Assessment of centanafadine in adults with attention-deficit/hyperactivity disorder: A matching-adjusted indirect comparison vs lisdexamfetamine dimesylate, atomoxetine hydrochloride, and viloxazine extended-release.

BACKGROUND: Head-to-head trials comparing centanafadine, an investigational therapy for adults with attention-deficit/hyperactivity disorder (ADHD), with other treatment options are lacking. OBJECTIVE: To compare safety and efficacy outcomes of centanafadine sustained-release vs lisdexamfetamine dimesylate (lisdexamfetamine), atomoxetine hydrochloride (atomoxetine), and viloxazine extended-release (viloxazine ER), respectively, using matching-adjusted indirect comparison (MAIC). METHODS: This MAIC included patient-level data pooled from 2 centanafadine trials (NCT03605680 and NCT03605836) and published aggregate data from comparable trials of 3 comparators-lisdexamfetamine (NCT00334880), atomoxetine (NCT00190736), and viloxazine ER (NCT04016779)-in adult patients with ADHD. Propensity score weighting was used to match characteristics of individual patients from the centanafadine trials to aggregate baseline characteristics from the respective comparator trials. Safety outcomes were rates of adverse events for which information was available in the centanafadine and respective comparator trials. Efficacy outcome was mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) score (ADHD Rating Scale [ADHD-RS] was used as proxy in the comparison with lisdexamfetamine). Anchored indirect comparisons were conducted across matched populations of the centanafadine and respective comparator trials. RESULTS: After matching, baseline characteristics in the centanafadine trials were the same as those in the respective comparator trials. Compared with lisdexamfetamine, centanafadine was associated with a significantly lower risk of lack of appetite (risk difference [RD] in percentage points: 23.42), dry mouth (19.27), insomnia (15.35), anxiety (5.21), nausea (4.90), feeling jittery (3.70), and diarrhea (3.47) (all P < 0.05) but a smaller reduction in the AISRS/ADHD-RS score (6.58-point difference; P < 0.05). Compared with atomoxetine, centanafadine was associated with a significantly lower risk of nausea (RD in percentage points: 18.64), dry mouth (17.44), fatigue (9.21), erectile dysfunction (6.76), lack of appetite (6.71), and urinary hesitation (5.84) (all P < 0.05) and no statistically significant difference in the change in AISRS score. Compared with viloxazine ER, centanafadine was associated with a significantly lower risk of fatigue (RD in percentage points: 11.07), insomnia (10.67), nausea (7.57), and constipation (4.63) (all P < 0.05) and no statistically significant difference in the change in AISRS score. CONCLUSIONS: In an anchored MAIC, centanafadine showed a significantly better short-term safety profile than lisdexamfetamine, atomoxetine, and viloxazine ER; efficacy was lower than with lisdexamfetamine and comparable (ie, nondifferent) with atomoxetine and viloxazine ER. This MAIC provides important insights on the relative safety and efficacy of common treatment options to help inform treatment decisions in adults with ADHD. Safety assessment was limited to rates of adverse events reported in both trials of a given comparison. STUDY REGISTRATION NUMBERS: NCT03605680, NCT03605836, NCT00334880, NCT00190736, and NCT04016779.

Assessment of lisdexamfetamine on executive function in rats: A translational cognitive research.

Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.

Medication Use in the Management of Comorbidities Among Individuals With Autism Spectrum Disorder From a Large Nationwide Insurance Database.

Importance: Although there is no pharmacological treatment for autism spectrum disorder (ASD) itself, behavioral and pharmacological therapies have been used to address its symptoms and common comorbidities. A better understanding of the medications used to manage comorbid conditions in this growing population is critical; however, most previous efforts have been limited in size, duration, and lack of broad representation. Objective: To use a nationally representative database to uncover trends in the prevalence of co-occurring conditions and medication use in the management of symptoms and comorbidities over time among US individuals with ASD. Design, Setting, and Participants: This retrospective, population-based cohort study mined a nationwide, managed health plan claims database containing more than 86 million unique members. Data from January 1, 2014, to December 31, 2019, were used to analyze prescription frequency and diagnoses of comorbidities. A total of 26 722 individuals with ASD who had been prescribed at least 1 of 24 medications most commonly prescribed to treat ASD symptoms or comorbidities during the 6-year study period were included in the analysis. Exposures: Diagnosis codes for ASD based on International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Main Outcomes and Measures: Quantitative estimates of prescription frequency for the 24 most commonly prescribed medications among the study cohort and the most common comorbidities associated with each medication in this population. Results: Among the 26 722 individuals with ASD included in the analysis (77.7% male; mean [SD] age, 14.45 [9.40] years), polypharmacy was common, ranging from 28.6% to 31.5%. Individuals' prescription regimens changed frequently within medication classes, rather than between classes. The prescription frequency of a specific medication varied considerably, depending on the coexisting diagnosis of a given comorbidity. Of the 24 medications assessed, 15 were associated with at least a 15% prevalence of a mood disorder, and 11 were associated with at least a 15% prevalence of attention-deficit/hyperactivity disorder. For patients taking antipsychotics, the 2 most common comorbidities were combined type attention-deficit/hyperactivity disorder (11.6%-17.8%) and anxiety disorder (13.1%-30.1%). Conclusions and Relevance: This study demonstrated considerable variability and transiency in the use of prescription medications by US clinicians to manage symptoms and comorbidities associated with ASD. These findings support the importance of early and ongoing surveillance of patients with ASD and co-occurring conditions and offer clinicians insight on the targeted therapies most commonly used to manage co-occurring conditions. Future research and policy efforts are critical to assess the extent to which pharmacological management of comorbidities affects quality of life and functioning in patients with ASD while continuing to optimize clinical guidelines, to ensure effective care for this growing population.

