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Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators

Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study.... Background: Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (Neurology 2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD. Methods: Subjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale. Results: Of the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg). Conclusions: TBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia. Trial Registration: Clinicaltrials.gov registration number (initial study): NCT00219804 Page 1 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Background dopamine D receptor blockers, selective and non-selec- Huntington disease (HD) is a hereditary, progressive neu- tive monoamine-oxidase inhibitors, amantadine, levo- rodegenerative disease clinically characterized by a triad dopa, or dopamine agonists. Participants were permitted of chorea, cognitive symptoms and behavioral changes. to be on antidepressants, antianxiety agents and other Although there is no established treatment to delay the psychotropic medications at stable doses. Clinically, sub- onset or forestall the progression of HD, symptomatic jects could not have disabling dysarthria, dysphagia or treatment of chorea may be beneficial in some individuals depression present at screening or have an unstable or as it may have a favorable impact on motor function, serious medical or psychiatric illness, untreated depres- quality of life and safety [1,2]. sion or lack of a caregiver. Many agents and surgical procedures have been evaluated The subjects completed the double-blind study within in HD for their anti-choreic efficacy including dopamine eight weeks of enrollment but were subsequently depleting agents, dopamine antagonists, benzodi- excluded if they had suffered from a serious adverse event azepines, glutamate antagonists, acetylcholinesterase (AE) judged to be possibly or probably related to study inhibitors, dopamine agonists, anti-seizure medications, drug. There were three possible lengths of enrollment in cannabinoids, lithium, deep brain stimulation, and fetal the open-label study (Figure 1). The initial protocol con- cell transplantation [3-5]. A preponderance of the mostly sisted of a total of 24 weeks, with 12 weeks of titration and uncontrolled studies to date supports the use of TBZ in 12 weeks of maintenance. Subjects had the option of patients with a variety of hyperkinetic movement disor- enrolling in an extension of the 24 week study to a total of ders, including HD [6-8]. The efficacy of TBZ as an anti- 48 weeks. At 48 weeks, they had the option of enrolling choreic drug was convincingly demonstrated in a double- for total study duration of 80 weeks. There was a one week blind, placebo-controlled trial, which demonstrated clear washout following each study phase. Since all participants short-term symptomatic relief of chorea [9]. There is pau- had been off TBZ for at least one week following washout city of data on the long term use of TBZ, but a few studies from the double-blind study, baseline for this study was have provided evidence of its long-term efficacy and toler- considered to be the day of enrollment in the open-label ability [7,10]. study. TBZ is a reversible dopamine depleting agent that is highly Written informed consent was obtained from all study selective for the central vesicular monoamine transporter participants and accompanying caregivers. In compliance type 2 (VMAT2) [11]. TBZ depletes dopamine more selec- with the Declaration of Helsinki, this study was approved tively over norepinephrine and serotonin by inhibiting by the Research Subjects Review Board at the University of transport into presynaptic vesicles [12,13]. The highest Rochester as the coordinating site and by the ethics review binding density for TBZ is in the caudate nucleus, puta- boards at all individual sites that enrolled subjects. men and nucleus accumbens, areas known to bear the brunt of pathology in HD [14,15]. VMAT2 binding and TBZ Dosing monoamine depletion by TBZ is reversible, lasts hours, TBZ was titrated over a maximum of 12 weeks every 3-7 and is not modified by chronic treatment [16,17]. days to the best individual dose (maximum of 200 mg/ day). All subjects started at 12.5 mg per day and were Far too little evidence is available to guide long term titrated upward at the end of each week by 12.5 mg incre- symptomatic treatment in HD. Double-blind and long- ments to doses equal to or lower than 125 mg/day, and term studies assessing various treatment strategies in HD then by 25 mg increments for doses higher than 125 mg/ are urgently needed [18]. The objective of this open-label day. If at any time during the titration phase, moderate to extension study was to assess the long-term safety and effi- severe, possibly or probably drug-related AEs occurred, cacy of TBZ in the treatment of chorea in HD. the dose of TBZ was decreased to the patient's previous well-tolerated dose. Study drug titration (up or down) was Methods permitted only during the first 11 weeks of the study. Participants Patients with HD who were ambulatory, had a Total Func- Assessments tional Capacity (TFC) score of greater than 5 and a Total Participants were examined at the end of weeks 2, 6, 12, Maximal Chorea (TMC) score of greater than 9 from the 24 and then every 12 weeks; and had a safety follow-up Unified Huntington Disease Rating Scale (UHDRS), were visit one week after the end of treatment. Characteristics initially enrolled in the thirteen-week, double-blind, pla- of participants and non-participants were compared using cebo-controlled study [9,19]. Subjects were excluded if chi-square tests and Kruskal-Wallis tests, as appropriate. they were taking concurrent dopamine depleting drugs, Page 2 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Th Figure 1 e flow of subjects (including number of subjects) through the trial from enrollment and into each of the extension phases The flow of subjects (including number of subjects) through the trial from enrollment and into each of the extension phases Analysis of Efficacy Endpoints Analysis of Safety and Tolerability Endpoints The primary efficacy endpoint was the TMC score from the Tolerability was assessed using adverse events, UHDRS UHDRS at week 80 compared with the baseline TMC parkinsonism score (total of the following UHDRS motor score. TMC score at week 80 was also compared to week items: finger taps, pronation/supination, rigidity, bradyki- 81 (after washout) to determine the degree of re-emergent nesia, gait, tandem gait and retropulsion pull test), Barnes chorea. To determine if TBZ may have worsened overall Akathisia Scale (BAS) [20], Unified Parkinson's Disease underlying chorea over time, TMC at week 81 was com- Rating Scale (UPDRS) dysphagia and dysarthria scores pared with baseline. T-tests and analysis of covariance [21], and the 17-item Hamilton Depression Measure (ANCOVA), adjusted for site and baseline value, were (HAM) [22]. Changes from baseline were