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26 Correlates of Neuropsychological Decline Following Deep Brain Stimulation in Patients with Parkinson's Disease
- Sofia Magee, Christine G. St Clair, Joohi Jimenez-Shahed, Christina A. Palmese
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 542-543
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Objective:
Deep Brain Stimulation (DBS) is an FDA-approved treatment for Parkinson's Disease (PD), for which the medical workup includes routine pre- and post- operative neuropsychological assessment to determine potential surgical cognitive risk. Existing research suggests that cognitively normal individuals experience good cognitive outcome, whereas those with pre-existing cognitive deficits are prone to accelerated cognitive decline post-DBS. The goal of this study is to identify characteristics that determine which individuals with PD are at risk for accelerated post-DBS cognitive loss, and to characterize the nature of the decline in this population.
Participants and Methods:We conducted a retrospective chart review of PD- DBS patients who completed their DBS workup and surgery at Mount Sinai Hospital NYC between 2015 and 2022. Non-English speakers were excluded from this study due to small sample size and use of a neurocognitive battery different from that of English speakers. Using repeated measures t-tests, chi square, and regression analyses, we explored variables related to disease (e.g., duration, L-Dopa burden, DBS target), socio-demographic background (e.g., age onset, current age, education), assessment modality (telehealth vs in-office), neurocognitive performances (e.g., WMS-IV Logical Memory (LM), HVLT-R, WASI-II Matrix & Similarities, WAIS-IV Digit Span), and cognitive diagnosis (amnestic vs non-amnestic MCI) for all individuals in the sample. At the individual level, we utilized Reliable Change Indices (RCI) to identify clinically significant cognitive differences from pre- to post-DBS exam. We considered LM- Delayed Recall (LMDR) as a proxy for memory loss, as this cognitive function is expected to remain generally unchanged post PD-DBS. Therefore, decline on this measure in the first year after DBS could indicate a change in global memory function and possible evidence of accelerated postoperative decline.
Results:Of 65 charts reviewed, 44 patients were native English-speaking and included in our analyses. At the group level, there were no significant differences in disease characteristics, socio-demographic variables, or cognitive classification between those who declined versus those who did not decline on LMDR. Regression statistics for predictors of cognitive decline also were non-significant. Of the eight individuals who declined on LMDR, one patient declined on a total of one neuropsychological measure, four declined on a total of two measures, two declined on a total of three measures, and one declined on a total of four measures. Two of these eight individuals had a diagnosis that changed to amnestic MCI based on concomitant interval history of ADL compromise. Of these two individuals, one declined in two tests and the other declined in four tests. Six of the eight individuals who declined also showed abnormalities in their imaging with either edema or hemorrhage.
Conclusions:Our analysis is unique in that we explored cognitive decline at both the group and individual levels. Despite this, we did not find predictors of post-DBS cognitive decline. Further detailed analysis of additional post-operative factors that might play a greater role in our understanding of this phenomenon is warranted. This said, our data do support that the majority of individuals with non-amnestic MCI did not decline cognitively.
Chapter 14 - Managing Deep Brain Stimulation Patients with Tourette Syndrome and Other Emerging Applications
- Edited by William J. Marks, Stanford University, California, Jill L. Ostrem, University of California, San Francisco
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- Book:
- Deep Brain Stimulation Management
- Published online:
- 09 June 2022
- Print publication:
- 30 June 2022, pp 215-228
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Summary
The management of deep brain stimulation (DBS) patients after surgery is an iterative process that entails stimulator adjustment, observation, and medication adjustment (where relevant) until the DBS settings are optimized and the desired clinical effect is achieved. Although such procedures and outcomes are better defined in the treatment of patients with more common indications such as Parkinson’s disease or obsessive-compulsive disorder, they are less clear when considering the postoperative management of individuals with less well-studied conditions.
