PET Study Examining the Dopaminergic Activity of Armodafinil in Adults

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Thomas J. Spencer, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00592943
First received: December 28, 2007
Last updated: October 21, 2013
Last verified: October 2013
  Purpose

The specific aims of this study are 1) to document the Dopamine Transporter (DAT) receptor occupancy of armodafinil using positron emission tomography (PET) scanning with C-11 altropane as the ligand and 2) to document the increased intrasynaptic dopamine produced by armodafinil using PET scanning with C-11 raclopride as the ligand. We hypothesize that DAT occupancy will be low with armodafinil; less than the DAT occupancy produced by therapeutic doses of methylphenidate. We also hypothesize that increases in intrasynaptic dopamine will be relatively low with armodafinil.


Condition Intervention Phase
Healthy
Drug: armodafinil
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: A PET Study Examining the Dopaminergic Activity of Armodafinil in Adults

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Armodafinil DAT Occupancy in Caudate [ Time Frame: DAT occupancy was measured using the PET scan at 1 hour and 2.5 hours after oral administration of 100mg or 250 mg Armodafinil ] [ Designated as safety issue: No ]
    Subjects received each dose level (100 and 250 mg) of armodafinil, followed by PET scans, in an open-label protocol. Repeat PET scans, using [1 1 C]altropane, determined DAT occupancy at 1 hour and 2.5 hours postdose (compared with baseline).

  • Armodafinil Extracellular Dopamine in Caudate at 2.5 Hours (With Outlier) [ Time Frame: Extracellular DAT was measured using the PET scan at 2.5 hours after oral administration of 100mg or 250 mg Armodafinil on three different study visits ] [ Designated as safety issue: No ]
    Each subject received each dose level (one dose per day of 100 or 250 mg) of armodafinil, followed by PET scans using [11C]raclopride, to determine the change in extracellular dopamine at 2.5 hours postdose.

  • Armodafinil Extracellular Dopamine in Caudate at 2.5 Hours (Without Outlier) [ Time Frame: Extracellular DAT was measured using the PET scan at 2.5 hours after oral administration of 100mg or 250 mg Armodafinil on three different study visits ] [ Designated as safety issue: No ]
    Each subject received each dose level (one dose per day of 100 or 250 mg) of armodafinil, followed by PET scans using [11C]raclopride, to determine the change in extracellular dopamine at 2.5 hours postdose.


Enrollment: 12
Study Start Date: October 2007
Study Completion Date: May 2010
Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Armodafinil (100mg) Drug: armodafinil
tablet, taken by mouth, once each study day
Other Name: Nuvigil
Active Comparator: Armodafinil (250 mg) Drug: armodafinil
tablet, taken by mouth, once each study day
Other Name: Nuvigil

Detailed Description:

Modafinil produces a unique spectrum of pharmacological effects including enhanced vigilance, arousal, and wakefulness in human subjects (Bastuji and Jouvet 1988). The drug is widely used to treat narcolepsy (Banerjee, Vitiello et al. 2004), but is also effective in Attention Deficit Hyperactivity Disorder (ADHD) (Biederman, Swanson et al. 2005). Notwithstanding the expanding clinical indications for modafinil, the neurochemical mechanisms that produce therapeutic improvement remain unresolved. Pre-clinically, modafinil is a weak inhibitor of the DAT, and displays no affinity for dopamine receptor subtypes (Mignot, Nishino et al. 1994). Further evidence supporting low dopaminergic activity is the low abuse potential of modafinil (Jasinski 2000). Various theories have been proposed as alternative modes of action including enhancement of glutamate release and inhibition of Gamma-aminobutyric acid (GABA) release in various brain regions (Ferraro, Antonelli et al. 1997; Ferraro, Antonelli et al. 1997; Ferraro, Antonelli et al. 1999). However, the exact mechanisms of action of modafinil and the principle active metabolite, armodafinil, are unknown. Understanding these mechanisms of action is important in assessing the potential therapeutic role of armodafinil. We will test to see if there are differences in the degree of DAT occupancy and D2 binding of armodafinil compared with that of traditional stimulants.

