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The Arizona Twin Project is an ongoing longitudinal study designed to elucidate gene–environment interplay underlying the development of risk and resilience to common mental and physical health problems during infancy, childhood and adolescence. Specificity of risk is carefully examined across mental and physical health and how these influences vary across socioeconomic and sociocultural environments. Participants are a sample of approximately 700 twins (31% Latinx) recruited from birth records in the state of Arizona, USA. Twins are 32% monozygotic twins, 36% same-sex dizygotic (DZ), 32% opposite-sex DZ, currently 10–11 years of age. Primary caregivers were interviewed on twins’ development and early physical and social environments when twins were 1, 2 and 5 years of age. In-depth objective measurement commenced in middle childhood, with in-person assessments at 8–11 years of age, with plans to continue to follow the sample across adolescence. Middle childhood measures focus on children’s physical and mental health, including diurnal cortisol, actigraphy-based measures of sleep and activity, cold pressor task assessing acute pain, and reaction time tasks assessing executive functioning. Preliminary findings illustrate that objective assessments of children’s health are highly heritable, but they do not always share genetic etiology with more commonly used subjective assessments. Exposure to early adversity moderates genetic influences on both executive functioning and health, with higher heritability typically seen under adverse conditions. Future directions include an examination of how pubertal stage affects genetic and environmental influences on diurnal cortisol, sleep, chronic pain, and mental health.
To develop and validate the Discrepancy-based Evidence for Loss of Thinking Abilities (DELTA) score. The DELTA score characterizes the strength of evidence for cognitive decline on a continuous spectrum using well-established psychometric principles for improving detection of cognitive changes.
DELTA score development used neuropsychological test scores from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (two tests each from Memory, Executive Function, and Language domains). We derived regression-based normative reference scores using age, gender, years of education, and word-reading ability from robust cognitively normal ADNI participants. Discrepancies between predicted and observed scores were used for calculating the DELTA score (range 0–15). We validated DELTA scores primarily against longitudinal Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Functional Activities Questionnaire (FAQ) scores (baseline assessment through Year 3) using linear mixed models and secondarily against cross-sectional Alzheimer’s biomarkers.
There were 1359 ADNI participants with calculable baseline DELTA scores (age 73.7 ± 7.1 years, 55.4% female, 100% white/Caucasian). Higher baseline DELTA scores (stronger evidence of cognitive decline) predicted higher baseline CDR-SOB (ΔR2 = .318) and faster rates of CDR-SOB increase over time (ΔR2 = .209). Longitudinal changes in DELTA scores tracked closely and in the same direction as CDR-SOB scores (fixed and random effects of mean + mean-centered DELTA, ΔR2 > .7). Results were similar for FAQ scores. High DELTA scores predicted higher PET-Aβ SUVr (ρ = 324), higher CSF-pTau/CSF-Aβ ratio (ρ = .460), and demonstrated PPV > .9 for positive Alzheimer’s disease biomarker classification.
Data support initial development and validation of the DELTA score through its associations with longitudinal functional changes and Alzheimer’s biomarkers. We provide several considerations for future research and include an automated scoring program for clinical use.
Belonging to a social group is one of the most important factors contributing to well-being. The Belonging Regulation model proposes that humans possess a social monitoring system (SMS) that evaluates social inclusion and monitors belonging needs. Here, we used a prospective longitudinal design to examine links between peer victimization experienced across 7 years and social monitoring at the behavioral and neural level in adolescent girls (n = 38, Mage = 15.43 years, SD = .33). Participants completed a social evaluation task during a functional magnetic resonance imaging (fMRI) scan. More severe peer victimization was associated with increased activation to in-group versus out-group peers in the amygdala, ventral striatum, fusiform gyrus, and temporoparietal junction. Moreover, participants who displayed increased activation in these regions reported lower social self esteem and higher levels of internalizing and externalizing symptoms. These results suggest that exposure to peer victimization across the school years is associated with heightened social monitoring at the neural level during adolescence, which has potential adverse implications for girls’ adjustment and well-being.
Uninsured patients are more likely than the general population to use tobacco and less likely to quit.