assessed using t- used to determine significance. Secondary endpoints tests. included the Clinical Global Impression scale and the individual sections of the UHDRS. Treatment emergent AEs were designated to be those AEs that emerged after the start of the open-label study, excluding those for which subjects had a prior history and those that had been present during the double-blind Page 3 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 study, including those without resolution. Those AEs that decided not to participate due to moving away from the carried over from the double-blind portion of the study study site, decision with the caregiver not to enroll due to were not considered new events as they have been previ- lethargy, intensity of protocol, and lost to follow-up. ously reported [9]. The time period examined for all AEs Although one subject who withdrew from the double- was baseline to last day on study medication, prior to ini- blind study early due to pre-existing breast cancer was ini- tiation of washout. tially excluded, once medically cleared, she was permitted to enroll, making a total of 75 subjects who enrolled in The total number (%) of subjects experiencing at least one the open-label study (Table 1). Three of the 75 subjects AE was calculated separately for the titration and mainte- were excluded from analysis because they terminated at or nance periods. McNemar's test was used to compare the prior to the week 12 visit. Forty-two subjects completed number of subjects experiencing at least one AE during the 80-week extension and washout period (Figure 1). the titration phase with the number experiencing at least one AE during the maintenance phase. AEs starting in the Excluding subjects who had stopped medication, the period from the date of baseline visit to week 12 were des- mean daily dosage at week 24 (n = 66) was 74.2 mg (± ignated as having occurred during the titration period. AEs 40.9, range 12.5 mg-200 mg), week 48 (n = 54) was 71.5 starting in the period from the first day of week 12 to week (± 41.5, range 12.5 mg-200 mg) and at week 80 (n = 41) 24 were designated as having occurred during the mainte- was 63.4 mg (± 34.2, range 12.5 mg-175 mg). For the 44 nance period. AEs designated as mild and/or not related subjects with complete dosage data at week 80 (including to study medication were excluded, and three subjects three subjects with zero dose), 24 (55%) of participants with fewer than 13.5 weeks in this study period were were taking either 37.5 mg or 50 mg per day (Figure 2). omitted from this analysis. Regarding adjustment of dosage for subjects who com- pleted 80 weeks, 7 (16%) increased their dosage between To determine if 12 additional weeks of exposure to study weeks 24 and 48, 31 (70%) stayed on the same dose, and medication impacted chorea or HD, efficacy and safety 6 (14%) decreased. Between weeks 48 and 80, 6 (14%) of measures were compared between subjects originally these subjects increased their dosage, 26 (59%) stayed on assigned to placebo and TBZ in the double-blind study the same dose, and 12 (27%) decreased (including 3 with using ANCOVA. week 80 dose = 0 who washed out early). Tolerability Results Subject Characteristics Twenty subjects terminated from the study. There was one Of the 84 subjects enrolled in the double-blind study, 6 death due to metastatic breast cancer. Three participants subjects were ineligible to enroll in the open-label study withdrew due to AEs attributed by the investigators to due to early terminations or serious AEs. Four subjects TBZ, including vocal tics, depression, and delusions. One subject terminated because of an elevated bilirubin level but also reported akathisia, while another subject experi- Table 1: Baseline characteristics (n = 75) enced a significant increase in liver enzymes. One subject Characteristic was started on exclusionary medications, and two subjects were non-compliant with study medications. One subject Age (mean ± SD, range) 50.9 ± 11.5, 29.2-77.4 was institutionalized, one moved out of the state, and two were lost to follow-up. The remaining seven terminations CAGn (mean ± SD, range) 44.5 ± 3.4, 39-54 were due to withdrawal of patient consent or by caregiver or physician request. An additional ten subjects decided Women, n (%) 49 (65%) not to continue in ensuing extension phases. Subjects who completed the study were more likely to be female (p Caucasian, n (%) 71 (95%) < 0.01), have higher CAG repeat length (45 vs. 43.5, p < 0.05), and have a lower total functional assessment score Affected Parent, n (%) Mother 33 (44%) at baseline (18.0 vs. 20.5, p < 0.02). There were no differ- Father 33 (44%) ences in race, affected parent, history of depression, cho- Unspecified 9 (12%) rea score, TFC, total motor score, age, years of education or duration of illness. Years of Illness duration (mean ± SD, range) 8.5 ± 4.5, 1.9-25.9 There were 12 serious AEs including two falls, two cancer History of Depression, n (%) 42 (56%) diagnoses, a single suicide attempt, pneumonia, hip Page 4 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Dosag th Figure 2 rouge h week 80 distribution by percent of subjects at weeks 24, 48 and 80 for the 44 subjects who continued to take tetrabenazine Dosage distribution by percent of subjects at weeks 24, 48 and 80 for the 44 subjects who continued to take tetrabenazine through week 80. replacement (elective) with post-op agitation, agitation, or BAS. Marked or severe akathisia (4 or 5 on the BAS anxiety, akathisia and one abnormal CA 27-29 titer in a scale) was experienced by only one participant, who ter- participant who later died due to metastatic breast cancer. minated due to elevated bilirubin, rather than akathisia. During the study, 56 subjects reported 170 AEs. Seventeen Three participants (4%) had mild or moderate akathisia at subjects reported depressed mood as an AE during this baseline. Ten other participants (13.3%) developed mild study with a prior history of depression in 15 of those sub- or moderate akathisia during the course of the study. jects. All AEs with an incidence of 5% or more are listed in Table 2. There was no association between any adverse There were 3 participants with isolated elevation of AST, event and concomitant medications. greater than 3 times the upper limit of normal. Two occur- rences were at baseline and one at week 24. All abnormal When mild or unrelated events were excluded, 39 subjects liver tests returned to normal by week 80 or at the end of reported at least one AE during titration while 20 subjects study participation except in one participant with >2 reported at least one AE during maintenance (p < 0.001). times upper limit of normal AST in isolation. No partici- Insomnia, somnolence and diarrhea emerged during titra- pant experienced clinical liver dysfunction, but one partic- tion and subsequently resolved during maintenance. The ipant was terminated early due to elevated AST and ALT at number of subjects with somnolence decreased from 36 baseline and one subject terminated due to elevated to 11 (p < 0.0001), insomnia