Vitamin D as a Therapeutic Adjunct in the Stimulant Treat... | NCT03103750

NCT03103750

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
M# 25288	Other Grant/Funding Number	Brain and Behavior Research Foundation
1R01AT010508-01A1	U.S. NIH Grant/Contract		View source

Status Module

Name	Class
Brain & Behavior Research Foundation	OTHER
National Center for Complementary and Integrative Health (NCCIH)	NIH

Description Module

Detailed Description

Increases in the rates of childhood ADHD over the past two decades have lead to speculation that calcitriol deficiency (e.g., secondary to the increased use of sunscreen and/or increases in sedentary, indoor lifestyles in children) plays a causal/contributory role in the etiology of ADHD. To date, evidence of a direct link is lacking. One study showed higher maternal circulating Vitamin D levels in pregnancy are associated with lower risk of developing ADHD-like symptoms in childhood. On the other hand, another study did not replicate the above association, and a prospective study using umbilical cord samples stored at the time of birth reported no difference in serum vitamin D levels between ADHD group versus healthy controls. In terms of clinical trials, one randomized double blind study among adults with ADHD reported a beneficial effect of the intervention, measured with the Conners Adult ADHR rating scale, in comparison with placebo, but the intervention included the combination of vitamin D and several other micronutrients. An analysis of moderators of a positive response to ADHD behaviors did not reveal a significant predictive effect of vitamin D.

However, recent studies provide intriguing indirect evidence of an inverse relationship between solar intensity (SI) and/or altitude (a proxy for greater sun/UV light exposure) and regional rates of ADHD. One study examined three large datasets across 49 U.S. states for 2003 and 2007, and across 9 non-U.S. countries. This study examined the prevalence of ADHD and Solar Intensity (SI) maps. They found an inverse association between solar intensity and prevalence of ADHD. Another study examined two national survey datasets. They found an inverse relationship between altitude and prevalence of ADHD. Investigators hypothesize, as suggested by Huber, that a common denominator on the above studies is the increased vitamin D levels in those exposed to a higher solar intensity, which is known to increase with altitude.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Calcitriol then placebo	Experimental	Healthy volunteers will receive a baseline MRI. On the night before and day of testing, subjects will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan #1. After PET Scan #1, subjects will receive a Dexedrine dose, followed by PHNO injection and PET Scan #2. A minimum of six days later, subjects will receive two doses of placebo for the night before and day of testing, followed by a third PHNO injection and PET scan #3. After PET scan #3, subjects will receive another Dexedrine dose, followed by PHNO injection and PET scan #4.	Procedure: Magnetic Resonance Imaging (MRI) Drug: PHNO Dietary Supplement: calcitriol Drug: Placebo oral capsule Procedure: high-resolution research tomography Drug: Dextro Amphetamine
Placebo then Calcitriol	Experimental	Healthy volunteers will receive a baseline MRI. On the night before and day of testing, subjects will receive two doses of placebo, followed by PHNO injection and PET Scan #1. After PET Scan #1, subjects will receive a Dexedrine dose, followed by PHNO injection and PET Scan #2. A minimum of six days later, subjects will receive two doses of calcitriol (3.0mcg total) for the night before and day of testing, followed by a third PHNO injection and PET scan #3. After PET scan #3, subjects will receive another Dexedrine dose, followed by PHNO injection and PET scan #4.	Procedure: Magnetic Resonance Imaging (MRI) Drug: PHNO Dietary Supplement: calcitriol Drug: Placebo oral capsule Procedure: high-resolution research tomography Drug: Dextro Amphetamine

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Magnetic Resonance Imaging (MRI)	Procedure	Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Non-displaceable Tracer Binding Potentials	non-displaceable tracer binding potentials (BPND = VT - VREF / VREF), which are linearly proportional to the density of available D2/3 Rs, computed using a simplified reference tissue model (SRTM) utilizing the cerebellum as a reference region.	day 1
Non-displaceable Tracer Binding Potentials	non-displaceable tracer binding potentials (BPND = VT - VREF / VREF), which are linearly proportional to the density of available D2/3 Rs, computed using a simplified reference tissue model (SRTM) utilizing the cerebellum as a reference region.	day 7

