Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

OBJECTIVE: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD). METHOD: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change. RESULTS: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8). CONCLUSIONS: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD. TRIAL REGISTRATION NUMBER: NCT02198794.

The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability.

BACKGROUND: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. OBJECTIVES: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. METHODS: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. CONCLUSION: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS ( http://www.cdisc.org/therapeutic#MS ) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing-remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study.

BACKGROUND: The 1-year placebo-controlled (PC) phase of the Glatiramer Acetate Low-Frequency Administration (GALA) study showed that glatiramer acetate 40 mg/mL three times weekly (GA40) significantly reduced annualized relapse rate (ARR) and magnetic resonance imaging (MRI) activity in patients with relapsing-remitting multiple sclerosis. Patients completing the PC phase were invited to an open-label (OL) extension. OBJECTIVE: To evaluate the effects of early start (ES) and delayed start (DS) of GA40 over 3 years. METHODS: A total of 97.2% of patients completing the PC phase received GA40 in the OL extension. ES ( n = 943) patients received GA40 throughout; DS ( n = 461) patients received placebo during the PC phase and GA40 during the OL phase. Relapse, MRI, disease progression, and safety were evaluated. RESULTS: A total of 1041 patients completed 3 years of follow-up. During the OL phase, ES and DS patients showed comparable ARRs (0.20-0.22) and similar numbers of gadolinium-enhancing T1 ( p = 0.49) and new or enlarging T2 lesions ( p = 0.51) at Year 3. ES patients showed significantly smaller changes in gray matter volume than DS patients from Months 12 to 36 (mean difference, 0.371%; p = 0.015), with similar trend in whole-brain volume ( p = 0.080). Adverse events were mild, consistent with the well-established glatiramer acetate (GA) safety profile. CONCLUSION: GA40 conferred treatment benefit over 3 years: sustained low ARR and lesion activity and favorable safety.

Determining agreement using rater characteristics.

When evaluating the usefulness of clinical information for the diagnosis of disease, multiple raters provide a diagnosis for the same set of data. These ratings provide important insights into the performance of the diagnosis, determining the accuracy of each rater's diagnosis compared to the truth standard and the level of agreement among the raters. We demonstrate that the intraclass correlation coefficient (ICC) is dependent on the sensitivities and specificities of the raters involved in the study. Given the sensitivity and specificity of any number of raters, along with the prevalence of disease, the expected ICC can be determined.

Long-term efficacy and safety of three times weekly dosing regimen of glatiramer acetate in relapsing multiple sclerosis patients: Seven-year results of the Glatiramer Acetate Low-frequency Administration (GALA) open-label extension study.

OBJECTIVE: Describe the long-term outcomes of early-start (ES) and delayed-start (DS) glatiramer acetate 40 mg/mL treatment three times weekly (GA40) for up to seven years in the Glatiramer Acetate Low-frequency Administration (GALA) study in patients with relapsing multiple sclerosis (RMS). METHODS: Patients were evaluated every three to six months. The primary efficacy endpoint was annualized relapse rate (ARR); additional endpoints were exploratory or post hoc. For efficacy, data from the entire exposure period were used for the ES and DS cohorts. For safety, exposure only under GA40 was considered. RESULTS: Of the patients who continued into the open-label extension (OLE), 580/834 (70%) ES and 261/419 (62%) DS completed the OLE. For the entire placebo-controlled and OLE study period, ARR was 0.26 for ES and 0.31 for DS patients (risk ratio = 0.83; 95% confidence interval [CI]: 0.70-0.99). ES prolonged median time to first relapse versus DS (4.9 versus 4.3 years; hazard ratio = 0.82; 95% CI: 0.6-0.96). OLE-only results showed DS patients experienced similar efficacy for relapse and disability outcomes as ES patients. Adverse events were consistent with the well-established GA safety profile. CONCLUSIONS: GA40 treatment conferred clinical benefit up to seven years, resulting in sustained efficacy and was generally well tolerated in RMS patients.

Time course of glatiramer acetate efficacy in patients with RRMS in the GALA study.

OBJECTIVE: To determine the time to efficacy onset of glatiramer acetate (GA) 40 mg/mL 3-times-weekly formulation (GA40). METHODS: This post hoc analysis of data from the 1-year, double-blind, placebo-controlled phase of the Glatiramer Acetate Low-Frequency Administration study (NCT01067521) of GA40 in patients with relapsing-remitting MS (RRMS) sought to determine the timing of efficacy onset using a novel data-censoring approach. RESULTS: Compared with placebo-treated patients, those receiving GA40 exhibited a >30% reduction in the accumulated annualized relapse rate (ARR) within 2 months of initiating treatment and generally sustained this treatment difference during the 1-year study. Similarly, the proportion of GA40-treated patients who remained relapse-free was distinctly greater by month 2 and continued to increase up to a 10.8% difference at the end of the study. In addition, GA40 treatment was associated with a significant reduction in the number of gadolinium-enhancing T1 lesions and new/enlarging T2 lesions by month 6, with full treatment effect observed after 1 year. CONCLUSIONS: GA40 contributes to efficacy within 2 months of the start of treatment in patients with RRMS. These results are consistent with the observed time to efficacy onset for patients treated with GA 20 mg/mL daily in previous randomized, placebo-controlled clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, a 3-times-weekly formulation of GA 40 mg/mL leads to a >30% reduction in the ARR within 2 months.

