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Vitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03103750
Recruitment Status : Active, not recruiting
First Posted : April 6, 2017
Last Update Posted : October 9, 2020
Sponsor:
Collaborator:
Brain & Behavior Research Foundation
Information provided by (Responsible Party):
Yale University

Tracking Information
First Submitted Date  ICMJE March 30, 2017
First Posted Date  ICMJE April 6, 2017
Last Update Posted Date October 9, 2020
Actual Study Start Date  ICMJE August 15, 2017
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 30, 2017)
  • non-displaceable tracer binding potentials [ Time Frame: day 1 ]
    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.
  • non-displaceable tracer binding potentials [ Time Frame: day 7 ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 30, 2017)
  • continuous Performance Task (CPT-AX) [ Time Frame: day 1 ]
    In this computer based test the subjects are shown a random sequence of different letters and are instructed to press a button as quickly and accurately as possible (with their preferred hand) upon detection of an X after an A, and to withhold their response to any other sequence of letters.
  • continuous Performance Task (CPT-AX) [ Time Frame: day 7 ]
    In this computer based test the subjects are shown a random sequence of different letters and are instructed to press a button as quickly and accurately as possible (with their preferred hand) upon detection of an X after an A, and to withhold their response to any other sequence of letters.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD
Official Title  ICMJE Vitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD: a Proof-of-concept Study of Stimulant-induced Dopamine Release Using [11C]-PHNO PET in Healthy Humans
Brief Summary

Specific Aim 1: As part of a within-subject, two-days, study design, to determine whether acute calcitriol (vs. placebo) pre-treatment is associated with greater amphetamine (Amp)-induced dopamine (DA) release in the caudate, putamen, ventral striatum (VST), and substantia nigra / ventral tegmental area (SN/VTA) of healthy human subjects.

Specific Aim 2: To determine whether acute calcitriol (vs. placebo) pre-treatment is associated with better performance on a test of attention (e.g., the continuous Performance Task or CPT-AX), after treatment with amphetamine. Hypothesis: Investigators hypothesize that Subjects pre-treated with calcitriol will have faster reaction times/higher accuracy on the CPT-AX vs. subjects pre-treated with placebo, after treatment with amphetamine.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
This is a within-subject, two-day four-scan, randomized, double-blind, placebo-controlled study design.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE ADHD
Intervention  ICMJE
  • Procedure: 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
  • Drug: PHNO
    Used as a tracer for in vivo imaging.
  • Dietary Supplement: calcitriol
    three 0.5 mcg capsules
  • Drug: Placebo oral capsule
    three 0.5 mcg capsules
  • Procedure: high-resolution research tomography
    A functional imaging technique that is used to observe metabolic processes in the body.
    Other Name: PET scan
  • Drug: Dextro Amphetamine
    Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg
    Other Name: Dexedrine
Study Arms  ICMJE
  • Experimental: 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 or placebo, followed by PHNO injection & PET Scan #1. A minimum of six days later, subjects will receive a Dexedrine Dose followed by a second PHNO injection and PET scan #2.
    Interventions:
    • Procedure: Magnetic Resonance Imaging (MRI)
    • Drug: PHNO
    • Dietary Supplement: calcitriol
    • Drug: Placebo oral capsule
    • Procedure: high-resolution research tomography
    • Drug: Dextro Amphetamine
  • Experimental: Placebo then Calcitriol
    Healthy volunteers will receive a baseline MRI. On the night before, and day of testing subjects will receive two doses of calcitriol or placebo, followed by PHNO injection & PET Scan #1. A minimum of six days later, subjects will receive a Dexedrine Dose followed by a second PHNO injection and PET scan #2.
    Interventions:
    • Procedure: Magnetic Resonance Imaging (MRI)
    • Drug: PHNO
    • Dietary Supplement: calcitriol
    • Drug: Placebo oral capsule
    • Procedure: high-resolution research tomography
    • Drug: Dextro Amphetamine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: March 30, 2017)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2022
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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-V psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depression, etc.) as determined by the Structured Clinical Interview for DSM-V (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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03103750
Other Study ID Numbers  ICMJE 1612018712
M# 25288 ( Other Grant/Funding Number: Brain and Behavior Research Foundation )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Yale University
Study Sponsor  ICMJE Yale University
Collaborators  ICMJE Brain & Behavior Research Foundation
Investigators  ICMJE
Principal Investigator: Marc Potenza, PhD, MD Yale University
PRS Account Yale University
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP