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| Name | Class |
|---|---|
| Eli Lilly and Company | INDUSTRY |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 40 milligram twice a day atomoxetine | Experimental | Participants received 40 milligram twice a day atomoxetine for 4 weeks. |
|
| Twice a day matching placebo | Placebo Comparator | Participants received twice a day matching placebo for 4 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| atomoxetine | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Conners' Adult Attention Rating Scale (CAARS) | 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. | There are two time points for this measure: baseline and after 4 weeks of treatment |
| Attention Composite Score | 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. | There are two time points for this measure: baseline and after 4 weeks of treatment |
| Executive Composite Score | 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. | There are two time points for this measure: baseline and after 4 weeks of treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Symptom Checklist-90-Revised (SCL-90-R) | 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. | There are two time points for this measure: baseline and after 4 weeks of treatment |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Leigh J Beglinger, Ph.D. | University of Iowa | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The University of Iowa | Iowa City | Iowa | 52242 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8458085 | Background | 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. | |
| 9745236 | Background | 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. |
| Label | URL |
|---|---|
| University of Iowa Huntington's Disease Center of Excellence | View source |
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Participants were screened before baseline for the presence of attentional problems through interview, medical status (including safety laboratories and electrocardiogram), and history for inclusion/exclusion criteria.
Participants (number = 20) were recruited using advertisements and through the University of Iowa Huntington Disease (HD) Registry at a rate of 1.40 individuals per month from September 2006 through November 2007 (i.e., 14.3 months).
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| ID | Title | Description |
|---|---|---|
| FG000 | Atomoxetine (4 Weeks) Then Placebo (4 Weeks) | Participants received 40 milligram twice a day atomoxetine for four weeks. After a two week wash out, they then received twice a day matching placebo for four weeks. |
| FG001 | Placebo (4 Weeks) Then Atomoxetine (4 Weeks) | Participants received twice a day matching placebo for four weeks. After a two week washout, they then received 40 milligram twice a day atomoxetine for four weeks. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Age, sex, and region of enrollment were available for all 20 participants. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Conners' Adult Attention Rating Scale (CAARS) | 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. | Analysis was based on number of completers | Posted | Mean | Standard Error | units on a scale | There are two time points for this measure: baseline and after 4 weeks of treatment |
|
Adverse events were reported from September 2006 through November 2007 (14.3 months)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Atomoxetine | Individuals in this arm received 40 milligram twice a day atomoxetine. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Inpatient Hospitalization | Psychiatric disorders |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Weight Loss | Metabolism and nutrition disorders |
We cannot rule out carryover effects. Additionally, the sample size may be too low to detect small treatment changes, the treatment duration may have been too brief, and our participants had only early-stage HD which may have limited the drug effect.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Leigh J. Beglinger, Ph.D. | The University of Iowa | 319-335-8765 | leigh-beglinger@uiowa.edu |
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| ID | Term |
|---|---|
| D006816 | Huntington Disease |
| D002819 | Chorea |
| D001289 | Attention Deficit Disorder with Hyperactivity |
| ID | Term |
|---|---|
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D000069445 | Atomoxetine Hydrochloride |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D011437 | Propylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D002241 | Carbohydrates |
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|
| Matching Placebo | Drug | 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. |
|
|
| Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score | 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. | There are two time points for this measure: baseline and after 4 weeks of treatment |
| 9679784 | Background | 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. |
| 11524475 | Background | 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. |
| 10668713 | Background | 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. |
| 11198293 | Background | 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. |
| Background | 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 |
| 9878201 | Background | 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. |
| Background | Nopoulos, P. et al., (under review). Structural Brain Abnormalities in pre-symptomatic Huntington's disease. |
| 9443488 | Background | 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. |
| 9055518 | Background | 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. |
| 10982499 | Background | 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. |
| 2002218 | Background | 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. |
| 9585725 | Background | 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. |
| 12547466 | Background | 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. |
| Background | Conners, CK et al. Conners' Adult ADHD Rating Scales (CAARS). 1999. North Tonawanda, NY: Multi-Health Systems. |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Individuals in this arm received twice a day matching placebo. |
|
|
|
| Primary | Attention Composite Score | 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. | Analysis was based on number of completers. | Posted | Mean | Standard Error | Units on a scale | There are two time points for this measure: baseline and after 4 weeks of treatment |
|
|
|
|
| Primary | Executive Composite Score | 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. | Analysis was based on number of completers. | Posted | Mean | Standard Error | units on a scale | There are two time points for this measure: baseline and after 4 weeks of treatment |
|
|
|
|
| Secondary | Symptom Checklist-90-Revised (SCL-90-R) | 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. | Analysis was based on number of completers. | Posted | Mean | Standard Error | units on a scale | There are two time points for this measure: baseline and after 4 weeks of treatment |
|
|
|
|
| Secondary | Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score | 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. | Analysis was based on number of completers. | Posted | Mean | Standard Error | units on a scale | There are two time points for this measure: baseline and after 4 weeks of treatment |
|
|
|
|
| 0 |
| 20 |
| 10 |
| 18 |
| EG001 | Matching Placebo | Individuals in this arm received twice a day matching placebo. | 3 | 20 | 7 | 20 |
| An Important Medical Event | Renal and urinary disorders | Elevated Creatinine Level |
|
| An Important Medical Event | Psychiatric disorders | Worsening Depression |
|
| Constipation | Gastrointestinal disorders |
|
| Appetite Loss | Metabolism and nutrition disorders |
|
| Nausea | Gastrointestinal disorders |
|
| Xerostomia | Gastrointestinal disorders |
|
| Dizziness | Nervous system disorders |
|
| Insomnia | Nervous system disorders |
|
| Headache | Nervous system disorders |
|
| Difficulty Urinating | Renal and urinary disorders |
|
| Urine Retention | Renal and urinary disorders |
|
| Dyspepsia | Gastrointestinal disorders |
|
| Somnolence | Nervous system disorders |
|
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| D003704 | Dementia |
| D020820 | Dyskinesias |
| D009069 | Movement Disorders |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |