Objective: To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory classroom study conducted in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD).Methods: A post hoc analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (N = 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham [SKAMP]-C) and key secondary (secondary efficacy assessments included the SKAMP attention [SKAMP-A], SKAMP-deportment subscale [SKAMP-D], Permanent Product Measure of Performance-number of problems attempted [PERMP-A], PERMP-number of problems correct [PERMP-C]) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's d, to determine "small," (0.2), "medium," (0.5), or "large" (0.8) magnitudes of treatment effects.Results: Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point.Conclusions: AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6-12 years. Trial Registration: clinicaltrials.gov identifier: NCT02083783

ADHD is a risk factor for motor vehicle accidents, including injuries and fatalities, and traffic citations for speeding and license suspension. The focus of this study was to assess the impact of a single dose of amphetamine extended-release tablets (AMPH ER) on driving performance in young adult drivers with ADHD in a laboratory-based simulation environment.

AbstractBackgroundAttention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by pervasive impairment in symptoms of inattention, hyperactivity, and impulsivity. Psychopharmacologic treatment is targeted at the management of symptoms of ADHD, and evidence exists that ADHD persists into adulthood. Clinical practice guidelines recommend a combination of behavior therapy and psychostimulant medication for the treatment of ADHD in children, adolescents, and adults. Psychostimulants are often prescribed for ADHD in adults, and amphetamine long has been considered a mainstay of treatment for this population. As adult patients seek relief from ADHD symptoms early in the workday and into the early evening hours, with fewer required doses, extended-release formulations with an early onset of efficacy and an extended duration of effect are considered very desirable. The amphetamine-extended release tablet (AMPH ER TAB) was developed to provide a portable, easy-to-use amphetamine tablet dosage option that can be chewed or swallowed whole.ObjectivesTo evaluate the efficacy and safety of an Amphetamine Extended-Release Tablet (AMPH ER TAB) in adults with ADHD aged 18 to 60 years. Methods: In a 5-week forced dose-titration phase, eligible subjects were randomized to either oral double-blind AMPH ER TAB 5 mg starting dose or matching placebo, once daily in the morning beginning the day after the Baseline Visit. Subjects were titrated up (5 mg increments) each week. Safety and efficacy assessments were done weekly. After Visit 3, subjects received 20 mg for 14 (3) days before Visit 5 (V5). Subjects who could not tolerate study drugs discontinued. A Permanent Product Measure of Performance (PERMP) placement test was done at Screening or Baseline. At V5, efficacy assessments included the administration of serial PERMPs predose, 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours postdose. The primary efficacy endpoint was the mean PERMP-T score across postdose time points during the Visit 5 serial PERMPs. Safety was monitored by AEs assessed at each visit, C-SSRS, vital signs, weight, and assessment of sleep, appetite, mood, and psychotic AEs.ResultsThe mean postdose PERMP-T score over all postdose time points at V5 was statistically significantly higher in the AMPH ER TAB group vs placebo (302.8 vs 279.6; P = .0043). Common adverse events were decreased appetite, insomnia, and dry mouth. The majority of TEAEs were mild to moderate in severity, and no SAEs were reported.ConclusionThe AMPH ER TAB demonstrated efficacy in the treatment of symptoms of ADHD in adults, with an anticipated safety profile.FundingTris Pharma, Inc.

Objective: To evaluate the efficacy and safety of amphetamine extended-release tablets (AMPH ER TAB) in adults with attention-deficit/hyperactivity disorder (ADHD).Methods: In a 5-week forced-dose titration phase, subjects were randomized to either oral double-blind AMPH ER TAB 5-mg starting dose or matching placebo, once daily in the morning. Safety and efficacy assessments were completed weekly. After visit 3, subjects received 20 mg for 14 ± 3 days before visit 5. At visit 5, efficacy assessments included the administration of serial Permanent Product Measure of Performance (PERMP) tests predose and at 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours postdose. The primary efficacy endpoint was the mean PERMP Total score (PERMP-T) across postdose time points during the visit 5 serial PERMPs. Safety was monitored by adverse events (AEs) assessed at each visit, Columbia Suicide Severity Rating Scale (C-SSRS), vital signs, weight, physical examination, and assessment of sleep, appetite, mood, and psychotic AEs. The study was conducted from February 2019 to October 2019.Results: Of 130 randomized subjects, 127 were in the intent-to-treat (ITT) population and 91 completed the study. The mean PERMP-T across all postdose time points at visit 5 was statistically significantly higher in the AMPH ER TAB group than in the placebo group (302.8 vs 279.6; P = .0043). Numerical differences favoring AMPH ER TAB were seen at all time points, with statistically significant improvements in the AMPH ER TAB group at 30 minutes and 1, 2, 4, 8, and 13 hours postdose, although the 10-, 12-, and 14-hour time points were not significant. Common AEs included decreased appetite, insomnia, and dry mouth. The majority of treatment-emergent AEs were mild to moderate in severity, and no serious AEs, as defined by the US Food and Drug Administration, were reported.Conclusions: AMPH ER TAB demonstrated efficacy in treatment of symptoms of ADHD in adults, with an anticipated safety profile.Trial Registration: ClinicalTrials.gov identifier: NCT03834766.

AbstractBackgroundTo evaluate the relative bioavailability of a single dose of amphetamine extended-release oral suspension (AMPH EROS) compared with a single dose of extended-release mixed amphetamine salts (ER MAS) in healthy, fasted adult subjects.MethodsThe study population consisted of healthy adult volunteers. The study drug used in this study was 7.5 mL of 2.5 mg/mL AMPH EROS equivalent to 18.8 mg of amphetamine base administered after an overnight fast of at least 10 hours. AMPH EROS comprises a 3.2:1 enantiomeric ratio of d-amphetamine to l-amphetamine. The reference product was one 30 mg ER MAS capsule (equivalent to 18.8 mg of amphetamine base). Relative bioavailability between the products was determined by a statistical comparison of the area under the curve and maximum concentration (Cmax) for d-amphetamine and l-amphetamine. PK (PK) blood samples were collected prior to dosing (0-hour) and at 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 36, 48, and 60 hours after drug administration, totaling 20 samples in each period.ResultsThe mean subject age was 35.0 (standard deviation ±8) years, and the overall study population comprised 19 (63.3%) males and 11 (36.7%) females. The contrasts for geometric mean ratios for all assessed PK parameters (for both l- and d-amphetamine) between the test article AMPH EROS and reference product ER MAS fell within the prescribed 80% to 125% limits.ConclusionsThe overall PK profile of single-dose AMPH EROS 7.5 mL was found to be comparable with a single dose of oral ER MAS 30 mg.

PURPOSEThis open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study evaluated the comparative bioavailability between amphetamine extended-release oral suspension (treatment A: AMPH EROS, Dyanavel XR 2.5 mg/mL, 18.8 mg amphetamine base per 7.5 mL) and extended-release mixed amphetamine salts (treatment B: ER MAS, Adderall XR 30 mg capsules, equivalent to 18.8 mg amphetamine base per capsule) after a single dose in healthy adult subjects, under fasted conditions.METHODSThe crossover design allowed for intra-subject PK comparisons. Relative comparable bioavailability was determined by a statistical comparison of the AUC and Cmax parameters for both d- and l-amphetamine, where the geometric mean ratios for AUC and Cmax were within the 90% confidence limits (80.0%-125.0%) to determine comparable bioavailability between test products. Subjects in sequence 1 received treatment A followed by B; subjects in sequence 2 received treatment B followed by treatment A. PK samples were obtained at 0 (pre-dose) through 60 hours post-dose. The safety assessment was based on reported frequency and severity of adverse events.RESULTSThirty (30) subjects were enrolled and 28 completed. The mean age of subjects was 35 years, with a mean BMI of 25.9 kg/m2. Most subjects were Male (63.3%) and Black (56.7%). The geometric mean ratios for Cmax and all AUC measurements were within the 80-125% bound indicating comparable bioavailability between both test products. Both test products were generally well-tolerated with no serious AEs reported.CONCLUSIONSThe bioavailability of a single 7.5 mL dose of AMPH EROS 2.5 mg/mL was comparable to a single 30 mg capsule dose of ER MAS. AMPH EROS (both d- and l-amphetamine) showed equivalent peak and overall exposure to ER MAS under fasted conditions.FUNDINGTris Pharma, Inc.