from 14 to 2 (p < 0.003) and bilirubin without clear etiology. diarrhea from 5 to 1 (p < 0.05) when comparing titration to maintenance phases. Efficacy When TMC at week 80 was compared to baseline, there Safety Measures was a reduction in mean TMC score by 4.6 (SD 5.5) Between baseline and week 80, the mean parkinsonism UHDRS units (p < 0.001). At week 81 after washout, cho- score increased 2.1 (SD 4.3) UHDRS units (p = 0.002) and rea re-emerged with a mean TMC score increase of 5.3 (SD the mean UPDRS dysarthria score increased 0.4 (SD 0.8) 3.2) UHDRS units (p < 0.001 compared to week 80) (Fig- UPDRS units (p < 0.002). There were no significant ure 3). For the 41 participants with complete data, there changes in the HAM scale scores, UPDRS dysphagia score, Page 5 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Table 2: Treatment emergent AEs reported in >5% of subjects (3 was no difference in TMC at week 81 (14.9 ± 5.1) when or more), excluding mild and not related to treatment compared to baseline (15.1 ± 4.3). Adverse Event # of Subjects At 48 weeks, chorea reduction in the 45 participants who completed 80 weeks was not significantly different com- Sedation/Somnolence 18 pared to the 11 subjects who completed week 48 but did Depressed Mood 17 not complete the study. After adjusting for study site and baseline chorea score, there was no association with the Anxiety 13 effect of TBZ on chorea related to age, gender, trinucle- otide repeat length, gender of affected parent, or baseline Insomnia 10 clinical global impression of severity. Baseline chorea score itself was a predictor for greater reduction in chorea Akathisia 9 (p = 0.013). Fatigue 7 Secondary Efficacy Outcomes At week 80, there was a significant change in the CGI score Agitation 5 of 0.3 (SD 0.7, p = 0.0054). Of the 45 completers, there was improvement in 16 (36%) and worsening of 4 (9%) Fall 4 with the remainder unchanged compared to baseline. Dysphagia 3 In the 45 participants who completed 80 weeks, there was no significant change in total motor score, but there were Dystonia 3 significant declines in cognitive measures, including ver- bal fluency, symbol digit and Stroop (reading, color and Mean total maximal chorea score (± SE) Figure 3 by week Mean total maximal chorea score (± SE) by week Page 6 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Table 3: Baseline scores and changes from baseline in efficacy outcome measures at weeks 24, 48 and 80 [Mean (SD)]. Measure Baseline Week 24 Week 48 Week 80 N = 75 N = 73 N = 57 N = 45 UHDRS Motor Score 47.9 (15.9) -7.4 (9.8) * -5.6 (12.1) * -0.2 (11.0) Total Chorea 14.9 (3.7) -5.8 (5.0) * -5.6 (5.5) * -4.6 (5.5) * Gait 1.3 (0.6) -0.1 (0.6) 0.0 (0.7) 0.2 (0.7) Parkinsonism 14.5 (5.7) -0.5 (2.7) 0.9 (4.1) 2.1 (4.3) * Barnes Akathisia 0.2 (0.6) 0.1 (1.0) 0.1 (0.9) 0.0 (0.7) Hamilton 4.1 (3.7) -0.0 (3.8) 0.7 (3.4) 0.4 (3.8) Functional Checklist 18.1 (4.7) -0.3 (2.5) -1.1 (2.3) * -2.6 (3.3) * Independence 75.7 (11.5) -2.4 (7.2) * -4.4 (6.0) * -7.0 (8.1) * Behavioral Score (freq*severity) 6.7 (9.7) 3.4 (14.4) * 2.9 (9.3) * 3.5 (14.4) Weight (kg) 72.4 (18.8) -1.2 (4.8) * -1.4 (7.4) -1.7 (6.5) N = 47 N = 45 N = 38 N = 30 Total Functional Capacity 7.6 (2.4) -0.5 (1.5) * -1.1 (1.4) * -2.0 (2.3) * Verbal 17.2 (10.3) -2.0 (5.6) * -2.0 (5.8) * -3.6 (7.9) * Symbol Digit 19.3 (11.2) -0.3 (5.5) -1.9 (4.7) * -4.8 (10.3) * Stroop Color 42.6 (17.3) -4.4 (9.5) * -8.9 (11.4) * -11.0 (14.8) * Stroop Words 49.8 (20.6) -1.2 (9.3) -7.9 (15.4) * -9.0 (17.4) * Stroop Interference 23.2 (11.4) -2.7 (7.1) * -4.5 (7.0) * -5.0 (10.4) * * p < 0.05 (t-test) interference) and functional measures as measured by the ated with HD for up to 12 weeks with the main AEs functional checklist, independence score and TFC (Table including drowsiness and insomnia [9]. In this open label 3). extension study, TBZ continued to effectively suppress chorea for up to 80 weeks in HD. TBZ was generally well Placebo vs. TBZ tolerated, but treatment emergent AEs included sleep dis- When the groups initially randomized to placebo and TBZ turbance, depression, anxiety, and akathisia. Akathisia in were compared, there were no differences in numbers of particular may be difficult to identify due to confusion subjects with AEs, change in TMC score, change in chorea with chorea combined with the lack of insight associated after withdrawal, best dosage, or any of the secondary with HD. During initiation and titration of therapy, measures. There was a reduction in the total number of patients may be more prone to sedation, insomnia and AEs (p < 0.002) and somnolence (p < 0.01) in mainte- gastrointestinal problems but these tend to improve over nance for those subjects initially assigned to TBZ. time. Although clinicians should screen for and treat depression in all patients with HD, those with pre-existing depression may be at higher risk for developing depres- Discussion The double-blind, randomized controlled trial preceding sion while taking TBZ [23,24]. this study demonstrated that TBZ reduced chorea associ- Page 7 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 In this study, there were no completed suicides, but one at week 80, but there was no correlation to support the attempt listed as a serious AE and an additional subject association of global improvement with either motor or who expressed suicidal ideation. Depression was not chorea change. The UHDRS measures of cognition and assessed by formal psychiatric criteria, but depressed function while taking TBZ declined at a rate consistent mood was screened for using the Hamilton Depression with the natural history of HD. The TFC scale declined 1.6 Scale and item 25 of the UHDRS. During the double-blind ± 0.4 points over almost two years in those initially phase of this study, there was a completed suicide in a assigned to TBZ, consistent with previously published subject randomized to the TBZ group, despite scoring measures of TFC [31,32]. Although TBZ is unlikely to within the normal range on the Hamilton Depression accelerate any aspect of decline in HD, it also does not Scale two weeks prior to the event [9]. Clinicians should appear to have any clinical long-term neuroprotective be cautious about the heightened risk of suicide in HD role, despite some evidence of potential neuroprotective regardless of depression indexes or use of monoamine effects demonstrated in animal models of HD [33]. depleters, as overall completed suicide rates are estimated at 7.3% and up to 25% of patients may attempt suicide at The main limitation of this open-label study was the loss some point in the illness [25,26]. In patients already diag- of subjects at each extension phase. The reasons for the nosed with HD, there may be an increased risk of suicide attrition were related to administrative issues and a deci- particularly when patients enter stage 2 of the disease, a sion not to continue rather than any specific AEs. The time when independence diminishes [27]. majority of patients elected to complete 80 weeks on ther- apy, and in fact, once the study concluded, some subjects At the