Dimesilato de lisdexanfetamina para indivíduos adultos com Transtorno do Déficit de Atenção com Hiperatividade / Lisdexamphetamine dimesylate for individuals adults with Attention Deficit Disorder with hyperactivity

INTRODUÇÃO: O transtorno de déficit de atenção/hiperatividade (TDAH) é um dos transtornos neuropsiquiátricos mais comuns e se manifesta ainda na infância podendo persistir na vida adulta em até 60% a 70% dos casos, sendo mais frequente no sexo masculino e tendo como sintomas hiperatividade, impulsividade ou desatenção, que podem se manifestar em diferentes graus de comprometimento e intensidade. Em adultos, é comum haver o comprometimento de funções executivas e a desregulação emocional é frequente. Em relação à prevalência do TDAH, um estudo epidemiológico nos EUA encontrou que 4,4% dos adultos entre 18 e 44 anos de idade possuíam o transtorno, e outro, 3,4% (variando de 1,2 a 7,3%) internacionalmente. O tratamento do TDAH é complexo e inclui intervenções sociais, psicológicas e comportamentais. O Brasil ainda não possui um Protocolo Clínico e Diretrizes Terapêuticas (PCDT) para o manejo de pacientes com TDAH. TECNOLOGIA: dimesilato de lisdexanfetamina (LDX). PERGUNTA: Dimesilato de lisdexanfetamina é eficaz e seguro para o tratamento de adultos com transtorno do déficit de atenção/hiperatividade comparado ao placebo? EVIDÊNCIAS CLÍNICAS: Para esta avaliação foi utilizada uma revisão sistemática elaborada pela Colaboração Cohrane com o objetivo de avaliar eficácia e segurança das anfetaminas no tratamento de adultos com TDAH, a qualidade metodológica foi avaliada como alta pela ferramenta AMSTAR2. O risco de viés dos estudos primários foi avaliado como incerto pelos autores da revisão. A qualidade da evidência foi avaliada pela ferramenta GRADE (Grades of Recommendation, Assessment, Development, and Evaluation). Dimesilato de lisdexanfetamina é mais eficaz que placebo na redução da gravidade dos sintomas de TDAH avaliado por médicos (DMP -1,06, IC 95% -1,26; -0,85 ­ equivalente a uma redução na gravidade dos sintomas > 35%, os estudos apresentam heterogeneidade moderada I2 = 40%). Um estudo com 61 participantes avaliou a proporção de participantes que alcançaram uma redução de pelo menos 30% na gravidade dos sintomas de TDAH e uma pontuação na escala CGI-I (do inglês Clinical Global Impression of Improvement) de 1 ou 2 e RR 2,54 (IC 95% 1,34; 4,82). AVALIAÇÃO ECONÔMICA: Foi realizada uma análise de custo-utilidade com modelo de árvore de decisão, na perspectiva do Sistema Único de Saúde (SUS). Como os estudos são de curto prazo (em média 5 semanas), os dados de custo e utilidade foram extrapolados para o período da análise. Como independente da faixa etária (18 a 55 anos) os efeitos permanecem constantes, o horizonte temporal foi de 1 ano. Como o SUS não tem tratamento medicamentoso incorporado, o comparador foi placebo. Foram estimados os custos médicos diretos. Aplicada uma taxa de desconto de 5%. Adotou-se um limiar de aproximadamente 1 PIB (cerca de 32.000,00). O custo incremental foi de R$ 3.258,94 e o QALY incremental de 0,05. A razão de custo efetividade incremental (RCEI) foi de R$ 61.563,36. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A AIO resultou em um impacto orçamentário de cerca de R$ 7,67 bilhões no primeiro ano, variando de R$ 6,88 bilhões a R$ 12,77 bilhões nos cenários alternativos propostos. O impacto orçamentário incremental do primeiro ano foi estimado em 4,97 bilhões. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Detectaram-se quatro medicamentos potenciais para a TDAH em adultos: centanafadine, SHP465 (Mydayis®), viloxazina (Supernus®) e TRN-110. O centanafadine é um medicamento de uso oral que está sendo desenvolvido em formulação de liberação sustentada. É um agente não estimulante com ação tripla de inibição na recaptação de norepinefrina, dopamina e serotonina, numa proporção de 1:6:14, respectivamente. O medicamento foi testado em adultos com TDAH em dois estudos clínicos concluídos no ano de 2020, que avaliaram a eficácia e segurança de diferentes doses do centanafadine contra placebo. Além disso, está em andamento um ensaio clínico de fase 3 cujo objetivo é aferir a eficácia e tolerabilidade. O SHP465 (Mydayis®) tem indicação em bula para o tratamento de pacientes com TDAH a partir de 13 anos de idade. A viloxazina está em fase de pré-registro no FDA para o tratamento de pacientes com TDAH de 6 a 17 anos. O TRN-110 é um medicamento oral de liberação prolongada que está em desenvolvimento para a o tratamento de crianças e adultos com TDAH. Com relação à lisdexanfetamina, localizou-se no Instituto Nacional da Propriedade Intectual (INPI), a patente PI 040792-6, depositada em 2004, concedida em 2017 e que estará vigente até 21/02/2027. CONSIDERAÇÕES FINAIS: Os resultados encontrados mostram que o dimesilato de lisdexanfetamina é mais eficaz do que o placebo para o tratamento de curto prazo de TDAH. Na revisão sistemática utilizada como base para este parecer os resultados foram consistentes em todas as análises que foram realizadas usando diferentes definições de eficácia e modelos estatísticos. As evidências foram avaliadas como de baixa qualidade. A maioria dos estudos tem um número pequeno de participantes e o período de acompanhamento da maior parte é curto. Diante disso, a possibilidade de que a eficácia do dimesilato de lisdexanfetamina em adultos com TDAH seja menor após o tratamento a longo prazo não pode ser descartada e deve ser estudada por meio de ensaios clínicos com um longo período de acompanhamento. O dimesilato de lisdexanfetamina não melhora a retenção no tratamento. Uma outra revisão sistemática concluiu que a tecnologia é menos eficaz e menos bem tolerada em adultos do que em crianças e adolescentes. RECOMENDAÇÃO PRELIMINAR: Pelo exposto, o Plenário da Conitec, em sua 95ª Reunião Ordinária, no dia 04 de março de 2021, deliberou que a matéria fosse disponibilizada em Consulta Pública com recomendação preliminar desfavorável à incorporação de dimesilato de lisdexanfetamina para o tratamento de pacientes adultos com transtorno de déficit de atenção/hiperatividade (TDAH) no SUS. Os membros da Conitec consideraram o número pequeno de participantes da maioria dos estudos primários, o curto tempo de acompanhamento (máximo 20 semanas), o grau de confiança das evidências (avaliado como baixo e muito baixo) e o elevado impacto orçamentário para a tomada de decisão. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: Foram recebidas 67 contribuições, sendo 13 técnico-científicas e 54 sobre experiência ou opinião. A grande maioria destas discordou da recomendação inicial da Conitec. A Takeda Pharma Ltda., demandante e importadora do medicamento, reiterou a necessidade do funil populacional (exclusão de hipertensos e percentual da população alvo que recebe tratamento medicamentoso) para o cálculo do impacto orçamentário, que foi utilizado para realização de nova estimativa. A nova AIO resultou em um impacto orçamentário de cerca de R$ 738 milhões no primeiro ano, variando de R$ 400 milhões a R$ 998 milhões nos cenários alternativos propostos. O impacto orçamentário incremental do primeiro ano foi estimado em 478 milhões. Após apreciação das contribuições recebidas na Consulta Pública, o Plenário da Conitec entendeu que não foram apresentadas novas evidências que mudassem seu entendimento sobre o tema. Dessa maneira, não houve motivos para alterar sua recomendação preliminar, a qual foi desfavorável à incorporação do dimesilato de lisdexanfetamina para o tratamento de transtorno de déficit de atenção/ hiperatividade (TDAH) em pacientes adultos no SUS. RECOMENDAÇÃO FINAL DA CONITEC: Pelo exposto, o Plenário da Conitec, em sua 97ª Reunião Ordinária, no dia 05 de maio de 2021, deliberou por unanimidade recomendar a não incorporação do dimesilato de lisdexanfetamina para o tratamento de transtorno de déficit de atenção/ hiperatividade (TDAH) em pacientes adultos. Assim, foi assinado o Registro de Deliberação nº 605/2021. DECISÃO: Não incorporar o dimesilato de lisdexanfetamina para indivíduos adultos com Transtorno do Déficit de Atenção com Hiperatividade, no âmbito do Sistema Único de Saúde ­ SUS, conforme Portaria nº 20, publicada no Diário Oficial da União nº 103, Seção 1, página 118, em 2 de junho de 2021.(AU)

