Serdexmethylphenidate/dexmethylphenidate for children with attention-deficit/hyperactivity disorder: dose optimization from a laboratory classroom study.

Objective: To evaluate treatment responder rate using the Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) score based on optimized dose level of serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) and changes in ADHD severity in children (aged 6-12 years) with ADHD. Methods: During a 21-day dose-optimization phase, 155 patients initiated treatment with 39.2/7.8 mg SDX/d-MPH in the first week and then were titrated to an optimum dose; 5 patients were downtitrated to 26.1/5.2 mg, 76 were uptitrated to 52.3/10.4 mg, and 69 remained at 39.2/7.8 mg during the following 2 weeks. Responder threshold values were 30% and 50% based on the percent change from baseline (day 0) to days 7, 14, and 21 in the ADHD-RS-5 score. The Conners 3rd Edition-Parent score was used to assess weekly changes in ADHD severity during the dose-optimization and treatment phases. Results: Of the 5 subjects whose dose was optimized at 26.1/5.2 mg, ≥80% across all days had ≥50% responder rate. Of the 69 subjects whose dose was optimized at 39.2/7.8 mg, 81.2% had ≥50% responder rate by day 21. Of the 76 subjects whose dose was optimized to 52.3/10.4 mg, 72.4% had ≥50% responder rate by day 21. Changes in ADHD severity, based on mean Conners 3rd Edition-Parent scores, improved from baseline at each visit during dose optimization for each subscale. At the dose-optimization phase, Conners 3rd Edition-Parent scores improved from baseline for SDX/d-MPH in all subscales. Conclusion: A high percentage of subjects were responders upon reaching their final optimized dose. SDX/d-MPH demonstrated significant reductions in ADHD severity in children based on the Conners 3rd Edition-Parent scores. Determining the optimal dosage of SDX/d-MPH and its effect on ADHD severity could enable the development of a more clinically relevant treatment regimen in children with ADHD.

A study of once-a-week donepezil transdermal system's bioequivalence to oral donepezil in healthy volunteers: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article published in the Journal of Alzheimer's Disease. It describes an adhesive patch placed on the skin's surface, also referred to as a transdermal delivery system (or TDS), that delivers donepezil (called donepezil TDS going forward) through the skin of patients with mild, moderate, and severe dementia of the Alzheimer's type. This summary focuses on how fast and how much of the medication donepezil enters the body through the skin, and how it compares with taking a pill form of donepezil by mouth (oral donepezil). This summary also looks at how much donepezil is circulating through the body with the use of the once-a-week donepezil TDS versus the once-a-day donepezil pill. We show that the same amount of donepezil circulates through the body when donepezil TDS is used once a week as when a participant takes an oral donepezil pill once a day. WHY IS THIS STUDY IMPORTANT?: Dementia is a term used to describe a person's decreasing ability to remember, think, or make decisions necessary to successfully complete daily activities. Alzheimer's disease is a disorder that progresses slowly, with the symptoms of dementia getting worse over many years. When viewed under a microscope, the visible features of Alzheimer's disease within the brain are protein deposits called plaques between brain cells and protein strands within brain cells that appear as tangles. One of the many features that cannot be seen with the naked eye in the Alzheimer's brain is the low level of a chemical called acetylcholine that allows certain nerve cells in the brain involved with memory to communicate with one another. Donepezil, a drug that is widely used to treat dementia associated with Alzheimer's disease, increases the amount of acetylcholine in the brain. Donepezil is usually in pill form and taken by mouth. However, one problem with taking oral donepezil is that it can cause stomach or intestinal side effects like diarrhea, nausea, and vomiting. These side effects may be bad enough that people stop taking their medication. In 2022, for the first time, the United States Food and Drug Administration approved a donepezil TDS marketed under the name Adlarity. Donepezil TDS is for use in patients who have mild, moderate, and severe dementia caused by Alzheimer's disease. It is applied once a week to skin on the patient's back, upper buttocks, or thigh. Donepezil TDS allows the drug donepezil to be absorbed into the body directly through the skin, which means that the drug does not go through the digestive system. This means that many stomach and intestinal side effects (the undesirable effects of the drug) can potentially be reduced. WHAT WERE THE RESULTS?: In healthy volunteers, we showed that donepezil TDS allows a similar amount of the drug into the body as the oral donepezil pill. This is done using a type of examination known as pharmacokinetics (how much, how fast, and how steadily donepezil is taken into the bloodstream). In healthy participants, donepezil TDS had overall fewer stomach and intestinal side effects (like constipation, diarrhea, nausea, and vomiting) than the oral donepezil pill, although more participants reported abdominal pain with donepezil TDS than with oral donepezil. Donepezil TDS also had fewer instances of nervous system side effects (like dizziness and sleepiness) than the oral donepezil pill. These findings support using donepezil TDS to treat patients with Alzheimer's disease.

Analysis of Growth Velocity in Children with Attention-Deficit/Hyperactivity Disorder Treated for up to 12 Months with Serdexmethylphenidate/Dexmethylphenidate.