conclusion of this study, the majority of partici- refused to stop taking TBZ and found other sources of the pants were taking either 50 or 75 mg of TBZ. Notably, study medication prior to its availability on the US mar- even after subjects had been on TBZ for over one year, dos- ket. The findings support the clinical impression that cho- age adjustments continued. In two other open-label, long rea suppression in this large cohort of patients can be term studies of TBZ used for a variety of hyperkinetic con- valuable to patients and families. The unblinded nature of ditions including HD, the mean doses after more than two this study limits the degree to which we can make conclu- years were 60.4 and 106.2 mg, respectively [6,7]. sions about effectiveness, but the reduction in chorea was consistent with that seen in the double-blind trial. Further Discontinuation of TBZ after 80 weeks of treatment investigation is needed to determine the effectiveness and appears to be safe and is associated with the return of cho- adverse event profile, particularly regarding cognition, rea, without significant worsening compared to baseline. when TBZ is combined with other commonly used medi- Participants with higher baseline chorea scores experi- cations. enced a greater reduction in chorea. When TBZ was dis- continued, no subject developed signs consistent with Conclusions neuroleptic withdrawal such as nausea, excessive sweat- Chorea, the most striking physical manifestation of HD, ing, tachycardia or akathisia. We did not identify AEs may be disabling and stigmatizing. Frequent or large related to the withdrawal of TBZ, but other studies have amplitude involuntary movements can cause embarrass- specifically examined subjects when TBZ is stopped ment or frustration and physical harm due to direct injury [9,28]. One subject withdrew due to the development of or falls as well as impact quality of life. The impact of sup- "vocal tics". This AE has not been previously reported and pressing chorea on weight, gait, behavior and functioning in fact TBZ has been found to be an effective treatment of deserves further study, as do the indications for suppress- tics [29]. It is possible that the "vocal tic" described was ing chorea in the ambulatory high functioning patient not a TBZ-related AE, but the emergence of tourettism as and the more advanced patient in whom chorea may be a symptom of HD [30]. injurious. In lieu of discovering therapy that modifies the global course of the disease, identifying targeted sympto- Participants did not demonstrate a faster than expected matic treatments for HD, such as those for chorea, is a way rate of motor or functional decline due to HD. Although to palliate some of the more disabling and stigmatizing parkinsonism and dysphagia were increased in subjects at aspects of the disorder. This study confirms efficacy in week 80, this finding was likely a result of the natural pro- long term use and may guide clinicians in dosing and gression of disease. Had the parkinsonism been due to a treatment emergent, long-term adverse effects. pharmacological impact of tetrabenazine, we would have anticipated that the signs would have emerged more Competing interests quickly and found on exams throughout the study. TBZ This study was funded by a grant from Prestwick Pharma- does not appear to have an effect on cognition or function ceuticals, Inc. (subsequently acquired by Biovail Pharma- after two years of therapy. Participants experienced an ceuticals) to the University of Rochester and in turn overall improvement on TBZ as demonstrated by the CGI through subcontracts to the participating research sites. Page 8 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 versity School of Medicine); Penny Stanton, CCRP; Tetsuo Ashizawa, MD The Huntington Study Group (HSG) is a non-profit con- (University of Texas Medical Branch At Galveston); Jeana Jaglin, RN; Kath- sortium of HD investigators http://www.huntington- leen Shannon, MD (Rush University Medical Center); Mary Matthews, RN; study-group.org/. None of the HSG investigators or staff Amy Colcher, MD (University of Pennsylvania); Mira Guzijan, MA; Michael had equity interests with Prestwick Pharmaceuticals, Inc. Geschwind, MD, PhD (University of California, San Francisco); Lynn Bartos, Dr. Fahn received consulting fees of less than $10,000 RN; Karen Blindauer, MD (Medical College of Wisconsin); Kelly Dustin, from Prestwick Pharmaceuticals. After the study was com- RN; Karen Anderson, MD (University of Maryland School of Medicine); pleted, Dr. Frank received consulting fees of less than Chinekwu Anyanwu, MD; Philip Hanna, MD (New Jersey Neuroscience $10,000 from Ovation Pharmaceuticals. Dr. Marshall pre- Institute). sented data at meetings for which he received travel reim- Coordination Center and Biostatistics: Patricia Lindsay; Shirley bursement from Prestwick Pharmaceuticals, Inc. Dr. Eberly, MS; (University of Rochester School of Medicine and Dentistry). Stamler and Ms. Wilson were employees of Prestwick Pharmaceuticals, Inc. The HSG Coordination and Biosta- Prestwick Pharmaceuticals Inc. Authors: David Stamler, MD; Lucinda tistics Centers at the University of Rochester independ- Wilson. ently compiled and analyzed the data for this study. References Acknowledgements 1. 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Thibaut F, Faucheux BA, Marquez J, Villares J, Menard JF, Agid Y, Hir- Jody Corey-Bloom, MD, PhD (University of California, San Diego); Marcia sch EC: Regional distribution of monoamine vesicular uptake McCall, MS; Juan Sanchez-Ramos, MD, PhD (University of South Florida); sites in the mesencephalon of control subjects and patients Nonna Stepanov, MD; Sandra Kostyk, MD, PhD (Ohio State University); with Parkinson's disease: a postmortem study using tritiated Constance Nickerson, LPN; Donald Higgins, MD (Albany Medical College); tetrabenazine. Brain Res 1995, 692:233-243. Joann Belden, RN; Joanne Wojcieszek, MD (Indiana University School of 16. Kenney C, Hunter C, Davidson A, Jankovic J: Short-term effects of tetrabenazine on chorea associated with Huntington's dis- Medicine); Margaret Marie Cox, RN; Andrew Feigin, MD (North Shore-LIJ ease. Mov Disord 2007, 22:10-13. Health System); Dawn Radtke, RN; Martha Nance, MD (Hennepin County 17. Scherman D, Henry JP: Reserpine binding to bovine chromaffin Medical Center); Christine Hunter, RN; William Ondo, MD (Baylor Col- granule membranes. Characterization and comparison with lege of Medicine); Joan Harrison, RN; Claudia Testa, MD, PhD (Emory Uni- dihydrotetrabenazine binding. Mol Pharmacol 1984, 25:113-122. Page 9 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 18. Bonelli RM, Wenning GK: Pharmacological management of Huntington's disease: an evidence-based review. Curr Pharm Des 2006, 12:2701-2720. 19. Huntington Study Group: Unified Huntington's Disease Rating Scale: reliability and consistency. Mov Disord 1996, 11:136-142. 20. Barnes TR: A rating scale for drug-induced akathisia. Br J Psy- chiatry 1989, 154:672-676. 