Effects of Long-Term Deutetrabenazine Treatment in Patients with Tardive Dyskinesia and Underlying Psychiatric or Mood Disorders
- Robert A. Hauser, Hadas Barkay, Hubert H. Fernandez, Stewart A. Factor, Joohi Jimenez-Shahed, Nicholas Gross, Leslie Marinelli, Amanda Wilhelm, Mark Forrest Gordon, Juha-Matti Savola, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 27 / Issue 2 / April 2022
- Published online by Cambridge University Press:
- 28 April 2022, pp. 245-246
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Introduction
Deutetrabenazine is FDA-approved for the treatment of tardive dyskinesia (TD) in adults. In two 12-week pivotal trials (ARM-TD/AIM-TD), deutetrabenazine significantly improved Abnormal Involuntary Movement Scale (AIMS) scores and was well-tolerated. This post hoc analysis examined the efficacy and safety of long-term deutetrabenazine treatment in TD patients with comorbid psychiatric illness, including schizophrenia/schizoaffective disorder and mood disorders (bipolar/depression/other).
MethodsPatients who completed ARM-TD or AIM-TD enrolled in the 3-year, open-label extension (OLE) study. Deutetrabenazine was titrated based on dyskinesia control and tolerability. Change from baseline in total motor AIMS score, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and adverse events (AEs) were analyzed in subgroups by comorbid psychiatric illness.
ResultsA total of 337 patients in the OLE study were included in the analysis: 205 patients with schizophrenia/schizoaffective disorder (mean age, 55 years; 50% male; 6.4 years since diagnosis; 92% taking DRA) and 131 patients with mood disorders (mean age, 60 years; 35% male; 4.6 years since diagnosis; 50% taking DRA). At week 145, mean ± SE dose was 40.4 ± 1.1 mg/day for schizophrenia/schizoaffective disorder (n = 88) and 38.5 ± 1.2 mg/day for mood disorders (n = 72). Mean ± SE change from baseline in AIMS score at week 145 was −6.3 ± 0.49 and −7.1 ± 0.58, 56% and 72% achieved PGIC treatment success, and 66% and 82% achieved CGIC treatment success in schizophrenia/schizoaffective disorder and mood disorder patients, respectively. Overall AE incidence (exposure-adjusted incidence rates [incidence/patient-years]) was low: any, 1.02 and 1.71; serious, 0.10 and 0.12; leading to discontinuation, 0.07 and 0.05).
ConclusionLong-term deutetrabenazine treatment provided clinically meaningful improvements in TD-related movements, with a favorable safety profile, regardless of underlying comorbid psychiatric illness.
FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Long-Term Efficacy and Safety of Deutetrabenazine in Patients with Tardive Dyskinesia by Concomitant Dopamine-Receptor Antagonist Use
- Robert A. Hauser, Hadas Barkay, Hubert H. Fernandez, Stewart A. Factor, Joohi Jimenez-Shahed, Nicholas Gross, Leslie Marinelli, Amanda Wilhelm, Mark Forrest Gordon, Juha-Matti Savola, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 27 / Issue 2 / April 2022
- Published online by Cambridge University Press:
- 28 April 2022, p. 246
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Introduction
Tardive dyskinesia (TD) is an involuntary movement disorder that can result from exposure to dopamine-receptor antagonists (DRAs). Deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores in the 12-week pivotal trials (ARM-TD/AIM-TD). This post hoc analysis assessed the long-term efficacy and safety of deutetrabenazine by baseline DRA use.
MethodsPatients who completed ARM-TD or AIM-TD enrolled in the 3-year, open-label extension (OLE) study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in total motor AIMS score, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and adverse event (AE) rates were analyzed in subgroups by baseline DRA use.
ResultsOf 337 patients in the OLE study, 254 were taking DRAs at baseline (mean age, 56 years; 48% male; 6.0 years since diagnosis) and 83 were not (mean age, 60 years; 31% male; 4.9 years since diagnosis). Mean ± SE dose at week 145 was 39.9 ± 1.0 mg/day in patients taking DRAs (n = 108) and 38.5 ± 1.5 mg/day in patients not taking DRAs (n = 53). At week 145, mean ± SE change from baseline in AIMS score was −6.1 ± 0.43 and −7.5 ± 0.71; 64% and 62% achieved PGIC treatment success; and 69% and 81% achieved CGIC treatment success, respectively. Overall AE incidence was low (exposure-adjusted incidence rates [incidence/patient-years]: any, 1.08 and 1.97; serious, 0.10 and 0.12; leading to discontinuation, 0.06 and 0.05).