Objective: Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A 12-month, open-label safety study with SDX/d-MPH in children with ADHD showed that SDX/d-MPH was well tolerated and comparable with other methylphenidate products. In this post hoc analysis of the 12-month study, the objective was to characterize the effect of SDX/d-MPH on growth in children with ADHD over 12 months. Methods: This was a post hoc analysis of a dose-optimized, open-label, phase 3 safety study of SDX/d-MPH in children aged 6-12 years with ADHD (NCT03460652). Weight and height Z-score analyses were conducted. Z-score change from baseline was calculated based on the baseline values for the subjects remaining in the study at the observation time point. Results: Subjects (N = 238) from the treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. During treatment, the mean weight and height Z-scores decreased over time from their respective baselines. At the 12-month time point, mean (standard deviation [SD]) Z-score changes from baseline for weight and height for the subjects remaining in the study were -0.20 (0.50) and -0.21 (0.39), respectively; however, these mean changes in Z-scores were not clinically significant (change <0.5 SD). Long-term treatment with SDX/d-MPH was associated with modest reductions in expected weight and lower-than-expected increases in height: effects that plateaued or diminished later in treatment. Conclusion: The overall effects of SDX/d-MPH on growth velocity (the change in weight and height from one time point to the next) were minimal, and the range of changes was not considered clinically significant. ClinicalTrials.gov identifier: NCT03460652.

Safety and Tolerability of Serdexmethylphenidate/Dexmethylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder: A 12-Month, Open-Label Safety Study.

Objective: Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A pivotal double-blind (DB) study of children aged 6-12 years with ADHD demonstrated efficacy for ADHD with good tolerability. In this study, we assessed the safety and tolerability of daily oral SDX/d-MPH for up to 1 year in children with ADHD. Methods: This was a dose-optimized, open-label safety study with SDX/d-MPH in children aged 6-12 years with ADHD that included subjects who successfully completed the DB study (rollover) and new subjects. The study consisted of a 30-day screening phase, a dose optimization phase for new subjects only, a 360-day treatment phase, and follow-up. Adverse events (AEs) were assessed from the first day of SDX/d-MPH administration to the end of the study. During the treatment phase, ADHD Rating Scale-5 (ADHD-RS-5) and Clinical Global Impressions-Severity (CGI-S) scale assessments were used to evaluate ADHD severity. Results: Of the 282 subjects enrolled (70 rollover; 212 new), 28 discontinued treatment in the dose optimization phase and 254 entered the treatment phase. By study completion, 127 had discontinued and 155 had completed the study. The treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. Of 238 subjects assessed in the treatment-phase safety population, 143 (60.1%) had ≥1 treatment-emergent adverse events (TEAEs), and 36 (15.1%), 95 (39.9%), and 12 (5.0%) had mild, moderate, or severe TEAEs, respectively. The most common TEAEs were decreased appetite (18.5%), upper respiratory tract infection (9.7%), nasopharyngitis (8.0%), decreased weight (7.6%), and irritability (6.7%). There were no clinically meaningful trends in electrocardiograms, cardiac events, or blood pressure events, and none led to discontinuation. Two subjects had eight serious AEs that were unrelated to treatment. There were overall reductions in ADHD symptoms and severity as assessed by ADHD-RS-5 and CGI-S during the treatment phase. Conclusions: In this 1-year study, SDX/d-MPH was found to be safe and well tolerated and comparable with other methylphenidate products, with no unexpected safety findings. SDX/d-MPH also showed sustained efficacy during the 1-year treatment period. ClinicalTrials.gov identifier: NCT03460652.

Comparison of Steady-State Pharmacokinetics of Donepezil Transdermal Delivery System with Oral Donepezil.

BACKGROUND: Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States. OBJECTIVE: To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil. METHODS: Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5. RESULTS: All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively). CONCLUSION: Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.

Dose Proportionality and Steady-State Pharmacokinetics of Serdexmethylphenidate/Dexmethylphenidate, a Novel Prodrug Combination to Treat Attention-Deficit/Hyperactivity Disorder.

Objective: The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new treatment containing d-MPH and a novel prodrug, serdexmethylphenidate (SDX); (2) the dose proportionality of the different SDX/d-MPH dosages; and (3) the steady-state PK profile of d-MPH and SDX after multiple dosing of SDX/d-MPH. Methods: Twenty-three healthy volunteers (aged 18-55 years) under fasted conditions received in a crossover design SDX/d-MPH 26.1/5.2 mg (Treatment A), 39.2/7.8 mg (Treatment B), and 52.3/10.4 mg (Treatment C) for a total d-MPH hydrochloride equivalent dose of 20, 30, and 40 mg, respectively. After a 96-hour washout period, all participants received four consecutive daily doses of SDX/d-MPH 52.3/10.4 mg. Blood samples were collected for measurement of plasma d-MPH and SDX and for PK analysis. Results: Administration of all three doses of SDX/d-MPH resulted in a rapid rise and slow decline in the plasma concentration of d-MPH. For Treatments A, B, and C, mean (± standard deviation) maximum concentrations (Cmax) were 7.1 ± 2.1, 9.8 ± 2.8, and 13.8 ± 3.8 ng/mL, and overall exposures (AUC0-last) were 97.2 ± 28.8, 142.5 ± 41.2, and 199.8 ± 57.2 h*ng/mL, respectively. Dose-normalized Cmax, AUC0-last, and AUC0-inf for d-MPH were similar when comparing the high and low doses versus the middle dose. Power model regression analysis revealed that Cmax and AUC0-inf proportionally increased with an increase in SDX/d-MPH dose. In the multiple-dose study, d-MPH reached steady state before the third dose, and SDX after the first dose. Conclusion: The PK profile of SDX/d-MPH is characterized by a rapid rise and a gradual decline in d-MPH concentration, with proportional Cmax and AUC0-inf across doses. The PK attributes of SDX/d-MPH may optimize symptom control from early morning to early evening, while the demonstrated dose proportionality may facilitate initial dose titration and ongoing dose adjustment.

