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Relationship Between Efficacy of Lumateperone and Brain Glutamate and Dopamine (Lumafep)

Primary Purpose

Psychosis

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Lumateperone
Risperidone
Sponsored by
University of New Mexico
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Psychosis

Eligibility Criteria

18 Years - 40 Years (Adult)All SexesAccepts Healthy Volunteers

Patient group: Inclusion: Diagnosis of DSM-5 schizophrenia, bipolar-I mania and mixed episodes with psychotic features, schizophreniform, schizoaffective, delusional, and unspecified schizophrenia spectrum and other psychotic disorders, established with SCID-P for DSM-5; age between 18 and 40 years old; antipsychotic exposure no greater than 50 mg of olanzapine equivalents (Gardner et al. AJP, 2010) in the 7 days previous to baseline assessments. Exclusion: neurological disorder, intellectual disability, history of severe head trauma (unconciousness >10 min); diagnosis of active substance use disorder (except for nicotine and cannabinoids [cannabinoids use is a risk factor for psychosis]). Healthy Volunteers (HV) group: Inclusion: a) age between 18 and 40 years old. Exclusion: current or past psychiatric disorder (assessed with the SCID-NP; subjects with past history of anxiety or depressive disorders receiving no active treatment in the previous 12 months may be included); past or current diagnosis of neurological disorder, history of severe head trauma or diagnosis of active substance use disorder (except for nicotine or cannabinoids); and c) history of a psychotic disorder in first-degree relatives.

Sites / Locations

  • University of New MexicoRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Lumateperone

Risperidone

Arm Description

Lumateperone 42 mg capsule 1 PO QD for 6 weeks

Risperidone starts 1 mg capsule PO QD for 1 week; then titrated blindly per clinical response and tolerability up to: 2 mg capsule QD starting in week 2; up to 3 mg capsule QD starting in week 3; and up to 4 mg capsule QD starting in week 4. Total risperidone exposure of 6 weeks.

Outcomes

Primary Outcome Measures

Positive symptoms
Positive Scale, Negative Scale, and General Psychopathology Scale (PANSS) positive symptoms. Scale: min 1 to max 7; higher score is worse outcome.

Secondary Outcome Measures

Extrapyramidal symptoms
Simpson-Angus Scale (SAS). Scale: min 1 to max 5; higher score is worse outcome.
Correlation between positive symptoms and brain glutamate
Positive Scale, Negative Scale, and General Psychopathology Scale (PANSS; Scale: min 1 to max 7; higher score is worse outcome.) and brain spectroscopy glutamate
Correlation between positive symptoms and brain dopamine
Positive Scale, Negative Scale, and General Psychopathology Scale (PANSS, Scale: min 1 to max 7; higher score is worse outcome.) and brain neuromelanin
Correlation between extrapyramidal symptoms and brain dopamine
Simpson-Angus Scale (SAS, Scale: min 1 to max 5; higher score is worse outcome.) and brain neuromelanin
Correlation between SAS and prolactin
Simpson-Angus Scale (SAS, Scale: min 1 to max 5; higher score is worse outcome.) and serum prolactin
Correlation between weight gain and lipids
Weight gain and changes in cholesterol and triglycerides
Correlation between weight gain and blood sugar
Weight gain and changes in fasting blood sugar
Correlation between circular RNAs and positive symptoms
Positive Scale, Negative Scale, and General Psychopathology Scale (PANSS, Scale: min 1 to max 7; higher score is worse outcome.) and circular RNAs in blood

Full Information

First Posted
February 22, 2023
Last Updated
May 25, 2023
Sponsor
University of New Mexico
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1. Study Identification

Unique Protocol Identification Number
NCT05890768
Brief Title
Relationship Between Efficacy of Lumateperone and Brain Glutamate and Dopamine
Acronym
Lumafep
Official Title
The Relationship Between the Efficacy of Lumateperone and Central Glutamate and Dopaminergic Metabolism: A Comparison With Risperidone in First Episode Psychosis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 11, 2023 (Actual)
Primary Completion Date
June 2025 (Anticipated)
Study Completion Date
June 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of New Mexico