AbstractMethodsThis Phase 1, open-label, single-dose, one-period, one-treatment PK study enrolled 12 children 6–12 y with ADHD. PK parameters for d- and l-amphetamine in plasma (Cmax, tmax, AUC0–8, and t1/2) were calculated and expressed as means, geometric means, and standard deviations. The primary endpoint was all objective PK measurements at 28 hours post-dose. PK was evaluated for 2 cohorts (6 pts ages 6–9 y and 6 pts aged 10–12 y). Safety was monitored continuously and assessed based on occurrence of adverse events.ResultsA single dose of 10 mg (4 ml) AMPH EROS (2.5 mg/ml) administered under fasted conditions resulted in a rapid rise in mean plasma concentration in d-amphetamine, reaching maximum concentrations within 5 hours. The overall study population mean (SD) plasma AUC0–8 (d-amphetamine) was 1061.2 (309) h*ng/mL, and for l-amphetamine was 380.5 (112) h*ng/mL. The mean maximum concentration (Cmax) for the overall study population was 54.91 ng/mL and 17.1 (5.2) ng/mL for d- and l-amphetamine, respectively. The overall study population median time to maximum concentrations (Tmax) for d-amphetamine were reached at 3.4 hours, and for l-amphetamine at 4.1 hours. The elimination half-life (t1/2) for the entire study cohort was 10.6 (2.0) hours for d-amphetamine, and 12.5 (3.2) hours for l-amphetamine. Directionally, a higher mean Cmax, AUC0–8, AUCt, and median Tmax were observed in the younger (6 to 9-year-old) age group, and this result was consistent with both the d- and l-amphetamine enantiomers. The mean elimination t1/2 for both d- and l-amphetamine was higher in the older cohort (10–12 years) than in the 6 to 12-year-olds. Study drug was well-tolerated by the subjects in this study. Two TEAEs were reported in one subject TEAEs (diarrhea and rash on legs) occurred approximately 12 hours postdose.ConclusionsThis study confirmed that the PK profile of AMPH EROS in 6 to 12-year-olds provided a consistent, predictable extended-release profile in a highly titratable liquid formulation, and this finding was relatively consistent and directionally predictable between the age groups assessed, with higher maximum concentrations and AUCs and shorter elimination half-lives noted in the younger population, with no anomalous parameters demonstrated, and no untoward or unexpected safety issues noted.FundingTris Pharma, Inc.

INTRODUCTION/OBJECTIVE:ADHD is, for many people, a lifelong disease that requires chronic medication use. Stimulant therapy is often recommended as first-line treatment for ADHD. Adherence to stimulant treatment among patients diagnosed with ADHD is poor. Major regulatory agencies have recommended measurement of palatability for new tablet formulations. A new amphetamine extended-release tablet (AMPH ER TAB) for the treatment of attention-deficit/hyperactivity disorder (ADHD) was developed. The AMPH ER TAB has a bubblegum flavor and can be chewed or swallowed whole. In 2016, the FDA developed a draft guidance document on the topic of chewable drug tablet formulation palatability.METHODS:A palatability study of the AMPH ER TAB using the 2016 FDA guidance was conducted. Subjects were asked to assess the taste, aftertaste, and mouthfeel of the tablet formulation using a short questionnaire. Scores from the questionnaire were rated and presented.RESULTS:The substudy assessed 35 subjects with a mean age of 38 (±11) years. Subjects were predominantly male, non-Hispanic, and White. Most subjects rated the oral sensation/mouth feel and taste of the tablet as positive (pleasant to very pleasant) (70.1% and 83.6%, respectively). Additionally, 86.6% of the subjects rated the strength of the taste as neutral (moderate taste) or positive (mild to no taste). Finally, 82.1% of all subjects rated the aftertaste as positive (pleasant to very pleasant) and 92.5% of subjects rated the strength of the aftertaste as neutral or positive (mild to no taste). The trends in evaluation scores for each question were similar regardless of whether the ER chewable tablet was administered under fasted or fed conditions.CONCLUSION:The positive palatability data presented here will be useful for future "real-world" assessments of adherence to treatment with the AMPH ER TAB. Enhanced adherence may bolster the argument that taste, mouthfeel, and aftertaste are critical determinants of treatment adherence.