Comparative utility of disability progression measures in PPMS: Analysis of the PROMiSe data set.

OBJECTIVE: To assess the comparative utility of disability progression measures in primary progressive MS (PPMS) using the PROMiSe trial data set. METHODS: Data for patients randomized to placebo (n = 316) in the PROMiSe trial were included in this analysis. Disability was assessed using change in single (Expanded Disability Status Scale [EDSS], timed 25-foot walk [T25FW], and 9-hole peg test [9HPT]) and composite disability measures (EDSS/T25FW, EDSS/9HPT, and EDSS/T25FW/9HPT). Cumulative and cross-sectional unconfirmed disability progression (UDP) and confirmed disability progression (CDP; sustained for 3 months) rates were assessed at 12 and 24 months. RESULTS: CDP rates defined by a ≥20% increase in T25FW were higher than those defined by EDSS score at 12 and 24 months. CDP rates defined by T25FW or EDSS score were higher than those defined by 9HPT score. The 3-part composite measure was associated with more CDP events (41.4% and 63.9% of patients at 12 and 24 months, respectively) than the 2-part measure (EDSS/T25FW [38.5% and 59.5%, respectively]) and any single measure. Cumulative UDP and CDP rates were higher than cross-sectional rates. CONCLUSIONS: The T25FW or composite measures of disability may be more sensitive to disability progression in patients with PPMS and should be considered as the primary endpoint for future studies of new therapies. CDP may be the preferred measure in classic randomized controlled trials in which cumulative disability progression rates are evaluated; UDP may be feasible for cross-sectional studies.

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses. We aimed to assess the efficacy, safety, and tolerability of fixed doses of deutetrabenazine-a novel vesicular monoamine transporter-2 inhibitor-in patients with tardive dyskinesia. METHODS: We did this double-blind, randomised, placebo-controlled, phase 3 trial at 75 centres in the USA and Europe. Patients aged 18-80 years with tardive dyskinesia (≥3 months before screening) were randomly assigned centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomisation was stratified by baseline use of dopamine receptor antagonists. Patients were started on oral deutetrabenazine 12 mg/day, and this dose was increased through week 4 until the randomised dose was achieved, then maintained over 8 weeks. During the treatment period, patients, investigators, their site personnel, and sponsor were masked to group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to week 12 in patients with at least one post-baseline rating. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at least one post-baseline rating). The safety analysis was done in patients who received any study drug. This trial is registered with ClinicalTrials.gov, number NCT02291861. FINDINGS: Between Oct 29, 2014, and Aug 19, 2016, we randomly assigned 298 patients to receive at least one dose of placebo (n=74), deutetrabenazine 12 mg/day (n=75), 24 mg/day (n=74), or 36 mg/day (n=75); 222 patients comprised the modified intention-to-treat population and 293 patients comprised the safety population. From baseline to week 12, the least-squares mean AIMS score improved by -3·3 points (SE 0·42) in the deutetrabenazine 36 mg/day group, -3·2 points (0·45) in the 24 mg/day group, and -2·1 points (0·42) in the 12 mg/day group, with a treatment difference of -1·9 points (SE 0·58, 95% CI -3·09 to -0·79; p=0·001), -1·8 points (0·60, -3·00 to -0·63; p=0·003), and -0·7 points (0·57, -1·84 to 0·42; p=0·217), respectively, versus -1·4 points (0·41) in the placebo group. The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 [51%]), 24 mg/day group (n=32/73 [44%]), and 12 mg/day group (n=36/74 [49%]), and those in the placebo group (n=34/72 [47%]). Serious adverse events were reported in four (5%) patients given deutetrabenazine 36 mg/day, six (8%) patients given 24 mg/day, and two (3%) patients given 12 mg/day, compared with four (6%) patients given placebo. Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor. INTERPRETATION: Deutetrabenazine 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with favourable safety and tolerability. These findings suggest that dosing regimens could be individualised and tailored for patients on the basis of dyskinesia control and tolerability. FUNDING: Teva Pharmaceutical Industries.

Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study.

OBJECTIVE: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD). METHODS: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change. RESULTS: For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] -3.0 [0.45] vs -1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group. CONCLUSIONS: In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores.