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
This study will examine the differential relationships between antipsychotic efficacy and changes in dopaminergic and glutamatergic brain metabolism in lumateperone and risperidone treated early psychosis patients. Baseline glutamate and dopamine brain scans, and symptom severity measures will be collected, followed by repeated measures at 6 weeks. Half of the early psychosis patients will be treated with lumateperone, half with risperidone. Healthy control subejcts will also be examined once.
Detailed Description
Efficacy. To examine the differential relationships between antipsychotic efficacy and changes in central dopaminergic and glutamatergic metabolism in lumateperone and risperidone treated early psychosis patients. Hypothesis 1a). Lumateperone efficacy will be directly related to both striatal neuromelanin and medial cingulate glutamate changes. Hypothesis 1b). With risperidone, the relationship with efficacy will be restricted to striatal neuromelanin changes. Brain glutamate and dopamine measures will be collected once in healthy controls to assist in the interpretation of baseline psychosis findings. Safety. To examine the differential extra-pyramidal and peripheral metabolic side-effects in lumateperone and risperidone-treated early psychosis patients. Hypothesis 2a). Risperidone will cause more EPS than lumateperone, and this will be related to greater increases in prolactin. Hypothesis 2b). Risperidone will cause greater weight gain than lumateperone, and this will be related to increments in plasma lipids. Background: Lumateperone is an effective atypical antipsychotic with dopamine, serotonin and glutamate effects, a benign safety profile in terms of EPS and metabolic syndrome and the advantage of a single dose. Efficacy and safety have been established compared to placebo in chronically-ill psychotic patients. However, lumateperone has not been tested against an active comparator or examined in first episode psychosis. With the recognition of the importance of reducing duration of untreated psychosis, establishing efficacy and safety of antipsychotics early in psychosis becomes critical. Early psychosis patients tend to respond more robustly than chronically ill patients, but may be more sensitive to side-effects. In addition, because of the absent or minimal previous antipsychotic exposure, an early psychosis sample offers a better opportunity to examine brain mechanisms underlying efficacy of novel compounds. Glutamate abnormalities have been documented in schizophrenia mainly with single-voxel proton magnetic resonance spectroscopy (1H-MRS). Whole brain measurement of glumate (glutamate plus glutamine i.e.: Glx) with three dimentional echo planar spectroscopic imaging (3D-EPSI) and magnatic resonance scanning of neuromelanin, a sensitive proxy for dopamine concentration in the substantia nigra (S-N) has been recently implemented. The S-N is the origin of the dorsal-striatal terminal fields, where an increased dopamine release has been documented in-vivo in schizophrenia and bipolar-I subjects with positron emission tomography (PET). The lumateperone effects on brain dopamine and glutamate have been documented in rodent models of psychosis. This pilot study is proposed to examine the in-vivo effects of lumateperone on central measures of dopamine and glutamate metabolism and their relationship with efficacy, in early psychosis patients. Significance. There are three significant specific implications for this proposal. First, data supporting the efficacy and tolerability of lumaterperone in first episode psychosis will encourage clinical use of this agent early in the course of schizophrenia and other related disorders. The single dose profile of lumateperone is clearly an advantage in these patients who often have compliance issues. Second, identifying the location of glutamatergic deficits is critical to inform probe placement for future neuromodulation studies, aimed to improve persistent psychotic symptoms. For example, if a particular cortical area (like the medial cingulate) has persistently increased Glx in partially-responsive patients, low-frequency transcranial magnetic stimulation (TMS) targeting the medial cingulate may result in symptomatic improvement for patients who fail available antipsychotic therapy. Alternatively, clinically-relevant reductions in Glx would support high-frequency TMS targeting specific locations. Finally, these studies will also inform anatomical site selection for future postmortem studies of schizophrenia and bipolar-I aimed at examining the molecular underpinnings of these illnesses. This is critical for the development of novel compounds for psychosis that go beyond DA-2 blockade. Experimental Design and Methods. Subjects. Two groups at baseline: first episode psychosis (FEP) patients and HVs. Subsequently, FEP will be randomized to risperidone or lumateperone for 6 weeks. All FEP subjects will be scanned twice with MRI for 3D 1H-MRS and S-N neuromelanin, at baseline and following 6 weeks of assigned antipsychotic therapy. The HV group will be scanned once at baseline. Clinical phases of the study. The study will have three clinical phases: Screening, Double Blind and Transition. i) Screening. After informed consent, subjects will be screened for inclusion and exclusion criteria. If included, subjects will complete a SCID interview and a medical history. HV will also complete the MATRICS cognitive battery, one MRI scan and will be finished with the study. FEP will complete baseline MRI and laboratory work (CBC, UA, chemistry, TSH, liver panel, prolactin, lipids and fasting blood sugar -FBS) as well as a physical exam. ii) Double Blind. Baseline clinical measures will include