Abstract:Objectives:Evaluate comparative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB, Tris Pharma, Inc., Monmouth Junction, NJ) 20 mg, swallowed whole or chewed and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; and evaluate whether a PK food effect exists on AMPH ER TAB (contains a 3.2:1 ratio of d- to l-amphetamine).METHODS:Healthy volunteers (18-55 yr) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted).A crossover design was used. Samples were collected each period pre-dose and at time points to 60 h post-dose. D-and l-amphetamine were measured, and PK was calculated (90% CIs of the ratios of the geometric mean plasma levels) for Cmax, AUCt, and AUC0∞. Comparative bioavailability was determined when ratios were within 80 and 125%. Safety was also assessed.RESULTS:32 subjects completed the study. Based on the calculated bioavailability ratios, for AMPH ER TAB swallowed vs. AMPH EROS fasted: d-amphetamine total and peak exposures were found to be similar: AUC0-t: 100.68-108.08%, AUC0-∞:101.47-109.52%, Cmax: 98.10-103.17%. For l-amphetamine, the total and peak exposures were similar: AUC0-t: 100.31-108.57%, AUC0-∞:101.27-111.09%, Cmax: 98.2-103.37%.AMPH ER TAB chewed vs. AMPH EROS fasted: For d-amphetamine, the total and peak exposures were similar: AUC0-t: 99.23-106.62%, AUC0-∞: 99.58-107.59%, Cmax: 99.91-105.14%. For l-amphetamine, the total and peak exposure was similar: AUC0-t: 98.16-106.35%, AUC0-∞: 98.44-108.11%, Cmax: 99.53-104.75%.Food effect: AMPH ER TAB, chewed, fasted vs. fed: For d-amphetamine, the total and peak exposure was similar: AUC0-t: 92.57-99.49%, AUC0-∞: 91.12-98.48%, Cmax: 94.22-99.17%.For l-amphetamine, the total and peak exposure was similar: AUC0-t: 91.27-98.91%, AUC0-∞: 88.44-97.17%, Cmax: 94.52-99.50%).No serious AEs were reported during the conduct of this study, and the AE profiles were observed to be similar in frequency of events and severity to other amphetamine formulations used in ADHD.CONCLUSIONS:Bioavailability of single dose of AMPH ER TAB for both d- and l-amphetamine was comparable, swallowed whole or chewed, to an equivalent 20 mg dose of the reference product AMPH EROS, 2.5 mg/mL fasted, and showed equivalent peak and overall exposure.No food effect was observed for AMPH ER TAB administered chewed. All AEs were mild in severity and AE profiles were similar to other amphetamine formulations used for treatment of ADHD.Funding Acknowledgements:Tris Pharma, Inc.

Most subjects rated the oral sensation and taste as pleasant or very pleasant, whether chewed under fasted conditions or after a meal. With respect to the taste strength, most subjects rated it as moderate (chewed under fasted conditions) or mild/no taste (chewed after a meal). Aftertaste was rated as pleasant or very pleasant in most subjects, with the strength as moderate (chewed under fasted conditions) or mild/no aftertaste (chewed after a meal). AMPH ER Tablets provided an overall pleasant taste and mouthfeel experience for patients.Funding Acknowledgements: Tris Pharma, Inc.