A Randomized, Controlled Laboratory Classroom Study of Serdexmethylphenidate and d-Methylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: To evaluate the efficacy and safety of once-daily serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) capsules (Azstarys™) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD) in a randomized, double-blind, dose-optimized laboratory classroom study. Methods: Children ages 6-12 with ADHD were enrolled. During a 3-week, open-label, Dose Optimization Phase, subjects initiated treatment with 39.2 mg/7.8 mg/day of SDX/d-MPH and were titrated weekly to an optimal dose (maximum dose of 52.3/10.4 mg). During the double-blind Treatment Phase, subjects were randomized to receive their optimal dose of SDX/d-MPH or placebo for 7 days. On day 7, efficacy was assessed in the laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP). To evaluate safety, adverse events (AEs), vital signs, and electrocardiograms were assessed, and suicide risk was assessed. Results: A total of 149 subjects completed the study. In the primary efficacy analysis, the mean postdose change from baseline in SKAMP-Combined scores averaged over the laboratory classroom day was significantly improved with SDX/d-MPH versus placebo (least-squares mean treatment difference [95% confidence interval]: -5.41 [-7.10 to -3.71]; p < 0.001). A significant treatment effect for SDX/d-MPH compared with placebo was observed from 1 to 10 hours postdose. A post hoc analysis more comparable with that conducted in similar studies indicated a 0.5- to 13-hour onset and duration of efficacy. Both average postdose PERMP-Attempted and PERMP-Correct score changes from baseline were significantly improved among those treated with SDX/d-MPH versus placebo (p < 0.001 for both). No serious AEs were reported. During the Dose Optimization Phase, two-thirds of subjects reported AEs; the most common being insomnia and decreased appetite. Conclusions: SDX/d-MPH showed significant improvement in ADHD symptoms compared with placebo in children 6-12 years of age, with a rapid onset and extended duration of treatment effect. SDX/d-MPH was safe, with AEs comparable with those observed with other stimulant treatments.

Natural history of lung function over one year in patients with Parkinson's disease.

BACKGROUND: Little is known about decline in lung function in Parkinson's disease (PD). To assess these changes, we assessed the changes in lung function that occurred over 12 months in patients on standard PD therapy as part of the observational cohort of an open-label study of inhaled levodopa (CVT-301) in PD. METHODS: PD patients on stable oral PD therapy and no chronic respiratory disease had spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) measured at 3, 6, 9, and 12 months. RESULTS: 106 patients (81.5%) in the observational cohort on no investigational therapy completed the study. Mean FEV1 declined at 12 months from 2.88L at baseline with a mean change of -0.11L, greater than the -0.030-0.045L/year observed in healthy, non-smokers aged 60-70 years. FVC declined from 3.77L (mean change -0.19L); FEV1/FVC ratio remained relatively constant. DLCO mean change was -0.48 mL/min/mmHg from a baseline of 24.24 mL/min/mmHg. This change in DLCO, while not significant, was similar to that seen in non-smokers aged 60-70 years (DLCO -0.42-0.63 mL/min/mmHg/year). Decreases in alveolar volume (VA) and inspiratory vital capacity (IVC) rather than the transfer coefficient (DLCO/VA) were observed. CONCLUSIONS: PD patients had greater declines in FEV1, and FVC, but not in DLCO, compared to healthy non-smokers of similar age. Declines in FEV1 and FVC with little change in FEV1/FVC, and decline in VA and IVC with little change in DLCO/VA, suggest these changes were due to decreases in lung volume and are compatible with progressive PD-associated respiratory muscle weakness. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02352363 Registered January 26, 2015 [https://clinicaltrials.gov/ct2/show/NCT02352363]) and EudraCT (2014-003799-22).

A 12-month, dose-level blinded safety and efficacy study of levodopa inhalation powder (CVT-301, Inbrija) in patients with Parkinson's disease.

