d-Amphetamine Transdermal System in Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Secondary Endpoint Results and Post Hoc Effect Size Analyses from a Pivotal Trial.

Objectives: Amphetamines are a preferred treatment for attention-deficit/hyperactivity disorder (ADHD), with the dextroamphetamine transdermal system (d-ATS) providing an alternative to oral formulations. A pivotal trial of d-ATS in children and adolescents with ADHD met primary and key secondary endpoints. This analysis reports additional endpoints and safety findings from the pivotal trial and evaluates effect size and number needed to treat (NNT) for d-ATS. Methods: In this study, a 5-week, open-label dose-optimization period (DOP) preceded a 2-week, randomized, crossover double-blind treatment period (DBP). Eligible patients received d-ATS 5 mg during the DOP, with weekly evaluations for increase to 10, 15, and 20 mg (equivalent to labeled doses of 4.5, 9, 13.5, and 18 mg/9 hours, respectively) until reaching and maintaining the optimal dose, which was utilized for the DBP. Secondary endpoints included assessment of Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV), Conners' Parent Rating Scale Revised Short Form (CPRS-R:S), and Clinical Global Impression (CGI) scores. NNT was calculated for ADHD-RS-IV and CGI-Improvement (CGI-I). Safety assessments included treatment-emergent adverse events (TEAEs) and dermal safety. Results: In total, 110 patients entered the DOP, with 106 patients randomized (DBP). During the DBP, the least-squares mean (95% confidence interval) difference for d-ATS versus placebo in ADHD-RS-IV total score was -13.1 (-16.2 to -10.0; p < 0.001), with effect size of 1.1 and NNT of 3 for ADHD-RS-IV remission, ≥30% improvement, and ≥50% improvement. Significant differences between placebo and d-ATS were also observed for CPRS-R:S and CGI-I scales (p < 0.001), with NNT of 2 for CGI-I response. Most TEAEs were mild or moderate, with three leading to study discontinuation in the DOP and none in the DBP. No patients discontinued due to dermal reactions. Conclusions: d-ATS was effective in treating ADHD in children and adolescents, meeting all secondary endpoints, with a large effect size and NNT of 2-3 to achieve a clinically meaningful response. d-ATS was safe and well tolerated, with minimal dermal reactions. Clinical Trial Registration: NCT01711021.

Efficacy of HP-3070, an Asenapine Transdermal System, on Symptoms of Hostility in Adults With Schizophrenia: A Post Hoc Analysis of a 6-Week Phase 3 Study.

Objective: Patients with schizophrenia may exhibit symptoms of hostility. HP-3070 is the first antipsychotic patch approved by the US Food and Drug Administration (FDA) for adults with schizophrenia. Its efficacy was demonstrated in a phase 3 study. This post hoc analysis assessed the efficacy of HP-3070 in treating hostility in schizophrenia.Methods: In the pivotal phase 3 study, conducted between August 2016 and November 2017, adults with schizophrenia (per DSM-5 criteria) were randomized to HP-3070 3.8 mg/24 h, HP-3070 7.6 mg/24 h, or placebo. Least-squares mean (LSM) changes in Positive and Negative Syndrome Scale (PANSS) hostility item and PANSS-Excited Component (PANSS-EC) scores from baseline to week 6 were assessed post hoc using a mixed-effects model for repeated measures adjusted for selected PANSS-Positive symptoms and presence of somnolence or akathisia.Results: Among 442 patients with baseline PANSS hostility item score > 1 (n = 151, HP-3070 7.6 mg/24 h; n = 147, 3.8 mg/24 h; n = 144, placebo), week 6 LSM (95% CI) change from baseline (CFB) in hostility score was superior with HP-3070 versus placebo for 7.6 mg/24 h (-0.4 [-0.6 to -0.2]; P < .001) and 3.8 mg/24 h (-0.3 [-0.6 to -0.1]; P < .01), with similar results for 7.6 mg/24 h after adjusting for covariates (P < .05). For all patients regardless of baseline PANSS hostility item score, PANSS-EC week 6 LSM CFB was greater for HP-3070 7.6 mg/24 h (-1.1 [-1.9 to -0.4]; n = 203; P < .01) and 3.8 mg/24 h (-1.3 [-2.0 to -0.6]; n = 201; P < .001) than for placebo (n = 203), with similar results observed in patients with baseline hostility item score > 1.Conclusions: In this post hoc analysis, HP-3070 was superior to placebo in reducing schizophrenia-associated hostility, even after adjusting for covariates, suggesting these effects are at least partially independent of general antipsychotic effects or effects on sedation or akathisia. These findings suggest HP-3070 has a specific antihostility effect in patients with schizophrenia.Clinical Trials Registration: ClinicalTrials.gov identifier: NCT02876900; EudraCT number: 2015-005134-21.