AMPH EROS is an extended-release oral suspension amphetamine (ratio of 3.2 to 1 d- to l-amphetamine) for the treatment of ADHD in patients aged ≥6 years old. To support product labeling, the pharmacokinetics (PK) of AMPH EROS in adults (≥17 years old) and children (6-12 years old) were described in Studies A and B, respectively. We simulated adolescent PK using the PK of AMPH EROS in adults and children. PK simulations were employed to project the PK in adolescents to guide dosing.

ObjectiveTo determine whether amphetamine extended-release oralsuspension (AMPH EROS) has an onset of effect at 30minutes postdose inchildren with ADHD.MethodsThis randomized, double-blind, 2-treatment, 2-sequence, placebo-controlled crossover pilot study enrolled subjects aged 6 to 12 years withattention-deficit/hyperactivity disorder (ADHD) and ADHD-Rating Scale-5 scores of ≥90th percentile for sex and age. A dose of 5 to 20mg/day of AMPH EROS was determined during a 1-week open-label phase based on medication history, symptom control, and tolerability. Subjects completed a practice laboratory classroom then received one day of double-blind active drug or placebo each in random sequence during 2 double-blind laboratory classroom days. Subjects completed the first double-blind laboratory classroom session, returned to open label drug for 5days then crossed over on day 6 during a second double-blind laboratory classroom session. DB dose was fixed at AMPH EROS 15, 17.5, or 20mg . The primary endpoint was change from predose in the Swanson, Kotkin, Agler, M-Flynn, Pelham rating scale-combined score (SKAMP-C) at 30minutes postdose on two DB days. The key secondary endpoint was change from predose in the SKAMP-C score at 3hours postdose for AMPH EROS compared with placebo. Safety assessments included vital signs and adverse events.ResultsEighteen subjects were enrolled in the study (14 males and 4 females) with a mean age of 9 years. At both 30minutes and 3hours postdose, changes from baseline in SKAMP-C for AMPH EROS vs. placebo were statistically significant (p<0.01 and p=0.0002, respectively) with corresponding effect sizes of 0.96 and 1.57. Adverse events (>10%) during the open-label phase included upper respiratory tract infection, fatigue, upper abdominal pain, headache, decreased appetite, and affect lability.ConclusionsAMPH EROS was effective in reducing ADHD symptoms at 30minutes postdose. AEs were mild or moderate and consistent with those of other extended-release amphetamines.Funding Acknowledgements: Support was provided by Tris Pharma, Inc.

The objective of this study was to evaluate the pharmacokinetics (PK) of fasting conditions with a single dose of 10 mg of amphetamine extended-release oral suspension (AMPH EROS; 2.5 mg/ml) in pediatric patients with ADHD (ages 6–12 years). AMPH EROS comprises a 3.2:1 ratio of d- and l-amphetamine delivered using the LiquiXR drug technology.