The Effect of Three Times a Week Glatiramer Acetate on Cerebral T1 Hypointense Lesions in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND PURPOSE: Two definitions of T1 hypointense (T1H) lesions can be derived from pre-contrast images: those that may or may not have a corresponding gadolinium-enhancing correlate on post-contrast images (T1H total), and those that are simultaneously non-gadolinium-enhancing on post-contrast scans (T1H non-enhancing). To determine the differences in lesion evolution between these two T1H definitions, we examined the effect of glatiramer acetate 40 mg/mL three times weekly subcutaneous injection (GA40) on the number of new or enlarging T1H total and T1H non-enhancing lesions in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: The Phase III GALA study randomized 1404 RRMS subjects 2:1 to receive GA40 or placebo for 12 months. MRI scans were obtained at baseline and at months 6 and 12. Cumulative numbers of T1H total and of T1H non-enhancing lesions were analyzed using an adjusted negative binomial regression model. A total of 1,357 patients had MRI data collected at either the month 6 or month 12 visit. RESULTS: Among the 1,357 patients with MRI scans performed at either the month 6 or month 12 visit, 883 treated with GA40 developed an adjusted cumulative mean of 1.72 T1H total lesions versus 2.62 in 440 placebo controls (risk ratio, .66; 95% CI, .54-.80; P < .0001). On T1H non-enhanced scans, GA40-treated patients developed an adjusted cumulative mean of 1.35 T1H non-enhancing lesions versus 1.91 in placebo controls (risk ratio, .71; CI, .58-.87; P = .0009). CONCLUSIONS: GA40 significantly reduced the number of new or enlarging T1H total lesions and T1H non-enhancing lesions compared with placebo. Although the treatment effect magnitude was comparable with both definitions, the use of T1H non-enhancing lesions may be more relevant for more uniform standardization in future clinical trials.

Discordance between non-HDL-cholesterol and LDL-particle measurements: results from the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Cardiovascular risk assessment incorporates measurement of atherogenic lipids such as non-HDL cholesterol (non-HDL-C). It remains uncertain under which circumstances atherogenic lipoprotein enumeration such as LDL particle number (LDL-P) differs from simultaneously acquired non-HDL-C. METHODS: Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) were deemed LDL-P > non-HDL-C discordant if they exhibited higher LDL-P than expected for simultaneously measured non-HDL-C, given the observed distribution of both in MESA. Conversely, a lower LDL-P than would be suggested from non-HDL-C characterized LDL-P < non-HDL-C discordance. Regression models were used to estimate associations of demographics and comorbidities with discordance and of LDL-P and non-HDL-C with carotid intima-media thickness (CIMT) and detectable coronary artery calcium (CAC) among discordance groups. RESULTS: Discordance was observed among 44% of subjects. LDL-P > non-HDL-C compared to LDL-P < non-HDL-C discordance was more common among Hispanics and smokers; among subjects with lower HDL-C, lower triglycerides, or greater insulin resistance by homeostatic model assessment of insulin resistance (HOMA-IR); and among subjects on lipid-lowering therapy, anti-hypertensive therapy, or hormone replacement therapy. In the setting of discordance, LDL-P exhibited a modestly greater association with CIMT than did non-HDL-C (+0.024-0.025 mm vs +0.018-0.021 mm per SD increase). In the presence of LDL-P < non-HDL-C discordance, LDL-P demonstrated a modestly greater association with detectable CAC than did non-HDL-C (OR 1.51 vs 1.46 per SD increase). CONCLUSIONS: Our results demonstrated that disagreement between LDL-P and non-HDL-C was common and significantly associated with several clinical characteristics. In the setting of discordance, LDL-P was more closely associated with CIMT and CAC than non-HDL-C, though observed differences were small.

Amyloid deposition detected with florbetapir F 18 ((18)F-AV-45) is related to lower episodic memory performance in clinically normal older individuals.

The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 ((18)F-AV-45) amyloid positron emission tomography, and cognition in healthy older control (HC) subjects. Seventy-eight HC subjects were assessed with a brief cognitive test battery and positron emission tomography (PET) imaging with (18)F-AV-45. A standard uptake value ratio was computed for mean data from 6 cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive or amyloid negative by 3 readers. Higher standard uptake value ratio correlated with lower immediate memory (r = -0.33; p = 0.003) and delayed recall scores (r = -0.25; p = 0.027). Performance on immediate recall was also lower in the visually rated amyloid positive compared with amyloid negative HC (p = 0.04), with a similar trend observed in delayed recall (p = 0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether (18)F-AV-45 may also predict subsequent cognitive decline.

Amyloid-ß assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study.

OBJECTIVES: Florbetapir F 18 PET can image amyloid-ß (Aß) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aß pathology using florbetapir PET in subjects at risk for progressive cognitive decline. METHODS: A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aß+) or negative (Aß-) for pathologic levels of ß-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline. RESULTS: In both MCI and CN, baseline Aß+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating-sum of boxes (CDR-SB) (p < 0.02). In MCI Aß+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aß+ MCI tended to convert to AD dementia at a higher rate than Aß- subjects (p < 0.10). CONCLUSIONS: Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.