Efficacy and Safety of Dextroamphetamine Transdermal System for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results from a Pivotal Phase 2 Study.

Objectives: To assess efficacy and safety of the new Dextroamphetamine Transdermal System (d-ATS) to treat children and adolescents (aged 6-17 years) with attention-deficit/hyperactivity disorder (ADHD). Methods: In this phase 2, randomized, placebo-controlled study, 4 d-ATS patches of differing doses (5, 10, 15, and 20 mg) were evaluated. Patients began a 5-week, open-label, stepwise dose-optimization period in which they received a 5-mg d-ATS patch (applied to hip) for 9 hours. During weekly visits, patients were evaluated for possible adjustments to the next dose level based on efficacy and safety. Once at the optimal dose, that dose was maintained during a 2-week, crossover double-blind treatment period. Primary endpoint was to assess efficacy of d-ATS versus placebo as measured by Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP) total score; key secondary endpoints included assessing onset and duration of efficacy by SKAMP total score, and additional secondary endpoints included Permanent Product Measure of Performance (PERMP) scores. Safety was assessed throughout. Results: d-ATS treatment resulted in significant improvements versus placebo in ADHD symptoms as measured by SKAMP total score, with overall least-squares mean difference (95% confidence interval) versus placebo of -5.87 (6.76, -4.97; p < 0.001) over the 12-hour assessment period. Onset of efficacy was observed at 2 hours postdose (p < 0.001), and duration of effect continued through 12 hours (patch removed at 9 hours), with significant differences between d-ATS and placebo at all time points from 2 hours onward (all p ≤ 0.003). Significant improvements versus placebo in PERMP-A and PERMP-C scores were also observed from 2 to 12 hours postdose with d-ATS treatment. d-ATS was safe and well-tolerated, with a systemic safety profile similar to that observed with oral amphetamines. Conclusions: This study demonstrates that d-ATS is an effective and well-tolerated treatment for children and adolescents with ADHD. These data indicate that d-ATS can deliver sustained levels of efficacy along with the advantages of transdermal drug delivery, making it a beneficial new treatment option. Clinical Trial Registration no.: NCT01711021.

Systematic review of transdermal treatment options in attention-deficit/hyperactivity disorder: implications for use in adult patients.

BACKGROUND: Adults with attention-deficit/hyperactivity disorder (ADHD) often face delays in diagnosis and remain untreated, despite significant negative impacts. To evaluate the safety and efficacy of transdermal treatment options in children, adolescents, and adults, a systematic literature review was conducted, with a focus on the implications of transdermal therapies for ADHD in adults. METHODS: A MEDLINE/Embase/BIOSIS/SCOPUS database search was conducted December 4, 2019, for English-language articles of interventional clinical trials using transdermal formulations for the treatment of ADHD without publication date limit. Assessed outcomes included efficacy, safety, adherence, abuse potential, cost efficacy, and health-related quality of life. RESULTS: Of 23 eligible publications, 18 were in children or adolescents (n = 1699; range 23-305), and 5 in adults (n = 274; range 14-90); all included methylphenidate transdermal system (MTS). All seven pediatric publications reporting change in ADHD symptomology from baseline reported a significant improvement with MTS treatment. Similarly, in three adult publications, ADHD symptoms improved significantly with MTS treatment. Safety findings in pediatric and adult studies were comparable; the most frequently reported treatment-emergent adverse events (TEAEs), namely, headache, decreased appetite, and insomnia, were reported in 13/16 (81%) of publications reporting specific TEAEs. MTS-related dermal reactions were mostly mild and transient. Discontinuation due to dermal reactions was reported in 10 studies (range 0%-7.1% [1 of 14 patients]). MTS compliance was high when assessed (97%-99%). CONCLUSIONS: Transdermal therapies provide a useful treatment formulation for ADHD. Studies of MTS and other transdermal formulations, such as amphetamine, in adult patients are needed in this underserved population.

Pharmacokinetic Profile of the Asenapine Transdermal System (HP-3070).