Secondary Outcomes

Measure	Description	Time Frame
Continuous Performance Task (CPT-IP)	In this computer based test, subjects are shown a random sequence of numbers (2-digit, 3-digit, and 4-digit) and are instructed to press a button as quickly and accurately as possible (with their preferred hand) when a number repeats. Subjects are instructed to withhold their response for any other sequence of numbers. The measure is presented as dprime, which is calculated: d' = z(H) - z(F), where z(H) is the z-score of the hit rate and z(F) is the z-score of the false positive rate. A z-score of 0 represents the population mean. d' is indicates better performance on the task with higher values, z(H) indicates better performance on the task with higher values due to higher hit rate, and z(F) indicates worse performance on the task with higher values due to higher false positive rates.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Age 18-50 years
Voluntary, written, informed consent
Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations
For females, non-lactating, with a negative serum or urine pregnancy test
Lab results without clinically relevant findings (e.g. renal function, electrolytes, and vitamin D levels)
English speaking

Exclusion Criteria:

Medical contraindication to Dexedrine administration (e.g., history of cardiac problems, seizures, glaucoma, hypertension, hyperthyroidism, etc.)
Medical contraindication to calcitriol administration (e.g., history of hypersensitivity to calcitriol or any component of the formulation, hypercalcemia or vitamin D toxicity)
History of substance dependence (e.g., alcohol, opiates, sedative hypnotics), except for nicotine
A primary major DSM-5 psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depression, etc.) as determined by the Structured Clinical Interview for DSM-5 (SCID)
A history of significant medical (e.g., cardiovascular, diabetic/metabolic) or neurological (e.g., cerebrovascular accidents, seizure, traumatic brain injury) illness
Positive answers on the cardiac history questionnaire that may place the subject at higher risk, as determined by an internal medicine specialist or cardiologist's review of both the questionnaire responses and screening ECG
Current use of psychotropic and/or potentially psychoactive prescription medications
For females, laboratory (β-HCG) or physical evidence of pregnancy/lactation 9) MRI-incompatible implants and other contraindications for MRI (i.e., aneurysm clip, metal fragments, internal electrical devices such as a cochlear implant, spinal cord stimulator or pacemaker)
History of claustrophobia or feeling of inability to lie still on his/her back for the PET or MRI scans
History of any bleeding disorder or current anticoagulant therapy
Donation or loss of 550 mL of blood or more (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to the first test day.
Use of any prescription medications and/or over-the-counter medications, vitamins and/or herbal supplements which could have a negative clinical interaction with calcitriol/Dexedrine or which could confound scientific results of the study, within 2 weeks prior to each test day (e.g., thiazide diuretics, Mg based antiacids, digoxin, etc,.).
Serum levels of 25(OH)D3 below 20 ng/ml.
Obesity i.e. BMI over 30 (more prone to lower vitamin D levels)
Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over Radioactive Drug Research Committee (RDRC) limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year.
Subjects with current, past or anticipated exposure to radiation in the work place
History of kidney stones within the past 5 years
Any degree of renal failure
History of parathyroid disorder (hyper or hypoparathyroidism)
History of osteoporosis or any pathologic fractures
Vitamin D supplementation in any form in the past 3 months
Known hypersensitivity to Dexedrine, [11C]PHNO, or calcitriol
Malabsorption syndromes (i.e. Celiac sprue)
Serum corrected calcium > 10.5 mg/dl or phosphate > 4.2 mg/dl

Name	Affiliation	Role
Marc Potenza, PhD, MD	Yale University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Connecticut Mental Health Center		New Haven	Connecticut	06519	United States