INTRODUCTION: CVT-301 (Inbrija®) is a levodopa inhalation powder for on-demand treatment of OFF episodes in Parkinson's disease patients treated with carbidopa/levodopa. Safety and efficacy results of a 12-month, dose-level blinded extension study of a phase 3 trial (SPAN℠-PD) of CVT-301 are presented. METHODS: Patients were receiving oral carbidopa/levodopa and adjunctive CVT-301 treatment, blinded to dose (60 mg or 84 mg, N = 325). Study visits occurred every 3 months. Pulmonary function was assessed by spirometry. Other safety assessments included dyskinesia and adverse events (AEs). Secondary objectives of the study included maintenance of improvement assessments for occurrence of an ON state during the 60-min post-dose period, change in total daily OFF time, and Patient Global Impression of Change (PGIC). RESULTS: Most frequent AEs (≥5%) were cough (15.4%), fall (13.1%), upper respiratory tract infection (7.1%), and dyskinesia (5.1%). Severe AEs (>1 event) were cough (1.9%) and dyskinesia (0.6%). Twelve-month mean changes from baseline for FEV1, FVC, and DLCO were -0.092 L, -0.097 L, and -0.922 mL/min/mmHg, respectively. At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min. Total daily OFF time was reduced by 0.55 h (month 1) and 0.88 h (month 12) for the 84 mg dose. Percentage of patients self-reported as improved by PGIC was 65.5-91.9% over 12 months. CONCLUSION: CVT-301 was generally well-tolerated. Twelve-month decline in pulmonary function was consistent with a prior PD control group. Exploratory efficacy results showed CVT-301 maintained improvement at achieving ON states in patients experiencing OFF episodes, decreasing daily OFF time, and maintaining improvement in PGIC.

Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease.

PURPOSE: Levodopa (LD) is the most effective oral pharmacotherapy for the management of motor symptoms in Parkinson's disease. However, LD use is complicated by a progressive shortening of the duration of efficacy of a dose, resulting in episodes of inadequate responsiveness, or OFF periods. OFF periods may also occur unpredictably, partly due to the pharmacokinetic (PK) variability of oral LD, resulting from gastrointestinal dysfunction and from the effects of food on absorption. CVT-301 is a levodopa inhalation powder for the treatment of OFF period symptoms in patients on oral dopa-decarboxylase inhibitor/LD. PK and safety profiles of single dose CVT-301, administered with oral carbidopa (CD) and oral CD/LD, were examined in patients with Parkinson's disease in the fed state. METHODS: Eligible patients were aged 30-85 years, with a clinical diagnosis of Parkinson's disease and a body mass index of 18-32 kg/m2, and were receiving treatment with a stable regimen that included oral CD/LD (25/100 mg) (total LD, ≤800 mg/d). A high-fat/protein meal was eaten 4-5 h after the administration of the morning oral CD/LD dose. Blood samples for predose PK analysis were obtained after the meal, followed by a single inhaled dose of CVT-301 84 mg (+25 mg of oral CD) or oral CD/LD (25/100 mg) or vice versa in 2 dosing periods in a crossover design. Blood was sampled at 0, 5, 10, 15, 30, and 45 min and at 1, 1.5, 2, 3, and 4 h postdose. Tolerability assessments included treatment-emergent adverse events. FINDINGS: Twenty-three patients were enrolled (65.2% male; 87.0% white; mean age, 69.3 years; mean body mass index, 26.9 kg/m2; mean Parkinson's disease duration, 8.2 years; mean baseline LD dosage, 460.9 mg/d; 73.9% at Hoehn and Yahr stage <2.5). PK analyses were based on LD concentrations without baseline adjustment. Median Tmax values with CVT-301 and oral CD/LD were 15 and 120 min (P < 0.001). Cmax with CVT-301 was lower than with oral CD/LD (590.3 vs 844.3 ng/mL). C10min and C30min values with CVT-301 were approximately twice those with CD/LD (522.9 and 531.5 ng/mL vs 247.3 and 300.9 ng/mL, respectively). %CV for C5min to Cmax with CVT-301 was lower than that with oral CD/LD. The most common treatment-emergent adverse event was cough (CVT-301, 7 patients [30.4%]; oral CD/LD, 1 patient [4.5%]). IMPLICATIONS: PK properties showed that CVT-301 was more rapidly absorbed, with higher plasma LD concentrations in the first 45 min, and demonstrated lower interpatient variability, than was oral CD/LD in the fed condition. The study findings suggest that CVT-301 can be used without regard to food intake. ClinicalTrials.gov identifier: NCT03887884.

Inhaled levodopa in Parkinson's disease patients with OFF periods: A randomized 12-month pulmonary safety study.

