A Randomized,Phase 3,Double-Blind,Crossover Comparison of Multilayer,Extended-Release Methylphenidate (PRC-063),and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD

Abstract

Objective:

To compare PRC-063 (multilayer-release methylphenidate) and lisdexamfetamine dimesylate (LDX) on the driving performance of young adults with attention deficit hyperactivity disorder (ADHD) in a randomized, double-blind, crossover study.

Method:

Following up to 21 days of each treatment in each treatment course (PRC-063/LDX or LDX/PRC-063), subjects completed a 15-hour driving simulator laboratory assessment. The primary outcome measure was the Tactical Driving Quotient (TDQ) and the Clinical Global Impressions-Improvement (CGI-I) scale was a secondary outcome measure.

Results:

Forty-four subjects completed the study. PRC-063 and LDX had equivalent effects on driving performance through a 15-hour time period (least square mean difference −0.3 [standard error 1.08], 95% confidence interval [−2.4, 1.8], p = .793). Consistent improvement in CGI-I was observed. The incidence of treatment-emergent adverse events was similar for each treatment sequence.

Conclusions:

PRC-063 and LDX had comparable effects on driving performance, from 1 through 15 hours, the last time point measured.

Keywords

ADHD simulated driving performance methylphenidate lisdexamfetamine dimesylate PRC-063

Introduction

ADHD is characterized by a persistent pattern of inattention, hyperactivity, and impulsivity (American Psychiatric Association, 2013). Sixty percent of individuals diagnosed with ADHD in childhood and adolescence demonstrate symptom persistence in adulthood (Sibley et al., 2017). The overall prevalence of ADHD in adults in the United States is 4.4% (Kessler et al., 2006). In adulthood, ADHD has implications for academic performance, work performance, driving safety, and social and emotional functioning (Weiss & Hechtman, 1993).

Adults and adolescents with ADHD have a greater risk of collisions when driving than those without ADHD (Chang et al., 2014) and untreated ADHD is associated with an increased risk of automobile accidents (Barkley & Cox, 2007; Chang et al., 2014). Motor vehicle collisions are a leading cause of death among teenagers (Cunningham et al., 2018). Teenagers with ADHD are two to four times more likely to be in an accident, four times more likely to be involved in an at-fault accident, and three times more likely to be injured in an accident (Barkley & Cox, 2007; Barkley et al., 1996). Adults with ADHD perform worse than those without ADHD on driving simulator studies, even when their self-rated driving skills are comparable (Knouse et al., 2005). Collision rates of male ADHD drivers increase with age, while female ADHD drivers experience fewer collisions during middle age, similar to the general population (D. J. Cox, Cox, & Cox, 2011). Because of these potentially serious impairments, management of ADHD is not limited to one’s school, college, or workplace, but extends to several other aspects of life, such as driving (Madaan & Cox, 2017). There is a paucity of real-world functional outcomes, such as driving assessments, in the young adult ADHD population to support the standard Phase 3 clinical trials that are typically centered on ADHD symptom reduction.

Stimulants are widely considered the treatment of choice for managing ADHD. In particular, long-acting stimulants are accepted as the optimal first choice as they diminish the need for multiple dosages during the day and augment compliance, symptom coverage, and treatment response (Canadian ADHD Resource Alliance [CADDRA], 2018). While both classes of stimulant medication (methylphenidate [MPH] and amphetamines) have similar efficacy overall, individual patients may respond preferentially to or tolerate one class of medication better than the other (Arnold, 2000). It is useful to have rapid- and long-acting preparations for each class of stimulant molecule to facilitate individualization of patient treatment and to help manage ADHD symptoms during early morning and late evening driving.