ConclusionThis analysis suggests that deutetrabenazine for long-term treatment of TD is beneficial, with a favorable safety profile, regardless of concomitant DRA use.
FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Effect of Deutetrabenazine on Metabolic Parameters in the Treatment of Tardive Dyskinesia
- Joohi Jimenez-Shahed, Hadas Barkay, Karen E. Anderson, Hubert H. Fernandez, Stewart A. Factor, Robert A. Hauser, Maria Wieman, Mark Forrest Gordon, Juha-Matti Savola
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, pp. 159-160
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Background
Deutetrabenazine, a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. Dopamine-receptor antagonists (DRAs) are associated with worsening of metabolic parameters, including weight gain, hyperlipidemia, and elevated blood glucose. This post hoc analysis assessed the short- and long-term effects of deutetrabenazine treatment on weight and metabolic parameters in individuals treated for TD.
MethodsTwo 12-week, randomized placebo-controlled trials (RCTs) of deutetrabenazine for patients with TD evaluated either fixed dosing (AIM-TD; 12, 24, or 36 mg) or dose titration (ARM-TD; max dose, 48 mg/day). Patients completing ARM-TD or AIM-TD were included in an open-label extension (OLE) study, in which all patients underwent response-driven titration of deutetrabenazine from 12 mg/day up to a maximum total dose of 48 mg/day. Weight, body mass index (BMI), serum glucose, serum total cholesterol, and serum triglycerides were evaluated at baseline and during treatment in the RCTs and in the OLE.
ResultsIn the RCTs, 282 and 133 patients received deutetrabenazine or placebo. At baseline, 77% of patients used DRAs. At Week 12, no meaningful changes in weight were observed, with mean (standard error) weight changes of 0.9–1.2 (0.3–0.5) and 0.2 (0.3) kg in the deutetrabenazine and placebo groups, respectively, and mean BMI changes of 0.3–0.5 (0.1–0.2) and 0.1 (0.1) kg/m2. 337 patients were included in the analysis of the OLE study. No meaningful changes were observed in weight (mean change: 0.4 [0.4] kg at Week 54, –0.5 [0.6] kg at Week 106, and –1.1 [0.6] kg at Week 145) or BMI (mean change: 0.1 [0.2] kg/m2 at Week 54, –0.2 [0.2] kg/m2 at Week 106, and –0.3 [0.2] kg/m2 at Week 145). Across the studies, no meaningful changes were observed in triglyceride, cholesterol, or glucose levels.
ConclusionDeutetrabenazine does not affect common metabolic parameters in patients with TD, even during long-term exposure.
FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Long-Term Deutetrabenazine Treatment Is Associated With Continued Improvement in Tardive Dyskinesia in the Completed 3-Year Open-Label Extension Study
- Robert A. Hauser, Hadas Barkay, Hubert H. Fernandez, Stewart A. Factor, Joohi Jimenez-Shahed, Nicholas Gross, Leslie Marinelli, Amanda Wilhelm, Mark Forrest Gordon, Juha-Matti Savola, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, p. 162
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Background
The 12-week ARM-TD and AIM-TD studies in tardive dyskinesia (TD) patients showed statistically significant improvements in TD symptoms with deutetrabenazine. The completed open-label extension (OLE) study (SD-809-C−20) evaluated long-term efficacy and safety of deutetrabenazine in TD.
MethodsPatients who completed ARM-TD or AIM-TD enrolled in the OLE study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in Abnormal Involuntary Movement Scale (AIMS) score was assessed by local site raters. Treatment success was evaluated locally as patients being “much improved” or “very much improved” on Clinical Global Impression of Change (CGIC).