INTRODUCTION: CVT-301 is an orally inhaled levodopa therapy approved for the intermittent treatment of OFF episodes in Parkinson's disease patients who are taking a standard oral levodopa regimen. This open-label, randomized, controlled study over 12 months characterizes the safety, including pulmonary safety, of CVT-301 84 mg (nominal respirable levodopa fine-particle dose, 50 mg). METHODS: Patients experiencing motor fluctuations were randomized 2:1 to CVT-301 or an observational cohort (OC) receiving oral standard of care. Pulmonary safety was assessed using spirometry and carbon monoxide diffusion capacity (DLCO). Exploratory efficacy endpoints, assessed only for CVT-301, included change in Unified Parkinson's Disease Rating Scale Part III (UPDRS-III), patients achieving ON within 60 min and remaining ON at 60 min, Patient Global Impression of Change (PGIC) scale, and total daily OFF time. RESULTS: Of 408 patients randomized, 310 completed the study (204 in CVT-301 and 106 in OC). Mean 12-month changes from baseline for CVT-301 were -0.105 L (FEV1) and -0.378 mL/min/mm Hg (DLCO), and for OC were -0.117 L and -0.722 mL/min/mm Hg, respectively. Between-group comparisons were not statistically significant. For FEV1/FVC the 12-month change was -0.3 and -1.6, respectively, which was a significant between-group difference. However, between-group differences were not significant at 3 and 9 months and all changes from baseline were small (<2.0%). UPDRS-III scores improved from predose to 60 min postdose at all assessments; 80%-85% of patients switched ON within 60 min and remained ON; and >75% reported improvement in PGIC. OFF time decreased by 1.32-1.42 h/day. CONCLUSION: CVT-301 84 mg induced no clinically significant differences in pulmonary function compared with the OC. Improvements in motor scores, OFF time, and patient-reported outcomes support clinical efficacy for up to 12 months.

Orally inhaled levodopa (CVT-301) for early morning OFF periods in Parkinson's disease.

BACKGROUND: CVT-301 (Inbrija) is a self-administered orally inhaled levodopa approved for the intermittent treatment of OFF episodes in patients with Parkinson's disease (PD) treated with carbidopa/levodopa. Prior studies only evaluated CVT-301 after the first ON of the day. OBJECTIVE AND METHODS: The objective of this study was to evaluate the safety and tolerability of CVT-301 for early morning OFF. Using a randomized, double-blind, 2-way crossover design, eligible patients in the morning OFF state (having not received PD medication overnight) received a single dose of CVT-301 84 mg or placebo on 2 dosing days, immediately after their first morning oral carbidopa/levodopa dose. Safety assessments included treatment-emergent adverse events, vital signs, and patient- and examiner-reported dyskinesia. An exploratory efficacy assessment was examiner-rated time-to-ON with carbidopa/levodopa + CVT-301 vs carbidopa/levodopa + placebo. RESULTS: Of the 36 patients (mean age 62.9 years) who enrolled and completed the study, 9 (25.0%) reported treatment-emergent adverse events following CVT-301 administration; 4 (11.1%) reported treatment-emergent adverse events following placebo. The most common adverse event was cough (4 [11.1%] for CVT-301 vs 1 [2.8%] for placebo), which was typically mild and transient. Incidence of asymptomatic orthostatic hypotension (CVT-301, 6; placebo, 7) and examiner-rated dyskinesia were similar for both (36-39% mild, 3-6% moderate, and 0% severe). Median time-to-ON was 25.0 min following carbidopa/levodopa + CVT-301 and 35.5 min following carbidopa/levodopa + placebo (P = 0.26). At 30 min, more patients had turned ON following carbidopa/levodopa + CVT-301 administration (66.7%), compared with carbidopa/levodopa + placebo (44.5%) (P = 0.040). CONCLUSION: Single doses of CVT-301 84 mg administered with oral carbidopa/levodopa for early morning OFF symptoms were well-tolerated, with no notable safety concerns.

Activator protein-1 and caspase 8 mediate p38α MAPK-dependent cardiomyocyte apoptosis induced by palmitic acid.

Lipoapoptosis of cardiomyocytes may underlie diabetic cardiomyopathy. Numerous forms of cardiomyopathies share a common end-pathway in which apoptotic loss of cardiomyocytes is mediated by p38α mitogen activated protein kinase (MAPK). Although we have previously shown that palmitic acid (PA), a saturated fatty acid (SFA) elevated in plasma of type 2 diabetes mellitus and morbid obesity, induces apoptosis in cardiomyocytes via p38α MAPK-dependent signaling, the downstream cascade events that cause cell death remain unknown. The objective of this study was to investigate mechanisms involved in palmitic acid-induced cardiomyocyte apoptosis. Human adult ventricular cardiomyocyte line (AC16 cells) exposed to high physiological levels of PA for 16 h showed enhanced transcription and phosphorylation of c-fos and c-jun subunits of AP-1 and transcription of caspase 8. When AC16 cells were transfected with small interfering RNA specific against p38α MAPK (si-p38α) for 24 or 48 h, the amplified phosphorylation of c-fos was dose-dependently attenuated, and procaspase 8 was dose-dependently reduced. With translational knockdown of c-fos, PA-induced apoptosis was diminished. Inhibition of caspase 8 for 24 h reduced apoptosis in PA-treated cardiomyocytes. These findings provide evidence for induction of apoptosis in cardiomyocytes exposed to high SFA by a novel pathway requiring activation of c-fos/AP-1 and caspase 8. These results demonstrate how elevated plasma SFA may lead to continual and cumulative loss of cardiomyocytes and potentially contribute to the development of diabetic cardiomyopathy.

Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Patients with Parkinson's disease chronically treated with levodopa commonly have delayed or unpredictable onset of its benefits after oral intake. In this study, we assessed the safety and efficacy of CVT-301, a self-administered levodopa oral inhalation powder, for the treatment of patients with Parkinson's disease during off periods. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, patients were recruited at 65 sites in Canada, Poland, Spain, and the USA. Eligible participants were patients with Parkinson's disease aged 30-85 years, who had daily off periods of 2 h or longer and showed an improvement of 25% or greater in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score from off to on state after use of an oral levodopa plus a dopa-decarboxylase inhibitor combination. Patients were assigned (1:1:1) with a computer-generated randomisation code, in fixed blocks of six, to either CVT-301 60 mg, CVT-301 84 mg, or placebo. Spirometry results and modified Hoehn and Yahr disease stage at screening were used for stratification of treatment groups. Patients, the sponsor, and site personnel were masked to treatment assignment. Each study dose consisted of two capsules administered with an inhaler. Patients were instructed to use the study drug as needed for off periods, and could self-administer up to five doses per day. The primary endpoint was the change in UPDRS motor score from predose to 30 min postdose, assessed at week 12 during an in-clinic off period, in the CVT-301 84 mg group compared with the placebo group. Analysis was by intention to treat. Safety was assessed in all patients who received at least one dose of experimental treatment. This trial is registered with ClinicalTrials.gov, number NCT02240030. FINDINGS: Between Dec 4, 2014, and Aug 26, 2016, 351 patients were enrolled and randomly assigned to receive CVT-301 60 mg (115 patients), CVT-301 84 mg (120 patients), or placebo (116 patients). Of these, 339 received the assigned study treatment (CVT-301 60 mg, n=113; CVT-301 84 mg, n=114; placebo, n=112) and 290 completed the study (CVT-301 60 mg, n=96; CVT-301 84 mg, n=97; placebo, n=97). The least-squares mean difference in UPDRS motor score change from predose to 30 min postdose was -5·91 (SE 1·50, 95% CI -8·86 to -2·96) for the placebo group and -9·83 (1·51; -12·79 to -6·87) for the CVT-301 84 mg group (between-group difference -3·92 [-6·84 to -1·00]; p=0·0088). Treatments were safe and well tolerated. Severe adverse events were reported by 2 (2%) of 112 patients in the placebo group, 7 (6%) of 113 in the CVT-301 60 mg group, and 5 (4%) of 114 in the CVT-301 84 mg group, with no severe adverse event occurring in more than one patient in any treatment group. 11 (3%) of 339 patients had 19 serious adverse events (three [3%] of 112 patients in placebo, six [5%] of 113 in CVT-301 60 mg, and two [2%] of 114 in CVT-301 84 mg). Of these, hypotension and atrial fibrillation were assessed by investigators to be possibly related to the study drug. INTERPRETATION: CVT-301 can improve UPDRS motor scores of patients with Parkinson's disease during in-clinic off periods, with few severe or serious adverse events. The long-term safety and efficacy of CVT-301 need to be investigated in future studies. FUNDING: Acorda Therapeutics.

p38α mitogen-activated kinase mediates cardiomyocyte apoptosis induced by palmitate.

RATIONALE: The mechanisms underlying lipotoxic/diabetic cardiomyopathy remain poorly understood. Saturated fatty acid (SFA) levels, elevated in obesity and type 2 diabetes, induce apoptosis in many cell types including cardiomyocytes. Signaling pathways, including the p38α mitogen-activated kinase (MAPK)-dependent pathway, have been implicated in apoptosis due to a diverse range of insults. OBJECTIVE: We tested the hypothesis that SFA-induced cardiomyocyte apoptosis is dependent on p38α activation. METHODS AND RESULTS: Human adult ventricular cardiomyocytes (AC16 cells) were exposed to high physiological levels of palmitate (PA), a SFA. The apoptotic response was measured using annexin-V by flow cytometry, and the p38α-dependent pathway was evaluated using a p38 inhibitor PD169316, and by p38α small interfering RNA (siRNA) knockdown. PA exposure for 16 h dose-dependently increased apoptosis in AC16 cardiomyocytes (control: 2.6±0.6%, 150 µM PA: 3.5±0.9%, 300 µM PA: 11.5±1.6%, n=4, p<0.01). PA did not change total p38α protein levels, but increased p38α phosphorylation dose-dependently (n=5, p<0.01). PD169316 tended to reduce PA-induced apoptosis (n=4, p=0.05). Specific p38α siRNA markedly reduced the expression of p38α but not p38ß (n=3, p<0.0001), and dose-dependently attenuated PA-induced apoptosis (control siRNA: 7.7±1.0%, 300 µM PA: 34.4±5.0%, 300 µM PA+30 pmol siRNA: 23.7±4.4%, 300 µM PA+60 pmol siRNA: 19.7±2.6%, 300 µM PA+120 pmol siRNA: 17.3±2.8%, n=4, p<0.0001). CONCLUSIONS: These results demonstrate that PA induces p38α activation, and reducing p38α expression attenuates PA-induced cardiomyocyte apoptosis. Our results support a potential mechanism by which high plasma SFA levels through p38α activation may lead to the development of lipotoxic/diabetic cardiomyopathy.

Growing collateral arteries on demand.