The efficacy of MPH, amphetamine salts, and lisdexamfetamine dimesylate (LDX) on ADHD-related driving performance in adolescents and young adults has been demonstrated in numerous systematic reviews and meta-analyses (Boland et al., 2020; Gobbo & Louza, 2014; Pievsky & McGrath, 2018; Surman et al., 2017). Cox et al. have shown improvements in driving performance (D. J. Cox, Merkel, et al., 2004) and fewer attentive errors (D. J. Cox, Humphrey et al., 2004) with osmotic-release oral system-MPH (OROS-MPH). In a driving simulator study that compared two extended-release stimulants (72 mg OROS MPH and 30 mg extended-release mixed amphetamine salts [se-AMPH ER]) and placebo in 35 ADHD adolescents at 9, 12, and 15 hours post-dose, greater improvements in impaired driving scores were reported with OROS-MPH compared to placebo (D. J. Cox et al., 2006). Adults treated with OROS MPH had significantly less time driving off the road, fewer instances with speeding, less erratic speed control, more time at stop signs, and less “inappropriate” use of breaks compared to adults treated with placebo (D. J. Cox et al., 2006). In a randomized, double-blind, placebo-controlled study of LDX using a driving simulator in 61 young adults with ADHD, a reduction in risky behaviors associated with driving and faster reaction time were observed when subjects received LDX versus placebo (Biederman et al., 2012).

PRC-063 capsules (currently marketed as Foquest^® in Canada and Adhansia XR^® in the United States) are a once-daily, multilayer, extended-release formulation of MPH hydrochloride formulated using multilayer-release (MLR^®) bead technology, which allows for an initial peak concentration at approximately 1.5 hours post-dose and a subsequent, more prolonged peak later in the day (Katzman et al., 2020). When titrated to optimal dose, PRC-063 has demonstrated efficacy from 1 hour post-dose to 16 hours post-dose in a double-blind, placebo-controlled adult laboratory classroom study (A. Childress et al., 2022) and from 1 hour post-dose to 13 hours post-dose (the last time point measured) in a double-blind, placebo-controlled laboratory classroom study of children aged 6 to 12 years (A. C. Childress et al., 2020). The rapid onset and long duration of symptom reduction effects of PRC-063 may prove beneficial in the reduction of risky driving behavior and collision rates in young adults with ADHD. There have been few head-to-head, randomized, double-blind comparisons of ADHD treatments on functional outcomes. This randomized, double-blind, crossover study compared the treatment effects of PRC-063 and LDX on driving performance of young adult participants with ADHD in a driver simulator setting over a 15-hour period following dosing. This study hypothesized that both medications would lead to similar performances on a sophisticated driving simulator.

Method

Study Design

This was a dose-optimized, randomized, double-blind, crossover, phase 3, single-center, non-inferiority study conducted at the University of Virginia Center for Psychopharmacology Research in Youth and at the University of Virginia Medical Center’s Virginia Driving Safety Laboratory.

The study consisted of six components: (1) screening; (2) phase one titration; (3) driving simulator laboratory day 1; (4) phase two titration; (5) driving simulator laboratory day 2; and (6) study completion and safety follow-up (Figure 1).

Figure 1.

Study design schematic.

During screening, subjects provided informed consent and were assessed for inclusion/exclusion criteria and medical history, and evaluated using Structured Clinical Interview for DSM-5 Clinical Trials version (SCID-5-CT) and Columbia Suicide Severity Rating Scale (C-SSRS). A physical exam was conducted and subjects were required to discontinue any current medication for ADHD. Subjects completed the Kaufman Brief Intelligence Test, Second Edition (KBIT-2), provided self-report of risky driving behaviors using the Cox Assessment of Risky Driving-3 (CARD-3), and completed an abbreviated simulator screening test to familiarize with the simulator and determine the potential for developing “Simulation Adaptation Syndrome,” which includes disruptive symptoms such as nausea, dizziness, and disorientation. This is experienced by some individuals sensitive to incongruent visual cues of motion with vestibular sensations of being stationary (D. J. Cox, Singh, & Cox, 2011; Galvez-Garcia et al., 2017).

