Atomoxetine and Huntington's Disease

• ClinicalTrials.gov Identifier: NCT00368849
• Recruitment Status: Completed
• First Posted: August 29, 2006
• Results First Posted: November 27, 2012
• Last Update Posted: December 20, 2012
• Sponsor: University of Iowa
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Beglinger, Leigh J, University of Iowa

Study Description

Brief Summary:

The purpose of this research study is to evaluate the effect of atomoxetine (also known as Strattera) compared to placebo (inactive substance) on daily activities such as attention and focus, thinking ability and muscle movements in subjects with early Huntington Disease (HD) and attention deficit disorder (ADD).

Condition or disease	Intervention/treatment	Phase
Huntington Disease; Chorea	Drug: atomoxetine; Drug: Matching Placebo	Phase 2

Detailed Description:

No medications have been investigated to improve attention and executive functions in patients with Huntington's disease, despite the evidence that these cognitive domains can be abnormal even before motor symptom onset. Because cognitive symptoms are highly associated with functional disability, treatments aimed at improving cognitive functions would be of significant benefit to patients in the early stages of the disease. Atomoxetine is the ideal choice for such a trial. It has proven efficacy in adults with attention deficit hyperactivity disorder (ADHD) and it selectively targets norepinephrine and dopamine in the prefrontal cortex rather than in subcortical areas. This selectivity is an advantage for patients with HD, because motor side effects are less likely to be facilitated than with a psychostimulant. The present study is a feasibility study in which we propose to administer either 80 milligram (mg) atomoxetine for 4 weeks or placebo to 20 patients with early HD who also complain of mild cognitive symptoms. The groups will then crossover to the other condition (atomoxetine or placebo). Participants will be assessed on measures of ADHD symptoms and a sensitive battery of neuropsychological tests. Based on the shared neural circuitry in ADHD and HD, and the demonstrated effectiveness of atomoxetine on attention in adults with ADHD, improved performance on cognitive tests of attention and executive functions and on subjects' report of ADHD symptoms are expected in the atomoxetine treatment phase. No changes in motor status are predicted during the study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Atomoxetine for Attention Deficits in Adults With Mild HD: A Randomized, Placebo-Controlled Crossover Study
• Study Start Date: November 2005
• Actual Primary Completion Date: February 2008
• Actual Study Completion Date: February 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: 40 milligram twice a day atomoxetine; Participants received 40 milligram twice a day atomoxetine for 4 weeks.	Drug: atomoxetine; This study utilizes a crossover design. Accordingly, half of the participants receive 40 milligram twice a day atomoxetine at arm one while the remaining half receive this intervention at arm two.; Other Name: Strattera
Placebo Comparator: Twice a day matching placebo; Participants received twice a day matching placebo for 4 weeks.	Drug: Matching Placebo; This study utilizes a crossover design. Accordingly, half of the participants receive twice a day matching placebo at arm one while the remaining half receive this intervention at arm two.; Other Name: Sugar pill

Outcome Measures

Primary Outcome Measures :

1. Conners' Adult Attention Rating Scale (CAARS) [ Time Frame: There are two time points for this measure: baseline and after 4 weeks of treatment ]
   The Conners' Adult Attention Rating Scale (CAARS) is one of the most frequently used self-rating measures for adult Attention Deficit Hyperactivity Disorder (ADHD) and was given as a self-report measure of attention. It has 66 items with each item ranging from 0 to 3 points. Higher total scores represent greater impairment. The outcome reported was change in score from baseline for each treatment arm.
2. Attention Composite Score [ Time Frame: There are two time points for this measure: baseline and after 4 weeks of treatment ]
   The attention composite comprises performance on Wechsler Adult Intelligence Scale III Symbol-Digit and Letter Number Sequencing Subtests, Trail Making Test Part A, computerized simple-choice reaction time, and computerized working memory (i.e., 2-Back). The composite score is the average combined z score for each test. Higher, positive values indicate better than average performance and negative and lower values indicate worse than average. The outcome reported was change in score from baseline for each treatment arm.
3. Executive Composite Score [ Time Frame: There are two time points for this measure: baseline and after 4 weeks of treatment ]
   The executive composite comprises performance on Trail Making Test Part B, Stroop Color and Word Test, and the Controlled Oral Word Association Test (i.e., Verbal Fluency). The composite score is the average combined z score for each test. Positive values indicate better than average performance and negative values worse than average. The outcome reported was change in score from baseline for each treatment arm.

Secondary Outcome Measures :

1. Symptom Checklist-90-Revised (SCL-90-R) [ Time Frame: There are two time points for this measure: baseline and after 4 weeks of treatment ]
   Psychiatric symptoms were evaluated with the Symptom Checklist-90-Revised, a self report measure of psychiatric symptoms. The measure produces raw scores and normed scores (T scores Mean = 50), with higher values representing greater impairment. The outcome reported was change in score from baseline for each treatment arm.
2. Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score [ Time Frame: There are two time points for this measure: baseline and after 4 weeks of treatment ]
   Although changes in motor symptoms were not hypothesized, the Unified Huntington Disease Rating Scale motor examination was administered at every visit. An experienced motor rater completes a motor examination and rates the participant on several motor tasks. Total score ranges from 0 - 124, with higher scores indicating a worse outcome. The outcome reported was change in score from baseline for each treatment arm.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Confirmed Huntington's disease (HD) diagnosis
• Age 18 to 65
• Must have mild HD
• Must have complaints of poor attention

