Lurasidone Effects on Tissue Glutamate in Schizophrenia

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02199743
• Collaborator: Sunovion (Industry)
• Enrollment: 35
• Location: 1
• Arms: 3
• Duration (Months): 40
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

24 individuals with schizophrenia or schizoaffective disorders, who are currently considered stable, will be recruited, screened for entry criteria into a blinded study with a 4-week randomization to either lurasidone, haloperidol, or perphenazine to examine glutamate-related outcomes with lurasidone as compared to haloperidol and perphenazine.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Schizoaffective Disorder	Drug: Lurasidone; Drug: Haloperidol; Drug: Perphenazine	Phase 4

Detailed Description

At study start all volunteers will be discontinued from their current antipsychotic drug (APD) and switched to haloperidol 4mg for 5 days. At the end of this discontinuation period, all baseline symptom ratings and cognition testing will be done, as well as the baseline imaging procedures. At the end of the baseline procedures, volunteers will be blindly randomized, either to lurasidone at 40mg (N=12), or to haloperidol at 4mg/d or perphenazine at 16mg/d (N=12). Doses will increase to 80mg/d lurasidone, 8 mg/d haloperidol, or 32 mg/d of perphenazine at the beginning of week two. Dose should be stable for the last 3 weeks of treatment unless side effects are prominent, then the dose can be decreased to 40 lurasidone/4 haloperidol/16 perphenazine mg/d for optimal clinical management. The randomization strategy will be designed and implemented by the research pharmacist in four blocks of six volunteers; drug will be dispensed by the research pharmacy according to the randomization schedule. The randomization will be followed by a four week treatment period at optimal dose levels. On the last two days of the 4 week stable dosing period, the specified glutamate outcome measures will be completed (neuroimaging and cognitive testing) along with all the symptom outcome measures, testing for drug plasma levels, and usual blood safety measures. Patients will be seen weekly for clinical evaluation; suicidality will be monitored weekly. All medications other than study drugs will be discontinued, as much as possible, for the 24-48 hr assessment period. After the evaluation phase, patients will be cross-titrated back to their original treatment medication and dosing.

This design will generate outcomes from 12 patients on lurasidone vs. 12 patients on haloperidol/ perphenazine.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Lurasidone Effects on Tissue Glutamate in Schizophrenia
• Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lurasidone Lurasidone 40mg po qhs with food x 1 week; Lurasidone 80mg po qhs with food x 3 weeks	Drug: Lurasidone; Compare to haloperidol and perphenazine; Other Names: Latuda ; Drug: Haloperidol; Compare to lurasidone; Other Names: Haldol ; Drug: Perphenazine; Compare to lurasidone; Other Names: Trilafon
Active Comparator: Haloperidol Haloperidol 4mg po qhs with food x 1 week; Haloperidol 8mg po qhs with food x 3 weeks.	Drug: Lurasidone; Compare to haloperidol and perphenazine; Other Names: Latuda ; Drug: Haloperidol; Compare to lurasidone; Other Names: Haldol ; Drug: Perphenazine; Compare to lurasidone; Other Names: Trilafon
Active Comparator: Perphenazine Perphenazine 16mg po qhs with food x 1 week; Perphenazine 32mg po qhs with food x 3 weeks.	Drug: Lurasidone; Compare to haloperidol and perphenazine; Other Names: Latuda ; Drug: Haloperidol; Compare to lurasidone; Other Names: Haldol ; Drug: Perphenazine; Compare to lurasidone; Other Names: Trilafon

Outcome Measures

Primary Outcome Measures

1. Cerebral Glutamate Levels [Baseline and 4 weeks]

   Mean values of cerebral glutamate levels was measured by high resolution 3T magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC). Data were acquired from the dorsal anterior cingulate cortex (ACC) using single voxel localized PRESS (TE1, TE2) = (32, 65) ms with an 8-channel head coil in a 3T whole-body scanner (Philips Medical Systems). Voxel size was 30x20x15 mm3 (9 mL) and were placed over the bilateral anterior cingulate cortex (ACC). All values are normalized to water. More negative values represent less cerebral glutamate levels.

Secondary Outcome Measures

1. Brief Assessments of Cognition in Schizophrenia Scores (BACS) [Baseline and 4 weeks]

   Mean of cognition was assessed by BACS, which measures neurocognitive function in schizophrenia. BACs is a validated, composite measure of cognition which is used in schizophrenia. It is composed of Verbal memory (range: 0-75), Working memory (range: 0-28), Motor speed (range: 0-100), Verbal Fluency (number of words generated), Information processing (range: 0-110) and Executive functions (range: 0-22). Higher z-scores indicate a better performance and outcome. BACS composite score are represented as z-scores which can be positive or negative. There is no minimum or maximum as this is a continuous measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject at least 18 years old

• Subject meets criteria diagnosis of schizophrenia or schizoaffective disorder.

• Subject is not pregnant and is not planning pregnancy within the projected duration of the study.

• Female subject who is of reproductive potential agrees to remain abstinent or use adequate and reliable contraception throughout the study

• Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening.

• Eyesight corrected to 20-40 or better

• Able to read, speak, and understand English*

Exclusion Criteria:

• Any medications being used as mood stabilizers (i.e., anticonvulsants)

• Subject currently has a clinically significant medical condition(s) that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study.

• Subject demonstrates evidence of acute/chronic hepatitis which is clinically significant

• Subject has a history of malignancy < 5 years prior

• Subject has a history of neuroleptic malignant syndrome (NMS).

• Subject has a history of alcohol or substance abuse within 3 months prior to screening or alcohol or substance dependence within 12 months prior to screening

• Subject tests positive for drugs of abuse at screening. In the event a subject tests positive for cannabis, the investigator will evaluate the subject's ability to abstain from cannabis during the study.

• Subjects diagnosed with type 1 diabetes

• Subject has a prolactin concentration > 200 ng/mL at screening

• Subject has a history or presence of abnormal ECG which is clinically significant

• Subject has a history of hypersensitivity to more than two distinct chemical classes of drug (e.g., sulfas and penicillins).

• Subjects have received depot neuroleptics within 12 weeks prior to randomization.

• Subject has a history of treatment with clozapine for refractory psychosis and/or subject has been treated with clozapine within 4 months of randomization.

• Subject does not have a stable residence for the 3 months prior to randomization.

• Subject requires treatment with any potent CYP3A4 inhibitors or inducers during the study.

• Subject has received electroconvulsive therapy (ECT) within 90 days prior to

• Subject has been randomized in a prior clinical trial of lurasidone.

• History of serious head injury with unconsciousness for >30 minutes

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• University of Texas Southwestern Medical Center
• Sunovion

Investigators

• Principal Investigator: Carol A Tamminga, M.D., UT Southwestern Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Tamminga Lab and Clinic Website

Publications

None provided.

• Responsible Party: Carol A. Tamminga, Professor of Medicine, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT02199743
• Other Study ID Numbers: STU 032012-053
• First Posted: Jul 24, 2014
• Last Update Posted: Mar 1, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Carol A. Tamminga, Professor of Medicine, University of Texas Southwestern Medical Center: schizophrenia; schizoaffective; cognition; lurasidone; Latuda
• Additional relevant MeSH terms: Schizophrenia; Psychotic Disorders; Haloperidol; Haloperidol decanoate; Lurasidone Hydrochloride; Perphenazine

Study Results

Participant Flow

Pre-assignment Detail	35 individuals initially signed the Informed Consent and began the Screening procedures. Only 24 made it to Randomization, with only 22 making it to the end of the study. Generally participants were discontinued because they were lost to follow-up (which requires 3 telephone calls and a letter) and irregular labs that were exclusionary.

Arm/Group Title	Lurasidone	Non-Lurasidone
Arm/Group Description	Lurasidone 40mg po qhs with food x 1 week; Lurasidone 80mg po qhs with food x 3 weeks This group was compared to the "Non-Lurasidone" group (with both haloperidol and perphenazine together) in the final analysis.	Haloperidol 4mg po qhs with food x 1 week; Haloperidol 8mg po qhs with food x 3 weeks. OR Perphenazine 8mg po qhs with food x 1 week; Perphenazine 32mg po qhs with food x 3 weeks. Each of these drug groups were treated individually in the study but grouped together into a "Non-Lurasidone" group for analysis.
Period Title: Overall Study
STARTED	14	10
COMPLETED	14	8
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Lurasidone	Non-Lurasidone	Total
Arm/Group Description	Lurasidone 40mg po qhs with food x 1 week; Lurasidone 80mg po qhs with food x 3 weeks Compare to haloperidol and perphenazine groups combined to lurasidone group.	Haloperidol 4mg po qhs with food x 1 week; Haloperidol 8mg po qhs with food x 3 weeks. OR Perphenazine 16mg po qhs with food x 1 week; Perphenazine 32mg po qhs with food x 3 weeks. Compare haloperidol and perphenazine groups combined to lurasidone.	Total of all reporting groups
Overall Participants	14	10	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	10 100%	24 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	51	46	49
Sex: Female, Male (Count of Participants)
Female	5 35.7%	6 60%	11 45.8%
Male	9 64.3%	4 40%	13 54.2%
Region of Enrollment (participants) [Number]
United States	14 100%	8 80%	22 91.7%