AbstractThe proprietary immediate and extended drug delivery technology LiquiXR™ utilizes an ion-exchange resin that complexes with amphetamine or any other active moiety that can be protonated and is water-soluble. The active drug product forms a complex with ion-exchange polymers contained in the resin, which is then formed into micron-sized particles. Some of these particles are coated with an aqueous, pH-independent polymer designed to provide immediate or sustained release of active drug product. The polymer coating applied to the ion-exchange resin particles is of varying thickness, allowing for programmed, extended release of active drug product. Solid, coating-free particles provide for immediate release of active drug product.The micron-sized particles are formulated into an appropriate dosage form (solid or chewable tablet, liquid suspension, orally disintegrating tablet, film, or capsules). Active drug product is subsequently released from the dosage form in millions of particles, with the release driven by a combination of ion exchange and diffusion. After drug release, the ion-exchange resin is excreted in the feces.The release characteristics of LiquiXR™ are programmable and allow for a customized, sustained release of active drug product for up to 24hours post-dose. Mechanistically, drug particles enter the gastrointestinal tract. As positively-charged ions from gastrointestinal (GI) fluids diffuse across the coating, ionically-charged drug product diffuses through the coating and into the GI fluids for absorption. As the coating is of variable thickness, some drug product takes longer to diffuse and absorb, providing for the programmable delayed drug release characteristic.The LiquiXR™ drug delivery technology is utilized in Dyanavel® XR (amphetamine extended-release oral suspension; AMPH EROS), which is indicated for the treatment of attention-deficit hyperactivity disorder. It comprises 2.5mg/mL amphetamine base complexed with LiquiXR technology to provide an immediate release component followed by an extended-release profile. The efficacy of AMPH EROS was established in children ages 6 to 12 years in a Phase 3, placebo-controlled laboratory classroom study. In that study, attention-deficit/hyperactivity disorder (ADHD) symptoms in children on an individually optimized dose of amphetamine (range 10–20mg/day) were statistically significantly improved compared with symptoms in children treated with placebo. For children treated with AMPH EROS, onset of effect was demonstrated at 1hour after dosing, and efficacy was observed through 13hours post-dose. The effect size was comparable to effect sizes demonstrated for other psychostimulants tested in studies using a similar design. The efficacy data reported for AMPH EROS provides an excellent example of the potential utility and clinical application for other active drug products requiring an immediate release and extended release profile.Funding Acknowledgements: This work was funded by Tris Pharma, Inc.

OBJECTIVESTo determine the efficacy and safety of amphetamine extended-release oral suspension (AMPH EROS) in the treatment of attention-deficit/hyperactivity disorder (ADHD) compared with placebo in a dose-optimized, randomized, double-blind study.METHODSThe efficacy of AMPH EROS was evaluated in a laboratory classroom study conducted in 108 pediatric patients (aged 6-12 years) with ADHD. The study began with an open-label dose optimization (5weeks) with an initial AMPH EROS dose of 2.5 or 5mg once daily in the morning. The dose could be titrated every 4-7 days in increments of 2.5-10mg until an optimal dose or the maximum dose of 20mg/day was reached. Subjects were required to tolerate a minimal dose of 10mg/day. Subjects then entered a 1-week randomized, double-blind treatment phase with the individually optimized dose or placebo. At the end of the week, raters evaluated the attention and behavior of the subjects in a laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP-C) rating scale. SKAMP-C is a 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting.The primary efficacy endpoint was change from pre-dose in the SKAMP-C score at 4hours post dose. The key secondary endpoint efficacy parameters were onset and duration of clinical effect. The change scores from pre-dose SKAMP-C scores at post dose time points (1, 2, 6, 8, 10, 12 and 13hours) were used to evaluate the key secondary efficacy endpoints.RESULTSMore boys (68.7%) than girls participated in the study. The study population was 55.6% white, most patients had inattentive or combined type ADHD presentations. The primary efficacy endpoint, the change from pre-dose SKAMP-C score at 4hours post dose was statistically significantly improved (p5%) reported during the dose optimization phase were decreased appetite, insomnia, affect lability, upper abdominal pain, mood swings, and headache.CONCLUSIONSAMPH EROS was effective in reducing symptoms or ADHD from 1 to 13hours after dosing. Adverse events reported were consistent with those of other amphetamine products.Funding Acknowledgements: This study was supported by Tris Pharma, Inc.

The primary objective of this pharmacokinetic (PK) study was to evaluate the primary PK of amphetamine extended-release oral suspension (AMPH EROS) in preschool-age children (ages 4–5 years) after a single dose of 2.5 mg/mL. The data from the present study are intended to guide appropriate dosing for future safety and efficacy studies with AMPH EROS in the preschool-aged patient population (ages 4–5 years).