The main target of typical stimulants in the brain is the dopamine transporter (DAT) (Volkow, Wang et al. 1998). We have an exquisitely sensitive methodology to measure DAT occupancy using C-11 altropane and Positron Emission Tomography (PET) (Fischman, Bonab et al. 2001). Our group has previously documented the central nervous system pharmacokinetics of several psychiatric drugs (including methylphenidate) using similar techniques. (Christian, Livni et al. 1996; Fischman, Bonab et al. 1996; Fischman, Alpert et al. 1997; Salazar and Fischman 1999; Fischman, Alpert et al. 2002; Spencer, Biederman et al. 2006).

Increases in intrasynaptic (extracellular) dopamine concentrations associated with medications are routinely measured by changes in C-11 raclopride binding in PET scans. C-11 raclopride binds to postsynaptic D-2 receptors. If the intrasynaptic concentration of dopamine increases, it competes with raclopride leading to a weaker signal (i.e. decreased raclopride binding to D-2 receptors). After administration of a stimulant, associated increases in intrasynaptic dopamine compete with C-11 raclopride binding in this manner (Volkow, Wang et al. 2002). By using this technology we can document the change in D-2 binding in the intrasynaptic space achieved by armodafinil, and compare it to that achieved by a typical stimulant.

To this end, using two PET ligands (C-11 altropane and C-11 raclopride), this protocol seeks to compare the DAT receptor occupancy and the increased intrasynaptic dopamine produced by armodafinil to previous studies of methylphenidate. This research will provide novel and unique information toward better understanding the mechanisms of action of armodafinil in comparison to those of typical stimulants.

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Signed written informed consent to participate in the study.
  2. Age: 18 - 35
  3. If female, non-pregnant, non-nursing with a negative serum pregnancy test and using an adequate form of birth control.
  4. Supine and standing blood pressure within the range 110/60 to 150/95 mmHg.
  5. Heart rate, after resting for 5 minutes, within the range 46-90 beats/min.
  6. Right-handed.

Exclusion Criteria:

  1. Diagnosis of any psychotic disorder, bipolar disorder, severe depression, severe anxiety, or Autism.

    Subjects with mild mood, oppositional, conduct, and anxiety disorders may be permitted to participate if considered appropriate by the investigator.

  2. Scores of Baseline Scales:

    Hamilton Depression Scale > 17 (out of a possible 67 on the 21-item scale)(Hamilton 1960) Beck Depression Inventory > 19 (out of a possible 63 on the 21-item scale)(Beck, Ward et al. 1961) Hamilton Anxiety Scale > 21 (out of a possible 56 on the 14-item scale) (Hamilton 1959)

  3. Tics or Tourette's Syndrome.
  4. History of head trauma with loss of consciousness, organic brain disorders, seizures, or neurosurgical intervention.
  5. Any clinically significant chronic medical condition, in the judgment of the investigator.
  6. Mental impairment as evidenced by an I.Q. <75.
  7. Exposure to dopamine receptor antagonists within the previous three (3) months.
  8. Exposure to radiopharmaceuticals within four (4) weeks prior to PET scan.
  9. Subjects receiving psychotropic medication.
  10. Any clinically significant abnormality in the screening laboratory tests, vital signs, or 11-lead ECG, outside of normal limits.
  11. Any woman of childbearing potential who is seeking to become pregnant or suspects that she may be pregnant.
  12. Subjects with a known recent history (within the past six (6) months) of illicit drug or alcohol dependence.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00592943

Locations
United States, Massachusetts
Massachusetts General Hospital
Cambridge, Massachusetts, United States, 02138
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: Thomas Spencer, MD Massachusetts General Hospital
  More Information

Additional Information:
No publications provided by Massachusetts General Hospital

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Thomas J. Spencer, MD, Associate Chief, Clinical and Research Program, Pediatric Psychopharmacology, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00592943     History of Changes
Other Study ID Numbers: 2007-P-001659
Study First Received: December 28, 2007
Results First Received: February 15, 2011
Last Updated: October 21, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:
Adults
Healthy Volunteers
Nuvigil
Armodafinil
DAT occupancy in healthy volunteers

Additional relevant MeSH terms:
Dopamine
Dopamine Agents
Dopamine Agonists
Armodafinil
Modafinil
Cardiotonic Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents
Wakefulness-Promoting Agents
Central Nervous System Stimulants
Central Nervous System Agents

ClinicalTrials.gov processed this record on August 19, 2014