Results343 patients enrolled in the OLE study; 6 patients were excluded from analyses. At Week 54 (n=249; dose [mean±SE]: 38.7±0.66mg/day), mean change from baseline in AIMS score was –4.8±0.28; 66% of patients experienced treatment success. At Week 106 (n=194; dose: 39.3±0.75mg/day), mean change from baseline in AIMS score was –5.4±0.33; 65% of patients experienced treatment success. At Week 145 (n=160; dose: 39.4±0.83mg/day), mean change from baseline in AIMS score was –6.6±0.37; 73% of patients experienced treatment success. Treatment was generally well tolerated across 723 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) for akathisia/restlessness were 0.01, somnolence/sedation were 0.07, and symptoms which may represent parkinsonism or depression were 0.08 each.
ConclusionsPatients who received long-term treatment with deutetrabenazine achieved sustained improvement in AIMS scores. Findings from this open-label trial with response-driven dosing suggest the possibility of increasing benefit over time.
FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel
151 Confirmed Safety of Deutet.rabenazine for Tardive Dyskinesia in a 3-Year Open-Label Extension Study
- Hubert H. Fernandez, Hadas Barkay, Robert A. Hauser, Stewart A. Factor, Joohi Jimenez-Shahed, Nicholas Gross, Leslie Marinelli, Mark Forrest Gordon, Juha-Matti Savola, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 296-297
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Background:
Deutetrabenazine (Austedo) is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The objective of this study was to evaluate the long-term safety and tolerability of deutetrabenazine in patients with TD at 3 years.
METHODS:Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used for calculating AE frequencies. This analysis reports results up to Week 158.
RESULTS:A total of 343 patients were enrolled (111 received placebo and 232 received deutetrabenazine in the parent studies). At the time of this analysis, 183 patients were still receiving treatment; 259 completed 1 year, 172 completed 2 years, and 41 completed 3 years. There were 623 patient-years of exposure. More than 40% of patients reached the maximum dose. EAIRs of AEs were comparable to or lower than those observed in the ARM-TD and AIM-TD short-term randomized trials of deutetrabenazine vs. placebo. The frequency of SAEs (EAIR 0.10) was similar to that observed with short-term placebo (0.33) and short-term deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.06), dose reduction (0.10), and dose suspension (0.05) were uncommon.
CONCLUSION:These results support the safety outcomes observed in the ARM-TD and AIM-TD parent studies and the safety of deutetrabenazine for long-term use in patients with TD.
Funding Acknowledgements: This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel
134 Long-Term Deutetrabenazine Treatment Is Associated with Sustained Treatment Response in Tardive Dyskinesia: Results from an Open-Label Extension Study
- Robert A. Hauser, Hadas Barkay, Hubert H. Fernandez, Stewart A. Factor, Joohi Jimenez-Shahed, Nicholas Gross, Leslie Marinelli, Mark Forrest Gordon, Juha-Matti Savola, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 284-285
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Background:
In the 12-week ARM-TD and AIM-TD studies evaluating deutetrabenazine for the treatment of tardive dyskinesia (TD), the percentage of patients achieving ≥50% response was higher in the deutetrabenazine-treated group than in the placebo group. These studies also showed low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The current open-label study evaluated the long-term efficacy and safety of deutetrabenazine in patients with TD.
Methods:Patients with TD who completed ARM-TD or AIM-TD could enroll in this open-label, single-arm extension study, titrating up over 6 weeks to a maximum total daily dose of deutetrabenazine 48 mg/day on the basis of dyskinesia control and tolerability. The proportion of Abnormal Involuntary Movement Scale (AIMS; items 1-7) responders was assessed based on response rates for achieving ≥50% improvement from baseline in the open-label extension study. AlMS score was assessed by local site raters for this analysis.
