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PET Study Examining the Dopaminergic Activity of Armodafinil in Adults

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ClinicalTrials.gov Identifier: NCT00592943
Recruitment Status : Completed
First Posted : January 14, 2008
Results First Posted : June 10, 2011
Last Update Posted : November 13, 2013
Sponsor:
Information provided by (Responsible Party):
Thomas J. Spencer, MD, Massachusetts General Hospital

December 28, 2007
January 14, 2008
February 15, 2011
June 10, 2011
November 13, 2013
October 2007
May 2008   (Final data collection date for primary outcome measure)
  • 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 ]
    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 ]
    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 ]
    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.
DAT occupancy from PET scan results [ Time Frame: each visit ]
Complete list of historical versions of study NCT00592943 on ClinicalTrials.gov Archive Site
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PET Study Examining the Dopaminergic Activity of Armodafinil in Adults
A PET Study Examining the Dopaminergic Activity of Armodafinil in Adults
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.

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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Healthy
Drug: armodafinil
tablet, taken by mouth, once each study day
Other Name: Nuvigil
  • Active Comparator: Armodafinil (100mg)
    Intervention: Drug: armodafinil
  • Active Comparator: Armodafinil (250 mg)
    Intervention: Drug: armodafinil
Spencer TJ, Madras BK, Bonab AA, Dougherty DD, Clarke A, Mirto T, Martin J, Fischman AJ. A positron emission tomography study examining the dopaminergic activity of armodafinil in adults using [¹¹C]altropane and [¹¹C]raclopride. Biol Psychiatry. 2010 Nov 15;68(10):964-70. doi: 10.1016/j.biopsych.2010.08.026.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
12
Same as current
May 2010
May 2008   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years to 35 Years   (Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00592943
2007-P-001659
No
Not Provided
Not Provided
Thomas J. Spencer, MD, Massachusetts General Hospital
Massachusetts General Hospital
Not Provided
Principal Investigator: Thomas Spencer, MD Massachusetts General Hospital
Massachusetts General Hospital
October 2013

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