21. Fahn S, Elton RL, Members of the UPDRS Developmental Committee: Unified Parkinson's Disease Rating Scale. In Recent development in Parkinson's disease Volume 2. Edited by: Fahn S, Marsden CD, Calne DB, Goldstein M. Florham Park, NJ: Macmillan Healthcare Informa- tion; 1987:153-163. 22. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psy- chiatry 1960, 23:56-62. 23. Kenney C, Hunter C, Mejia N, Jankovic J: Is history of depression a contraindication to treatment with tetrabenazine? Clin Neu- ropharmacol 2006, 29:259-264. 24. Schreiber W, Krieg JC, Eichhorn T: Reversal of tetrabenazine induced depression by selective noradrenaline (norepine- phrine) reuptake inhibition. J Neurol Neurosurg Psychiatry 1999, 67:550. 25. Di ML, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Con- neally PM: Suicide risk in Huntington's disease. J Med Genet 1993, 30:293-295. 26. Farrer LA: Suicide and attempted suicide in Huntington dis- ease: implications for preclinical testing of persons at risk. Am J Med Genet 1986, 24:305-311. 27. Paulsen JS, Hoth KF, Nehl C, Stierman L: Critical periods of sui- cide risk in Huntington's disease. 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Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2377/9/62/prepub Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 10 of 10 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Neurology Springer Journals

Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators

BMC Neurology , Volume 9 (1) – Dec 18, 2009

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Springer Journals
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Copyright © 2009 by Frank; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Neurology; Neurochemistry; Neurosurgery
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1471-2377
DOI
10.1186/1471-2377-9-62
pmid
20021666
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Abstract

Background: Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (Neurology 2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD. Methods: Subjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale. Results: Of the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg). Conclusions: TBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia. Trial Registration: Clinicaltrials.gov registration number (initial study): NCT00219804 Page 1 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Background dopamine D receptor blockers, selective and non-selec- Huntington disease (HD) is a hereditary, progressive neu- tive monoamine-oxidase inhibitors, amantadine, levo- rodegenerative disease clinically characterized by a triad dopa, or dopamine agonists. Participants were permitted of chorea, cognitive symptoms and behavioral changes. to be on antidepressants, antianxiety agents and other Although there is no established treatment to delay the psychotropic medications at stable doses. Clinically, sub- onset or forestall the progression of HD, symptomatic jects could not have disabling dysarthria, dysphagia or treatment of chorea may be beneficial in some individuals depression present at screening or have an unstable or as it may have a favorable impact on motor function, serious medical or psychiatric illness, untreated depres- quality of life and safety [1,2]. sion or lack of a caregiver. Many agents and surgical procedures have been evaluated The subjects completed the double-blind study within in HD for their anti-choreic efficacy including dopamine eight weeks of enrollment but were subsequently depleting agents, dopamine antagonists, benzodi- excluded if they had suffered from a serious adverse event azepines, glutamate antagonists, acetylcholinesterase (AE) judged to be possibly or probably related to study inhibitors, dopamine agonists, anti-seizure medications, drug. There were three possible lengths of enrollment in cannabinoids, lithium, deep brain stimulation, and fetal the open-label study (Figure 1). The initial protocol con- cell transplantation [3-5]. A preponderance of the mostly sisted of a total of 24 weeks, with 12 weeks of titration and uncontrolled studies to date supports the use of TBZ in 12 weeks of maintenance. Subjects had the option of patients with a variety of hyperkinetic movement disor- enrolling in an extension of the 24 week study to a total of ders, including HD [6-8]. The efficacy of TBZ as an anti- 48 weeks. At 48 weeks, they had the option of enrolling choreic drug was convincingly demonstrated in a double- for total study duration of 80 weeks. There was a one week blind, placebo-controlled trial, which demonstrated clear washout following each study phase. Since all participants short-term symptomatic relief of chorea [9]. There is pau- had been off TBZ for at least one week following washout city of data on the long term use of TBZ, but a few studies from the double-blind study, baseline for this study was have provided evidence of its long-term efficacy and toler- considered to be the day of enrollment in the open-label ability [7,10]. study. TBZ is a reversible dopamine depleting agent that is highly Written informed consent was obtained from all study selective for the central vesicular monoamine transporter participants and accompanying caregivers. In compliance type 2 (VMAT2) [11]. TBZ depletes dopamine more selec- with the Declaration of Helsinki, this study was approved tively over norepinephrine and serotonin by inhibiting by the Research Subjects Review Board at the University of transport into presynaptic vesicles [12,13]. The highest Rochester as the coordinating site and by the ethics review binding density for TBZ is in the caudate nucleus, puta- boards at all individual sites that enrolled subjects. men and nucleus accumbens, areas known to bear the brunt of pathology in HD [14,15]. VMAT2 binding and TBZ Dosing monoamine depletion by TBZ is reversible, lasts hours, TBZ was titrated over a maximum of 12 weeks every 3-7 and is not modified by chronic treatment [16,17]. days to the best individual dose (maximum of 200 mg/ day). All subjects started at 12.5 mg per day and were Far too little evidence is available to guide long term titrated upward at the end of each week by 12.5 mg incre- symptomatic treatment in HD. Double-blind and long- ments to doses equal to or lower than 125 mg/day, and term studies assessing various treatment strategies in HD then by 25 mg increments for doses higher than 125 mg/ are urgently needed [18]. The objective of this open-label day. If at any time during the titration phase, moderate to extension study was to assess the long-term safety and effi- severe, possibly or probably drug-related AEs occurred, cacy of TBZ in the treatment of chorea in HD. the dose of TBZ was decreased to the patient's previous well-tolerated dose. Study drug titration (up or down) was Methods permitted only during the first 11 weeks of the study. Participants Patients with HD who were ambulatory, had a Total Func- Assessments tional Capacity (TFC) score of greater than 5 and a Total Participants were examined at the end of weeks 2, 6, 12, Maximal Chorea (TMC) score of greater than 9 from the 24 and then every 12 