Following 5 to 14 days of washout, patients returned to the clinic and were randomized to receive either a 21-day course of PRC-063 followed by a 21-day course of LDX capsules, or vice versa. Subjects and staff were blinded to the identity of the treatment being administered.

During phase 1 and phase 2, dose titration occurred weekly with both treatments. Subjects were randomized to receive a starting dose of either 45 mg/day of PRC-063 or 30 mg/day of LDX and were titrated to a final dose of the same medication (45, 70, or 100 mg/day of PRC-063 or 30, 50, or 70 mg/day of LDX) over two subsequent visits. Subjects were deemed to have reached optimal dose if they were rated “much improved” or “very much improved” on the Clinical Global Impressions Improvement (CGI-I) scale based upon the prior week or if the subject was rated “minimally improved,” but treatment emergent adverse events (TEAEs) prevented a dose increase.

Following 21 days of treatment, with at least 7 days of treatment at optimal dose, subjects completed driving simulator laboratory day 1. Subsequently, subjects were crossed over to the opposite treatment for phase two dose titration for an additional 21 days of treatment and underwent dose optimization and driving simulator laboratory day 2 in an identical fashion. Since steady state for both treatments is reached by Day 5, and both laboratory days were 21 days apart, no washout period was added between treatments (Katzman et al., 2020; Krishnan & Stark, 2008). A safety follow-up was conducted 14-days after study completion

The study was conducted in compliance with the study protocol, Good Clinical Practice, and the applicable regulatory requirements. The sponsor (Rhodes Pharma LP) maintained oversight and management of the study. The protocol was registered on the National Institute of Health’s National Library of Medicine Web site (clinicaltrials.gov, identifier NCT02555150) and was approved by the University of Virginia IRB for Health Sciences Research.

Subjects

Enrolled subjects must have been male or female young adult drivers aged 18 to 35 years meeting the current DSM-5 diagnosis for ADHD based on clinician assessment using the SCID-5-CT. To be eligible for the study, subjects were required to have a valid driver’s license and ≥6 months driving experience with driving activity at least twice per week; willing to use a reliable method contraception; an IQ score of ≥80 based on the Kaufman Brief Intelligence Test, Second Edition (KBIT-2); and provided written consent to participate in the study.

Exclusion criteria included allergy to or a history of serious adverse reactions to MPH or LDX; non-response (defined as MPH or LDX use at various doses for ≥4 weeks at each dose with little or no clinical benefit in the last 10 years) to MPH or LDX treatment; history of motion, sea, or “big screen” sickness; report of greater than “a little” dizziness or nausea following the abbreviated simulator screening test; coexisting medical condition or medication usage known to interfere with the safe administration of stimulant medications; or any clinically-significant abnormalities in ECG, laboratory values, or vital signs, as assessed at screening.

Driving Simulator and Procedures

On the driving simulator laboratory day, subjects registered into the clinic at 7:30 a.m. and were observed taking study medication. Each subject completed four driving simulator laboratory sessions at 1, 9, 12, and 15 hours post-dose. The Driver Guidance System simulator recorded the driving performance scores during four approximately 90-minute simulator sessions, which included tactical drives of approximately 20 minutes designed to evaluate tactical driving skills. The simulator consisted of a driver’s seat, steering wheel, gas and brake pedals, turn signal, dashboard, right, center and left rear-view mirrors, and air conditioning, situated within an 8-foot cylinder displaying a 210° image of a virtual world on a curved white screen. The display was created by aligning and synchronizing 70° images from three projectors (InFocus, model IN2106, with a resolution of 1,280 × 800 and a refresh rate of 120 frames/second). Subjects were seated 4 ft. from the display screen.

