Chorea, Huntington Disease
Conditions
Keywords
Huntington Disease, Chorea, Attention, ADHD, ADD, Strattera, Atomoxetine
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).
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.
Interventions
DRUGatomoxetine
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.
DRUGMatching 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.
Sponsors
Eli Lilly and Company
University of Iowa
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Conners' Adult Attention Rating Scale (CAARS) | 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. |
| Attention Composite Score | 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. |
| Executive Composite Score | 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
| Measure | Time frame | Description |
|---|---|---|
| Symptom Checklist-90-Revised (SCL-90-R) | 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. |
| Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score | 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. |
Countries
United States
Participant flow
Recruitment details
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).
Pre-assignment details
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 by arm
| Arm | Count |
|---|---|
| All Participants Age, sex, and region of enrollment were available for all 20 participants. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age Continuous | 46.20 years STANDARD_DEVIATION 10.288 |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 18 | 7 / 20 |
| serious Total, serious adverse events | 0 / 20 | 3 / 20 |
Outcome results
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.
Time frame: There are two time points for this measure: baseline and after 4 weeks of treatment
Population: Analysis was based on number of completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atomoxetine | Attention Composite Score | -0.13 Units on a scale | Standard Error 0.07 |
| Placebo | Attention Composite Score | 0.02 Units on a scale | Standard Error 0.06 |
Comparison: The primary measures were analyzed as pretreatment and posttreatment difference scores using a series of analyses of covariance controlling for age. The results were screened for model violations (e.g., outliers). Preliminary analyses assured no treatment order effects by examining block by treatment interactions.p-value: 0.09ANCOVA
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.
Time frame: There are two time points for this measure: baseline and after 4 weeks of treatment
Population: Analysis was based on number of completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atomoxetine | Conners' Adult Attention Rating Scale (CAARS) | -2.88 units on a scale | Standard Error 1.1 |
| Placebo | Conners' Adult Attention Rating Scale (CAARS) | -2.24 units on a scale | Standard Error 1.1 |
Comparison: The primary measures were analyzed as pretreatment and posttreatment difference scores using a series of analyses of covariance controlling for age. The results were screened for model violations (e.g., outliers). Preliminary analyses assured no treatment order effects by examining block by treatment interactions.p-value: 0.63ANCOVA
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.
Time frame: There are two time points for this measure: baseline and after 4 weeks of treatment
Population: Analysis was based on number of completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atomoxetine | Executive Composite Score | -1.68 units on a scale | Standard Error 1.4 |
| Placebo | Executive Composite Score | -2.94 units on a scale | Standard Error 1.4 |
Comparison: The primary measures were analyzed as pretreatment and posttreatment difference scores using a series of analyses of covariance controlling for age. The results were screened for model violations (e.g., outliers). Preliminary analyses assured no treatment order effects by examining block by treatment interactions.p-value: 0.46ANCOVA
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.
Time frame: There are two time points for this measure: baseline and after 4 weeks of treatment
Population: Analysis was based on number of completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atomoxetine | Symptom Checklist-90-Revised (SCL-90-R) | -4.20 units on a scale | Standard Error 1.9 |
| Placebo | Symptom Checklist-90-Revised (SCL-90-R) | -4.64 units on a scale | Standard Error 1.8 |
Comparison: The secondary measures were analyzed as pretreatment and posttreatment difference scores using a series of analyses of covariance controlling for age. The results were screened for model violations (e.g., outliers). Preliminary analyses assured no treatment order effects by examining block by treatment interactions.p-value: 0.84ANCOVA
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.
Time frame: There are two time points for this measure: baseline and after 4 weeks of treatment
Population: Analysis was based on number of completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atomoxetine | Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score | 0.42 units on a scale | Standard Error 1.8 |
| Placebo | Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score | -0.35 units on a scale | Standard Error 1.7 |
Comparison: The secondary measures were analyzed as pretreatment and posttreatment difference scores using a series of analyses of covariance controlling for age. The results were screened for model violations (e.g., outliers). Preliminary analyses assured no treatment order effects by examining block by treatment interactions.p-value: 0.76ANCOVA