Clinical trial NCT03994965: The Sub-Sero Study
Official title: Identification of a Serotonin 2A Receptor Subtype of Schizophrenia Spectrum Disorders With Pimavanserin: The Sub-Sero Proof-of-principle Study
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Schizophrenia
Psychosis
Keywords: Pimavanserin
serotonin 2AR
MR
PET
Lead sponsor: University of Copenhagen
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: GCP unit, Copenhagen University Hospital
name: ACADIA Pharmaceuticals Inc.
First posted: 2019-06-21
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Proof-of-principle study, investigator initiated, open label study
Primary purpose: TREATMENT

Brief 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 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).

Eligibility criteria: 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

Primary outcomes:
measure: Reduction in positive symptoms - Clinical response in patients after 6 weeks of treatment
timeFrame: 6 weeks
Secondary outcomes:
measure: Reduction in positive symptoms after week 2 and 4 - Secondary clinical endpoints
timeFrame: 6 weeks
measure: Reduction in negative symptoms after 6 weeks of treatment, measured with the Brief Negative Symptom Scale (BNSS).
timeFrame: 6 weeks
measure: Reduction in obsessive symptoms after 6 weeks of treatment, measured with The Brief Obsessive Compulsive Scale (BOCS).
timeFrame: 6 weeks
measure: The proportion of patients achieving symptomatic remission (using the Andreasen criteria) at week 6.
timeFrame: 6 weeks
measure: The serotonin 2AR binding potential in relation to treatment response
timeFrame: 6 weeks
measure: Characterization of response in Magnetic Resonance Imaging parameters after 6 weeks of treatment.
timeFrame: 6 weeks
measure: Response in cognitive functioning using CANTAB after 6 weeks of treatment.
timeFrame: 6 weeks
measure: Characterization of para-clinical parameters in patients using both genetic high-density-snip-arrays and clinical blood markers.
timeFrame: 6 weeks
Other outcomes:
Locations:
Study officials:
affiliation: University of Copenhagen
name: Bjørn H Ebdrup, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.