Outcomes

Primary Outcome

The primary outcome measure was the Tactical Driving Quotient (TDQ), an overall measure of driving performance that consisted of 15 unique performance variables from the tactical driving test. The tactical driving test is performed in a virtual environment and involves driving on a standardized route, which includes 2.6 miles of rural, 4.3 miles of highway, and 2 miles of urban roads. The test monitors 31 performance variables which are grouped conceptually into four primary skill areas: swerving, rolling stops, speeding, and collisions. The 15 selected variables (see Supplemental Table 1) were selected a priori based on evidence from the Virginia Department of Motor Vehicles (DMV) VRDS normative sample (448 adults, ages: 25–70 years; Cox, 2014), These variables significantly predict on-road accident rates and have been used in previously published studies (S. M. Cox et al., 2016). For each patient, the raw score for each tactile variable was converted to a z-score, calculated based on the mean and standard deviation (SD) of performance of all participants during all four drives across both driving laboratory days. These z-scores were then normalized to a mean of 100 and a standard deviation of 15 (e.g., for a participant achieving a z-score of +1.0 for driving “off road” during the 08:00 testing, the performance during that testing was one standard deviation better than all participants’ performances across four testing days on both medications). The z-scores for each variable were averaged to calculate a Tactical Composite score for each simulator run for each patient. The normal range of driving (±1.0 SD) is 85 to 115. A TDQ of <100 represents worse-than-average driving and a TDQ >100 represents better-than-average driving.

Secondary Outcomes

The Cox Assessment of Risky Driving-3 (CARDS-3; D. J. Cox et al., 2008) was included as a secondary outcome measure. Participants completed the CARDS-3 questionnaire each time they were evaluated for a psychiatric assessment. The questionnaire presented 31 risk driving maneuvers (e.g., ran a red light) that the participant had to report how often the event happened in the past week (0, 1, 2, 3, or 4 or more times). The CARDS-3 was scored by summing the numbers endorsed, with total scores ranging from 0 to 124.

The Clinical Global Impressions-Improvement (CGI-I) scale provides a global evaluation of baseline severity and improvement over time and measures global impressions of severity from visit to visit but not over the course of the day (Guy, 1976). The clinician used the CGI-I to rate improvement relative to baseline on a scale ranging from 1 (very much improved) to 7 (very much worse) plus a “not assessed” option.

Also examined as secondary outcomes were the CGI-Improvement (CGI-I) scale, pairwise comparisons of TDQ at individual time points (1, 9, 12, and 15 hours), as well as a comparison of the mean z-scores of the 15 individual performance variables that comprise the TDQ.

Safety Outcomes

Safety outcomes included spontaneously reported adverse events (AEs), clinical laboratory chemistry, hematology and urinalysis, electrocardiograms (ECGs), vital signs, physical examination, and the C-SSRS. The C-SSRS is a clinician-administered tool that covers the wide spectrum of suicidality from ideation to behavior that facilitates prospective, systematic monitoring for emergence of suicidality within clinical trials (Posner et al., 2011). Baseline/Screening version and Since Last Visit versions were used in this study. The investigator sought information on AEs by questioning and examination. Questions about AEs were asked in a general, non-directed manner (e.g., “how has your health been since your last visit?”, “did you notice anything unusual?”) and avoided directed questions (e.g., “did you have any headaches since your last visit?”).

Statistical Analysis

The primary efficacy analysis population was the Full Analysis (FA) population and included all consented and randomized subjects who did not fail screening, had taken ≥1 dose of study medication, and had 1 post-dose time point assessment based on the TDQ. The Safety population included all randomized subjects who had taken ≥1 dose of study medication and had ≥1 post-dose safety assessment.

For the primary outcome measure (TDQ), non-inferiority was assessed using a confidence interval (CI) approach. The non-inferiority margin was a TDQ score difference of 7.5 points, equivalent to 0.5 SD. If the lower limit of the 95% CI for the difference between treatments (PRC-063 − minus LDX) was above this boundary value (i.e., >−7.5), non-inferiority was established. The primary efficacy analysis used the likelihood-based mixed effect model for repeated measures for the FA population containing fixed effect terms for treatment, period, hour, sequence, and time by treatment interaction. To explore the effect of missing data, sensitivity analyses were conducted for the primary efficacy analysis for the FA population.