Results:343 patients enrolled in the extension study. At Week 54 (n=249; total daily dose [mean ± standard error]: 38.6±0.66 mg), the mean percentage change from baseline in AIMS score was –40%; 48% of patients achieved a ≥50% response and 59% of those had already achieved a ≥50% response at Week 15. Further, 34% of those who had not achieved a ≥50% response at Week 15 achieved a ≥50% response at Week 54. At Week 106 (n=169; total daily dose: 39.6±0.77 mg), the mean percentage change from baseline in AIMS score was –45%; 55% of patients achieved a ≥50% response, 59% of those patients had already achieved a ≥50% response at Week 15, and 41% of those who had not achieved a ≥50% response at Week 15 but who reached Week 106 achieved a ≥50% response. At Week 132 (n=109; total daily dose: 39.7±0.97 mg), the mean percentage change from baseline in AIMS score was –61%; 55% of patients achieved a ≥50% response, 61% of those patients had already achieved a ≥50% response at Week 15, and 43% of those who had not achieved a ≥50% response at Week 15 but who reached Week 132 achieved a ≥50% response. Completer analysis suggests that long-term efficacy was not due to dose increases over time. Treatment with deutetrabenazine was generally well tolerated. There were 623 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) of adverse events of special interest were 0.01 for akathisia and restlessness, 0.07 for somnolence and sedation, 0.04 for parkinsonism, and 0.05 for depression.
Conclusions:Patients who received long-term treatment with deutetrabenazine achieved response rates that were indicative of clinically meaningful long-term benefit. Results from this open-label trial suggest the possibility of increasing benefit over time with individual dose titration of deutetrabenazine.
Funding Acknowledgements:This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.
34 Long-Term Deutetrabenazine Treatment Response in Tardive Dyskinesia by Concomitant Dopamine-Receptor Antagonists and Baseline Comorbidities
- Karen E. Anderson, David Stamler, Mat D. Davis, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, Joseph McEvoy, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 193
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Background
Tardive dyskinesia (TD) results from exposure to dopamine-receptor antagonists (DRAs), such as typical and atypical antipsychotics. Clinicians commonly manage TD by reducing the dose of or stopping the causative agent; however, this may cause psychiatric relapse and worsen quality of life. In the 12-week ARM-TD and AIM-TD trials, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores versus placebo and was generally well tolerated, regardless of baseline DRA use or comorbidities.
Study ObjectiveTo evaluate the impact of underlying disease and current DRA use on efficacy and safety of long-term therapy of deutetrabenazine in patients with TD.
MethodPatients with TD who completed ARM-TD or AIM-TD were eligible to enter this open-label, single-arm, long-term extension after completing the 1-week washout period and final evaluation in the blinded portion of the trial. Change in AIMS scores from baseline to Week 54 and patients “Much Improved” or “Very Much Improved” (treatment success) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) at Week 54 were analyzed by baseline psychiatric illness type, including mood disorders (bipolar disorder/depression/other) or psychotic disorders (schizophrenia/schizoaffective disorder), and presence or absence of current DRA use.
ResultsAt Week 54, meaningful improvements from baseline in mean (standard error) AIMS scores were observed for patients with baseline mood disorders (–5.2[0.93]) and psychotic disorders (–5.0[0.63]), and in patients currently using DRAs (–4.6[0.54]) or not using DRAs (–6.4[1.27]). Most patients with mood disorders (73%) and psychotic disorders (71%) were “Much Improved” or “Very Much Improved” on CGIC at Week 54, similar to patients currently using (71%) or not using (74%) DRAs. The majority of patients with mood disorders (62%) and psychotic disorders (57%), as well as patients currently using (58%) or not using (63%) DRAs, were also “Much Improved” or “Very Much Improved” on PGIC at Week 54. Prior treatment in ARM-TD and AIM-TD did not impact the long-term treatment response. Underlying psychiatric disorder and concomitant DRA use did not impact the occurrence of adverse events (AEs). The frequencies of dose reductions, dose suspensions, and withdrawals due to AEs were low, regardless of baseline psychiatric comorbidities and DRAuse.
ConclusionsLong-term deutetrabenazine treatment demonstrated meaningful improvements in abnormal movements in TD patients, which were recognized by clinicians and patients, regardless of underlying psychiatric illness or DRAuse.
Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
45 Long-term Treatment with Deutetrabenazine Is Associated with Continued Improvement in Tardive Dyskinesia: Results from an Open-label Extension Study
- Robert A. Hauser, Hubert H. Fernandez, David Stamler, Mat D. Davis, Stewart A. Factor, Joohi Jimenez-Shahed, William G. Ondo, L. Fredrik Jarskog, Scott W. Woods, Mark S. LeDoux, David R. Shprecher, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 200-201
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Study Objective
To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.