To determine if the mode of delivering the PHS Guidelines influenced the effectiveness of smoking cessation among patients in a safety net setting.
Six free clinics were randomly assigned to a training program delivered by an academic physician or community partner plus video support. A repeated cross-sectional survey of patients was conducted at three waves to assess effectiveness to promote quitting.
Tobacco use was triple the rate of the US population: 57.7% (Wave 1), 44.7% (Wave 2), and 48.9% (Wave 3). Patients were more likely to report receipt of at least one evidence-based strategy to promote quitting at Wave 2 (AOR = 2.33, 95% CI (1.18–4.58)). Patients treated in clinics trained by the community partner were significantly more likely to report receiving cessation assistance at Wave 2 (AOR 2.54, 95%CI 1.29–5.00) and the trend was similar, but not significant at Wave 3. Patients in the community partner-led arm were significantly less likely to report tobacco use at Wave 3 (AOR 0.59, 95% CI 0.35–0.99).
Implementation of the PHS Guidelines in free clinics demonstrates preliminary efficacy, with delivery by community partners offering greater scalability.
South Africa, in its attempt to encourage foreign investment by enthusiastically embracing bilateral investment treaties (BITs), encountered a conflict between two policy objectives: the establishment of a conducive legal framework for attracting direct foreign investment and the pursuit of economic justice for all South Africans.
After 1994, at the dawn of democracy in South Africa, the country eagerly endorsed the idea of entering into BITs, none of which had been concluded by the apartheid government. By 2012, South Africa had concluded 48 foreign investment protection and promotion treaties. This rush to treaty must be placed into context.
When the African National Congress (ANC) came to power, it was anxious to ensure that the international community regarded the country as a sound investment destination. Foreign investors were concerned about the legacy of the history of postcolonial African states, which had embarked on a course of economic nationalization together with a proclamation of redistribution of economic growth. With this history in mind, the British government, under the leadership of the then prime minister, John Major, who was concerned that the ANC might expropriate British assets in South Africa, was the first to approach the newly installed South African government with a BIT proposal.
This initiative was launched during a BIT-signing frenzy in which more than 3,600 treaties were concluded worldwide during the following decade. At the very moment that democracy dawned in South Africa, the Washington Consensus macroeconomic model propagated by the World Bank and the International Monetary Fund had achieved hegemonic status. This consensus encouraged developing countries to enter into BITs with capital-exporting countries as a means to incorporate key economic values into developing countries’ economic development. This aimed to ensure that the national regulatory system of developing countries was congruent with a transnational legal and policy regime. At the same time, the Washington Consensus induced the belief that the conclusion of BITs would attract foreign direct investment, which was seen as an important component of government policy at the time. It was assumed that the attraction of foreign investment would significantly boost developing countries’ manufacturing and export industries.
Filarial nematodes possess glutathione transferases (GSTs), ubiquitous enzymes with the potential to detoxify xenobiotic and endogenous substrates, and modulate the host immune system, which may aid worm infection establishment, maintenance and survival in the host. Here we have identified and characterized a σ class glycosylated GST (OoGST1), from the cattle-infective filarial nematode Onchocerca ochengi, which is homologous (99% amino acid identity) with an immunodominant GST and potential vaccine candidate from the human parasite, O. volvulus, (OvGST1b). Onchocerca ochengi native GSTs were purified using a two-step affinity chromatography approach, resolved by 2D and 1D SDS-PAGE and subjected to enzymic deglycosylation revealing the existence of at least four glycoforms. A combination of lectin-blotting and mass spectrometry (MS) analyses of the released N-glycans indicated that OoGST1 contained mainly oligomannose Man5GlcNAc2 structure, but also hybrid- and larger oligommanose-type glycans in a lower proportion. Furthermore, purified OoGST1 showed prostaglandin synthase activity as confirmed by Liquid Chromatography (LC)/MS following a coupled-enzyme assay. This is only the second reported and characterized glycosylated GST and our study highlights its potential role in host-parasite interactions and use in the study of human onchocerciasis.