Results of the secondary outcome analyses of the pairwise time point comparisons were presented by treatment overall and by time point (if applicable), and included the mean, median, standard deviation, minimum, maximum, and 95% Cl. Treatment differences were reported based on the results of the mixed-model analyses.

TEAEs were defined as any event, regardless of relatedness of treatment, that began on or after the date of the first treatment or worsened in severity or frequency after treatment was initiated. TEAEs were categorized by System Organ Class (SOC) and preferred-term coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1. TEAEs were evaluated for severity using the Common Toxicity Criteria for Adverse Events (CTCAE). All analyses were conducted using SAS version 9.2 or higher.

Results

Subjects

Subject disposition is presented in Figure 2. A total of 63 subjects met the entry criteria, 45 subjects (24 male and 21 female) were randomized into the study. Of 45 randomized subjects (safety population), 44 completed the study (FA population). One subject prematurely terminated from the study due to scheduling conflicts.

Figure 2.

Subject disposition in the safety population.

Patient demographics and baseline characteristics for the safety population are presented in Table 1 and were similar across the treatment sequences. Overall, 66.7% (16/24) patients in the PRC-063/LDX treatment sequence had prior stimulant therapy compared to 33.3% (7/21) patients in the LDX/PRC-063 treatment sequence. All vital signs at baseline were within normal limits. The majority of subjects had a rating of “markedly ill” at baseline, as per the CGI-severity scale.

Table 1.

Demographics and Baseline Characteristics in the Safety Population.

	PRC-063/LDXn = 24	LDX/PRC-063n = 21	All SubjectsN = 45
Age (years), mean (SD)	24.5 (4.34)	24.5 (4.77)	24.5 (4.50)
Sex, n (%)
Male	13 (54.2%)	11 (52.4%)	24 (53.3%)
Female	11 (45.8%)	10 (47.6%)	21 (46.7%)
Height (cm), mean (SD)	172.5 (9.27)	172.9 (9.17)	172.7 (9.12)
Weight (kg), mean (SD)	80.74 (26.21)	79.47 (28.04)	80.14 (26.78)
BMI (kg/m²), mean (SD)	26.759 (7.17)	26.101 (6.91)	26.452 (6.98)
CARD-3 (Q1–Q25), mean (SD)	21.1 (13.56)	28.8 (13.07)	25.2 (13.91)
CARD-3 (Q26–Q31), mean (SD)	0.8 (2.09)	0.7 (1.19)	0.7 (1.68)
KBIT-2 IQ score, mean (SD)	112.4 (10.92)	119.5 (11.70)	115.7 (11.72)
Baseline CGI-S, mean (SD)	5.2 (0.48)	5.1 (0.48)	5.2 (0.47)

Note. CARD-3 = Cox Assessment of Risky Driving Scale-3; CGI-S = Clinical Global Impressions-Severity; KBIT-2 = Kaufman Brief Intelligence Test, Second Edition; LDX = lisdexamfetamine dimesylate; SD = standard deviation.

Subjects were optimized to a mean dose of PRC-063 of 73.52 mg/day (45 mg/day: n = 7, 70 mg/day: n = 26, and 100 mg/day: n = 11). Subjects were optimized to a mean dose of LDX of 49.55 mg/day (30 mg/day: n = 8, 50 mg/day: n = 29, and 70 mg/day: n = 7).

Primary Efficacy Endpoint: TDQ

In the FA population, the least squares mean TDQ (SE) was 99.9 (1.84) for the PRC-063 treatment group and 100.1 (1.84) for the LDX treatment group, demonstrating non-inferiority of PRC-063 and LDX (LS mean difference −0.3 [1.08], 95% CI [−2.4, 1.8], p = .793). The sequence effect was not significant (p = .4025).