psychopathology and movement disorder ratings. FEP will be randomized 1:1 at baseline to treatment with lumateperone (single dose 42 mg/day) vs. risperidone (1 mg tablet, target dose between 1 to 4 mg/day). Tablets will be blinded and a 1-week supply will be dispensed by the research pharmacy staff at each visit, following clinical assessments by the research psychiatrist. Patients will take between 1 and 4 tablets in the evening of blinded medication targeting psychotic/manic symptoms. The following un-blinded supplemental psychotropic medications will be allowed at the discretion of the treating psychiatrist: a) benztropine 1- 4 mg/day (for parkinsonism or dystonia); b) lorazepam 1-4 mg/day (for akathisia, anxiety or insomnia); c) propranolol 20-120 mg/day (for akathisia); and d) trazodone 50 to 200 mg/day for insomnia. These supplemental medicines will not be provided by the research pharmacy as part of the study. The subject will get a regular prescription to fill at his/her local pharmacy. Patients will be seen weekly by the research psychiatrist and clinical coordinator to assess clinical response, tolerability, compliance and to adjust the blinded and any supplemental medication. The end of study (after 6 weeks of treatment) will also include the MATRICS, the second MRI and the second set of blood-work (prolactin, lipids and FBS). If patients experience any significant persistent intolerance to the assigned treatment (e.g.: parkinsonism that does not improve with benztropine or akathisia despite treatment with propranolol or lorazepam), their initial medication will be blindly switched to the alternative anti-psychotic. If the blinded medication switch occurs at or after 3 weeks of treatment with the original drug, the end of study assessments will be advanced to be completed as close as possible to the date of switching medications. If the switching occurs before 3 weeks of treatment, the end of study assessments will take place as planned, after a total of 6 weeks of blinded treatment (the goal is to ensure the maximum length of exposure to a particular antipsychotic before end of study assessments are implemented). If the patient's psychotic/manic symptoms are not responding as expected, the blinded medication will be gradually increased (up to 4 tab per day). However, if lack of response persists, the research psychiatrist will also have the option to switch the medication blindly (because of the gradual titration, we expect the medication switch due to lack of response to be very rare). End of study assessments will be advanced as when switching due to intolerance. iii) Transition Finally, patients will be transitioned to open-label antipsychotic treatment with lumateperone (provided by study sponsor for up to 6 months) or to any other agent as per standard of care (for which the patient will be responsible). Patients will be seen weekly for 4 weeks by the research psychiatrist for stabilization on the selected treatment before being referred back to a community-based provider of the patient's choosing. Any other therapies, pharmacological and psychosocial, that are consistent with the standard of care will also be recommended to the subject during this transition phase. c). Magnetic Resonance. MR scans will be performed once at baseline for all subjects and once after 6 weeks of double-blind treatment for FEP. The protocol consists of structural MRI, Neuromelanin and EPSI scans. d). Clinical Ratings. Patients will be evaluated for psychopathology with: the Positive And Negative Symptoms rating Scale (PANSS), mania with the Young Mania Rating Scale, depressive symptoms with the Calgary Depression Scale and the Columbia Suicide Severity Rating Scale. They will be assessed for movement side effects with the Simpson-Angus Scale (SAS) for parkinsonism, Barnes Akathisia Scale (BAS) and the Assessment of Involuntary Movement (AIMS) scale for tardive dyskinesia. e). Neurocognitive and functional measures. The MATRICS, the standard in psychosis research, is an overall neurocognitive outcome and will be collected in all subjects once. The MATRICS evaluates several domains: processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning & problem solving, and social cognition. It will be collected once at baseline in HV and once at the end of 6 weeks of treatment in FEP (so that it better reflects the underlying cognitive capacity apart from the impact of acute psychosis). Functional outcome will be assessed at baseline with the Specific Levels of Functioning scale (SLOF). The SLOF is administered to the caregiver of a psychotic patient and examines 6 domains: personal care skills, physical functioning, interpersonal relationships, social acceptability, activities of community living and work skills. The Validation of Everyday Real-World Outcomes study found the SLOF to be most robustly related to performance-based indices of neurocognition and everyday living skills. f). Laboratory measures. All FEP subjects will undergo baseline clinical measures to assess safety before starting double-blind treatment including hemogram (CBC), chemistry (chem7), hepatic function (hepatic panel), thyroid stimulating hormone (TSH) and urine analyses. To examine tolerability (as per Aim 2) serum prolactin, lipids and fasting blood sugar will be collected at baseline and following 6 weeks of double-blind treatment. All blood-work will be collected while fasting, in the AM. Also all subjects (FEP and HV) will have a urine drug screen done on the day of MR scanning. Finally, to prevent MRI exposure to pregnant females, a urine pregnancy test will be collected in all female participants of child-bearing age on the day of each MRI scans.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Psychosis