BackgroundIn the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.
MethodPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.
Results343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.
ConclusionsPatients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
46 Confirmed Safety of Deutetrabenazine for Tardive Dyskinesia in a 2-Year Open-label Extension Study
- Hubert H. Fernandez, David Stamler, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, Joohi Jimenez-Shahed, William G. Ondo, L. Fredrik Jarskog, Scott W. Woods, Mark S. LeDoux, David R. Shprecher, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 201
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Study Objective
To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
BackgroundIn the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.
MethodPatients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).
Results343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.
ConclusionsThese results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel
35 Long-term Improvements in Site-Rated Outcomes with Deutetrabenazine Treatment in Patients with Tardive Dyskinesia
- Karen E. Anderson, David Stamler, Mat D. Davis, Nicholas Gross, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, Joseph McEvoy, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 193-194
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Background
Tardive dyskinesia (TD) is an often-irreversible movement disorder that may intensify the stigma of patients with psychiatric disorders and worsen quality of life. In two randomized, double-blind, placebo (PBO)-controlled, 12-week trials, ARM-TD and AIM-TD (‘parent studies’), deutetrabenazine (DTB) demonstrated statistically significant improvements in centrally read Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with PBO and was generally well tolerated.
Study ObjectiveTo evaluate the long-term efficacy of DTB in an open-label safety study following double-blind treatment using site-rated efficacy measures: AIMS, the Clinical Global Impression of Change (CGIC) and the Patient Global Impression of Change (PGIC), which may be used in real-world clinical practice settings.
MethodPatients with TD who completed the parent studies were eligible to enter this open-label, long-term extension (OLE) after completing the 1-week washout period and final evaluation in the blinded portion of the trial. This extension comprised a 6-week titration period followed by a long-term maintenance phase. Patients began DTB at 12mg/day, titrating up to a maximum total dose of 48mg/day based on dyskinesia control and tolerability. Efficacy endpoints included in this analysis are the change in site-rated AIMS score (items 1–7) from parent study baseline, and the proportion of patients who were “Much Improved” or “Very Much Improved” (treatment success) on the CGIC and PGIC from OLE baseline.
ResultsAt the end of the parent studies (Week 12), patients treated with DTB had experienced greater mean (standard error) improvements in site-rated AIMS score (–5.0[0.40]) than patients given PBO (–3.2[0.47]). With long-term DTB treatment, both groups experienced improvements in site-rated AIMS scores (prior DTB, –7.9[0.62]; prior placebo, –6.6[0.64]) compared with parent study baseline. Similarly, at the end of the parent studies, a greater proportion of patients treated with DTB had treatment success on the CGIC (DTB, 51%; PBO, 32%) and the PGIC (DTB, 46%; PBO: 33%); whereas at Week 54 of the OLE study, treatment success on CGIC and PGIC were similar in both the CGIC (prior DTB: 66%; prior PBO: 68%) and PGIC (prior DTB: 62%; prior PBO: 62%) groups. DTB was generally well tolerated.
ConclusionsPatients treated with DTB showed improvements in abnormal movements, as measured by site-rated AIMS, CGIC, and PGIC scores, which may be used in real-world clinical practice settings. These results corroborate the previously reported efficacy of DTB as observed in the 12-week, double-blind ARM-TD and AIM-TD trials, in which central raters were used to evaluate AIMS scores.
Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
158 Long-Term Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia: Results From an Open-Label, Long-Term Study
- Karen E. Anderson, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, William G. Ondo, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, p. 97
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Introduction
In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.
ObjectiveTo evaluate the long-term safety/tolerability and efficacy of deutetrabenazine in patients with TD. Week 54 open-labelresults are reported in this interim analysis.
MethodsPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safetymeasures included incidence of adverse events (AEs), serious AEs (SAEs), drug-related AEs, and AEs leading to withdrawal, dose reduction, or dose suspension. This analysis reports results up to Week 54.