Arm/Group Information

ID	Title	Description
FG000	Calcitriol Then Placebo	Healthy volunteers will receive a baseline MRI. On the night before and day of testing, subjects will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan #1. After PET Scan #1, subjects will receive a Dexedrine dose, followed by PHNO injection and PET Scan #2. A minimum of six days later, subjects will receive two doses of placebo for the night before and day of testing, followed by a third PHNO injection and PET scan #3. After PET scan #3, subjects will receive another Dexedrine dose, followed by PHNO injection and PET scan #4. Magnetic Resonance Imaging (MRI): Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis PHNO: Used as a tracer for in vivo imaging. calcitriol: three 0.5 mcg capsules Placebo oral capsule: three 0.5 mcg capsules high-resolution research tomography: A functional imaging technique that is used to observe metabolic processes in the body. Dextro Amphetamine: Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg
FG001	Placebo Then Calcitriol	Healthy volunteers will receive a baseline MRI. On the night before and day of testing, subjects will receive two doses of placebo, followed by PHNO injection and PET Scan #1. After PET Scan #1, subjects will receive a Dexedrine dose, followed by PHNO injection and PET Scan #2. A minimum of six days later, subjects will receive two doses of calcitriol (3.0mcg total) for the night before and day of testing, followed by a third PHNO injection and PET scan #3. After PET scan #3, subjects will receive another Dexedrine dose, followed by PHNO injection and PET scan #4. Magnetic Resonance Imaging (MRI): Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis PHNO: Used as a tracer for in vivo imaging. calcitriol: three 0.5 mcg capsules Placebo oral capsule: three 0.5 mcg capsules high-resolution research tomography: A functional imaging technique that is used to observe metabolic processes in the body. Dextro Amphetamine: Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg

ID	Title	Description
BG000	Overall Participants	Baseline characteristics of all participants prior to group order randomization.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Non-displaceable Tracer Binding Potentials

non-displaceable tracer binding potentials (BPND = VT - VREF / VREF), which are linearly proportional to the density of available D2/3 Rs, computed using a simplified reference tissue model (SRTM) utilizing the cerebellum as a reference region.

Participants required complete imaging data (i.e., 4/4 completed PET scans and a completed MRI) in order to be included in analysis. Thus, only n = 18 participants were analyzed to assess BPND.

Posted

Mean

Standard Deviation

ratio

day 1

ID	Title	Description
OG000	Calcitriol	Healthy volunteers will receive a baseline MRI. On the night before and day of testing, subjects will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan #1. After PET Scan #1, subjects will receive a Dexedrine dose, followed by PHNO injection and PET Scan #2. A minimum of six days later, subjects will receive two doses of placebo for the night before and day of testing, followed by a third PHNO injection and PET scan #3. After PET scan #3, subjects will receive another Dexedrine dose, followed by PHNO injection and PET scan #4. Magnetic Resonance Imaging (MRI): Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis PHNO: Used as a tracer for in vivo imaging. calcitriol: three 0.5 mcg capsules high-resolution research tomography: A functional imaging technique that is used to observe metabolic processes in the body. Dextro Amphetamine: Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Calcitriol Then Placebo	Healthy volunteers will receive a baseline MRI. On the night before and day of testing, subjects will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan #1. After PET Scan #1, subjects will receive a Dexedrine dose, followed by PHNO injection and PET Scan #2. A minimum of six days later, subjects will receive two doses of placebo for the night before and day of testing, followed by a third PHNO injection and PET scan #3. After PET scan #3, subjects will receive another Dexedrine dose, followed by PHNO injection and PET scan #4. Magnetic Resonance Imaging (MRI): Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis PHNO: Used as a tracer for in vivo imaging. calcitriol: three 0.5 mcg capsules Placebo oral capsule: three 0.5 mcg capsules high-resolution research tomography: A functional imaging technique that is used to observe metabolic processes in the body. Dextro Amphetamine: Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg

ID	Term
D019958	Attention Deficit and Disruptive Behavior Disorders
D065886	Neurodevelopmental Disorders
D001523	Mental Disorders

ID	Term
D009682	Magnetic Resonance Spectroscopy
D002117	Calcitriol
D003913	Dextroamphetamine

ID	Term
D013057	Spectrum Analysis
D002623	Chemistry Techniques, Analytical
D008919	Investigative Techniques
D004100	Dihydroxycholecalciferols