Guanfacine Extended-Release (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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:

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.
Table 16: Fixed dose Studies

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)
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 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).

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).

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

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)
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 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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