7. Study Design

Primary Purpose
Other
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
35 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Lumateperone
Arm Type
Experimental
Arm Description
Lumateperone 42 mg capsule 1 PO QD for 6 weeks
Arm Title
Risperidone
Arm Type
Active Comparator
Arm Description
Risperidone starts 1 mg capsule PO QD for 1 week; then titrated blindly per clinical response and tolerability up to: 2 mg capsule QD starting in week 2; up to 3 mg capsule QD starting in week 3; and up to 4 mg capsule QD starting in week 4. Total risperidone exposure of 6 weeks.
Intervention Type
Drug
Intervention Name(s)
Lumateperone
Other Intervention Name(s)
Caplyta
Intervention Description
FDA approved antipsychotic drug
Intervention Type
Drug
Intervention Name(s)
Risperidone
Other Intervention Name(s)
Risperdol
Intervention Description
FDA approved antipsychotic drug
Primary Outcome Measure Information:
Title
Positive symptoms
Description
Positive Scale, Negative Scale, and General Psychopathology Scale (PANSS) positive symptoms. Scale: min 1 to max 7; higher score is worse outcome.
Time Frame
6 weeks
Secondary Outcome Measure Information:
Title
Extrapyramidal symptoms
Description
Simpson-Angus Scale (SAS). Scale: min 1 to max 5; higher score is worse outcome.
Time Frame
6 weeks
Title
Correlation between positive symptoms and brain glutamate
Description
Positive Scale, Negative Scale, and General Psychopathology Scale (PANSS; Scale: min 1 to max 7; higher score is worse outcome.) and brain spectroscopy glutamate
Time Frame
6 weeks
Title
Correlation between positive symptoms and brain dopamine
Description
Positive Scale, Negative Scale, and General Psychopathology Scale (PANSS, Scale: min 1 to max 7; higher score is worse outcome.) and brain neuromelanin
Time Frame
6 weeks
Title
Correlation between extrapyramidal symptoms and brain dopamine
Description
Simpson-Angus Scale (SAS, Scale: min 1 to max 5; higher score is worse outcome.) and brain neuromelanin
Time Frame
6 weeks
Title
Correlation between SAS and prolactin
Description
Simpson-Angus Scale (SAS, Scale: min 1 to max 5; higher score is worse outcome.) and serum prolactin
Time Frame
6 weeks
Title
Correlation between weight gain and lipids
Description
Weight gain and changes in cholesterol and triglycerides
Time Frame
6 weeks
Title
Correlation between weight gain and blood sugar
Description
Weight gain and changes in fasting blood sugar
Time Frame
6 weeks
Title
Correlation between circular RNAs and positive symptoms
Description
Positive Scale, Negative Scale, and General Psychopathology Scale (PANSS, Scale: min 1 to max 7; higher score is worse outcome.) and circular RNAs in blood
Time Frame
6 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Patient group: Inclusion: Diagnosis of DSM-5 schizophrenia, bipolar-I mania and mixed episodes with psychotic features, schizophreniform, schizoaffective, delusional, and unspecified schizophrenia spectrum and other psychotic disorders, established with SCID-P for DSM-5; age between 18 and 40 years old; antipsychotic exposure no greater than 50 mg of olanzapine equivalents (Gardner et al. AJP, 2010) in the 7 days previous to baseline assessments. Exclusion: neurological disorder, intellectual disability, history of severe head trauma (unconciousness >10 min); diagnosis of active substance use disorder (except for nicotine and cannabinoids [cannabinoids use is a risk factor for psychosis]). Healthy Volunteers (HV) group: Inclusion: a) age between 18 and 40 years old. Exclusion: current or past psychiatric disorder (assessed with the SCID-NP; subjects with past history of anxiety or depressive disorders receiving no active treatment in the previous 12 months may be included); past or current diagnosis of neurological disorder, history of severe head trauma or diagnosis of active substance use disorder (except for nicotine or cannabinoids); and c) history of a psychotic disorder in first-degree relatives.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Crystal Garcia
Phone
505-272-9552
Email
crabaca@salud.unm.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juan Bustillo, MD
Organizational Affiliation
UNM HSC
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of New Mexico
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87106
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Crystal A Garcia
Phone
505-272-9552
Email
crabaca@salud.unm.edu
First Name & Middle Initial & Last Name & Degree
Juan Bustillo, MD

12. IPD Sharing Statement

Plan to Share IPD
No
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