Metilfenidato e lisdexanfetamina para indivíduos com Transtorno do Déficit de Atenção com Hiperatividade / Methylphenidate and Lisdexamphetamine for Individuals with Attention Deficit Hyperactivity Disorder

INTRODUÇÃO: O TDAH é considerado uma condição do neurodesenvolvimento que se caracteriza por uma tríade de sintomas envolvendo desatenção, hiperatividade e impulsividade em um nível exacerbado e disfuncional para a idade. Os sintomas iniciam-se na infância, sendo capaz de persistir ao longo de toda a vida. Estas alterações ocorrem em diferentes contextos, podendo resultar em prejuízos afetivos, acadêmicos, ocupacionais, nas interações sociais e na qualidade de vida. O diagnóstico é feito com base em avaliação clínica e psicossocial completa. Geralmente, não são necessários exames de imagem ou laboratoriais para diagnóstico. Atualmente, o tratamento disponível no SUS é baseado em psicoterapias nas modalidades individual e em grupo. Entretanto, o tratamento medicamentoso pode ser necessário para o controle de sintomas e redução do impacto da doença nos diferentes domínios da vida do indivíduo. O objetivo do presente relatório é analisar as evidências científicas sobre o uso do metilfenidato (MPH) e da lisdexanfetamina (LDX) em paci

Assessment of Amphetamine Withdrawal Symptoms of Lisdexamfetamine Dimesylate Treatment for Adults With Binge-Eating Disorder.

OBJECTIVE: To determine whether physical dependence developed during lisdexamfetamine dimesylate treatment, as evidenced by presence of withdrawal symptoms after treatment cessation in adults with binge-eating disorder (BED) treated for up to 38 weeks. METHODS: Three studies enrolled adults with DSM-IV-TR-defined BED. In two 12-week, randomized, double-blind, placebo-controlled studies conducted from November 2012 to September 2013, participants were treated with placebo or dose-optimized lisdexamfetamine (50 or 70 mg). In a double-blind, placebo-controlled, randomized-withdrawal maintenance-of-efficacy study conducted from January 2014 to April 2015, participants categorized as responders after 12 weeks of open-label lisdexamfetamine (50 or 70 mg) were randomized to continued lisdexamfetamine or placebo for 26 weeks. The Amphetamine Cessation Symptom Assessment (ACSA), a 16-item self-report instrument (total score: 0-64), assessed withdrawal experiences. Mean ± SD ACSA scores and medians are presented for study completers. RESULTS: In the short-term efficacy studies, mean ± SD ACSA aggregate scores for placebo and lisdexamfetamine (pooled data) were 7.0 ± 7.60 (n = 275) and 4.9 ± 6.41 (n = 271), respectively, on the day of the last dose at week 12/early termination (ET) and 4.8 ± 6.82 (n = 234) and 5.5 ± 7.50 (n = 221) on day 7 after the last dose. In the maintenance-of-efficacy study, mean ± SD ACSA aggregate scores for placebo and lisdexamfetamine were 4.8 ± 6.67 (n = 44) and 4.7 ± 7.78 (n = 85) on the day of the last dose at week 38/ET and 3.9 ± 5.75 (n = 37) and 5.2 ± 7.93 (n = 71) on day 7 after the last dose. CONCLUSIONS: Study results suggest that abrupt lisdexamfetamine termination was not associated with amphetamine withdrawal symptoms at the exposure durations and therapeutic doses analyzed. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT01718483, NCT01718509, and NCT02009163.

Examining the heterogeneity of treatment patterns in attention deficit hyperactivity disorder among children and adolescents in the Texas Medicaid population: modeling suboptimal treatment response.

Objectives: To examine suboptimal responses (SR) in attention deficit hyperactivity disorder (ADHD) among pediatric patients in the Texas Medicaid program receiving osmotic-release oral system methylphenidate (OROS-MPH) or lisdexamfetamine (LDX) and apply an SR prediction model to identify patients most likely to experience an SR to either OROS-MPH or LDX therapies. Methods: A retrospective cohort study was conducted using Texas Medicaid claims data of ADHD children and adolescents (6-17 years of age) initiating OROS-MPH or LDX. Primary SR endpoints were drug discontinuation, switching, and augmentation 12-months post-ADHD drug initiation. Logistic regression models were developed to predict SR to OROS-MPH and LDX in 1:1 matched groups of children and adolescent cohorts. Results: A total of 3,633 children and 1,611 adolescents were matched for each cohort. SR was observed among more children (76.4% vs 72.3%; p < 0.001) and adolescents (82.7% vs 78.2%; p = 0.002) initiating OROS-MPH compared to LDX. Patient sub-groups with the highest predicted risk of OROS-MPH SR experienced significantly lower observed SR rates (p < 0.05) when initiating LDX (children: 80.6% for OROS-MPH vs 75.8% for LDX; OR = 0.75, 95% CI = 0.60-0.94; adolescents: 87.2% for OROS-MPH vs 80.6% for LDX; OR = 0.61, 95% CI = 0.41-0.89). For patients with highest predicted SR rates to LDX, observed SR rates were not significantly different between patients initiating LDX or OROS-MPH. Conclusions: This study demonstrated how a personalized medicine approach using administrative claims data can be used to identify sub-groups of child and adolescent ADHD patients with different risks for suboptimal response with OROS-MPH or LDX in a Medicaid population.

Assessment of lisdexamfetamine dimesylate stability and identification of its degradation product by NMR spectroscopy.

Lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant indicated for the treatment of the attention-deficit/hyperactivity disorder (ADHD), was subjected to forced degradation studies by acid and alkaline hydrolysis and the degradation profile was studied. To obtain between 10-30% of degraded product, acid and alkaline conditions were assessed with solutions of 0.01 M, 0.1 M, 0.5 M, and 1 M of DCl and NaOD. These solutions were analyzed through 1 H NMR spectra. Acid hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and 4.38%, 9.69%, and 17.75% of degradation LDX, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) DCl. And alkaline hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and a degradation LDX extension of 8.5%, 14.30%, and 22.91%, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) NaOD. LDX solutions subjected to 1 M (4 + 12 h) acid and alkaline hydrolysis were evaluated by NMR spectra (1 H NMR, 13 C NMR, HSQC and HMBC). LDX degradation product (DP) was identified and its structure elucidated as a diastereoisomer of LDX: (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl] hexanamide without their physical separation.

LiMA: a study protocol for a randomised, double-blind, placebo controlled trial of lisdexamfetamine for the treatment of methamphetamine dependence.

INTRODUCTION: Methamphetamine dependence is a growing public health concern. There is currently no pharmacotherapy approved for methamphetamine dependence. Lisdexamfetamine (LDX) dimesylate, used in the treatment of attention-deficit hyperactivity disorder and binge eating disorder, has potential as an agonist therapy for methamphetamine dependence, and possible benefits of reduced risk of aberrant use due to its novel formulation. METHODS AND ANALYSIS: A double-blind randomised controlled trial will be used to evaluate the efficacy of LDX in reducing methamphetamine use. The target sample is 180 participants with methamphetamine dependence of ≥2 years, using ≥14 days out of the previous 28, who have previously attempted but not responded to treatment for methamphetamine use. Participants will be randomly assigned to receive either a 15-week intervention consisting of induction (1 week of 150 mg LDX or placebo), maintenance (12 weeks of 250 mg LDX or placebo) and reduction (1 week of 150 mg LDX or placebo and 1 week of 50 mg LDX or placebo). All participants will be given access to four sessions of cognitive-behavioural therapy as treatment as usual and receive a 4-week follow-up appointment. The primary outcomes are efficacy (change from baseline in days of methamphetamine use by self-report for the last 28 days at week 13 and urinalyses confirmation of methamphetamine use) and safety (treatment-related adverse events). Secondary outcomes are total number of days of self-report methamphetamine use over the 12-week active treatment, longest period of abstinence during treatment period, percentage of achieving ≥21 days abstinence, craving, withdrawal, dependence, retention, bloodborne virus transmission risk behaviour, criminal behaviour, as well measures of abuse liability, physical and mental health, other substance use, cognitive performance, psychosocial functioning, treatment retention and satisfaction. Additionally, the study will assess the cost-effectiveness of LDX relative to the placebo control. ETHICS AND DISSEMINATION: The study has been approved by the Human Research Ethics Committee of St. Vincent's Hospital, Sydney, Australia (HREC/16/SVH/222). Contact the corresponding author for the full trial protocol. TRIAL REGISTRATION NUMBER: ACTRN12617000657325; Pre-results.

A cost-effectiveness analysis of lisdexamfetamine dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder in children that may persist into adulthood. Lisdexamfetamine dimesylate (LDX) is approved in many countries for ADHD treatment in children, adolescents, and adults. OBJECTIVES: Estimate the cost-effectiveness of LDX as a first- or second-line treatment for adults with ADHD from the United Kingdom (UK) National Health Service (NHS) perspective compared with methylphenidate extended release (MPH-ER) and atomoxetine (ATX). METHODS: A 1-year decision-analytic model was developed. Health outcomes included response, non-response and inability to tolerate. Efficacy data were obtained from a mixed-treatment comparison (MTC). Response was a score of 1 or 2 on the Clinical Global Impression-Improvement scale. Tolerability was assessed by discontinuation rates due to adverse events. Utilities were identified via a systematic literature review. Health care resource use estimates were obtained via a survey of clinicians. Daily drug costs were estimated from mean doses reported in the trials used in the MTC. One-way and probabilistic sensitivity analyses (PSAs) were performed. RESULTS: LDX dominated MPH-ER and ATX; reducing mean per-patient annual cost by £5 and £200, and increasing mean quality-adjusted life years (QALYs) by 0.005 and 0.009, respectively. In the PSA, the probability of cost-effectiveness for LDX vs. MPH-ER and ATX at a threshold of £20,000 per QALY was 61% and 80%, respectively. CONCLUSIONS: From the perspective of the UK NHS, LDX is likely to provide a cost-effective treatment for adults with ADHD. This conclusion may be drawn with more certainty in comparison with ATX than with MPH-ER.

A Cost-Utility Analysis of Lisdexamfetamine Versus Atomoxetine in the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Inadequate Response to Methylphenidate.

BACKGROUND: An economic analysis from the perspective of the UK National Health Service (NHS) evaluated the cost effectiveness of lisdexamfetamine dimesylate (LDX) compared with atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder who have had an inadequate response to methylphenidate. METHODS: A 1-year decision-analytic model was constructed, with the health outcomes "response", "nonresponse", and "unable to tolerate". Clinical data were taken from a head-to-head, randomized controlled trial in inadequate responders to methylphenidate. Response to treatment was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Improvement subscale. Tolerability was assessed by discontinuation rates owing to adverse events. Utility weights were identified via a systematic literature review. Healthcare resource use estimates were obtained via a survey of clinicians. Daily drug costs were derived from British National Formulary 2012 costs and mean doses reported in the trial. One-way and probabilistic sensitivity analyses (PSAs) were performed. RESULTS: The comparison of LDX with atomoxetine resulted in an estimate of an incremental cost-effectiveness ratio of £1802 per quality-adjusted life-year (QALY). The result was robust in a wide range of sensitivity analyses; results were most sensitive to changes in drug costs and efficacy. In the PSA, assuming a maximum willingness to pay of £20,000 per QALY, LDX versus atomoxetine had an 86 % probability of being cost effective. In 38 % of PSA runs, LDX was more effective and less costly than atomoxetine. CONCLUSIONS: From the perspective of the UK NHS, LDX provides a cost-effective treatment option for children and adolescents who are inadequate responders to methylphenidate.

The Cost Effectiveness of Lisdexamfetamine Dimesylate for the Treatment of Binge Eating Disorder in the USA.

BACKGROUND: Lisdexamfetamine dimesylate (LDX) demonstrated efficacy in terms of reduced binge eating days per week in adults with binge eating disorder (BED) in two randomized clinical trials (RCTs). OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of LDX versus no pharmacotherapy (NPT) in adults with BED from a USA healthcare payer's perspective. STUDY DESIGN AND METHODS: A decision-analytic Markov cohort model was developed using 1-week cycles and a 52-week time horizon. Markov health states were defined based upon the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria of BED. Model parameter estimates were obtained from RCTs, a survey, and literature. The primary outcome was incremental cost-effectiveness ratio (ICER). The analysis assumed a 12-week course of treatment, based upon RCTs' treatment duration. One-way deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the results. RESULTS: Patients on LDX therapy gained 0.006 quality-adjusted life years (QALY) compared to patients on the NPT arm, while the average total cost was US$175 higher for LDX therapy. The estimated ICER for LDX compared with NPT was US$27,618 per QALY, which was shown to be cost effective given a willingness-to-pay threshold of US$50,000. CONCLUSIONS: Treatment of BED with LDX showed increase in QALYs at an acceptable cost and is considered to be cost effective at the commonly used willingness-to-pay threshold in the USA. Based on the available evidence, the current model focused on short-term benefits only. There is a need to generate additional scientific evidence supporting long-term benefits of LDX therapy for BED.

Is adjunctive pharmacotherapy in attention-deficit/hyperactivity disorder cost-effective in Canada: a cost-effectiveness assessment of guanfacine extended-release as an adjunctive therapy to a long-acting stimulant for the treatment of ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in children, with worldwide prevalence of ADHD varying from 5.9 to 7.1 %, depending on the reporter. In case of inadequate response to stimulants, combination therapy of stimulants and an adjunctive medication may improve the control of ADHD symptoms, reduce the dose-limiting adverse events, and help control comorbidities. To date, the only medication to be used for adjunctive therapy to psychostimulants is guanfacine extended release (GXR). The aim of this study was to assess the economic impact of GXR as an adjunct therapy with long-acting stimulants (GXR + stimulant) compared to long-acting stimulant monotherapy (stimulant alone) in the treatment of children and adolescents with ADHD in Canada. METHOD: A Markov model was developed using health states defined based on the clinician-reported Clinical Global Impression-Severity (CGI-S) score (normal, mild, moderate, severe). Transition probabilities were calculated based on patient-level data from a published study. Long-acting stimulants available in Canada were considered in the base-case model: amphetamine mixed salts, methylphenidate HCl formulations, and lisdexamfetamine dimesylate. Analyses were conducted from a Canadian Ministry of Health (MoH; Ontario) and a societal perspective over a 1-year time horizon with weekly cycles. RESULTS: Over a 1-year time horizon, GXR + stimulant was associated with 0.655 quality-adjusted life year (QALY), compared to 0.627 QALY with stimulant alone, for a gain of 0.028 QALY. From a MoH perspective, GXR+ stimulant and stimulant alone were associated with total costs of $CA1,617 and $CA949, respectively (difference of $CA668), which resulted in an incremental cost-effectiveness ratio (ICER) of $CA23,720/QALY. From a societal perspective, GXR + stimulant and stimulant alone were associated with total costs of $CA3,915 and $CA3,582, respectively (difference of $CA334), which resulted in an ICER of $CA11,845/QALY. Probabilistic sensitivity analysis (PSA) of GXR + stimulant showed that it remains a cost-effective strategy in 100 % of the simulations from both perspectives in numerous PSA and one-way sensitivity analyses, relative to a willingness to pay threshold of $50,000/QALY. CONCLUSIONS: This economic evaluation demonstrates that GXR + stimulant is cost-effective compared to stimulant alone in the treatment of children and adolescents with ADHD in Canada.

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure.

BACKGROUND: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment's efficacy in decreasing cocaine consumption is unknown. METHODS: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. RESULTS: In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0-0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32-3.2mg/kg/day, i.m.) or d-amphetamine (0.032-0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. CONCLUSIONS: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine's efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.

Treatment persistence in attention deficit/hyperactivity disorder: a retrospective analysis of patients initiated on lisdexamfetamine vs other medications.

OBJECTIVE: To compare treatment persistence in attention-deficit/hyperactivity disorder (ADHD) of patients initiated on lisdexamfetamine (LDX) vs other ADHD medications. METHODS: A large US administrative claims database was used to select ADHD patients who initiated an ADHD medication (index treatment) during/after 2007. Patients were classified, based on age and previous treatment status, as treatment-naïve or previously treated children and adolescents (6-17 years) and treatment-naïve or previously treated adults (18 years and older). Furthermore, patients were classified into seven mutually exclusive treatment groups, based on their index treatment: LDX, atomoxetine (ATX), osmotic-release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate short-acting (MPH SA) and long-acting (MPH LA), and amphetamine/dextroamphetamine short acting (AMPH SA) and long-acting (AMPH LA). Treatment persistence, analyzed through discontinuation (interruption of the index treatment for ≥30 consecutive days), was compared between treatment groups using multivariate Cox proportional hazards. Patients were followed until first treatment discontinuation or up to 12 months after the initiation of the index treatment, whichever occurred first. RESULTS: Among children and adolescents, LDX patients had a significantly lower discontinuation rate compared to other treatment groups (range hazard ratios [HRs]; 1.04-2.26; all p < 0.05), except when compared to treatment-naïve patients on ATX and OROS MPH, where no statistically significant differences were found and where LDX had a higher risk of discontinuation, respectively. Among adults, LDX patients had a significantly lower discontinuation rate compared to patients in other treatment groups (range HR; 1.14-1.86; all p < 0.05), except for the comparison with AMPH LA patients, where differences were not statistically significant. LIMITATIONS: This study did not control for ADHD severity. CONCLUSION: LDX-treated patients were associated with higher persistence compared to patients initiated on other ADHD medications, except for the comparisons with OROS MPH and ATX treated patients in treatment-naïve children and adolescents and AMPH LA-treated patients in adults.