Secondary Endpoints

TDQ by Post-Dose Hours

The least square mean difference (SE) in TDQ scores was −2.4 ([2.15], 95% CI [−6.7, 1.8], p = .258) at 1 hour post-dose, −2.2 ([2.15], 95% CI [−6.4, 2.1], p = .318 at 9 hour post-dose, 3.1 ([2.15], 95% CI [−1.1, 7.4], p = .146) at 12 hour post-dose, and 0.3 ([2.15] 95% CI [−3.9, 4.6], p = .880) at 15 hour post-dose. The time course of response to the TDQ was flat for both PRC-063 and LDX over all time points (Figure 3). No worsening of driving performance was observed with either treatment at the 15-hour time point, suggesting treatment effect was maintained. TDQ scores for each subject in the FA population for 1, 9, 12, and 15 hours post-dose are presented in Figure 3.

Figure 3.

Tactical driving quotient by treatment group in the full analysis population.

CARDS-3

Mean (SD) baseline CARDS-3 sum of questions 1 to 25 measuring risky driving behaviors were 24.7 (13.74), which improved with both treatments, although there was no statistically significant difference in the least-squares mean (SE) CARDS-3 score between the PRC-063 (20.7 [1.32]) and LDX (19.0 [1.32]) groups. The difference in the least-squares mean was 1.8 (1.86; 95% CI [−2.0, 5.5], p = .351; ANCOVA model).

ADHD Symptom Change

Consistent improvement in the CGI-I scale scores was noted at each time point for each treatment sequence. CGI-I mean (SD) scores improved from 3.0 (1.00) at Visit 3 to 1.7 (0.75) for PRC-063 and 1.5 (0.67) for LDX during the last week of treatment.

Safety

In both treatment groups, 73.3% (n = 33) of patients experienced a TEAE with 89 and 106 events occurring during PRC-063 or LDX treatment, respectively. No subject experienced a severe TEAE, a TEAE leading to study withdrawal, or a serious adverse event (SAE). Table 2 displays AEs occurring in ≥2% (n > 1) of subjects. The most commonly occurring AEs were those previously observed in this class of medication and subject population. AEs were generally of mild to moderate severity, did not result in a change in dose, and were resolved. There was no dose-dependent difference in the incidence of TEAEs related to either study treatment (Supplemental Table 2).

Table 2.

Treatment Emergent Adverse Events Reported in ≥2% of Subjects in the Safety Population.

Event	Treatment sequence: LDX to PRC-063 (n = 21)		Treatment sequence: PRC-063 to LDX (n = 24)		Total (n = 45)
Event	PRC-063 (n)	LDX (n)	PRC-063 (n)	LDX (n)	PRC-063n (%)	LDXn (%)
Abdominal discomfort	1	—	1	—	2 (4.4%)	0 (0.0%)
Abdominal pain	1	—	1	—	2 (4.4%)	0 (0.0%)
Anxiety	2	2	—	1	2 (4.4%)	3 (6.7%)
Chest discomfort	1	—	1	—	2 (4.4%)	0 (0.0%)
Decreased appetite	6	14	7	9	13 (28.9%)	23 (51.1%)
Depressed mood	—	2	—	—	0 (0.0%)	2 (4.4%)
Dizziness	—	3	—	—	0 (0.0%)	3 (6.7%)
Dry mouth	1	4		2	1 (2.2%)	6 (13.3%)
Emotional disorder	—	1	1	1	1 (2.2%)	2 (4.4%)
Feeling jittery	—	3	—	—	0 (0.0%)	3 (6.7%)
Headache	6	9	6	5	12 (26.7%)	14 (31.1%)
Hyperhidrosis	—	1	—	1	0 (0.0%)	2 (4.4%)
Initial insomnia	6	5	8	3	14 (31.1%)	8 (17.8%)
Irritability	3	2	3	2	6 (13.3%)	4 (8.9%)
Middle insomnia	1	—	1	—	2 (4.4%)	0 (0.0%)
Nasal congestion	—	—	—	2	0 (0.0%)	2 (4.4%)

Note. LDX = lisdexamfetamine dimesylate; TEAE = treatment-emergent adverse event.