Antenna-pattern measurements obtained from a double-metal supra-terahertz-frequency (supra-THz) quantum cascade laser (QCL) are presented. The QCL is mounted within a mechanically micro-machined waveguide cavity containing dual diagonal feedhorns. Operating in continuous-wave mode at 3.5 THz, and at an ambient temperature of ~60 K, QCL emission has been directed via the feedhorns to a supra-THz detector mounted on a multi-axis linear scanner. Comparison of simulated and measured far-field antenna patterns shows an excellent degree of correlation between beamwidth (full-width-half-maximum) and sidelobe content and a very substantial improvement when compared with unmounted devices. Additionally, a single output has been used to successfully illuminate and demonstrate an optical breadboard arrangement associated with a future supra-THz Earth observation space-borne payload. Our novel device has therefore provided a valuable demonstration of the effectiveness of supra-THz diagonal feedhorns and QCL devices for future space-borne ultra-high-frequency Earth-observing heterodyne radiometers.
Introduction: Effective communication to develop a shared understanding of patient/caregiver (P/C) expectations is critical during emergency department (ED) encounters. However, there is limited research examining the use of communication tools of P/C expectations to improve communication in the ED. The objective of this study was to examine satisfaction with a patient expectations questionnaire, known as the PrEPP tool, and its impact on communication and management of patients in the ED. Methods: The PrEPP tool collected P/C expectations over 3 phases of the study. In phase1, the PrEPP tool was distributed to all P/Cs (CTAS score of 2 to 5) in four EDs in Nova Scotia. In phase 2 the PrEPP tool was refined to a 5-item questionnaire. In phase 3 the PrEPP tool was re-implemented over a six-month period. Follow-up surveys were distributed to P/Cs via email (phase 1, 3) and HCPs on iPads in the ED (phase 3) to determine the impact of the tool on communication and management of patients. Entries were compiled on a REDCap database and descriptive statistics were used to analyze responses related to satisfaction.The PrEPP tool collected P/C expectations over 3 phases of the study. In phase1, the PrEPP tool was distributed to all P/Cs (CTAS score of 2 to 5) in four EDs in Nova Scotia. In phase 2 the PrEPP tool was refined to a 5-item questionnaire. In phase 3 the PrEPP tool was re-implemented over a six-month period. Follow-up surveys were distributed to P/Cs via email (phase 1, 3) and HCPs on iPads in the ED (phase 3) to determine the impact of the tool on communication and management of patients. Entries were compiled on a REDCap database and descriptive statistics were used to analyze responses related to satisfaction. Results: In Phase 1, 11418 PrEPP tools and 147 surveys (29% response rate) were collected from January-June 2016. The majority of P/Cs found the PrEPP questionnaire easy to complete (95.9%) and felt HCPs met their expectations (87.1%). In Phase 3, 951 P/C (31.1% response rate) and 128 HCP surveys were collected. Of P/C respondents 45.9% felt PrEPP helped to communicate expectations, while 49.7% said that they would like to use it on future ED visits. The majority of P/C respondents (75.4%) indicated their expectations were met during their visit to the ED. Of those whose expectations were not met, 69% felt their expectations were not discussed. The majority of HCP respondents (90.4%) indicated they used the PrEPP tool at least sometimes. Also, 78.4% said it influenced patient communication and 42% indicated the tool influenced management of patients at least sometimes. Conclusion: Obtaining expectations early in the patient encounter may provide opportunities for improved communication in the ED. P/Cs found the PrEPP tool easy to use to communicate their expectations and HCPs felt it influenced communication and management of patients in the ED. Further qualitative thematic analysis is needed to explore how the PrEPP tool impacted ED visits.
