SchizophreniaPhase 2NCT02197286
Targeted Vitamin D Treatment of Schizophrenia-Associated Hyperprolinemia
A Phase 2 study testing Cholecalciferol in people with Schizophrenia and Schizoaffective Disorder, run by NYU Langone Health at 1 site in United States.
Trial summary
A ten week, blinded trial of vitamin D vs. placebo in 80 patients with schizophrenia or schizoaffective disorder who have low blood levels of vitamin D and elevated blood levels of the amino acid proline. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Schizophrenia, Schizoaffective Disorder
- What is being tested?
- Cholecalciferol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2015to Dec 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male and Female, all racial/ethnic groups, aged 18-65 years.
- Admission diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder.
- Capability to give informed consent.
- Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for females and 327.6 uM for males).
- 25(OH)D insufficiency (<30ng/ml).
- Confirmed diagnosis of schizophreniform disorder, schizophrenia or schizoaffective disorder.
Who cannot join
- Organic brain disorders.
- Valproate treatment within 14 days, because of known proline up-regulatory effects.
- Pregnant women or women of child-bearing potential, who are not surgically-sterile or who are not using appropriate methods of birth control.
- Amino acid metabolism disorder diagnosis.
- Hypercalcemia (>10.4mg/dL), hypercalciuria (>0.20mg/mg), hyperthyroidism (>65pg/ml) or history of renal stones, kidney disease, atherosclerosis, sarcoidosis, histoplasmosis and lymphoma.
- Chart record of HIV positive status.
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- Treatment with clozapine, as this may reflect general treatment resistance.
- Abnormal serum/ urine metabolic lab values suggesting hypercalcemia (serum Calcium >10.4mg/dL), hypercalciuria (urine calcium/urine creatinine >0.20 mg/mg), or hyperthyroidism (parathyroid hormone (PTH) > 65pg/ml).
- Initiation of Valproate treatment.
- Continued use of dietary supplementation, such as fish oil supplementation or vitamin D supplements (>400 IU/day).
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Vitamin-D Treatment Targeted to Hyperprolinemia-Associated Schizophrenia.
A ten week, blinded trial of vitamin D vs. placebo in 80 patients with schizophrenia or schizoaffective disorder who have low blood levels of vitamin D and elevated blood levels of the amino acid proline. The aims of the study are to evaluate an anticipated clinical response to vitamin D supplementation including negative symptoms and cognitive deficits, evaluate safety of vitamin D supplementation for schizophrenia patients and evaluate the relationship of changes in plasma proline levels and efficacy outcomes.
Read the detailed description
25-hydroxyvitamin D (vitD) insufficiency is associated with cognitive decline and has long-been considered important in schizophrenia susceptibility. VitD supplementation has been suggested for those at-risk, and recent studies have demonstrated that vitD insufficiency extends into both adolescent and adult schizophrenia.
The mechanism by which vitD deficits confers risk is unknown. However, vitD is a transcriptional regulator, and the investigators recently found that vitD significantly up-regulates PRODH gene expression. This is important because the highest known genetic risk of schizophrenia is conferred by hemizygous microdeletion of chromosome 22q11, to which PRODH maps. Furthermore, PRODH encodes proline oxidase, which catalyzes proline catabolism. Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with learning and memory deficits and neurotransmitter dysregulation in animal models, and in humans, with decreased intelligence quotient (IQ), cognitive impairment, and schizoaffective disorder. The investigators recently found that >25% of schizophrenia patients were hyperprolinemic and hypothesized a causal relationship between vitD, proline elevation, and schizophrenia, such that vitD insufficiency causes decreased PRODH expression and hyperprolinemia. Measuring fasting plasma 25hydroxyvitD and proline in 64 patients and 90 controls, the investigators found that vitD insufficiency (<30ng/ml) was significantly associated with schizophrenia (OR:2.1, p=0.044), vitD levels were negatively correlated with proline (p=0.01), and vitD insufficient subjects had three times greater odds of hyperprolinemia (p=0.046). Moreover, they demonstrated that hyperprolinemia explains >37% of the association between vitD insufficiency and schizophrenia, signifying that vitD insufficiency increases schizophrenia risk, at least in part by elevating proline. These findings advocate that targeting schizophrenia-associated hyperprolinemia by alleviating vitD insufficiency, may improve symptoms including neurocognitive deficits.