Outcome Measures

1. Primary Outcome

Title	Cerebral Glutamate Levels
Description	Mean values of cerebral glutamate levels was measured by high resolution 3T magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC). Data were acquired from the dorsal anterior cingulate cortex (ACC) using single voxel localized PRESS (TE1, TE2) = (32, 65) ms with an 8-channel head coil in a 3T whole-body scanner (Philips Medical Systems). Voxel size was 30x20x15 mm3 (9 mL) and were placed over the bilateral anterior cingulate cortex (ACC). All values are normalized to water. More negative values represent less cerebral glutamate levels.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

Of the original 22 participants, only 15 have both Baseline and Week 4 scans to compare.

Arm/Group Title	Lurasidone	Non-Lurasidone
Arm/Group Description	Lurasidone 40mg po qhs with food x 1 week; Lurasidone 80mg po qhs with food x 3 weeks This group was compared to the "Non-Lurasidone" group (with both haloperidol and perphenazine together) in the final analysis.	Haloperidol 4mg po qhs with food x 1 week; Haloperidol 8mg po qhs with food x 3 weeks. OR Perphenazine 8mg po qhs with food x 1 week; Perphenazine 32mg po qhs with food x 3 weeks. Each of these drug groups were treated individually in the study but grouped together into a "Non-Lurasidone" group for analysis.
Measure Participants	8	7
Baseline (week 0)	-1.434662171 (0.741430931)	-1.933853656 (1.005387144)
week 4	-1.412294235 (0.952600355)	-1.838991525 (1.20411535)

2. Secondary Outcome

Title	Brief Assessments of Cognition in Schizophrenia Scores (BACS)
Description	Mean of cognition was assessed by BACS, which measures neurocognitive function in schizophrenia. BACs is a validated, composite measure of cognition which is used in schizophrenia. It is composed of Verbal memory (range: 0-75), Working memory (range: 0-28), Motor speed (range: 0-100), Verbal Fluency (number of words generated), Information processing (range: 0-110) and Executive functions (range: 0-22). Higher z-scores indicate a better performance and outcome. BACS composite score are represented as z-scores which can be positive or negative. There is no minimum or maximum as this is a continuous measure.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

Of the original 22 participants, only 15 have both Baseline and Week 4 to compare.

Arm/Group Title	Lurasidone	Non-Lurasidone
Arm/Group Description	Lurasidone 40mg po qhs with food x 1 week; Lurasidone 80mg po qhs with food x 3 weeks Compare to haloperidol and perphenazine groups combined to lurasidone group.	Haloperidol 4mg po qhs with food x 1 week; Haloperidol 8mg po qhs with food x 3 weeks. OR Perphenazine 16mg po qhs with food x 1 week; Perphenazine 32mg po qhs with food x 3 weeks. Compare haloperidol and perphenazine groups combined to lurasidone.
Measure Participants	8	7
Baseline (week 0)	-1.596573107 (0.929835487)	-1.933853656 (1.005387144)
week 4	-2.002433521 (1.596431421)	-1.500292967 (1.477111055)

Adverse Events

Arm/Group Title	Lurasidone (LUR)		NONLUR
Arm/Group Description	Lurasidone 40mg po qhs with food x 1 week; Lurasidone 80mg po qhs with food x 3 weeks Compare lurasidone (LUR) group to haloperidol and perphenazine (NONLUR) group		Haloperidol 4mg po qhs with food x 1 week; Haloperidol 8mg po qhs with food x 3 weeks. OR Perphenazine 16mg po qhs with food x 1 week; Perphenazine 32mg po qhs with food x 3 weeks. Compare haloperidol and perphenazine (NONLUR) group to lurasidone (LUR) group.
All Cause Mortality
	Lurasidone (LUR)		NONLUR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lurasidone (LUR)		NONLUR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)		0/8 (0%)
Endocrine disorders
diabetes mellitus	1/14 (7.1%)	1	0/8 (0%)	0
Other (Not Including Serious) Adverse Events
	Lurasidone (LUR)		NONLUR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/14 (21.4%)		4/8 (50%)
Gastrointestinal disorders
Nausea	0/14 (0%)	0	2/8 (25%)	2
General disorders
Insomnia	3/14 (21.4%)	3	0/8 (0%)	0
Restlessness	0/14 (0%)	0	3/8 (37.5%)	3
Dry mouth	0/14 (0%)	0	2/8 (25%)	2
Musculoskeletal and connective tissue disorders
Stiffness in jaw	2/14 (14.3%)	2	0/8 (0%)	0
Psychiatric disorders
Sedation	3/14 (21.4%)	3	4/8 (50%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.