Safety and efficacy of guanfacine extended-release in adults with attention-deficit/hyperactivity disorder: an open-label, long-term, phase 3 extension study

Background To assess the safety and efficacy of long-term administration of guanfacine extended-release (GXR) in adults with attention-deficit/hyperactivity disorder (ADHD). Methods In this open-label, long-term, phase 3 extension study in Japan, 150 patients transitioned from a double-blind trial, and 41 newly enrolled patients received once daily GXR (starting dose 2 mg/day, maintenance dose 4–6 mg/day) for 50 weeks. Primary outcome measures were the frequency and nature of treatment-emergent adverse events (TEAEs); secondary outcome measures included the change from week 0 in ADHD Rating Scale IV with Adult Prompts (ADHD-RS-IV; Japanese version) total and subscale scores, Conners’ Adult ADHD Rating Scales (CAARS), Clinical Global Impression-Improvement (CGI-I) and Patient Global Impression-Improvement (PGI-I) scales, and quality of life (QoL) and executive functioning measures. Results Of all patients, 94.2% (180/191) reported ≥1 TEAE and 19.9% (38/191) discontinued because of a TEAE. Most TEAEs were mild to moderate in severity; there were two serious TEAEs and no deaths. Commonly reported TEAEs (≥10% of patients) were somnolence, thirst, nasopharyngitis, decreased blood pressure, postural dizziness, bradycardia, malaise, constipation, and dizziness. Mean changes from week 0 in ADHD-RS-IV total and subscale scores and CAARS subscale scores were significantly improved in former placebo or GXR patients and new patients at last observation (p < .0001), and the percentage of patients with very much or much improved CGI-I and PGI-I scores increased. Conclusions There were no major safety concerns during long-term GXR administration in adults with ADHD. After long-term treatment, patients had significant improvements from baseline in ADHD symptoms, QoL, and executive functioning. Trial registration Japan Primary Registries Network (https://rctportal.niph.go.jp/en/): JapicCTI-163232, registered 04/21/2016.


Methods
This was an open-label, long-term, phase 3 study in adults with ADHD. The study (conducted at 71 Japanese centers from December 2016 through December 2018) was approved by the following local ethics committees:  [13] and this study were registered at the Japan Primary Registries Network (JapicCTI-163231).

Study population
Newly enrolled patients and the patients who completed the previous DBT and who consented to transition to this open-label study were eligible for inclusion. The main inclusion criteria for new patients were adult men or women (age ≥18 years) with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) ) [16], ADHD Rating Scale IV with Adult Prompts (ADHD-RS-IV; Japanese version) total score ≥24, and a Clinical Global Impression-Severity of Illness (CGI-S) scale score ≥4. Exclusion criteria were reported in detail previously [13]. In brief, the main exclusion criteria were a diagnosed or documented moderate/severe psychiatric disorder (based on DSM-5) requiring drug treatment, a history of substance use disorder or seizures, persons considered at risk of suicide, a history or evidence of cardiovascular disease, and use of medications affecting blood pressure or heart rate.

Study design
This open-label study was dose optimized and noncontrolled and comprised a 50-week treatment period, a 2week tapered dose-reduction period, and a 1-week follow-up period (Additional file 1). All patients received a single dose of GXR once daily at approximately the same time (morning or afternoon), starting at a minimum dose of 2 mg/day and increasing to a maintenance dose of 4-6 mg/day for 50 weeks. Forced dose increments of 1-mg increases up to a total of 4 mg, followed by 1-mg increases or reductions at ≥5-day intervals to maintain the dose between 4 and 6 mg, were allowed at the investigator's discretion for patients with no safety concerns and CGI-S scores ≥3. During the tapered dose-reduction period, doses were decreased by 1 mg at ≥3-day intervals over 2 weeks.

Outcome measures
Safety measures included the type and frequency of TEAEs (Medical Dictionary for Regulatory Activities, v19.0) and vital signs at each visit, and electrocardiogram (ECG) parameters and clinical laboratory tests (weeks 0, 10, 22, 34, 50, and study discontinuation).

Statistical analysis
The target sample size was 190 patients to allow for 100 patients completing 1 year of treatment. All patients who received at least one dose of GXR were included in the analyses. All TEAEs between the first intake of study drug and follow-up observation were analyzed. For analyses of ADHD-RS-IV total and subscale scores, CAARS scores, AAQoL scores, and BRIEF-A, mean (95% confidence intervals [CIs]) at each visit were reported. Mean differences in scores from week 0 (screening period) were assessed at each visit using two-sided t tests for ADHD-RS-IV total and subscale scores, CAARS scores, and AAQoL scores. Illness severity and improvement (CGI-S, CGI-I, or PGI-I) rates at each visit from week 0 were assessed using the Clopper-Pearson method. Missing data were not imputed for efficacy analyses; statistical analyses were performed using SAS Version 9.2 or higher (SAS Institute Inc., Cary, NC, USA).

Patient disposition and baseline characteristics
A total of 191 patients were enrolled, received at least one dose of study drug, and were included in the analyses (Fig. 1); 150 had transitioned from the previous DBT (former placebo or GXR patients) and 41 were newly enrolled (new patients). Of the enrolled patients, 124 (95 transitioned, 29 new) completed the study. The main reason for discontinuation was adverse events from all populations (Fig. 1).
In all patients, approximately half had combined presentation or predominantly inattentive presentation, and approximately half had been treated with ADHD medication previously (Table 1). At the start of the DBT for those who transitioned and at the start of long-term treatment for new patients, mean ADHD-RS-IV total scores were approximately 32 among all patients, but there was a higher proportion of new patients (70.7%) with ADHD-RS-IV total scores ≥30 than former placebo (51.6%) or GXR (53.4%) patients.