weeks; and had a safety follow-up Unified Huntington Disease Rating Scale (UHDRS), were visit one week after the end of treatment. Characteristics initially enrolled in the thirteen-week, double-blind, pla- of participants and non-participants were compared using cebo-controlled study [9,19]. Subjects were excluded if chi-square tests and Kruskal-Wallis tests, as appropriate. they were taking concurrent dopamine depleting drugs, Page 2 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Th Figure 1 e flow of subjects (including number of subjects) through the trial from enrollment and into each of the extension phases The flow of subjects (including number of subjects) through the trial from enrollment and into each of the extension phases Analysis of Efficacy Endpoints Analysis of Safety and Tolerability Endpoints The primary efficacy endpoint was the TMC score from the Tolerability was assessed using adverse events, UHDRS UHDRS at week 80 compared with the baseline TMC parkinsonism score (total of the following UHDRS motor score. TMC score at week 80 was also compared to week items: finger taps, pronation/supination, rigidity, bradyki- 81 (after washout) to determine the degree of re-emergent nesia, gait, tandem gait and retropulsion pull test), Barnes chorea. To determine if TBZ may have worsened overall Akathisia Scale (BAS) [20], Unified Parkinson's Disease underlying chorea over time, TMC at week 81 was com- Rating Scale (UPDRS) dysphagia and dysarthria scores pared with baseline. T-tests and analysis of covariance [21], and the 17-item Hamilton Depression Measure (ANCOVA), adjusted for site and baseline value, were (HAM) [22]. Changes from baseline were assessed using t- used to determine significance. Secondary endpoints tests. included the Clinical Global Impression scale and the individual sections of the UHDRS. Treatment emergent AEs were designated to be those AEs that emerged after the start of the open-label study, excluding those for which subjects had a prior history and those that had been present during the double-blind Page 3 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 study, including those without resolution. Those AEs that decided not to participate due to moving away from the carried over from the double-blind portion of the study study site, decision with the caregiver not to enroll due to were not considered new events as they have been previ- lethargy, intensity of protocol, and lost to follow-up. ously reported [9]. The time period examined for all AEs Although one subject who withdrew from the double- was baseline to last day on study medication, prior to ini- blind study early due to pre-existing breast cancer was ini- tiation of washout. tially excluded, once medically cleared, she was permitted to enroll, making a total of 75 subjects who enrolled in The total number (%) of subjects experiencing at least one the open-label study (Table 1). Three of the 75 subjects AE was calculated separately for the titration and mainte- were excluded from analysis because they terminated at or nance periods. McNemar's test was used to compare the prior to the week 12 visit. Forty-two subjects completed number of subjects experiencing at least one AE during the 80-week extension and washout period (Figure 1). the titration phase with the number experiencing at least one AE during the maintenance phase. AEs starting in the Excluding subjects who had stopped medication, the period from the date of baseline visit to week 12 were des- mean daily dosage at week 24 (n = 66) was 74.2 mg (± ignated as having occurred during the titration period. AEs 40.9, range 12.5 mg-200 mg), week 48 (n = 54) was 71.5 starting in the period from the first day of week 12 to week (± 41.5, range 12.5 mg-200 mg) and at week 80 (n = 41) 24 were designated as having occurred during the mainte- was 63.4 mg (± 34.2, range 12.5 mg-175 mg). For the 44 nance period. AEs designated as mild and/or not related subjects with complete dosage data at week 80 (including to study medication were excluded, and three subjects three subjects with zero dose), 24 (55%) of participants with fewer than 13.5 weeks in this study period were were taking either 37.5 mg or 50 mg per day (Figure 2). omitted from this analysis. Regarding adjustment of dosage for subjects who com- pleted 80 weeks, 7 (16%) increased their dosage between To determine if 12 additional weeks of exposure to study weeks 24 and 48, 31 (70%) stayed on the same dose, and medication impacted chorea or HD, efficacy and safety 6 (14%) decreased. Between weeks 48 and 80, 6 (14%) of measures were compared between subjects originally these subjects increased their dosage, 26 (59%) stayed on assigned to placebo and TBZ in the double-blind study the same dose, and 12 (27%) decreased (including 3 with using ANCOVA. week 80 dose = 0 who washed out early). Tolerability Results Subject Characteristics Twenty subjects terminated from the study. There was one Of the 84 subjects enrolled in the double-blind study, 6 death due to metastatic breast cancer. Three participants subjects were ineligible to enroll in the open-label study withdrew due to AEs attributed by the investigators to due to early terminations or serious AEs. Four subjects TBZ, including vocal tics, depression, and delusions. One subject terminated because of an elevated bilirubin level but also reported akathisia, while another subject experi- Table 1: Baseline characteristics (n = 75) enced a significant increase in liver enzymes. One subject Characteristic was started on exclusionary medications, and two subjects were non-compliant with study medications. One subject Age (mean ± SD, range) 50.9 ± 11.5, 29.2-77.4 was institutionalized, one moved out of the state, and two were lost to follow-up. The remaining seven terminations CAGn (mean ± SD, range) 44.5 ± 3.4, 39-54 were due to withdrawal of patient consent or by caregiver or physician request. An additional ten subjects decided Women, n (%) 49 (65%) not to continue in ensuing extension phases. Subjects who completed the study were more likely to be female (p Caucasian, n (%) 71 (95%) < 0.01), have higher CAG repeat length (45 vs. 43.5, p < 0.05), and have a lower total functional assessment score Affected Parent, n (%) Mother 33 (44%) at baseline (18.0 vs. 20.5, p < 0.02). There were no differ- Father 33 (44%) ences in race, affected parent, history of depression, cho- Unspecified 9 (12%) rea score, TFC, total motor score, age, years of education or duration of illness. Years of Illness duration (mean ± SD, range) 8.5 ± 4.5, 1.9-25.9 There were 12 serious AEs including two falls, two cancer History of Depression, n (%) 42 (56%) diagnoses, a single suicide attempt, pneumonia, hip Page 4 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Dosag th Figure 2 rouge h week 80 distribution by percent of subjects at weeks 24, 48 and 80 for the 44 subjects who continued to take tetrabenazine Dosage distribution by percent of subjects at weeks 24, 48 and 80 for the 44 subjects who continued to take tetrabenazine through week 80. replacement (elective) with