Clonidine Hydrochloride (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Clonidine Hydrochloride was not carcinogenic when administered in the diet of rats (for up to 132 weeks) or mice (for up to 78 weeks) at doses of up to 1,620 (male rats), 2,040 (female rats), or 2,500 (mice) mcg/kg/day. These doses are approximately 20, 25, and 15 times, respectively, the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m² basis.

Mutagenesis

There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.

Impairment of Fertility

In a reproduction study fertility of female rats appeared to be adversely affected at dose levels of 500 and 2000 mcg/kg/day (10 and 40 times the MRHD on a mg/ m² basis). Lower doses have not been adequately evaluated and a no adverse effect level could not be established.

14 CLINICAL STUDIES

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

• One short-term, placebo-controlled monotherapy trial (Study 1)
• One short-term adjunctive therapy to psychostimulants trial (Study 2)
• One randomized withdrawal trial as monotherapy (Study 3)

Short-term Monotherapy and Adjunctive Therapy to Psychostimulant Studies for ADHD

The efficacy of clonidine hydrochloride extended release tablets in the treatment of ADHD was established in 2 (one monotherapy and one adjunctive therapy) placebo-controlled trials in pediatric patients aged 6 to 17, who met DSM-IV criteria of ADHD hyperactive or combined hyperactive/inattentive subtypes. Signs and symptoms of ADHD were evaluated using the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS-IV) total score including hyperactive/impulsivity and inattentive subscales.

Study 1 (CLON-301), was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of children and adolescents aged 6 to 17 (N=236) with a 5-week primary efficacy endpoint. Patients were randomly assigned to one of the following three treatment groups: clonidine hydrochloride extended-release tablets (CLON) 0.2 mg/day (N=78), Clonidine hydrochloride extended-release Tablets 0.4 mg/day (N=80), or placebo (N=78). Dosing for the clonidine hydrochloride extended-release tablets groups started at 0.1 mg/day and was titrated in increments of 0.1 mg/week to their respective dose (as divided doses). Patients were maintained at their dose for a minimum of 2 weeks before being gradually tapered down to 0.1 mg/day at the last week of treatment. At both doses, improvements in ADHD symptoms were statistically significantly superior in clonidine hydrochloride extended-release tablets -treated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).

Study 2 (CLON-302) was an 8-week randomized, double-blind, placebo-controlled, flexible dose study in children and adolescents aged 6 to 17 (N=198) with a 5-week primary efficacy end point. Patients had been treated with a psychostimulant (methylphenidate or amphetamine) for four weeks with inadequate response. Patients were randomly assigned to one of two treatment groups: clonidine hydrochloride extended-release tablets adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The clonidine hydrochloride extended-release tablets dose was initiated at 0.1 mg/day and doses were titrated in increments of 0.1 mg/week up to 0.4 mg/day, as divided doses, over a 3-week period based on tolerability and clinical response. The dose was maintained for a minimum of 2 weeks before being gradually tapered to 0.1 mg/day at the last week of treatment. ADHD symptoms were statistically significantly improved in clonidine hydrochloride extended-release tablets plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).

Table 8: Short-Term Trials

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.
Study Number	Treatment Group	Primary Efficacy Measure: ADHDRS-IV Total Score
		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Differencea (95% CI)
Study 1	Clonidine Hydrochloride Extended-Release Tablets (0.2 mg/day)	43.8 (7.47)	-15.0 (1.38)	-8.5 (-12.2, — 4.8)
	Clonidine Hydrochloride Extended-Release Tablets (0.4 mg/day)	44.6 (7.73)	-15.6 (1.33)	-9.1 (-12.8, — 5.5)
	Placebo	45.0 (8.53)	-6.5 (1.35)	–
Study 2	Clonidine Hydrochloride Extended-Release Tablets (0.4 mg/day) + Psychostimulant	38.9 (6.95)	-15.8 (1.18)	-4.5 (-7.8, -1.1)
	Psychostimulant alone	39.0 (7.68)	-11.3 (1.24)	–

Maintenance Monotherapy for ADHD

Study 3 (SHN-KAP-401), was a double-blind, placebo-controlled, randomized-withdrawal study in children and adolescents aged 6 to 17 years (n=253) with DSM-IV-TR diagnosis of ADHD. The study consisted of a 10-week, open-label phase (4 weeks of dose optimization and 6 weeks of dose maintenance), a 26-week double-blind phase, and a 4-week taper-down and follow-up phase. All patients were initiated at 0.1 mg/day and increased at weekly intervals in increments of 0.1 mg/day until reaching personalized optimal dose (0.1, 0.2, 0.3 or 0.4 mg/day, as divided doses). Eligible patients had to demonstrate treatment response as defined by greater than or equal to 30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement score of 1 or 2 during the open label phase. Patients who sustained treatment response (n=135) until the end of the open label phase were randomly assigned to one of the two treatment groups, clonidine hydrochloride extended-release tablets (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of clonidine hydrochloride extended-release tablets in the double-blind phase. The primary efficacy endpoint was the percentage of patients with treatment failure defined as a greater than or equal to 30% increase (worsening) in ADHD-RS-IV total score and greater than or equal to 2 points increase (worsening) in Clinical Global Impression – Severity Scale in 2 consecutive visits or early termination for any reason. A total of 73 patients experienced treatment failure in the double-blind phase: 31 patients (45.6%) in the clonidine hydrochloride extended-release tablets group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring clonidine hydrochloride extended-release tablets (Table 9). The cumulative proportion of patients with treatment failure over time during the double-blind phase is displayed in Figure 2.

Table 9: Treatment Failure: Double-Blind Full Analysis Set (Study 3)

ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4th edition; CGI-S = Clinical Global Impression-Severitya At the same 2 consecutive visits a (1) 30% or greater reduction in ADHD-RS-IV, and (2) 2-point or more increase in CGI-S.b Two subjects (1 placebo and 1 clonidine hydrochloride extended-release tablets) withdrew consent, but met the clinical criteria for treatment failure.c Three subjects (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV.
Study 3	Double-Blind Full Analysis Set
	Clonidine Hydrochloride Extended-Release Tablets	Placebo
Number of subjects	68	67
Number of treatment failures	31 (45.6%)	42 (62.7%)
Basis of Treatment Failure
Clinical criteria a,b	11 (16.2%)	9 (13.4%)
Lack of efficacyc	1 (1.5%)	3 (4.5%)
Withdrawal of informed assent/consent	4 (5.9%)	20 (29.9%)
Other early terminations	15 (22.1%)	10 (14.9%)

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3)