponsor's protocol ID
- 2019-001722-10
- Other IDs
- 2019
- Status last verified
- Dec 2024
- First submitted
- 5 Jun 2019
- Last updated
- 9 Dec 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 32425802
Study at a glance
From the registry record, last updated by the sponsor on 9 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identification of a Serotonin 2A Receptor Subtype of Schizophrenia Spectrum Disorders With Pimavanserin: The Sub-Sero Proof-of-principle Study
- ClinicalTrials.gov ID
- NCT03994965
- Acronym / sponsor ID
- 2019-001722-10
- Conditions
- Schizophrenia, Psychosis
- Keywords
- Pimavanserin, serotonin 2AR, MR, PET
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Drug supply withdrawn (dec 2019)
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Bjorn H. EbdrupUniversity, hospital or other
- Collaborators
- Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, ACADIA Pharmaceuticals Inc.
- Study start
- 1 Dec 2024 (actual)
- Primary completion
- 2 Dec 2024 (actual)
- Study completion
- 4 Dec 2024 (actual)
- First posted
- 21 Jun 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
(More information will follow on study approval).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Proof-of-principle study, investigator initiated, open label study
| Arm | Type | Receives |
|---|---|---|
| Patients | Experimental | Drug: Pimavanserin 34 milligrams (MG) [Nuplazid]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). |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pimavanserin 34 milligrams (MG) [Nuplazid]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. | Drug | Patients |
Primary outcome
Reduction in positive symptoms - Clinical response in patients after 6 weeks of treatment
Time frame: 6 weeks
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.
8 secondary outcomes
Reduction in positive symptoms after week 2 and 4 - Secondary clinical endpoints
Time frame: 6 weeks
Reduction in negative symptoms after 6 weeks of treatment, measured with the Brief Negative Symptom Scale (BNSS).
Time frame: 6 weeks
Reduction in obsessive symptoms after 6 weeks of treatment, measured with The Brief Obsessive Compulsive Scale (BOCS).
Time frame: 6 weeks
The proportion of patients achieving symptomatic remission (using the Andreasen criteria) at week 6.
Time frame: 6 weeks
The serotonin 2AR binding potential in relation to treatment response
Time frame: 6 weeks
Characterization of response in Magnetic Resonance Imaging parameters after 6 weeks of treatment.
Time frame: 6 weeks
Response in cognitive functioning using CANTAB after 6 weeks of treatment.
Time frame: 6 weeks
Characterization of para-clinical parameters in patients using both genetic high-density-snip-arrays and clinical blood markers.
Time frame: 6 weeks
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Dec 2024.
- Derived from this study: PubMed 32425802Baltzersen 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bjørn H Ebdrup, MD, PhD principal investigator
University of Copenhagen
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pimavanserin 34 milligrams (MG) [Nuplazid] in people with Schizophrenia and Psychosis, run by Bjorn H. Ebdrup.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 9 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reduction in positive symptoms - Clinical response in patients after 6 weeks of treatment (time frame: 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03994965, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2024.