The Specific Aims of this study are:
Aim 1) To Evaluate a clinical response to vitamin D3 (vitD3) treatment, targeting patients with both vitD insufficiency and hyperprolinemia.
Aim 2) To Evaluate the relationship between fasting plasma proline change, PRODH expression, and symptoms, for development of an efficacy biomarker.
The aims will be accomplished via a ten week, double-blind, placebo controlled trial, in which schizophrenia or schizoaffective disorder subjects who are both vitD insufficient and hyperprolinemic, will be randomized to vitD3 (4,000 international units (IU)/day n=40) or placebo (n=40) as an adjunct to their antipsychotics.
- Conditions
- Schizophrenia, Schizoaffective Disorder
- Being tested
- Cholecalciferol, Placebo
- Medical subject headings
- Schizophrenia, Psychotic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CholecalciferolDrug
Also called Other name: Vitamin D3, Trade name:Biotech Pharmacal, Inc: Vitamin D3-4,, 4,000 IU per day
One capsule containing 4,000 IU of Cholecalciferol, per day
PlaceboDrug
Daily dose of a single gelatin placebo capsule.
| Study group | Role | What they receive |
|---|---|---|
| Vitamin D (cholecalciferol) | Experimental | Intervention: Capsules containing the active ingredient, cholecalciferol @ 4,000 international units (IU). One capsule daily, oral administration for 10 weeks. Receives: Drug: Cholecalciferol |
| Placebo | Placebo comparator | Daily matching placebo gelatin capsule (also contains microcrystalline cellulose).
Capsules are identical in size, color and taste to experimental drug. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical response to supplementation with vitamin D.
To evaluate an anticipated clinical response to supplementation with vitamin D including negative symptoms and cognitive deficits by the change in the Positive and Negative Symptom Scale (PANSS) total score and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive scale. Secondary outcomes will also involve investigation of individual domains of the PANSS and MATRICS.
Measured: Baseline (start of vitamin D supplementation) through ten weeks of treatment.
Secondary outcomes (1)
Biological response to supplementation with vitamin D.
Measure plasma proline levels and peripheral PRODH gene expression levels, and examine the relationship with clinical symptoms and cognitive deficits for efficacy biomarker development.
Measured: Lead-in phase visit, baseline visit and then at biweekly visits through ten weeks of treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jul 2014 (estimated)
- Study startFeb 2015
- Primary completionDec 2017 (estimated)
Why it stopped: Personnel changes at study site.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- More trials run by NYU Langone HealthThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- NYU Langone Health
- Sponsor type
- University, hospital or other
- Collaborators
- Stanley Medical Research Institute, Columbia University
- Responsible party
- Principal investigator, James D. Clelland, NYU Langone Health
- Investigators
- James D Clelland, Principal investigator, NYU Langone Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02197286
- Sponsor's protocol ID
- S13-01127
- Status last verified
- Oct 2015
- First submitted
- 16 Jul 2014
- Last updated
- 12 Oct 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Vitamin-D Treatment Targeted to Hyperprolinemia-Associated Schizophrenia.
- ClinicalTrials.gov ID
- NCT02197286
- Acronym / sponsor ID
- S13-01127
- Conditions
- Schizophrenia, Schizoaffective Disorder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Personnel changes at study site.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- NYU Langone HealthUniversity, hospital or other
- Collaborators
- Stanley Medical Research Institute, Columbia University
- Study start
- Feb 2015
- Primary completion
- Dec 2017 (estimated)
- First posted
- 22 Jul 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A ten week, blinded trial of vitamin D vs. placebo in 80 patients with schizophrenia or schizoaffective disorder who have low blood levels of vitamin D and elevated blood levels of the amino acid proline. The aims of the study are to evaluate an anticipated clinical response to vitamin D supplementation including negative symptoms and cognitive deficits, evaluate safety of vitamin D supplementation for schizophrenia patients and evaluate the relationship of changes in plasma proline levels and efficacy outcomes.
Detailed description
25-hydroxyvitamin D (vitD) insufficiency is associated with cognitive decline and has long-been considered important in schizophrenia susceptibility. VitD supplementation has been suggested for those at-risk, and recent studies have demonstrated that vitD insufficiency extends into both adolescent and adult schizophrenia.
