Guanfacine Extended-Release (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6.8 times the maximum recommended human dose of 0.12 mg/kg/day on a mg/m 2 basis.

Mutagenesis

Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study.

Impairment of Fertility

No adverse effects were observed in fertility studies in male and female rats at doses up to 22 times the maximum recommended human dose on a mg/m 2 basis.

14 CLINICAL STUDIES

Efficacy of guanfacine extended-release tablets in the treatment of ADHD was established in children and adolescents (6 to 17 years) in:

  • Five short-term, placebo-controlled monotherapy trials (Studies 1, 2, 4, 5, and 6).
  • One short-term, placebo-controlled adjunctive trial with psychostimulants (Study 3).
  • One long-term, placebo-controlled monotherapy maintenance trial (Study 7).

Studies 1 and 2: Fixed-dose Guanfacine Extended-Release Tablets Monotherapy

Study 1 (301 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with guanfacine extended-release tablets (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345) in children and adolescents aged 6 to 17 years. Study 2 (304 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324) in children and adolescents aged 6 to 17 years. In both studies, randomized patients in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started. The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. Patients who weighed less than 25 kg were not included in either study.

Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2).

The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for guanfacine extended-release tablets compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg guanfacine extended-release tablets randomized treatment groups in both studies, as well as the 1 mg guanfacine extended-release tablets treatment group that was included only in Study 2 (see Table 16 ).

Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01 to 0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05 to 0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit.

In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6 to 12 vs. 13 to 17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender. Analyses by age revealed a statistically significant treatment effect only in the 6 to 12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13 to 17) enrolled into these studies (approximately 25%), these data may not have been sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of guanfacine extended-release tablets rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01 to 0.04mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations.

Table 16: Fixed dose Studies
SD:standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. ^ The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg.
Study Number
  • (Age Range)
Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI)
Study 1 (6 to 17 years) Guanfacine Extended-Release Tablets 2 mg* 36.1 (9.99) -15.9 (1.37) -7.4 (-11.3, -3.5)
Guanfacine Extended-Release Tablets 3 mg* 36.8 (8.72) -16.0 (1.38) -7.5 (-11.4, -3.6)
Guanfacine Extended-Release Tablets 4 mg* 38.4 (9.21) -18.5 (1.39) -10.0 (-13.9, -6.1)
Placebo 38.1 (9.34) -8.5 (1.42)
Study 2 (6 to 17 years) Guanfacine Extended-Release Tablets 1 mg*^ 41.7 (7.81) -19.4 (1.69) -6.8 (-11.3, -2.2)
Guanfacine Extended-Release Tablets 2 mg* 39.9 (8.74) -18.1 (1.60) -5.4 (-9.9, -0.9)
Guanfacine Extended-Release Tablets 3 mg* 39.1 (9.22) -20.0 (1.64) -7.3 (-11.8, -2.8)
Guanfacine Extended-Release Tablets 4 mg* 40.6 (8.57) -20.6 (1.60) -7.9 (-12.3, -3.4)
Placebo 39.3 (8.85) -12.7 (1.60)

Study 3: Flexible-dose Guanfacine Extended-Release Tablets as Adjunctive Therapy to Psychostimulants

Study 3 (313 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6 to 17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Patients were started at the 1 mg guanfacine extended-release tablets dose level and were titrated weekly over a 5-week dose-optimization period to an optimal guanfacine extended-release tablets dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering. Patients took guanfacine extended-release tablets either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning. Allowable psychostimulants in the study were ADDERALL XR ® , VYVANSE ® , CONCERTA ® , FOCALIN XR ® , RITALIN LA ® , METADATE CD ® or FDA-approved generic equivalents.

Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8).

Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for guanfacine extended-release tablets given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening guanfacine extended-release tablets dosing (see Table 17 ). Nearly two-thirds (64.2%) of patients reached optimal doses in the 0.05 to 0.12 mg/kg/day range.

Studies 4, 5 and 6: Flexible-dose Guanfacine Extended-Release Tablets Monotherapy

Study 4 (314 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with guanfacine extended-release tablets (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6 to 12 years (n=340).

Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8).

Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for guanfacine extended-release tablets compared to placebo in both AM and PM dosing groups of guanfacine extended-release tablets (see Table 17 ).

Study 5 (312 study) was a 15-week, double-blind, randomized, placebo-controlled, dose-optimization study conducted in adolescents aged 13 to 17 years (n=314) to evaluate the efficacy and safety of guanfacine extended-release tablets (1 to 7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV). Patients receiving guanfacine extended-release tablets showed statistically significantly greater improvement on the ADHD-RS-IV total score compared with patients receiving placebo (see Table 17 ).

Study 6 (316 study) was a 12-week (for children aged 6 to 12) or 15-week (for adolescents aged 13 to 17), randomized, double-blind, parallel-group, placebo- and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6 to 17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1 to 4 mg/day, adolescents: 1 to 7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. Guanfacine extended-release tablets were statistically superior to placebo on symptoms of ADHD in patients 6 to 17 years as measured by change from baseline in ADHD-RS-IV total scores (see Table 17 ).

Table 17: Flexible-Dose studies
SD:standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Treatment was given in combination with a psychostimulant. b Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo.
Study Number
  • (Age Range)
Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference b (95% CI)
  • Study 3 a (6 to 17 years)
Guanfacine Extended-Release Tablets 1 to 4 mg AM* 37.6 (8.13) -20.3 (0.97) -4.5 (-7.5, -1.4)
Guanfacine Extended-Release Tablets 1 to 4 mg PM* 37.0 (7.65) -21.2 (0.97) -5.3 (-8.3, -2.3)
Placebo 37.7 (7.75) -15.9 (0.96)
Study 4 (6 to 12 years) Guanfacine Extended-Release Tablets 1 to 4 mg AM* 41.7 (6.39) -20.0 (1.23) -9.4 (-12.8, -6.0)
Guanfacine Extended-Release Tablets 1 to 4 mg PM* 41.6 (6.66) -20.4 (1.19) -9.8 (-13.1, -6.4)
Placebo 42.9 (6.29) -10.6 (1.20)
Study 5 (13 to 17 years) Guanfacine Extended-Release Tablets 1 to 7 mg* 39.9 (5.57) -24.6 (1.06) -6.03 (-8.87, -3.19)
Placebo 40.0 (6.11) -18.5 (1.08)
Study 6 (6 to 17 years) Guanfacine Extended-Release Tablets 1 to 7 mg* 43.1 (5.47) -23.89 (1.15) -8.88 (-11.94, -5.81)
Placebo 43.2 (5.60) -15.01 (1.16)

Study 7: Long-Term Maintenance of Guanfacine Extended-Release Tablets Efficacy

Study 7 (315 study) was a double-blind, placebo-controlled, randomized withdrawal trial in pediatric patients aged 6 to 17 years with DSM-IV-TR diagnosis of ADHD. The study consisted of an open-label phase, including a 7-week dose optimization period to titrate patients to an optimal dose (maximum 4 mg/day for children and 7 mg/day for adolescents; optimized dose range: 0.05 to 0.12 mg/kg/day) and a 6-week dose maintenance period. There were 526 patients included in the open-label phase. Among those, 315 patients who met response criteria in the open-label phase were then randomized (1:1, guanfacine extended-release tablets:placebo) in a 26-week, double-blind, randomized withdrawal phase. The response criteria were defined by ≥ 30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2 during the open-label phase. A statistically significantly lower proportion of treatment failures occurred among guanfacine extended-release tablets patients compared to placebo at the end of the randomized withdrawal period (Figure 4). Treatment failure was defined as a ≥ 50% increase (worsening) in ADHD-RS-IV total score and a ≥ 2-point increase in Clinical Global Impression-Severity (CGI-S) score. Patients who met the treatment failure criteria on two consecutive visits or discontinued for any reason were classified as treatment failure.

Figure 4. Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children and Adolescents Ages 6 to 17 (Study 7)

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