Exclusion Criteria:

• Childhood history of attention deficit hyperactivity disorder (ADHD) symptoms
• Diagnosis of schizophrenia, bipolar affective disorder, dementia, delirium or severe anxiety
• Current use of a monoamine oxidase inhibitor (MAOI) medication
• Pregnancy
• Uncontrolled hypertension
• Tachycardia
• Cardiovascular or cerebrovascular disease
• History of a loss of consciousness for greater than (or equal to) 5 minutes
• Having any neurological disorder or insult other than Huntington disease

Contacts and Locations

Locations

United States, Iowa

The University of Iowa

Iowa City, Iowa, United States, 52242

Sponsors and Collaborators

University of Iowa

Eli Lilly and Company

Investigators

• Principal Investigator: Leigh J Beglinger, Ph.D.; University of Iowa

More Information

Additional Information:

University of Iowa Huntington's Disease Center of Excellence 

Publications:

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993 Mar 26;72(6):971-83. doi: 10.1016/0092-8674(93)90585-e.

Campodonico JR, Aylward E, Codori AM, Young C, Krafft L, Magdalinski M, Ranen N, Slavney PR, Brandt J. When does Huntington's disease begin? J Int Neuropsychol Soc. 1998 Sep;4(5):467-73. doi: 10.1017/s1355617798455061.

Lawrence AD, Hodges JR, Rosser AE, Kershaw A, ffrench-Constant C, Rubinsztein DC, Robbins TW, Sahakian BJ. Evidence for specific cognitive deficits in preclinical Huntington's disease. Brain. 1998 Jul;121 ( Pt 7):1329-41. doi: 10.1093/brain/121.7.1329.

Paulsen JS, Zhao H, Stout JC, Brinkman RR, Guttman M, Ross CA, Como P, Manning C, Hayden MR, Shoulson I; Huntington Study Group. Clinical markers of early disease in persons near onset of Huntington's disease. Neurology. 2001 Aug 28;57(4):658-62. doi: 10.1212/wnl.57.4.658.

Marder K, Zhao H, Myers RH, Cudkowicz M, Kayson E, Kieburtz K, Orme C, Paulsen J, Penney JB Jr, Siemers E, Shoulson I. Rate of functional decline in Huntington's disease. Huntington Study Group. Neurology. 2000 Jan 25;54(2):452-8. doi: 10.1212/wnl.54.2.452. Erratum In: Neurology 2000 Apr 25;54(8):1712.

Gomez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel JP, Myers RH. Quantitative neuropathological changes in presymptomatic Huntington's disease. Ann Neurol. 2001 Jan;49(1):29-34.

Beglinger, L. et al. The association between speed of processing and cerebral white matter volume in patients with mild Huntington's disease [abstract]. Poster session accepted at the Annual Meeting of the Cognitive Neuroscience Society, April, 2004

Halliday GM, McRitchie DA, Macdonald V, Double KL, Trent RJ, McCusker E. Regional specificity of brain atrophy in Huntington's disease. Exp Neurol. 1998 Dec;154(2):663-72. doi: 10.1006/exnr.1998.6919.

Nopoulos, P. et al., (under review). Structural Brain Abnormalities in pre-symptomatic Huntington's disease.

Aylward EH, Anderson NB, Bylsma FW, Wagster MV, Barta PE, Sherr M, Feeney J, Davis A, Rosenblatt A, Pearlson GD, Ross CA. Frontal lobe volume in patients with Huntington's disease. Neurology. 1998 Jan;50(1):252-8. doi: 10.1212/wnl.50.1.252.

Casey BJ, Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Schubert AB, Vauss YC, Vaituzis AC, Dickstein DP, Sarfatti SE, Rapoport JL. Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1997 Mar;36(3):374-83. doi: 10.1097/00004583-199703000-00016.

Hale TS, Hariri AR, McCracken JT. Attention-deficit/hyperactivity disorder: perspectives from neuroimaging. Ment Retard Dev Disabil Res Rev. 2000;6(3):214-9. doi: 10.1002/1098-2779(2000)6:33.0.CO;2-M.

Heilman KM, Voeller KK, Nadeau SE. A possible pathophysiologic substrate of attention deficit hyperactivity disorder. J Child Neurol. 1991;6 Suppl:S76-81. doi: 10.1177/0883073891006001s09.

Spencer T, Biederman J, Wilens T, Prince J, Hatch M, Jones J, Harding M, Faraone SV, Seidman L. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry. 1998 May;155(5):693-5. doi: 10.1176/ajp.155.5.693.

Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich A, Milton D. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003 Jan 15;53(2):112-20. doi: 10.1016/s0006-3223(02)01671-2.

Conners, CK et al. Conners' Adult ADHD Rating Scales (CAARS). 1999. North Tonawanda, NY: Multi-Health Systems.

• Responsible Party: Beglinger, Leigh J, Associate Professor, University of Iowa
• ClinicalTrials.gov Identifier: NCT00368849
• Other Study ID Numbers: 200508775
• First Posted: August 29, 2006
• Results First Posted: November 27, 2012
• Last Update Posted: December 20, 2012
• Last Verified: December 2012

Keywords provided by Beglinger, Leigh J, University of Iowa:

Huntington Disease; Chorea; Attention; ADHD; ADD; Strattera; Atomoxetine

Additional relevant MeSH terms:

Huntington Disease; Chorea; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Neurologic Manifestations; Atomoxetine Hydrochloride; Adrenergic Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Adrenergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs