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Open-label pilot study of lisdexamfetamine for cocaine use disorder.

ABSTRACT: Background: Cocaine use disorder (CUD) is a substantial public health problem with no FDA-approved medication treatments. Psychostimulants have shown promise as pharmacotherapy for CUD. Lisdexamfetamine, a novel prodrug psychostimulant, is roughly 40-50% as potent as dextroamphetamine.Objectives: To evaluate the safety, tolerability, and optimal dosing of lisdexamfetamine for treating CUD.Methods: Open-label, 8-week trial of 17 CUD adults. Participants were titrated to the maximum tolerated dose of 140 mg over 2-week period and maintained for 4 weeks, followed by a two-week taper period. The primary outcome measures were the maximum daily dose achieved during the study period and tolerability as measured by medication-related study drop-out.Results: Among the 16 participants with post-enrollment data, the mean dose of lisdexamfetamine achieved was 118.1 mg (standard deviation (SD) = 40.4), mean retention was 6.5 weeks (SD = 2.0), and no participants discontinued study medication due to adverse effects. Four participants had dose reductions due to adverse effects and continued in the trial. Six participants (37.5%) were abstinent for the last 3 weeks of their study participation. Mean dollars of cocaine spent per day significantly decreased from $19.72 at baseline to $7.57 during the last 3 weeks of study participation (t₁₅ = 3.60, p = .003). The mean percent of using days significantly decreased from 25% at baseline to 12% during the last 3 weeks of study participation (t₁₅ = 3.33, p = .005).Conclusion: The use of lisdexamfetamine for CUD in doses ranging to 140 mg daily was safe and generally well tolerated.

SUBMITTER: Mariani JJ

PROVIDER: S-EPMC8266739 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE:The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS:Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS:All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS:Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required. CLINICALTRIALS. GOV IDENTIFIER:NCT01328756.

Project description:BACKGROUND:Stimulant medications for the treatment of attention-deficit/hyperactivity disorder have a history of safe and effective use; however, concerns exist that they may adversely affect growth trajectories in children and adolescents. OBJECTIVE:The objective of this study was to evaluate the longer-term effects of lisdexamfetamine dimesylate on weight, height, body mass index and pubertal development in children and adolescents with attention-deficit/hyperactivity disorder. METHODS:Children and adolescents aged 6-17 years with attention-deficit/hyperactivity disorder took open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) in this open-label 2-year safety and efficacy study. Safety evaluations included treatment-emergent adverse events, measurement of weight, height and body mass index, and self-reported pubertal status using Tanner staging. RESULTS:The safety analysis population comprised all enrolled participants (N = 314) and 191 (60.8%) completed the study. Weight decrease was reported as a treatment-emergent adverse event in 63 participants (20.1%) and two participants (0.6%) discontinued the study as a result of treatment-emergent adverse events of weight decrease. Growth retardation of moderate intensity was reported as a treatment-emergent adverse event for two participants. From baseline to the last on-treatment assessment, there were increases in mean weight of 2.1 kg (standard deviation 5.83) and height of 6.1 cm (standard deviation 4.90), and a body mass index decrease of 0.5 kg/m2 (standard deviation 1.72). Mean weight, height and body mass index z-scores decreased over the first 36 weeks of the study and then stabilised. Changes from baseline to the last on-treatment assessment in mean z-scores for weight, height and body mass index were significantly less than zero (- 0.51, - 0.24 and - 0.59, respectively; nominal p < 0.0001). The proportion of participants with a z-score of < - 1 ranged from 5.1% (baseline) to 22.1% (week 84) for weight, 8.2% (baseline) to 12.6% (week 96) for height, and 8.3% (baseline) to 28.8% (week 96) for body mass index. Thirteen participants (4.1%) shifted to a weight below the fifth percentile at the last on-treatment assessment from a higher weight category at baseline. At the last on-treatment assessment, most participants remained at their baseline Tanner stage or had shifted higher. CONCLUSIONS:Findings from this comprehensive examination of growth outcomes associated with lisdexamfetamine dimesylate treatment over 2 years were consistent with previous studies of stimulant medications. Whilst mean weight and height increased over the course of the study, there was a small but transient reduction in mean weight, height and body mass index z-scores. A small increase in the proportion of participants in the lowest weight and body mass index categories highlights the importance of the regular monitoring of weight and height. There was no evidence of delayed onset of puberty. CLINICALTRIALS. GOV IDENTIFIER:NCT01328756.