Recent studies have significantly advanced our understanding of arteriogenesis, raising hope that therapies to increase collateral arterial formation may become important new tools in the treatment of ischemic disease. The most important initiating trigger for arteriogenesis is the marked increase in shear stress which is sensed by the endothelium and leads to characteristic changes. Intracellularly, it was shown that platelet endothelial cell adhesion molecule (PECAM-1) becomes tyrosine-phosphorylated in response to increased shear stress, suggesting a role as a possible mechanoreceptor for dynamic and continual monitoring of shear stress. The signal generated by PECAM-1 leads to the activation of the Rho pathway among others. More than 40 genes have been shown to have a shear stress responsive element. The Rho pathway is activated early and appears to be essential to the arteriogenic response as inhibiting it abolished the effect of fluid shear stress. Overexpression of a Rho pathway member, Actin-binding Rho protein (Abra), led to a 60% increase in collateral perfusion over simple femoral artery occlusion. A patent for the Abra gene has been filed recently. It may be a harbinger of a future where collateral arteries grown on demand may become an effective treatment for ischemic vascular disease.

Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies.

STUDY OBJECTIVE: To evaluate the effects of acetaminophen, naproxen, and acetylsalicylic acid on the pharmacokinetics of the centrally acting analgesic tapentadol in healthy subjects. DESIGN: Two randomized, open-label, crossover, drug-drug interaction studies. SETTING: Clinical research facilities in the United States and Belgium. PARTICIPANTS: Twenty-four healthy adults (2-way crossover study) and 38 healthy adults (3-way crossover study). INTERVENTIONS: In both studies, tapentadol immediate release (IR) 80 mg was administered as a single oral dose alone. In the 2-way crossover study, tapentadol IR was also given with the fifth of seven doses of acetaminophen 1000 mg; in the 3-way crossover study, tapentadol IR was also given with the third of four doses of naproxen 500 mg and the second of two doses of acetylsalicylic acid 325 mg. All treatments were separated by a washout period of 7-14 days. MEASUREMENTS AND MAIN RESULTS: Overall, mean serum concentrations were similar after administration of tapentadol IR alone and after coadministration with acetaminophen or acetylsalicylic acid, and the 90% confidence intervals (CIs) for the ratios of the mean area under the serum concentration-time curve (AUC) from time zero to time of the last measurable concentration (AUC(0-t)) and from time zero extrapolated to infinity (AUC(0-infinity)) and the maximum serum concentration (C(max)) of the combined treatments to those parameters of tapentadol alone were well within 80-125%, representing the accepted range for bioequivalence. Coadministration of naproxen did not significantly alter the C(max) of tapentadol, although a slightly higher serum tapentadol exposure relative to tapentadol alone was observed. Coadministration of naproxen resulted in a mean increase of 17% in AUCs, and the upper limits of the 90% CIs for the ratios of the mean AUC(0-t) and AUC(0-infinity) were slightly outside the upper limit of bioequivalence range of 80-125%(126.47%AUC(0-t) and 126.14%AUC(0-infinity)). CONCLUSION: No clinically relevant changes were noted in the serum concentrations of tapentadol, and accordingly, no dosage adjustments with respect to the investigated pharmacokinetic mechanism of interaction are warranted for the administration of tapentadol given concomitantly with acetaminophen, naproxen, or acetylsalicylic acid.

A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain.

OBJECTIVE: To evaluate the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for management of moderate to severe pain following orthopedic surgery (bunionectomy). METHODS: Randomized patients (N = 901) received oral tapentadol IR 50 or 75 mg, oxycodone HCl IR 10 mg, or placebo every 4-6 h over a 72-h period following surgery. Acetaminophen (< or =2 g) was allowed in the first 12 h after the first dose of study drug. In the primary analysis, tapentadol IR (50 and 75 mg) was evaluated for efficacy superior to placebo and non-inferior to oxycodone HCl IR 10 mg (using sum of pain intensity difference [SPID] over 48 h), and tolerability superior to oxycodone IR (using incidence of treatment-emergent adverse events [TEAEs] of nausea and/or vomiting). RESULTS: Statistically significantly higher mean SPID(48) values were observed with tapentadol IR (50 and 75 mg) and oxycodone HCl IR 10 mg than placebo (all p < 0.001). The efficacy of tapentadol IR 50 mg and 75 mg was non-inferior to oxycodone HCl IR 10 mg. The incidence of TEAEs of nausea and/or vomiting was statistically significantly lower with tapentadol IR 50 mg versus oxycodone IR 10 mg (35 vs. 59%; p < 0.001). No statistically significant difference in the incidence of nausea and/or vomiting was observed between tapentadol IR 75 mg and oxycodone IR 10 mg (51 vs. 59%; p = 0.057). A possible limitation of this study was that the intense dose and patient monitoring may not represent real-world situations and may result in higher incidences of TEAEs than expected in a practice setting; this bias would be similar for all treatment groups. CONCLUSIONS: Clinically meaningful and statistically significant improvements were observed with tapentadol IR 50 mg and 75 mg compared with placebo for the relief of moderate-to-severe acute pain after orthopedic surgery. Tapentadol IR 50 mg and 75 mg were non-inferior to oxycodone HCl IR 10 mg for the treatment of acute pain based on the primary efficacy endpoint of SPID(48) and the pre-specified margin of 48 points. The incidence of nausea and/or vomiting was statistically significantly lower for tapentadol IR 50 mg and numerically lower for tapentadol IR 75 mg than for oxycodone HCl IR 10 mg.

Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study.

OBJECTIVES: The primary objective of this study was to assess the efficacy and tolerability of tapentadol immediate release (IR) in patients who were candidates for joint replacement surgery due to end-stage joint disease. A secondary objective was to compare tapentadol IR with oxycodone HCl IR with respect to efficacy and prespecified tolerability end points. METHODS: This 10-day, Phase III, randomized, double-blind, active- and placebo-controlled study compared the efficacy and tolerability of tapentadol IR, oxycodone HCl IR, and placebo in patients with uncontrolled osteoarthritis pain who were candidates for primary replacement of the hip or knee as a result of end-stage degenerative joint disease. Patients received tapentadol IR 50 mg, tapentadol IR 75 mg, oxycodone HCl IR 10 mg, or placebo every 4 to 6 hours during waking hours. The primary end point was the sum of pain intensity difference (SPID) over 5 days. Secondary efficacy end points included 2- and 10-day SPID; 2-, 5-, and 10-day total pain relief (TOTPAR); and the sum of total pain relief and pain intensity difference (SPRID). Prespecified noninferiority comparisons with oxycodone HCl IR were performed with respect to efficacy (based on 5-day SPID) and tolerability (based on incidence of the reported adverse events (AEs) of nausea and/or vomiting and constipation). RESULTS: Of 666 patients originally enrolled, 659 were included in the efficacy analysis (51% male; 91% white; mean age, 61.2 years; mean weight, 97 kg). Five-day SPID was significantly lower in those treated with tapentadol IR (tapentadol IR 50 mg: least squares mean difference [LSMD] = 101.2 [95% CI, 54.58- 147.89]; tapentadol IR 75 mg: LSMD = 97.5 [95% CI, 51.81-143.26]) or oxycodone HCl IR (LSMD = 111.9 [95% CI, 66.49-157.38]) (all, P < 0.001). Tapentadol IR 50 and 75 mg and oxycodone HCl IR 10 mg were associated with significant reductions in pain intensity compared with placebo, based on 2- and 10-day SPID and 2-, 5-, and 10-day TOTPAR and SPRID (all, P < 0.001). The efficacy of tapentadol IR 50 and 75 mg was noninferior to that of oxycodone HCl IR 10 mg; however, the incidence of selected gastrointestinal AEs (nausea, vomiting, and constipation) was significantly lower for both doses of tapentadol IR compared with oxycodone HCl IR 10 mg (nominal P < 0.001). The odds ratios for nausea and/or vomiting for tapentadol IR 50 and 75 mg relative to oxycodone HCl IR 10 mg were 0.21 (95% CI, 0.128-0.339) and 0.32 (95% CI, 0.204-0.501), respectively; for constipation, the corresponding odds ratios were 0.13 (95% CI, 0.057-0.302) and 0.20 (95% CI, 0.098-0.398). Rates of treatment discontinuation were 18% (28/157) in the tapentadol IR 50-mg group, 26% (43/168) in the tapentadol IR 75-mg group, 35% (60/172) in the oxycodone HCl IR 10-mg group, and 10% (17/169) in the placebo group. In a post hoc analysis, tapentadol IR 50 mg was associated with a significantly lower incidence of treatment discontinuation than was oxycodone HCl IR 10 mg (P < 0.001). CONCLUSIONS: In these patients with uncontrolled osteoarthritis pain who were awaiting joint replacement surgery, tapentadol IR 50 and 75 mg were associated with analgesia that was noninferior to that provided by oxycodone HCl IR 10 mg. Tapentadol treatment was associated with improved gastrointestinal tolerability.

Effects of irradiation on nerve graft vasculature.

Increasing doses of therapeutic irradiation are known to impair nerve regeneration after grafting. One possible factor is the effect of irradiation on the endoneurial vasculature. This study investigates the effects of postoperative irradiation on the size, number, and cross-sectional area of endoneurial vessels in the rat posterior tibial nerve graft model. Sixty-five Sprague-Dawley rats underwent 1.5-cm interposition grafts to the tibial nerve. Postoperatively, they were assigned to one of five groups. The animals in Group 1 were unirradiated controls. Groups 2 to 5 received postoperative irradiation in the amounts of 46, 66, 86, and 106 Gy, respectively. One hundred and twenty days after grafting, sections of the proximal, grafted, and distal nerve were harvested and analyzed with digital morphometry. Statistical analysis of the average vessel area, number of vessels, and total vascular area was performed. The grafted segments of Groups 4 and 5 and the distal segments of all irradiated groups showed a statistically significant decrease in the number of vessels, compared to controls. The average size of the vessel was smaller in the proximal segment of the irradiated groups, compared to controls. There was no difference in size in either the grafted or distal segments of the irradiated groups, compared to controls. The observed changes in the endoneurial vasculature resulted from both the action of regeneration and the effects of irradiation. The irradiation effects appear to be dose-dependent.