The Sub-Sero Study

NCT03994965 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 2019-001722-10
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Schizophrenia; Psychosis

Keywords

Pimavanserin; serotonin 2AR; MR; PET

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (8)

• Reduction in positive symptoms after week 2 and 4 - Secondary clinical endpoints

  6 weeks

• Reduction in negative symptoms after 6 weeks of treatment, measured with the Brief Negative Symptom Scale (BNSS).

  6 weeks

• Reduction in obsessive symptoms after 6 weeks of treatment, measured with The Brief Obsessive Compulsive Scale (BOCS).

  6 weeks

• The proportion of patients achieving symptomatic remission (using the Andreasen criteria) at week 6.

  6 weeks

• The serotonin 2AR binding potential in relation to treatment response

  6 weeks

Study Arms (1)

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).

Drug: Pimavanserin 34 milligrams (MG) [Nuplazid]

Interventions

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.

Patients

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may not qualify if:

• 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')
• 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.

Sponsors & Collaborators

• Bjorn H. Ebdrup: lead
• Rigshospitalet, Denmark: collaborator
• GCP unit, Copenhagen University Hospital: collaborator
• ACADIA Pharmaceuticals Inc.: collaborator

Related Publications (1)

• 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.

  PMID: 32425802 DERIVED

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders

Interventions

pimavanserin

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Study Officials

• Bjørn H Ebdrup, MD, PhD

  University of Copenhagen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD PhD, associate professor, vice-chair of research CNSR

Model Details: Proof-of-principle study, investigator initiated, open label study

Study Record Dates

• First Submitted: June 5, 2019
• First Posted: June 21, 2019
• Study Start: December 1, 2024
• Primary Completion: December 2, 2024
• Study Completion: December 4, 2024
• Last Updated: December 9, 2024

Record last verified: 2024-12