Background: Emergency Department (ED) communication between patients and clinicians is fraught with challenges. A local survey of 65 ED patients revealed low patient satisfaction with ED communication and resultant patient anxiety. Aim Statement: To increase patient satisfaction with ED communication and to decrease patient anxiety related to lack of ED visit information (primary aims), and to decrease clinician-perceived patient interruptions (secondary aim), each by one point on a 5-point Likert scale over a six-month period. Measures & Design: We performed wide stakeholder engagement, surveyed patients and clinicians, and conducted a patient focus group. An inductive analysis followed by a yield-feasibility-effort grid led to three interventions, introduced through sequential and additive Plan-Do-Study-Act (PDSA) cycles. PDSA 1: clinician communication tool (Acknowledge-Empathize-Inform [AEI] tool), based on survey themes and a literature review, and introduced through a multi-modal education approach. PDSA 2: patient information pamphlets developed with stakeholder input. PDSA 3: new waiting room TV screen with various informational ED-specific videos. Measures were conducted through anonymous surveys: Primary aims towards the end of the patient ED stay, and the secondary aim at the end of the clinician shift. We used Statistical Process Control (SPC) charts with usual special cause variation rules. Two-tailed Mann-Whitney tests were used to assess for statistical significance between means (significance: p < 0.05). Evaluation/Results: Over five months, 232 patient and 104 clinician surveys were collected. Wait times, ED processes, timing of typical steps, and directions were reported as the most important communication gaps, they and were included in the interventions. Patient satisfaction improved from 3.28 (5 being best, all means; n = 65) to 4.15 (n = 59, p < 0.0001). Patient anxiety improved from 2.96 (1 being best; n = 65) to 2.31 (n = 59, p < 0.01). Clinician-perceived interruptions went from 4.33 (1 being best; n = 30) to 4.18 (n = 11, p = 0.98). SPC charts using Likert scales did not show special cause variation. Discussion/Impact: A sequential, additive approach undertaken with pragmatic and low-cost interventions based on both clinician and patient input led to increased patient satisfaction with communication and decreased patient anxiety due to lack of ED visit information after PDSA cycles. These approaches could easily be replicated in other EDs to improve the patient experience.
Introduction: Effective communication to develop a shared understanding of patient expectations is critical to a positive encounter in the Emergency Department (ED). However, there is limited research examining Patient/Caregiver (P/C ) expectations in the ED and what factors lead to P/C presentation. This study aims to address this gap by answering the following questions: 1) What are common P/C reported factors affecting ED presentation? 2) What are common P/C expectations of an ED visit? 3) How do P/C expectations vary based on ED site or factors affecting presentation in the ED? Methods: The Preparing Emergency Patients and Providers (PrEPP) tool was designed to collect P/C expectations, worries, perceived causes of symptoms, and factors affecting presentation from a convenience sample of patient visits to the emergency department (ED). The PrEPP tool was provided to all P/Cs with CTAS 2-5 when they registered at one of 4 EDs in the Halifax area from January to June 2016. Completed tools were collected in a REDCap database where qualitative data was coded into categories (i.e. presenting illness, injury). Descriptive and chi-squared statistical analyses were performed. Results: In total, 11,418 PrEPP tools were collected; representing 12% of the total ED visits to the 4 ED sites during the study period. The main factors affecting ED presentation were: self-referral 68%, family/friends 20%, telehealth 8%, unable to see their GP 7%, GP referral 6%, or walk-in-clinic 5%. P/Cs main causes of worry were: presenting illness 19%, injury 15%, or pain 14%. The main expectations for the ED visit were to get a: physician's opinion 73%, x-ray 40%, or blood test 20%. Most P/Cs indicated they did not expect medication during (63%), or after (66%), their ED visit. There were significant differences in P/C expectations between adult and pediatric EDs (χ2 = 720.949, df = 14, P = 0.000) and those P/Cs unable or able to access primary care prior to ED presentation (χ2 = 38.980, df = 1, P = 0.000). The rate of expecting a physician's opinion at the pediatric ED was higher than the adult ED (77.6% vs 70.9%), while lower for expecting CT/MRIs (4.6% vs 11.4%). P/Cs who were unable to access primary care prior to ED presentation expected services which were available at primary care at a higher rate than those who accessed primary care (58.5% vs 36.7%). Conclusion: Our findings identify some of the factors that influence P/C's decision to present to the ED and their expectations of the ED visit.