AMPH EROS was effective in reducing symptoms of ADHD in this open-label dose optimization. The AE profile of AMPH EROS was consistent with those of other amphetamine products.Funding Acknowledgements: This work was funded by Tris Pharma, Inc.

Purpose: This single-dose pivotal study evaluated the pharmacokinetics of amphetamine extended-release oral suspension (AMPH EROS) under fasted and fed conditions and the relative bioavailability of AMPH EROS and immediate-release mixed amphetamine salts (IR MAS) in adults. Methods: This open-label, randomized, three-period, three-treatment, six-sequence crossover study enrolled 30 healthy adult participants who were randomly assigned to receive either 1 dose of AMPH EROS 18.8 mg under fed or fasted conditions or 30 mg of IR MAS under fasted conditions. Participants crossed over with a 7-day washout period between each of the three periods. Plasma samples were measured for Cmax, AUC0- t, AUC0-5, AUC5- t, and AUC0-∞ for comparative bioavailability. Results: The geometric mean ratios for Cmax, AUC0- t, and AUC0-∞ were within the 90% confidence limits [80.0%, 125.0%] for comparable bioavailability. There was no food effect for AMPH EROS. Both the AMPH EROS and IR MAS formulations were generally well tolerated with no serious adverse events reported. Conclusions: The bioavailability of a single dose of AMPH EROS was comparable to two 15 mg doses of IR MAS, given 4 hr apart, with no food effect or safety concerns observed.

Objective: To determine whether amphetamine extended-release oral suspension (AMPH EROS) has an onset of effect at 30 minutes postdose in children with attention-deficit/hyperactivity disorder (ADHD). Methods: This randomized, double-blind, two-treatment, two-sequence, placebo-controlled crossover pilot study enrolled subjects aged 6-12 years with ADHD and ADHD-Rating Scale-5 scores of 90th percentile for sex and age. An optimized dose of 5-20mg/day of AMPH EROS was determined during a 1-week open-label dose optimization phase based on medication history, symptom control, and tolerability. Subjects completed a practice laboratory classroom then received 1 day of double-blind active drug or placebo each in random sequence during two double-blind laboratory classroom days. Subjects completed the first double-blind laboratory classroom, returned to open-label drug for 5 days, and then crossed over on day 6 during a second double-blind laboratory classroom. Double-blind dose was fixed at AMPH EROS 15, 17.5, or 20mg. The primary end point was change from predose in the Swanson, Kotkin, Agler, M-Flynn, Pelham-Combined (SKAMP-C) Rating Scale score at 30 minutes postdose on two double-blind days. The key secondary end points were change from predose in the SKAMP-C score at 3 hours postdose for AMPH EROS compared with placebo and change from baseline Permanent Product Measure of Performance (PERMP) scores at 30 minutes and 3 hours postdose compared with placebo. Safety assessments included vital signs and adverse events (AEs). Results: Eighteen subjects were enrolled in the study (14 males and 4 females) with a mean age of 9 years. At both 30 minutes and 3 hours postdose, changes from baseline in SKAMP-C for AMPH EROS versus placebo were statistically significant (p<0.01 and p=0.0002, respectively). PERMP scores were not statistically significantly improved at 30 minutes postdose for AMPH EROS relative to the placebo group. PERMP scores were statistically significantly improved at 3 hours postdose for AMPH EROS relative to the placebo group (PERMP problems attempted treatment difference least-squares [LS] mean [SE]=60.3 [12.93], p=0.0003; PERMP problems correct treatment difference LS mean [SE]=61.6 [13.16], p=0.0003). AEs (>10%) during the open-label phase included upper respiratory tract infection, fatigue, upper abdominal pain, headache, decreased appetite, and affect lability. Conclusions: AMPH EROS was effective in reducing ADHD symptoms at 30 minutes postdose as indicated by SKAMP-C score improvement, although improvements in PERMP scores at 30 minutes were not statistically significant. AEs were mild or moderate and consistent with those of other extended-release amphetamines.