Project description:Objective: To evaluate the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in preschool-aged children (4-5 years of age inclusive) diagnosed with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 3 open-label study (ClinicalTrials.gov registry: NCT02466386) enrolled children aged 4-5 years meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for a primary ADHD diagnosis and having baseline ADHD Rating Scale-IV Preschool version total scores (ADHD-RS-IV-PS-TS) ≥24 for girls or ≥28 for boys and baseline Clinical Global Impressions-Severity scores ≥4. Participants were directly enrolled or enrolled after completing one of two antecedent short-term LDX studies. Over 52 weeks of treatment, participants received once-daily dose-optimized LDX (5-30 mg). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and vital sign changes. Clinical outcomes included ADHD-RS-IV-PS-TS changes from baseline. Results: Among 113 participants in the safety set, optimized LDX dose was 5, 10, 15, 20, and 30 mg in 1 (0.9%), 12 (10.6%), 21 (18.6%), 26 (23.0%), and 53 (46.9%) participants, respectively. Of the safety set, 69 participants (61.1%) completed the study. TEAEs were reported in 76.1% of participants; no serious TEAEs were reported. Only one type of TEAE was reported in >10% of participants (decreased appetite, 15.9%). Mean ± standard deviation (SD) changes in vital signs and body weight from baseline to week 52/or early termination (ET; n = 101) were 1.9 ± 7.73 mmHg for systolic blood pressure, 3.1 ± 7.58 mmHg for diastolic blood pressure, 4.7 ± 11.00 bpm for pulse, and 0.6 ± 1.38 kg for body weight. Over the course of the study, mean ± SD change in ADHD-RS-IV-PS-TS from baseline to week 52/ET was -24.2 ± 13.34 (n = 87). Conclusions: In this long-term 52-week study of children aged 4-5 years with ADHD, dose-optimized LDX (5-30 mg) was well tolerated and associated with reductions from baseline in ADHD symptoms.

Project description:BackgroundThis open-label, crossover study examined lisdexamfetamine dimesylate (LDX) and D-amphetamine pharmacokinetics in healthy adults after administration of an intact LDX capsule or after the capsule was emptied into orange juice or yogurt and the contents consumed.MethodsHealthy adult volunteers (N = 30) were administered a 70-mg LDX capsule or the contents of a 70-mg capsule mixed with yogurt or orange juice using a 3-way crossover design. Blood samples were collected serially for up to 96 hours after dose. Pharmacokinetic endpoints included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from zero to infinity (AUC0-∞) or to last assessment (AUClast). Relative LDX and D-amphetamine bioavailabilities from the contents of a 70-mg LDX capsule mixed with orange juice or yogurt were compared with those from the intact LDX capsule using bioequivalence-testing procedures.ResultsGeometric least squares mean ratios (90% confidence intervals [CIs]) for D-amphetamine (active moiety) were within the prespecified bioequivalence range (0.80-1.25) when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.971 (0.945, 0.998); AUC0-∞: 0.986 (0.955, 1.019); AUClast: 0.970 (0.937, 1.004)] or yogurt [Cmax: 0.970 (0.944, 0.997); AUC0-∞: 0.945 (0.915, 0.976); AUClast: 0.944 (0.912, 0.977)]. Geometric least squares mean ratios (90% CIs) for LDX (inactive prodrug) were below the accepted range when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.641 (0.582, 0.707); AUC0-∞: 0.716 (0.647, 0.792); AUClast: 0.708 (0.655, 0.766)]; the lower 90% CI for Cmax [0.828 (0.752, 0.912)] was below the accepted range when the contents of a 70-mg LDX capsule were mixed with yogurt.ConclusionsRelative bioavailability of D-amphetamine (the active moiety) did not differ across administrations, which suggests that emptying an LDX capsule into orange juice or yogurt and consuming it is an alternative to intact capsules.

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Open-label pilot study of lisdexamfetamine for cocaine use disorder.

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