The majority of paediatric Clostridioides difficile infections (CDI) are community-associated (CA), but few data exist regarding associated risk factors. We conducted a case–control study to evaluate CA-CDI risk factors in young children. Participants were enrolled from eight US sites during October 2014–February 2016. Case-patients were defined as children aged 1–5 years with a positive C. difficile specimen collected as an outpatient or ⩽3 days of hospital admission, who had no healthcare facility admission in the prior 12 weeks and no history of CDI. Each case-patient was matched to one control. Caregivers were interviewed regarding relevant exposures. Multivariable conditional logistic regression was performed. Of 68 pairs, 44.1% were female. More case-patients than controls had a comorbidity (33.3% vs. 12.1%; P = 0.01); recent higher-risk outpatient exposures (34.9% vs. 17.7%; P = 0.03); recent antibiotic use (54.4% vs. 19.4%; P < 0.0001); or recent exposure to a household member with diarrhoea (41.3% vs. 21.5%; P = 0.04). In multivariable analysis, antibiotic exposure in the preceding 12 weeks was significantly associated with CA-CDI (adjusted matched odds ratio, 6.25; 95% CI 2.18–17.96). Improved antibiotic prescribing might reduce CA-CDI in this population. Further evaluation of the potential role of outpatient healthcare and household exposures in C. difficile transmission is needed.
Because ethically and practically a randomized control trial of antipsychotics will never be done, we recently conducted and reported a 8- to 50-year, naturalistic follow-up from an academic clinic of patients with chronic schizophrenia on antipsychotic medication. We found that better medication adherence was a statistically significant predictor of better long-term global outcome and life satisfaction. Because there were important limitations on our findings, we now in this communication, using similar methodology, detail outcomes for a very different sample—inner city patients with chronic schizophrenia with a long past history of antipsychotic treatment, who were enrolled in clinical trials for new medications for schizophrenia.
This is a retrospective, naturalistic, longitudinal 6- to 49-years antipsychotic treatment (mean average, 20) follow-up of a consecutive series of patients volunteering for screening for studies with schizophrenia. Lifetime data were collected on (1) their medication adherence, (2) long-term global outcome, and (3) life satisfaction. Outcomes were rated by 2 different clinicians, 1 with information on medication adherence (nonblind rater) and 1 without (blind rater). We used linear regression models adjusted for age, family support, substance use disorder, race, marital status, and number of years in treatment to estimate the association between adherence and each outcome.
A total of 34 patients were assessed. Medication adherence was positively associated with the blind clinician’s rating of global outcome (P value=0.03) and the global assessment of functioning (P value=0.05). In the nonblinded clinician rating, medication adherence was unrelated to global outcome (P value=0.26) and to patients’ report of life satisfaction (P value=0.54).
This replication study, like our previous study, is not inconsistent with the recommendation for continuous, long-term treatment for chronic schizophrenia unless medically contraindicated.
We sought to define the prevalence of echocardiographic abnormalities in long-term survivors of paediatric hematopoietic stem cell transplantation and determine the utility of screening in asymptomatic patients. We analysed echocardiograms performed on survivors who underwent hematopoietic stem cell transplantation from 1982 to 2006. A total of 389 patients were alive in 2017, with 114 having an echocardiogram obtained ⩾5 years post-infusion. A total of 95 patients had echocardiogram performed for routine surveillance. The mean time post-hematopoietic stem cell transplantation was 13 years. Of 95 patients, 77 (82.1%) had ejection fraction measured, and 10/77 (13.0%) had ejection fraction z-scores ⩽−2.0, which is abnormally low. Those patients with abnormal ejection fraction were significantly more likely to have been exposed to anthracyclines or total body irradiation. Among individuals who received neither anthracyclines nor total body irradiation, only 1/31 (3.2%) was found to have an abnormal ejection fraction of 51.4%, z-score −2.73. In the cohort of 77 patients, the negative predictive value of having a normal ejection fraction given no exposure to total body irradiation or anthracyclines was 96.7% at 95% confidence interval (83.3–99.8%). Systolic dysfunction is relatively common in long-term survivors of paediatric hematopoietic stem cell transplantation who have received anthracyclines or total body irradiation. Survivors who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless otherwise indicated.
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.
To evaluate the impact of underlying disease and current DRA use on efficacy and safety of long-term therapy of deutetrabenazine in patients with TD.
Patients 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.
At 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.
Long-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.
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.
In 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.
Patients 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.
343 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.
Patients 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.
To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
In 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.
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 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).
343 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.
These 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
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.
To 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.
Patients 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.
At 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.
Patients 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.