Minimal clinically important change in Abnormal Involuntary Movement Scale score in tardive dyskinesia as assessed in pivotal trials of deutetrabenazine.

INTRODUCTION: Deutetrabenazine is approved by the US Food and Drug Administration to treat tardive dyskinesia (TD) based on 2 pivotal, 12-week, placebo-controlled studies (ARM-TD and AIM-TD) evaluating safety and efficacy in patients with baseline total motor Abnormal Involuntary Movement Scale (AIMS) score ≥6. This analysis estimated the minimal clinically important change (MCIC) in total motor AIMS score in TD patients treated with deutetrabenazine. METHODS: The pooled analysis population included all patients in ARM-TD and AIM-TD who received study drug and had ≥1 postbaseline AIMS assessment. MCIC analyses were performed using Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC) as anchors. MCIC was defined as the mean change from baseline in total motor AIMS score in patients treated with deutetrabenazine who were rated minimally improved on PGIC or CGIC at Week 12. RESULTS: This analysis included 295 patients (deutetrabenazine, n = 197; placebo, n = 98). At Week 12, the MCIC in deutetrabenazine-treated patients was -2.4 based on the PGIC and -2.1 based on the CGIC. Mean change from baseline in total motor AIMS score for placebo-treated patients rated minimally improved was -1.4 based on the PGIC and -1.5 based on the CGIC. The proportion of deutetrabenazine-treated patients who achieved improvement in total motor AIMS score by ≥2 and ≥3 points was 66% and 55%, respectively. CONCLUSION: Using anchor-based methodology, the MCIC on the AIMS for deutetrabenazine in patients with TD was approximately -2, suggesting that a reduction in total motor AIMS score of ∼2 is associated with clinically meaningful improvement in TD symptoms.

Periodic limb movements in patients with obstructive sleep apnea syndrome.

The aim of the study was to assess the factors associated with periodic limb movements during sleep (PLMS) among obstructive sleep apnea syndrome (OSAS) patients and identify the role of PLMS in patients with OSAS. 303 adult patients with OSAS were included in the study. All patients completed physical examination, Epworth sleepiness scale (ESS), and polysomnography. Diagnosis of PLMS was made if the periodic leg movements index (PLMI) was ≥ 15. Chi-square test, ANOVA, univariate and multivariate logistic regression analyses were conducted to identify factors associated with PLMS among OSAS patients. Statistical analyses were performed with SPSS 26.0 for mac. Statistically significant difference was considered if P value < 0 .05. Among the 303 adult patients with OSAS, 98 patients had significant PLMS and the other 205 had no significant PLMS. Compared with OSAS patients without PLMS, OSAS patient with PLMS were older, had shorter REM duration and greater apnea-hypopnea index (AHI) (P < 0.05). The study suggests that PLMS is a matter of concern among patients with OSAS. A better understanding of the role of PLMS among OSAS patients could be useful in better recognition, intervention and treatment of OSAS.

Correlates of the Abnormal Involuntary Movement Scale in Veterans With Tardive Dyskinesia.

PURPOSE/BACKGROUND: To add to limited evidence on the Abnormal Involuntary Movement Scale (AIMS) as a measure of tardive dyskinesia (TD) in clinical practice settings, the characteristics and correlates of AIMS scores were assessed. METHODS/PROCEDURES: Veterans with schizophrenia/schizoaffective, bipolar, or major depressive disorders receiving antipsychotics and at least 1 AIMS score during October 1, 2014, to September 30, 2015, were identified. Tardive dyskinesia was determined by the International Classification of Diseases, Ninth Revision, Clinical Modification, codes. Correlates of AIMS scores were examined using χ or t tests. Odds ratios and ß parameters with 95% confidence intervals for categorical and continuous variables associated with AIMS scores were derived from a multivariate logistic and linear regression, respectively. FINDINGS/RESULTS: Among 7985 veterans receiving antipsychotics, only 4706 (58.9%) had at least 1 AIMS examination. Of these, 229 (4.9%) were diagnosed with possible TD. The mean total AIMS scores and AIMS awareness/incapacitation scores were significantly higher for patients with TD (both P < 0.0001). Comparing diagnostic threshold criteria of AIMS ratings, only 17.5% to 37.1% of veterans with TD were successfully identified. Among TD patients, 21.4% had a total score of moderate-severe and 15.3% had ratings of at least mild movements in 2 or more body regions. In the regression analyses, being older, African-American, having schizophrenia/schizoaffective disorder, and receiving antipsychotics or benztropine significantly increased the severity of AIMS scores. Higher AIMS scores were not predictive of outcomes other than marital status in socioeconomic or healthcare domains. IMPLICATIONS/CONCLUSIONS: Although the AIMS is essential for TD research, its value in clinical practice without training and oversight remains unclear. Efforts to adapt screening procedures to clinical needs may be worthwhile.

Spontaneous movements in the first four months of life: An accelerometric study in moderate and late preterm infants.