post-op agitation, agitation, or BAS. Marked or severe akathisia (4 or 5 on the BAS anxiety, akathisia and one abnormal CA 27-29 titer in a scale) was experienced by only one participant, who ter- participant who later died due to metastatic breast cancer. minated due to elevated bilirubin, rather than akathisia. During the study, 56 subjects reported 170 AEs. Seventeen Three participants (4%) had mild or moderate akathisia at subjects reported depressed mood as an AE during this baseline. Ten other participants (13.3%) developed mild study with a prior history of depression in 15 of those sub- or moderate akathisia during the course of the study. jects. All AEs with an incidence of 5% or more are listed in Table 2. There was no association between any adverse There were 3 participants with isolated elevation of AST, event and concomitant medications. greater than 3 times the upper limit of normal. Two occur- rences were at baseline and one at week 24. All abnormal When mild or unrelated events were excluded, 39 subjects liver tests returned to normal by week 80 or at the end of reported at least one AE during titration while 20 subjects study participation except in one participant with >2 reported at least one AE during maintenance (p < 0.001). times upper limit of normal AST in isolation. No partici- Insomnia, somnolence and diarrhea emerged during titra- pant experienced clinical liver dysfunction, but one partic- tion and subsequently resolved during maintenance. The ipant was terminated early due to elevated AST and ALT at number of subjects with somnolence decreased from 36 baseline and one subject terminated due to elevated to 11 (p < 0.0001), insomnia from 14 to 2 (p < 0.003) and bilirubin without clear etiology. diarrhea from 5 to 1 (p < 0.05) when comparing titration to maintenance phases. Efficacy When TMC at week 80 was compared to baseline, there Safety Measures was a reduction in mean TMC score by 4.6 (SD 5.5) Between baseline and week 80, the mean parkinsonism UHDRS units (p < 0.001). At week 81 after washout, cho- score increased 2.1 (SD 4.3) UHDRS units (p = 0.002) and rea re-emerged with a mean TMC score increase of 5.3 (SD the mean UPDRS dysarthria score increased 0.4 (SD 0.8) 3.2) UHDRS units (p < 0.001 compared to week 80) (Fig- UPDRS units (p < 0.002). There were no significant ure 3). For the 41 participants with complete data, there changes in the HAM scale scores, UPDRS dysphagia score, Page 5 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Table 2: Treatment emergent AEs reported in >5% of subjects (3 was no difference in TMC at week 81 (14.9 ± 5.1) when or more), excluding mild and not related to treatment compared to baseline (15.1 ± 4.3). Adverse Event # of Subjects At 48 weeks, chorea reduction in the 45 participants who completed 80 weeks was not significantly different com- Sedation/Somnolence 18 pared to the 11 subjects who completed week 48 but did Depressed Mood 17 not complete the study. After adjusting for study site and baseline chorea score, there was no association with the Anxiety 13 effect of TBZ on chorea related to age, gender, trinucle- otide repeat length, gender of affected parent, or baseline Insomnia 10 clinical global impression of severity. Baseline chorea score itself was a predictor for greater reduction in chorea Akathisia 9 (p = 0.013). Fatigue 7 Secondary Efficacy Outcomes At week 80, there was a significant change in the CGI score Agitation 5 of 0.3 (SD 0.7, p = 0.0054). Of the 45 completers, there was improvement in 16 (36%) and worsening of 4 (9%) Fall 4 with the remainder unchanged compared to baseline. Dysphagia 3 In the 45 participants who completed 80 weeks, there was no significant change in total motor score, but there were Dystonia 3 significant declines in cognitive measures, including ver- bal fluency, symbol digit and Stroop (reading, color and Mean total maximal chorea score (± SE) Figure 3 by week Mean total maximal chorea score (± SE) by week Page 6 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 Table 3: Baseline scores and changes from baseline in efficacy outcome measures at weeks 24, 48 and 80 [Mean (SD)]. Measure Baseline Week 24 Week 48 Week 80 N = 75 N = 73 N = 57 N = 45 UHDRS Motor Score 47.9 (15.9) -7.4 (9.8) * -5.6 (12.1) * -0.2 (11.0) Total Chorea 14.9 (3.7) -5.8 (5.0) * -5.6 (5.5) * -4.6 (5.5) * Gait 1.3 (0.6) -0.1 (0.6) 0.0 (0.7) 0.2 (0.7) Parkinsonism 14.5 (5.7) -0.5 (2.7) 0.9 (4.1) 2.1 (4.3) * Barnes Akathisia 0.2 (0.6) 0.1 (1.0) 0.1 (0.9) 0.0 (0.7) Hamilton 4.1 (3.7) -0.0 (3.8) 0.7 (3.4) 0.4 (3.8) Functional Checklist 18.1 (4.7) -0.3 (2.5) -1.1 (2.3) * -2.6 (3.3) * Independence 75.7 (11.5) -2.4 (7.2) * -4.4 (6.0) * -7.0 (8.1) * Behavioral Score (freq*severity) 6.7 (9.7) 3.4 (14.4) * 2.9 (9.3) * 3.5 (14.4) Weight (kg) 72.4 (18.8) -1.2 (4.8) * -1.4 (7.4) -1.7 (6.5) N = 47 N = 45 N = 38 N = 30 Total Functional Capacity 7.6 (2.4) -0.5 (1.5) * -1.1 (1.4) * -2.0 (2.3) * Verbal 17.2 (10.3) -2.0 (5.6) * -2.0 (5.8) * -3.6 (7.9) * Symbol Digit 19.3 (11.2) -0.3 (5.5) -1.9 (4.7) * -4.8 (10.3) * Stroop Color 42.6 (17.3) -4.4 (9.5) * -8.9 (11.4) * -11.0 (14.8) * Stroop Words 49.8 (20.6) -1.2 (9.3) -7.9 (15.4) * -9.0 (17.4) * Stroop Interference 23.2 (11.4) -2.7 (7.1) * -4.5 (7.0) * -5.0 (10.4) * * p < 0.05 (t-test) interference) and functional measures as measured by the ated with HD for up to 12 weeks with the main AEs functional checklist, independence score and TFC (Table including drowsiness and insomnia [9]. In this open label 3). extension study, TBZ continued to effectively suppress chorea for up to 80 weeks in HD. TBZ was generally well Placebo vs. TBZ tolerated, but treatment emergent AEs included sleep dis- When the groups initially randomized to placebo and TBZ turbance, depression, anxiety, and akathisia. Akathisia in were compared, there were no differences in numbers of particular may be difficult to identify due to confusion subjects with AEs, change in TMC score, change in chorea with chorea combined with the lack of insight associated after withdrawal, best dosage, or any of the secondary with HD. During initiation and titration of therapy, measures. There was a reduction in the total number of patients may be more prone to sedation, insomnia and AEs (p < 0.002) and somnolence (p < 0.01) in mainte- gastrointestinal problems but these tend to improve over nance for those subjects initially assigned to TBZ. time. Although clinicians should screen for and treat depression in all patients with HD, those with pre-existing depression may be at higher risk for developing depres- Discussion The double-blind, randomized controlled trial preceding sion while taking TBZ [23,24]. this study demonstrated that TBZ reduced chorea associ- Page 7 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 In this study, there were no completed suicides, but one at week 80, but there was no correlation to support the attempt listed as a serious AE and an additional subject association of global improvement with either motor or who expressed suicidal ideation. Depression was not chorea change. The UHDRS measures