Kuvan in People With Schizophrenia and Schizoaffective Disorder

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01706965
• Collaborator: Stanley Medical Research Institute (Other)
• Enrollment: 27
• Location: 1
• Arms: 2
• Duration (Months): 44
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Rater blinded trial of six weeks of Kuvan vs. multivitamin in 60 outpatients with schizophrenia or schizoaffective disorder. The aims are to evaluate an anticipated clinical response to Kuvan treatment including negative symptom and cognitive deficits, evaluate safety of Kuvan treatment for schizophrenic patients and evaluate the relationship of changes in plasma Kuvan levels and efficacy outcomes.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Schizoaffective Disorder	Drug: Kuvan; Drug: Multivitamin	Phase 1/Phase 2

Detailed Description

Tetrahydrobiopterin (BH4) is a vital central nervous system (CNS) cofactor that maintains availability of amine neurotransmitters such as dopamine (DA) and serotonin (5HT), and stimulates and modulates the glutamatergic system. Dysregulation of these neurotransmitter systems has been implicated in the pathogenesis of schizophrenia (SZ). A central role of BH4 in schizophrenia is further supported by a study finding a relative deficit of 32% for SZ patients as compared to controls. The observed BH4 deficit is comparable to that reported for genetic BH4 deficiency disorders, supporting its characterization as having physiological significance. This highly significant finding, along with: a) the known roles of BH4 in neurotransmitter maintenance, b) dysregulation of CNS neurotransmitter synthesis observed in human BH4 deficiencies, c) evidence that plasma biopterin levels are correlated with CNS biopterin levels, and d) evidence that urinary biopterin excretion is not increased in SZ, all support our hypothesis that dysregulation of BH4 biosynthesis is involved in the pathophysiology of SZ. Moreover, additional data suggesting that mood stabilizer drugs can moderately increase levels of biopterin in patients with psychiatric disorders, and the reported efficacy of BH4 in pilot studies of neuropsychiatric disorders, suggest that alleviation of the schizophrenia BH4 deficit via treatment with synthetic BH4 supplement (Sapropterin dihydrochloride or Kuvan), may give rise to an improvement of the symptoms of schizophrenia, including positive and negative symptoms as well as neurocognitive deficits. Sapropterin dihydrochlorides, teh active pharmaceutical ingredient in Kuvan Tablets,is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4)

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 6R-BH 4 in People With Schizophrenia and Schizoaffective Disorder
• Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Kuvan Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study	Drug: Kuvan; 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight; Other Names: Sapropterin dihydrochloride
Active Comparator: Multivitamin Daily multivitamin tablet	Drug: Multivitamin; Multi-vitamin will be used as an active control in this study. Will be dosed daily

Outcome Measures

Primary Outcome Measures

1. Final Positive and Negative Symptom Scale (PANSS) [Baseline (start of Kuvan) and at six weeks of treatment]

   This is a is a 30 item rating scale widely used in the assessment of schizophrenia ranging from 30-210. Higher scores are worse

2. Final MATRICS Cognitive Battery [Baseline to week 6]

   MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female outpatients with schizophrenia or schizoaffective disorder

• Ages 18-64

• A score of 45 or greater on PANSS

• All oral and depot antipsychotics (with the exception of clozapine) are allowable. Patients must be on their antipsychotic medication for 3 months and stable on dose of antipsychotic and adjunctive medications for 2 weeks prior to study entry. If a patient is on depot medication, they must be stable in dose for 2 months

Exclusion Criteria:

• Organic brain disorder, including epilepsy; mental retardation; or a medical condition whose pathology or treatment would likely alter the presentation or treatment of schizophrenia

• Participated in any investigational study or taken an investigational drug within 30 days

• Current Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of drug/alcohol abuse in last month and current DSM-IV diagnosis drug/alcohol dependence in last 6 months. Subjects must have a negative drug screen at baseline (with one retest allowed for suspected false positive based on clinical judgement of the investigator)

• Diagnosis of any known BH4 deficiency disorder (other than schizophrenia or schizoaffective disorder), including dopa-responsive dystonia,phenylketonuria (PKU), and autism

• Current treatment with clozapine

• In the investigator's judgment, a significant risk of suicide or violent behavior

• Current use of levodopa and nitric oxide-mediated vasorelaxation or oral minoxidil

• Women will be excluded if they are pregnant, lactating, or not either surgically-sterile or using appropriate methods of birth control. Women must agree to continue using applicable birth control throughout the trial. All women of child-bearing potential must have a negative urine pregnancy test at the screening visit and visit 2 (1 week before beginning study medication)

• Absolute neutrophil count below 2.0 on screening

• Any contraindication or allergic reaction to previous multi-vitamin or unwillingness to stop use of current multi-vitamin during study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York State Psychiatric Institute	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute
• Stanley Medical Research Institute