Results304 patients enrolled in the extension study. There were 215 patient-years of exposure in this analysis, and exposure-adjusted incidence rates (EAIRs) of AEs (incidence/patient-years) were comparable to or lower than those observed with short-term deutetrabenazine treatment and placebo. The frequency of SAEs (EAIR 0.14) was similar to rates observed with short-termplacebo (EAIR 0.33) and deutetrabenazine (EAIR range 0.06–0.33) treatment. AEs leading to study discontinuation (EAIR 0.08), dose reduction (EAIR 0.17), and dose suspension (EAIR 0.09) were uncommon.
ConclusionsLong-term treatment with deutetrabenazine was generally safe and well tolerated in patients with TD, and did not result in cumulative toxicity.
Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.
Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
149 Deutetrabenazine for the Treatment of Tardive Dyskinesia: Results From an Open-Label, Long-Term Study
- Karen E. Anderson, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, FRCPC, Stanislaw Ochudlo, William G. Ondo, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, pp. 92-93
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Introduction
Tardive dyskinesia (TD) is an involuntary movement disorder resulting from exposure to dopamine-receptor antagonists. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.
ObjectiveTo evaluate the efficacy and safety of long-term deutetrabenazine therapy in patients with TD.
MethodsPatients with TD who completed the ARM-TD or AIM-TD studies were eligible to enter this open-label, single-arm, long-term safety study after they completed the 1-week washout period and final evaluation in the blinded portion of the trial. Efficacy endpoints included the change in AIMS score from baseline, and treatment success (defined as “much improved” or “very much improved”) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC). This analysis reports results up to Week 54.
Results304 patients enrolled in the extension study. At Week 54, the mean (standard error) change in AIMS score was –5.1 (0.52). After 6 weeks of deutetrabenazine treatment, the proportion of patients who achieved treatment success was 58% per the CGIC and 53% per the PGIC, and by Week 54 was 72% per the CGIC and 59% per the PGIC, thus demonstrating maintenance or enhancement of benefit over time. Deutetrabenazine was well tolerated for up to 54 weeks, and compared with the ARM-TD and AIM-TD studies, no new safety signals were detected.
Conclusions54 weeks of deutetrabenazine treatment was generally efficacious, safe, and well tolerated in patients with TD.
Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.
Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
134 Improvements in Clinical Global Impression of Change With Deutetrabenazine Treatment in Tardive Dyskinesia From the ARM-TD and AIM-TD Studies
- Hubert H. Fernandez, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, William G. Ondo, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, p. 84
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Introduction
Tardive dyskinesia (TD) is an involuntary movement disorder that is often irreversible, can affect any body region, and can be debilitating. In the ARM-TDand AIM-TD studies, deutetrabenazine treatment demonstrated statistically and clinically significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo (primary endpoint).
ObjectiveTo evaluate the efficacy of deutetrabenazine, as measured by the Clinical Global Impression of Change (CGIC) scale, in patients with TD from the pooled ARM-TDand AIM-TD (24 and 36 mg/day doses) data sets, as compared with the pooled placebo cohort.
MethodsARM-TD and AIM-TD were 12-week, randomized, double-blind, placebo-controlled studies that evaluated the safety and efficacy of deutetrabenazine for thetreatment of TD. The key secondary endpoint of each study was the proportion of patients “much improved” or “very much improved” (treatment success) at Week 12 on theCGIC.
ResultsAt Week 12, the odds of treatment success among patients treated with deutetrabenazine (n=152) was more than double that of patients given placebo (n=107; odds ratio: 2.12; P=0.005). In a categorical analysis of CGIC ratings, patients treated with deutetrabenazine showed greater improvement than patients given placebo (P=0.003). Patients treated with deutetrabenazine also had a significantly better treatment response than those given placebo (least-squares mean CGIC score treatment difference: –0.4; P=0.006).
ConclusionsDeutetrabenazine treatment led to statistically and clinically significant improvements in TD symptoms based on the CGIC result, suggesting that clinicians were able to recognize the benefit in patients treated with deutetrabenazine.
Presented at: The International Congress of Parkinson’s Disease and Movement Disorders; June 4–8, 2017; Vancouver, British Columbia, Canada.
Funding AcknowledgementsThese studies were funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.