of cognition and assessed by formal psychiatric criteria, but depressed function while taking TBZ declined at a rate consistent mood was screened for using the Hamilton Depression with the natural history of HD. The TFC scale declined 1.6 Scale and item 25 of the UHDRS. During the double-blind ± 0.4 points over almost two years in those initially phase of this study, there was a completed suicide in a assigned to TBZ, consistent with previously published subject randomized to the TBZ group, despite scoring measures of TFC [31,32]. Although TBZ is unlikely to within the normal range on the Hamilton Depression accelerate any aspect of decline in HD, it also does not Scale two weeks prior to the event [9]. Clinicians should appear to have any clinical long-term neuroprotective be cautious about the heightened risk of suicide in HD role, despite some evidence of potential neuroprotective regardless of depression indexes or use of monoamine effects demonstrated in animal models of HD [33]. depleters, as overall completed suicide rates are estimated at 7.3% and up to 25% of patients may attempt suicide at The main limitation of this open-label study was the loss some point in the illness [25,26]. In patients already diag- of subjects at each extension phase. The reasons for the nosed with HD, there may be an increased risk of suicide attrition were related to administrative issues and a deci- particularly when patients enter stage 2 of the disease, a sion not to continue rather than any specific AEs. The time when independence diminishes [27]. majority of patients elected to complete 80 weeks on ther- apy, and in fact, once the study concluded, some subjects At the conclusion of this study, the majority of partici- refused to stop taking TBZ and found other sources of the pants were taking either 50 or 75 mg of TBZ. Notably, study medication prior to its availability on the US mar- even after subjects had been on TBZ for over one year, dos- ket. The findings support the clinical impression that cho- age adjustments continued. In two other open-label, long rea suppression in this large cohort of patients can be term studies of TBZ used for a variety of hyperkinetic con- valuable to patients and families. The unblinded nature of ditions including HD, the mean doses after more than two this study limits the degree to which we can make conclu- years were 60.4 and 106.2 mg, respectively [6,7]. sions about effectiveness, but the reduction in chorea was consistent with that seen in the double-blind trial. Further Discontinuation of TBZ after 80 weeks of treatment investigation is needed to determine the effectiveness and appears to be safe and is associated with the return of cho- adverse event profile, particularly regarding cognition, rea, without significant worsening compared to baseline. when TBZ is combined with other commonly used medi- Participants with higher baseline chorea scores experi- cations. enced a greater reduction in chorea. When TBZ was dis- continued, no subject developed signs consistent with Conclusions neuroleptic withdrawal such as nausea, excessive sweat- Chorea, the most striking physical manifestation of HD, ing, tachycardia or akathisia. We did not identify AEs may be disabling and stigmatizing. Frequent or large related to the withdrawal of TBZ, but other studies have amplitude involuntary movements can cause embarrass- specifically examined subjects when TBZ is stopped ment or frustration and physical harm due to direct injury [9,28]. One subject withdrew due to the development of or falls as well as impact quality of life. The impact of sup- "vocal tics". This AE has not been previously reported and pressing chorea on weight, gait, behavior and functioning in fact TBZ has been found to be an effective treatment of deserves further study, as do the indications for suppress- tics [29]. It is possible that the "vocal tic" described was ing chorea in the ambulatory high functioning patient not a TBZ-related AE, but the emergence of tourettism as and the more advanced patient in whom chorea may be a symptom of HD [30]. injurious. In lieu of discovering therapy that modifies the global course of the disease, identifying targeted sympto- Participants did not demonstrate a faster than expected matic treatments for HD, such as those for chorea, is a way rate of motor or functional decline due to HD. Although to palliate some of the more disabling and stigmatizing parkinsonism and dysphagia were increased in subjects at aspects of the disorder. This study confirms efficacy in week 80, this finding was likely a result of the natural pro- long term use and may guide clinicians in dosing and gression of disease. Had the parkinsonism been due to a treatment emergent, long-term adverse effects. pharmacological impact of tetrabenazine, we would have anticipated that the signs would have emerged more Competing interests quickly and found on exams throughout the study. TBZ This study was funded by a grant from Prestwick Pharma- does not appear to have an effect on cognition or function ceuticals, Inc. (subsequently acquired by Biovail Pharma- after two years of therapy. Participants experienced an ceuticals) to the University of Rochester and in turn overall improvement on TBZ as demonstrated by the CGI through subcontracts to the participating research sites. Page 8 of 10 (page number not for citation purposes) BMC Neurology 2009, 9:62 http://www.biomedcentral.com/1471-2377/9/62 versity School of Medicine); Penny Stanton, CCRP; Tetsuo Ashizawa, MD The Huntington Study Group (HSG) is a non-profit con- (University of Texas Medical Branch At Galveston); Jeana Jaglin, RN; Kath- sortium of HD investigators http://www.huntington- leen Shannon, MD (Rush University Medical Center); Mary Matthews, RN; study-group.org/. None of the HSG investigators or staff Amy Colcher, MD (University of Pennsylvania); Mira Guzijan, MA; Michael had equity interests with Prestwick Pharmaceuticals, Inc. Geschwind, MD, PhD (University of California, San Francisco); Lynn Bartos, Dr. Fahn received consulting fees of less than $10,000 RN; Karen Blindauer, MD (Medical College of Wisconsin); Kelly Dustin, from Prestwick Pharmaceuticals. After the study was com- RN; Karen Anderson, MD (University of Maryland School of Medicine); pleted, Dr. Frank received consulting fees of less than Chinekwu Anyanwu, MD; Philip Hanna, MD (New Jersey Neuroscience $10,000 from Ovation Pharmaceuticals. Dr. Marshall pre- Institute). sented data at meetings for which he received travel reim- Coordination Center and Biostatistics: Patricia Lindsay; Shirley bursement from Prestwick Pharmaceuticals, Inc. Dr. Eberly, MS; (University of Rochester School of Medicine and Dentistry). Stamler and Ms. Wilson were employees of Prestwick Pharmaceuticals, Inc. The HSG Coordination and Biosta- Prestwick Pharmaceuticals Inc. Authors: David Stamler, MD; Lucinda tistics Centers at the University of Rochester independ- Wilson. ently compiled and analyzed the data for this study. References Acknowledgements 1. 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