Investigators

• Principal Investigator: Jeffrey A Lieberman, M.D., New York State Psychiatric

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT01706965
• Other Study ID Numbers: 6320
• First Posted: Oct 15, 2012
• Last Update Posted: Sep 13, 2017
• Last Verified: Aug 1, 2017

• Additional relevant MeSH terms: Schizophrenia; Psychotic Disorders

Study Results

Participant Flow

Arm/Group Title	Kuvan	Multivitamin
Arm/Group Description	Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight	Daily multivitamin tablet Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily
Period Title: Overall Study
STARTED	14	13
COMPLETED	13	12
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Kuvan	Multivitamin	Total
Arm/Group Description	Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight	Daily multivitamin tablet Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily	Total of all reporting groups
Overall Participants	13	12	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.15 (12.1)	46.1 (8.0)	43.0 (10.1)
Sex: Female, Male (Count of Participants)
Female	5 38.5%	3 25%	8 32%
Male	8 61.5%	9 75%	17 68%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 30.8%	1 8.3%	5 20%
Not Hispanic or Latino	9 69.2%	11 91.7%	20 80%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 7.7%	0 0%	1 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 61.5%	5 41.7%	13 52%
White	3 23.1%	6 50%	9 36%
More than one race	1 7.7%	1 8.3%	2 8%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Final Positive and Negative Symptom Scale (PANSS)
Description	This is a is a 30 item rating scale widely used in the assessment of schizophrenia ranging from 30-210. Higher scores are worse
Time Frame	Baseline (start of Kuvan) and at six weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Kuvan	Multivitamin
Arm/Group Description	Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight	Daily multivitamin tablet Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily
Measure Participants	13	12
Mean (Standard Deviation) [PANSS Total]	54.4 (10.9)	60.2 (13.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kuvan, Multivitamin
	Comments	Univariate ANOVA, controlling for baseline PANSS total
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.38
	Comments
	Method	ANOVA
	Comments

2. Primary Outcome

Title	Final MATRICS Cognitive Battery
Description	MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment.
Time Frame	Baseline to week 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Kuvan	Multivitamin
Arm/Group Description	Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight	Daily multivitamin tablet Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily
Measure Participants	13	12
Mean (Standard Deviation) [Total MATRICS score]	33.92 (17.1)	35.0 (12.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kuvan, Multivitamin
	Comments
	Type of Statistical Test	Superiority
	Comments	ANOVA, controlled for baseline MATRICS
Statistical Test of Hypothesis	p-Value	.99
	Comments
	Method	ANOVA
	Comments

Adverse Events

Arm/Group Title	Kuvan		Multivitamin
Arm/Group Description	Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight		Daily multivitamin tablet Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily
All Cause Mortality
	Kuvan		Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Kuvan		Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Kuvan		Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/13 (61.5%)		9/12 (75%)
Eye disorders
Eye swelling	0/13 (0%)	0	1/12 (8.3%)	1
Gastrointestinal disorders
constipation	2/13 (15.4%)	2	3/12 (25%)	3
Stomach disconfort	2/13 (15.4%)	2	0/12 (0%)	0
dry mouth	1/13 (7.7%)	1	1/12 (8.3%)	1
nausea	1/13 (7.7%)	1	1/12 (8.3%)	1
diarrhea	0/13 (0%)	0	3/12 (25%)	3
headache	0/13 (0%)	0	2/12 (16.7%)	2
anorexia	0/13 (0%)	0	1/12 (8.3%)	1
General disorders
Dizziness	4/13 (30.8%)	4	1/12 (8.3%)	1
Immune system disorders
urtiacia	0/13 (0%)	0	1/12 (8.3%)	1
Infections and infestations
URI	1/13 (7.7%)	1	0/12 (0%)	0
Musculoskeletal and connective tissue disorders
stiffness	1/13 (7.7%)	1	0/12 (0%)	0
hand pain	0/13 (0%)	0	1/12 (8.3%)	1
Psychiatric disorders
restlessnes	1/13 (7.7%)	1	2/12 (16.7%)	2
auditory hallucinatiuons	0/13 (0%)	0	1/12 (8.3%)	1
Renal and urinary disorders
nocturnal enuresis	1/13 (7.7%)	1	0/12 (0%)	0
Reproductive system and breast disorders
Vaginal Yeast infection	0/13 (0%)	0	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Difficulty speaking	1/13 (7.7%)	1	0/12 (0%)	0
sore throat	1/13 (7.7%)	1	2/12 (16.7%)	2
Skin and subcutaneous tissue disorders
bruising	1/13 (7.7%)	1	0/12 (0%)	0

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.