PURPOSE/BACKGROUND: The asenapine transdermal system (HP-3070) is the first antipsychotic patch approved in the United States for treatment of adults with schizophrenia. METHODS/PROCEDURES: Three phase 1, open-label, randomized studies characterized the pharmacokinetic (PK) profile of HP-3070 by assessing its relative bioavailability compared with sublingual asenapine, its single-/multiple-dose PK and dose proportionality, and the effects of application site, ethnicity, and external heat on bioavailability. Two studies were conducted in healthy subjects, and 1 was conducted in adults with schizophrenia. FINDINGS/RESULTS: During single HP-3070 administration, asenapine concentrations increased gradually over approximately 12 hours and remained steady until the patch was removed 24 hours after application. Asenapine area under the curve values at HP-3070 3.8 and 7.6 mg/24 hours doses were similar to those for sublingual asenapine 5 and 10 mg twice-daily doses, respectively, whereas peak exposure (maximum observed plasma concentration) was significantly lower. During daily application of HP-3070, steady-state PK was reached within approximately 72 hours after initiating daily dosing and was characterized by peak-to-trough asenapine plasma concentration ratio of approximately 1.5. HP-3070 PK was dose proportional in the dose range studied, not affected by administration site, and similar across the studied ethnic groups. Application of external heat increased the rate of asenapine absorption (time to reach maximum observed plasma concentration) but did not significantly affect peak and total exposure. IMPLICATIONS/CONCLUSIONS: HP-3070 exhibited a dose-dependent PK profile unaffected by site of administration or ethnicity. HP-3070 showed a predictable absorption profile with limited variability, with an area under the curve similar to that of sublingual asenapine. Based on these PK metrics, HP-3070 steadily delivers asenapine with lower peaks and troughs than sublingual administration of asenapine.

Efficacy and Safety of HP-3070, an Asenapine Transdermal System, in Patients With Schizophrenia: A Phase 3, Randomized, Placebo-Controlled Study.

OBJECTIVE: Asenapine is a second-generation antipsychotic used to treat individuals with schizophrenia. This phase 3 study assessed efficacy and safety of HP-3070, an asenapine transdermal system (patch), in adults with schizophrenia. METHODS: In this inpatient study, a 3- to 14-day screening/single-blind run-in washout period was followed by a 6-week double-blind period wherein patients with acutely exacerbated schizophrenia (DSM-5 criteria) were randomized 1:1:1 and received HP-3070 7.6 mg/24 h (n = 204), HP-3070 3.8 mg/24 h (n = 204), or placebo (n = 206). Primary endpoint was change from baseline (CFB) in week 6 Positive and Negative Syndrome Scale (PANSS) total score versus placebo; key secondary endpoint was CFB in week 6 Clinical Global Impression-Severity of Illness score versus placebo. Safety endpoints included treatment-emergent adverse events (TEAEs) and dermal assessments. RESULTS: Each of the HP-3070 doses demonstrated significant improvement versus placebo at week 6 for the primary and key secondary endpoints. Differences in the least-squares mean (LSM) (95% CI; adjusted P) of CFB for PANSS total scores were -4.8 (-8.06 to -1.64; adjusted P = .003) and -6.6 (-9.81 to -3.40; adjusted P < .001) for 7.6 mg/24 h and 3.8 mg/24 h, respectively. HP-3070 was well tolerated, with a systemic safety profile consistent with sublingual asenapine. Incidence of application site TEAEs was higher for HP-3070 (14.2%, 7.6 mg/24 h; 15.2%, 3.8 mg/24 h) versus placebo (4.4%). Discontinuations due to application site reactions or skin disorders (urticaria, pruritus) were infrequent (≤ 0.5% per treatment group). CONCLUSIONS: HP-3070 7.6 mg/24 h and 3.8 mg/24 h doses were efficacious and well tolerated. As the first transdermal antipsychotic patch available in the US, HP-3070 offers a novel treatment option for people with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02876900; EudraCT number: 2015-005134-21.

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients.

PURPOSE: Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate the relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer. METHODS: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients. RESULTS: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR 8.64, 95% CI 2.67-28.0, p < 0.001). Estrone and testosterone concentrations were positively correlated with MPS function (ρ = 0.57 and 0.53, p = 0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (ρ = - 0.75 and - 0.76, respectively, p = 0.02 for both). CONCLUSIONS: Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.