Safety and tolerability
In general, no new or unexpected adverse events were reported during long-term treatment ( Table 2). A total of 830 TEAEs were reported by 180 patients (94.2%), with most considered to be drug related (83.8% of all patients). Most TEAEs were mild to moderate in severity, and no deaths were reported ( Table 2). Compared with former placebo patients and new patients, a smaller proportion of former GXR patients experienced treatment-related TEAEs or moderate severity TEAEs or discontinued because of a TEAE (Table 2).
Two patients experienced a serious TEAE. One continuing patient was diagnosed with acute myeloid leukemia 380 days after starting treatment (81 days after completing the tapering period), which was considered unrelated to study drug. One new patient, with a preexisting condition requiring prescription of verapamil, experienced supraventricular tachycardia of moderate severity 255 days after starting GXR; the patient recovered following treatment and discontinuation of GXR.
The most commonly reported TEAEs (incidence ≥10%) in all patients were somnolence, thirst, nasopharyngitis, decreased blood pressure, postural dizziness, bradycardia, malaise, constipation, and dizziness ( Table  2). Except for nasopharyngitis, most events were considered related to GXR. Study drug discontinuation because of TEAEs was reported for 19.9% of all patients ( Table  2). The main TEAEs resulting in GXR discontinuation were somnolence (nine patients), blood pressure reduction (eight patients), malaise (six patients), bradycardia (four patients), and postural dizziness (three patients) or dizziness (three patients). All events resulting in GXR discontinuation were of mild or moderate severity except for one event of severe bradycardia, which occurred 70 days after commencing treatment. The GXR dose at onset was 6 mg. The patient discontinued GXR and recovered without treatment.
There were no clinically relevant changes in blood pressure, pulse rate, or ECG parameters (Table 3) or clinical laboratory tests after 50 weeks of treatment with GXR. For all patients, the mean change from week 0 in systolic blood pressure and diastolic blood pressure between week 1 and week 50 ranged from −9.54 to −3.82 mmHg and from −8.37 to −2.93 mmHg, respectively; the mean change in pulse rate ranged from −9.04 to −2.12 beats/minute; and the mean change in body weight between week 4 and week 50 ranged from −0.33  Efficacy

ADHD-RS-IV
Significant improvements in ADHD symptoms were reported in all patient populations during long-term treatment with GXR (Table 4). ADHD-RS-IV total and subscale scores significantly decreased (improved) compared with week 0 up to last observation and week 50 (  Table 4).

CGI-I, PGI-I, and CGI-S
The percentage of patients with "very much improved" or "much improved" physician-rated (CGI-I) and patient-rated (PGI-I) scores, and with "normal" or "borderline mentally ill" physician-rated CGI-S scores, increased during long-term GXR treatment (Table 4). Eighteen patients were rated as severely ill at week 0 (eight former placebo patients, four former GXR patients, and six new patients). At week 50, three were markedly ill (two former placebo patients, one new patient) and three remained severely ill (all former placebo patients), with the remainder rated as borderline, mildly, or moderately ill.  (Table 4). In addition, significant improvements were reported for almost all BRIEF-A T-score subscales in all populations (Table 4).

Discussion
This is the first study to assess long-term safety and efficacy of dose-optimized GXR in adult ADHD. The safety   findings during treatment for 50 weeks were consistent with the previous 10-week DBT [13] and the known safety profile of GXR, and no new or unexpected safety signals were identified. Adult patients experienced improvements in ADHD symptoms, QoL, and executive functioning that were sustained for up to 1 year. Given the complexity of treating ADHD, nonstimulant medication can be an important option for patients when other medications are not effective or well tolerated [6]. The findings from this study support the use of GXR as an alternative treatment for adult patients with ADHD in Japan. Consistent with the known safety profile of GXR in children [24][25][26][27], the most frequently reported TEAEs were sedative and included somnolence, decreased blood pressure, thirst, postural dizziness, bradycardia, malaise, constipation, and dizziness. Although nasopharyngitis was reported frequently, this TEAE was not considered related to GXR. Similar to the previous DBT [13], thirst was reported more frequently in adults than in studies of GXR in children [28,29]. This finding was not considered to be clinically relevant or related to any differences in ethnicity between Japanese and non-Japanese populations because thirst (dry mouth) has been reported in studies conducted with GXR in adults in the United States [30,31] and because direct comparison of the pharmacokinetics, safety, and tolerability of GXR showed no major differences in safety profiles between healthy Japanese and adults in the United States [32]. In line with the decreases in blood pressure and heart rate that have been observed during treatment with GXR in children [25][26][27], eight patients discontinued because of mild to moderate reductions in blood pressure and four discontinued because of bradycardia; only one case of bradycardia was severe and the patient recovered after treatment discontinuation. One patient experienced the serious TEAE, supraventricular tachycardia, which was moderately severe and for which relatedness to GXR was not excluded. GXR is not known to affect cardiac repolarization [31], and there were no clinically relevant changes in cardiovascular parameters, vital signs, or body weight for patients who continued treatment for 50 weeks. There were no substantial differences in the proportion of patients experiencing TEAEs among the treatment populations. However, former GXR patients reported fewer treatment-related TEAEs, fewer TEAEs leading to discontinuation, and fewer TEAEs of moderate severity compared with former placebo patients and new patients (Table 2), which is to be expected given that most sedative events are transitory, occur within the first few weeks of treatment, and resolve over time [13,26,27].
Treatments that provide sustained long-term improvements in ADHD symptoms are needed for adults