The C-SSRS showed no incidence of suicidal ideation or suicidal behavior in either treatment sequence. No clinically significant physical examination findings were reported for any subject. Minor weight loss was reported (−1.3 ± 2.71 kg for the PRC-063/LDX treatment sequence and −1.7 ± 1.79 kg for the LDX/PRC-063 treatment sequence). Vital signs were predominantly within normal ranges and any abnormal values did not meet criteria for an AE. Laboratory values and ECG results were mostly within normal range/parameter. Any abnormal values were not clinically significant and did not meet criteria for an AE.

Discussion

This randomized, double-blind, head-to-head study of PRC-063 and LDX found comparable effects on the driving performance of young adults with ADHD when titrated to an optimal dose through a weekly clinical assessment. Similar improvements in global clinical ratings and self-ratings of risky driving behaviors were observed with both treatments. Previous studies have also highlighted the benefit of ADHD treatments with longer duration of action in order to maintain performance improvements and avoid rebound effect (D. J. Cox, Humphrey et al., 2004; D. J. Cox et al., 2008). The time course of response in the current study was similar from 1 to 15 hours post-dose for both treatments, showing a rapid onset and consistency of effect on driving into the evening hours, without evidence of a loss of treatment effect. This finding is important, as more than half of all traffic fatalities occur after dark (Plainis et al., 2006).

At each weekly time point for both treatment sequences, ADHD severity was consistently improved, as assessed by the CGI-I scale. Subjects were titrated to an optimal dose over a 3-week period and 91.3% of subjects on LDX and 76.2% of subjects on PRC-063 were rated as “much improved” or “very much improved” by the third week of treatment. Improvements in symptoms of ADHD have been previously associated with improvement in driving performance (Biederman et al., 2012). In previous studies, despite small sample sizes, significant differences between driving performance of young adults with ADHD, with and without stimulant treatment, have been demonstrated (Biederman et al., 2012; D. J. Cox, Humphrey et al., 2004; D. J. Cox et al., 2006, 2008) and these results have been reinforced by the subjects’ self-reported, real-world traffic violations (D. J. Cox et al., 2012).

This is one of the only randomized, double-blind, crossover comparisons of a methylphenidate treatment and lisdexamfetamine dimesylate. In each arm, the same patients were titrated to an optimal dose of each medication by the same blinded physician. Although dosing choices were limited, mean ± SD doses of 73.52 ± 17.87 mg/day of PRC-063 and 49.55 ± 11.80 mg/day of LDX led to similar outcomes on driving performance as measured from 1 to 15 hours post-dose, along with self-reports on the CARDs and blinded physician ratings.

There are several limitations to this study. While a non-inferiority hypothesis does not require a placebo group, this study’s omission of a placebo group does not allow for quantification of the magnitude of simulator driving improvement on the two medications. However, the crossover design controlled for individual differences that were determined to be similar across testing. Although there was a numerical difference in the number of stimulant-naïve patients in each treatment sequence, there was no significant sequence effect. While performance on the driving simulator correlates with on-road driving, a supervised, low-threat simulator is not identical to driving in the real world where driving errors can have immediate and devastating consequences. Although there was a small sample size, a priori power analysis indicated that there was adequate power to detect statistical differences between groups. Finally, driving performance was not measured at pre-dose/baseline.

The findings of this study show that an optimal dose that balances both AEs and symptom improvements can be achieved with PRC-063 and LDX through titration over a 3-week period. PRC-063 and LDX were both well-tolerated. AEs were consistent to those reported with other extended-release stimulant treatments. AEs considered to be related to the study medication occurred in 73% of subjects for both treatments, AEs were not dose-dependent, and there were no SAEs and no deaths.