The mechanism by which vitD deficits confers risk is unknown. However, vitD is a transcriptional regulator, and the investigators recently found that vitD significantly up-regulates PRODH gene expression. This is important because the highest known genetic risk of schizophrenia is conferred by hemizygous microdeletion of chromosome 22q11, to which PRODH maps. Furthermore, PRODH encodes proline oxidase, which catalyzes proline catabolism. Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with learning and memory deficits and neurotransmitter dysregulation in animal models, and in humans, with decreased intelligence quotient (IQ), cognitive impairment, and schizoaffective disorder. The investigators recently found that >25% of schizophrenia patients were hyperprolinemic and hypothesized a causal relationship between vitD, proline elevation, and schizophrenia, such that vitD insufficiency causes decreased PRODH expression and hyperprolinemia. Measuring fasting plasma 25hydroxyvitD and proline in 64 patients and 90 controls, the investigators found that vitD insufficiency (<30ng/ml) was significantly associated with schizophrenia (OR:2.1, p=0.044), vitD levels were negatively correlated with proline (p=0.01), and vitD insufficient subjects had three times greater odds of hyperprolinemia (p=0.046). Moreover, they demonstrated that hyperprolinemia explains >37% of the association between vitD insufficiency and schizophrenia, signifying that vitD insufficiency increases schizophrenia risk, at least in part by elevating proline. These findings advocate that targeting schizophrenia-associated hyperprolinemia by alleviating vitD insufficiency, may improve symptoms including neurocognitive deficits.
The Specific Aims of this study are:
Aim 1) To Evaluate a clinical response to vitamin D3 (vitD3) treatment, targeting patients with both vitD insufficiency and hyperprolinemia.
Aim 2) To Evaluate the relationship between fasting plasma proline change, PRODH expression, and symptoms, for development of an efficacy biomarker.
The aims will be accomplished via a ten week, double-blind, placebo controlled trial, in which schizophrenia or schizoaffective disorder subjects who are both vitD insufficient and hyperprolinemic, will be randomized to vitD3 (4,000 international units (IU)/day n=40) or placebo (n=40) as an adjunct to their antipsychotics.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Vitamin D (cholecalciferol) | Experimental | Drug: CholecalciferolIntervention: Capsules containing the active ingredient, cholecalciferol @ 4,000 international units (IU). One capsule daily, oral administration for 10 weeks. |
| Placebo | Placebo comparator | Drug: PlaceboDaily matching placebo gelatin capsule (also contains microcrystalline cellulose). Capsules are identical in size, color and taste to experimental drug. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Male and Female, all racial/ethnic groups, aged 18-65 years.
- Admission diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder.
- Capability to give informed consent.
- Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for females and 327.6 uM for males).
- 25(OH)D insufficiency (<30ng/ml).
Key exclusion criteria (10 listed)
- Organic brain disorders.
- Valproate treatment within 14 days, because of known proline up-regulatory effects.
- Pregnant women or women of child-bearing potential, who are not surgically-sterile or who are not using appropriate methods of birth control.
- Amino acid metabolism disorder diagnosis.
- Hypercalcemia (>10.4mg/dL), hypercalciuria (>0.20mg/mg), hyperthyroidism (>65pg/ml) or history of renal stones, kidney disease, atherosclerosis, sarcoidosis, histoplasmosis and lymphoma.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CholecalciferolAlso: Other name: Vitamin D3, Trade name:Biotech Pharmacal, Inc: Vitamin D3-4,, 4,000 IU per dayOne capsule containing 4,000 IU of Cholecalciferol, per day | Drug | Vitamin D (cholecalciferol) |
| PlaceboDaily dose of a single gelatin placebo capsule. | Drug | Placebo |
Primary outcome
Clinical response to supplementation with vitamin D.
Time frame: Baseline (start of vitamin D supplementation) through ten weeks of treatment.
To evaluate an anticipated clinical response to supplementation with vitamin D including negative symptoms and cognitive deficits by the change in the Positive and Negative Symptom Scale (PANSS) total score and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive scale. Secondary outcomes will also involve investigation of individual domains of the PANSS and MATRICS.
1 secondary outcome
Biological response to supplementation with vitamin D.
Time frame: Lead-in phase visit, baseline visit and then at biweekly visits through ten weeks of treatment.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Oct 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James D Clelland principal investigator
NYU Langone Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cholecalciferol in people with Schizophrenia and Schizoaffective Disorder, run by NYU Langone Health at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 12 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical response to supplementation with vitamin D. (time frame: Baseline (start of vitamin D supplementation) through ten weeks of treatment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Oct 2015.