BACKGROUND: Moderate preterm infants (MPI) and late preterm infants (LPI) account for the majority of children born preterm. Up to 5% of MPI and LPI are estimated to manifest neurodevelopmental impairments. However, information about normal early motor development in these patients is lacking. AIM: To find characteristic patterns for motor development in the first four months of life among MPI and LPI without risk factors for developmental impairment by using accelerometry of spontaneous movements. STUDY DESIGN: Prospective and observational study. SUBJECTS: Twenty-three MPI and LPI (9 female, 14 male) without known risk factors for neurodevelopmental impairment were included in this study. Spontaneous movements were measured by accelerometry at the time of hospital discharge (mean: 36.6wks postmenstrual age (PMA)) and at the corrected age of three months (mean: 53.0wks PMA). OUTCOME MEASURES: Motor development was described by analyzing 36 parameters calculated from the acceleration signal. Normal neurodevelopmental outcome was confirmed by Bayley Scales of Infant Development at the corrected age of two years. RESULTS: Statistically significant differences (p < 0.05) between the two measurements could be shown in 26 out of the 36 parameters. Striking changes in motor development were an increase in acceleration and variability of the spontaneous movements, the main criterion for analyzing spontaneous movements. Furthermore, the regularity of spontaneous movements increased significantly. CONCLUSION: Characteristic patterns of normal motor development in MPI and LPI can be identified and provide a basis for future investigations aiming at the early detection of abnormal motor development for this specific patient group.

Revisiting the Abnormal Involuntary Movement Scale: Proceedings From the Tardive Dyskinesia Assessment Workshop.

OBJECTIVE: To provide an historic overview of the Abnormal Involuntary Movement Scale (AIMS) in clinical trials of tardive dyskinesia (TD), with current recommendations for analyzing and interpreting AIMS data. PARTICIPANTS: Seven psychiatrists and 1 neurologist were selected by the workshop sponsor based on each individual's clinical expertise and research experience. EVIDENCE: Using PubMed entries from January 1970 to August 2017, participants selected studies that used the AIMS to evaluate TD treatments. The selections were intended to be representative rather than prescriptive or exhaustive, and no specific recommendations for TD treatment are implied. CONSENSUS PROCESS: The Working Group met in October 2016 to discuss the AIMS as an assessment tool, outline the challenges of translating clinical trial results into everyday clinical practice, and propose different methods for reporting AIMS data in clinically relevant terms. Recommendations for selecting TD studies for review, analyzing and interpreting AIMS data, and synthesizing discussions among the participants were initiated during the onsite workshop and continued remotely throughout development of this report. Disagreements were resolved via group e-mails and teleconferences. Consensus was based on final approval of this report by all workshop participants. CONCLUSIONS: For both research and clinical practice, the AIMS is a valid measure for assessing TD and the effects of treatment, but alternative analyses of AIMS data (eg, effect size, minimal clinically important difference, response analyses, category shifts) may provide broader evidence of clinical effectiveness. No single analysis of AIMS data can be considered the standard of clinical efficacy; multiple analytic approaches are recommended.

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.

KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia.

OBJECTIVE: Tardive dyskinesia is a persistent movement disorder induced by dopamine receptor blockers, including antipsychotics. Valbenazine (NBI-98854) is a novel, highly selective vesicular monoamine transporter 2 inhibitor that demonstrated favorable efficacy and tolerability in the treatment of tardive dyskinesia in phase 2 studies. This phase 3 study further evaluated the efficacy, safety, and tolerability of valbenazine as a treatment for tardive dyskinesia. METHOD: This 6-week, randomized, double-blind, placebo-controlled trial included patients with schizophrenia, schizoaffective disorder, or a mood disorder who had moderate or severe tardive dyskinesia. Participants were randomly assigned in a 1:1:1 ratio to once-daily placebo, valbenazine at 40 mg/day, or valbenazine at 80 mg/day. The primary efficacy endpoint was change from baseline to week 6 in the 80 mg/day group compared with the placebo group on the Abnormal Involuntary Movement Scale (AIMS) dyskinesia score (items 1-7), as assessed by blinded central AIMS video raters. Safety assessments included adverse event monitoring, laboratory tests, ECG, and psychiatric measures. RESULTS: The intent-to-treat population included 225 participants, of whom 205 completed the study. Approximately 65% of participants had schizophrenia or schizoaffective disorder, and 85.5% were receiving concomitant antipsychotics. Least squares mean change from baseline to week 6 in AIMS dyskinesia score was -3.2 for the 80 mg/day group, compared with -0.1 for the placebo group, a significant difference. AIMS dyskinesia score was also reduced in the 40 mg/day group (-1.9 compared with -0.1). The incidence of adverse events was consistent with previous studies. CONCLUSIONS: Once-daily valbenazine significantly improved tardive dyskinesia in participants with underlying schizophrenia, schizoaffective disorder, or mood disorder. Valbenazine was generally well tolerated, and psychiatric status remained stable. Longer trials are necessary to understand the long-term effects of valbenazine in patients with tardive dyskinesia.