Conclusion

PRC-063 and LDX had comparable effects on the driving performance of young adults with ADHD, with a rapid onset that extended through a 15-hour period, the last time point measured. Long-acting stimulant medications that control ADHD symptomatology may enhance driving safety, while also improving the day-to-day functioning for individuals with ADHD. When considering driving safety, given a patient’s differential responsiveness to methylphenidate or amphetamine, a clinician should feel comfortable prescribing the medication to which a patient responds best.

Supplemental Material

sj-docx-1-jad-10.1177_10870547241226634 – Supplemental material for A Randomized, Phase 3, Double-Blind, Crossover Comparison of Multilayer, Extended-Release Methylphenidate (PRC-063), and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD

Supplemental material, sj-docx-1-jad-10.1177_10870547241226634 for A Randomized, Phase 3, Double-Blind, Crossover Comparison of Multilayer, Extended-Release Methylphenidate (PRC-063), and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD by Vishal Madaan, Sailaja Bhaskar, Graeme A. E. Donnelly and Daniel J. Cox in Journal of Attention Disorders

Supplemental Material

sj-docx-2-jad-10.1177_10870547241226634 – Supplemental material for A Randomized, Phase 3, Double-Blind, Crossover Comparison of Multilayer, Extended-Release Methylphenidate (PRC-063), and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD

Supplemental material, sj-docx-2-jad-10.1177_10870547241226634 for A Randomized, Phase 3, Double-Blind, Crossover Comparison of Multilayer, Extended-Release Methylphenidate (PRC-063), and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD by Vishal Madaan, Sailaja Bhaskar, Graeme A. E. Donnelly and Daniel J. Cox in Journal of Attention Disorders

Footnotes

Acknowledgements

Medical writing services were provided by Susan Bartko-Winters, PhD, of SBW Medical Writing Inc, which was funded by Purdue Pharma (Canada).

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Vishal Madaan: In his current role, Dr. Madaan is an employee with the American Psychiatric Association and has no current disclosures to make. In his prior role as a University of Virginia Health System employee, he received research support from Supernus, Allergan, Boehringer Ingelheim, Pfizer, Purdue, and the NICHD at the time the original manuscript was prepared. Daniel Cox: Dr Cox has received research support as a University of Virginia Health System employee from the National Institutes of Health, Eli Lilly, Purdue, Johnson & Johnson, Dexcom, and Abbott. Graeme Donnelly is an employee of Purdue Pharma (Canada). Sailaja Bhaskar: Sailaja Bhaskar is currently employed at Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research and medical writing support were funded by Purdue Pharma (Canada).

ORCID iD

Graeme A. E. Donnelly

Supplemental Material

Supplemental material for this article is available online.

Author Biographies

Vishal Madaan is Chief of Education and Deputy Medical Director, American Psychiatric Association, Washington, DC. He is also Clinical Professor, Creighton University School of Medicine. At the time of conduct of the study, Dr. Madaan served as tenured Associate Professor in Psychiatry and Neurobehavioral Sciences at University of Virginia Health System, and founding Director, Center of Psychopharmacology Research in Youth at UVA, Charlottesville, VA.

Dr Sailaja Bhaskar is a pharmaceutical executive with more than two decades of progressive experience in leading global drug development in various therapeutic areas. Dr Bhaskar has an undergraduate degree in Pharmacy and has earned her M.Sc. and PhD in Pharmacology from Temple University, Philadelphia and an MBA from Rotman School of Management, University of Toronto, Canada.

Graeme A. E. Donnelly is an employee of Elvium Life Sciences and has been involved in the clinical research of methylphenidate in the treatment of ADHD for over 20 years.

Daniel J. Cox is a clinical psychologist and Professor in the Department of Psychiatry and Neurobehavioral Sciences. He is the founder and Director of of the Virginia Driving Safety Laboratory at the University of Virginia Health Sciences Center, Charlottesville, VA, USA.

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