Comparison of therapy augmentation and deviation rates from the recommended once-daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults.

OBJECTIVE: To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants. METHODS: ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for ≥90 days and continuously enrolled in their healthcare plan for ≥12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (≥18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12-month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for ≥28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models. RESULTS: Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically significant when compared to OROS MPH and MPH LA patients. LIMITATION: This study did not control for ADHD severity. CONCLUSION: Overall, compared to LDX-treated patients, patients initiated on other ADHD medications were equally or more likely to have a therapy augmentation and more likely to deviate from the recommended once-daily dosing regimen.

Comparing treatment adherence of lisdexamfetamine and other medications for the treatment of attention deficit/hyperactivity disorder: a retrospective analysis.

OBJECTIVE: To assess treatment adherence in attention deficit/hyperactivity disorder (ADHD) patients initiated on Lisdexamfetamine (LDX) vs other FDA-approved stimulants and non-stimulant medications. METHODS: ADHD patients initiated on an ADHD medication (index medication) were selected from a large US administrative claims database. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (over 18 years old), and previously treated adults. Furthermore, based on their index medication, patients were classified into seven mutually exclusive treatment groups: LDX, atomoxetine (ATX), osmotic release methylphenidate hydrochloride long acting (OROS MPH), other methylphenidate/dexmethylphenidate long acting (MPH LA) and short acting (MPH SA), and amphetamine/dextroamphetamine short acting (AMPH SA) and long acting (AMPH LA). Treatment adherence (proportion of days covered by the index medication ≥0.8) over a 12-month period was compared across treatment groups using multivariate logistic regression models. RESULTS: In children and adolescents, LDX patients were more likely to be adherent compared to patients in each of the other treatment groups, except in treatment-naïve patients where LDX patients had a similar likelihood (p = 0.6925) and were less likely (p = 0.0004) to be adherent compared to ATX and OROS MPH patients, respectively. In adults, the LDX treatment group was also more likely to be adherent compared to each of the other treatment groups, except compared to AMPH LA, where statistically insignificant differences were observed (previously treated: p = 0.6471, treatment-naïve: p = 0.0733). LIMITATIONS: ADHD severity information was not available in the database. Accordingly, this study did not control for ADHD severity. CONCLUSION: Overall, LDX-treated patients demonstrated a better treatment adherence compared to patients initiated on other ADHD medications, except for AMPH LA in adult and OROS MPH and ATX in treatment-naïve children and adolescents.

Identifying patient subgroups who benefit most from a treatment: using administrative claims data to uncover treatment heterogeneity.

OBJECTIVES: To illustrate how claims data can be used to (1) develop outcome scores that predict response to a traditional treatment and (2) estimate the economic impact of individualized assignment to a newer treatment based on the outcome score. An example application is based on two treatments for attention deficit hyperactivity disorder (ADHD): osmotic-release oral system methylphenidate (OROS-MPH) and lisdexamfetamine dimesylate (LDX). METHODS: Adolescents with ADHD initiating OROS-MPH (n=6320) or LDX (n=6394) were selected from the MarketScan claims database. A model was developed for predicting risk of switching/augmentation with OROS-MPH using multiple baseline characteristics. The model was applied to an independent sample to stratify patients by their predicted risk and, within each stratum, risk of switching/augmentation and ADHD-related total costs were compared between OROS-MPH and LDX patients using inverse probability of treatment weighting. RESULTS: The prediction model resulted in substantial stratification, showing risk of switching/augmentation with OROS-MPH ranging from 11.3-42.1%. In the two strata where OROS-MPH had highest risk of switching/augmentation, LDX had significantly lower risk of switching/augmentation than OROS-MPH (by 7.0-8.2%) and lower ADHD-related annual total costs (by $264-$625 per patient). LIMITATIONS: The current study has used the risk of switching/augmentation as a proxy measure for treatment efficacy to establish the prediction model. Future research using a clinical measure for ADHD symptoms is warranted to verify the findings. CONCLUSIONS: Combining multiple patient characteristics into a predicted score for treatment outcomes with a traditional treatment can help identify subgroups of patients who benefit most from a new treatment. In this analysis, ADHD patients with a high predicted score for switching/augmentation with OROS-MPH had a lower rate of switching/augmentation with LDX. Assigning OROS-MPH and LDX treatments based on the predicted scores that are heterogeneous in a patient population may help improve clinical outcomes and the cost-effectiveness of care.

Attention-deficit hyperactivity disorder: recent advances in paediatric pharmacotherapy.

Throughout this decade, there has been significant research into pharmacotherapies for attention-deficit hyperactivity disorder (ADHD). This article considers the efficacy and safety of five of the more novel long-acting pharmacological treatments recently approved by the FDA for marketing in the US for paediatric ADHD, along with an alpha(2)-adrenoceptor agonist in preparation. Reviewed treatments include the non-stimulant atomoxetine, three novel extended-release (XR) stimulant preparations: dexmethylphenidate, lisdexamfetamine dimesylate and the methylphenidate transdermal system (TDS), and the recently approved XR alpha(2)-adrenoceptor agonist, guanfacine. Dexmethylphenidate XR is a stimulant treatment in a single isomer form, and has an efficacy and tolerability similar to two doses of immediate-release (IR) dexmethylphenidate when taken 4 hours apart, but is dosed at half of the usual d,l-methylphenidate dose. Dexmethylphenidate XR utilizes a beaded bimodal release, with 50% initially released and another 50% released 4 hours later to provide benefit lasting up to 10-12 hours. Lisdexamfetamine was the first stimulant treatment approved as a prodrug, whereby the single isomer d-amfetamine remains pharmacologically inactive until activated by cleaving the lysine. Its efficacy and tolerability are generally consistent with that of XR mixed amfetamine salts, with this activation method and more consistent absorption generally resulting in up to an 11- to 13-hour benefit. The methylphenidate TDS patch utilizes skin absorption to provide predictable and uniform delivery of methylphenidate when worn for 9 hours/day. The efficacy and tolerability of the methylphenidate TDS patch is generally consistent with that of osmotic-controlled release oral system (OROS) methylphenidate, providing benefit for about 11-12 hours. Because of their formulation, lisdexamfetamine and methylphenidate each have an onset of effect at about 2 hours after administration. An adjustable wear time for the methylphenidate TDS patch accommodates related adverse effects, but its disadvantages are frequent skin irritation and the need to remember to take the patch off. Atomoxetine is the first non-stimulant treatment approved by the FDA and employs weight-based dosing up to 1.4 mg/kg/day. Benefit is generally observed within 2-8 weeks of initiation and is considered to have a lesser therapeutic effect than that of stimulants. A recent parallel-group controlled study found that atomoxetine (up to 1.8 mg/kg/day) and OROS methylphenidate both improved ADHD symptoms, although subjects receiving OROS methylphenidate had a significantly better response. Interestingly, treatment-naive children had a similar beneficial response to atomoxetine as those receiving OROS methylphenidate. Subsequent crossover treatment revealed a subgroup of youths who did not respond well to OROS methylphenidate but did respond to atomoxetine. Also identified was a larger than expected subgroup who did not respond well to either active treatment, confirming the need to continue the pursuit of novel treatments. As of September of 2009, guanfacine in XR form is the first alpha(2)-adrenoceptor agonist to gain approval to treat ADHD, approved for the treatment of 6- to 17-year olds. A second alpha(2)-adrenoceptor agonist, clonidine, is in development as a potential XR treatment for paediatric ADHD. IR clonidine has a fast onset and short half-life, with its use historically limited by somnolence. Although early formulations did not improve inattention well, recent evidence suggests that clonidine XR may have potential use as monotherapy or in extending benefit when taken with a stimulant. Guanfacine has a more specific neuronal action and a longer action than that of clonidine. The approved dosing of guanfacine XR 1 to 4 mg daily generally provides symptom benefit lasting 8-14 hours, and up to 24 hours in some children and adolescents receiving a higher dose. Such recent developments and ongoing study of additional potential pharmacological interventions may lead to additional future treatment options for children with ADHD.

Effects of omeprazole on the pharmacokinetic profiles of lisdexamfetamine dimesylate and extended-release mixed amphetamine salts in adults.

OBJECTIVE: To evaluate the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant, and mixed amphetamine salts extended-release (MAS XR), alone or with omeprazole, a proton pump inhibitor (PPI). METHODS: This open-label, randomized, 4-period crossover study enrolled healthy adults (18-45 years). Subjects alternately received single doses of LDX 50 mg and MAS XR 20 mg at 4-day intervals. Following washout, subjects received omeprazole (40 mg/day x 14 days), with alternate single doses of LDX 50 mg or MAS XR 20 mg added on days 7 and 11. Blood samples were collected predose and 0 to 96 hours postdose for pharmacokinetic analysis. Safety assessments included adverse events (AEs). RESULTS: Overall, 24 subjects were randomized; 21 completed the study. For LDX monotherapy, d-amphetamine mean (SD) exposure was 45.0 (13.97) ng/mL and 713.0 (134.75) ng . h/mL; when coadministered with omeprazole it was 46.3 (9.71) ng/mL and 761.6 (191.13) ng . h/mL, for Cmax and AUCinf, respectively. The median Tmax was 3 hours with and without omeprazole. For MAS XR monotherapy, total amphetamine mean (SD) exposure was 36.6 (9.19) ng/mL and 640.8 (95.66) ng . h/mL; when coadministered with omeprazole it was 38.1 (7.35) ng/mL and 643.9 (143.16) ng . h/mL, for Cmax and AUCinf, respectively. The median Tmax was 5 hours and 2.75 hours without and with omeprazole, respectively; 57.1% to 61.9% of subjects receiving MAS XR and 25% receiving LDX showed an earlier (>or= 1 hour) Tmax with omeprazole. Both medications had AEs consistent with amphetamine use. CONCLUSIONS: Total exposure was unaffected by omeprazole for both compounds. However, approximately 50% of subjects receiving MAS XR showed an earlier Tmax while on omeprazole, indicating unpredictable release of active drug by the second bead of MAS XR, most likely related to reduced stomach acid while on a PPI compromising the pulsed delivery of MAS XR. No clear trend was observed for LDX.