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| __NOTOC__
| | #REDIRECT [[Guanfacine#Clinical Studies]] |
| {{Guanfacine}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Clinical Studies==
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| 14.1 Safety and Efficacy Studies
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| The efficacy of INTUNIV® in the treatment of ADHD was established in 3 placebo-controlled monotherapy trials (Studies 1, 2, and 4) and in 1 placebo-controlled adjunctive trial with psychostimulants (Study 3) in pediatric population. Studies 1, 2, and 3 were conducted in children and adolescents ages 6-17 and Study 4 was conducted in children ages 6-12 years.
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| ===Studies 1 and 2: Fixed-dose INTUNIV® Monotherapy===
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| Study 1 was a double-blind, placebo-controlled, parallel-group, fixed dose study, in which efficacy of once daily dosing with INTUNIV® (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345). Study 2 was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV®(1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324). In both studies, randomized subjects 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 assigned only to patients less than 50 kg (110 lbs). Patients who weighed less than 25 kg (55 lbs) were not included in either study.
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| 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).
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| The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® 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 INTUNIV® randomized treatment groups in both studies, as well as the 1 mg INTUNIV® treatment group (for patients 55-110 lbs) that was included only in Study 2 (see Table 6).
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| Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit.
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| Controlled, monotherapy long-term efficacy studies (>9 weeks) have not been conducted.
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| In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17). 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 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not be sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of INTUNIV® 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 0.01-0.04mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations.
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| Table 6: Fixed dose Studies
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| {|
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| |[[File:INTUNIV10.jpg|thumb|800px]]
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| |}
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| <small><small><small>LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted)<BR>
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| a Doses were shown to be statistically significantly superior to placebo.</small></small></small>
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| ===Study 3: Flexible-dose INTUNIV® as Adjunctive Therapy to Psychostimulants===
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| Study 3 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with INTUNIV® (1mg, 2mg, 3mg and 4mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Subjects were started at the 1 mg INTUNIV® dose level and were titrated weekly over a 5-week dose-optimization period to an optimal INTUNIV® 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. Subjects took INTUNIV® 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.
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| 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).
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| Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening INTUNIV® dosing (see Table 7). Nearly two-thirds (64.2%) of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range.
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| ===Study 4: Flexible-dose INTUNIV® Monotherapy===
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| Study 4 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with INTUNIV® (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6-12 years (n=340).
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| 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).
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| Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo in both AM and PM dosing groups of INTUNIV® (see Table 7).
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| {|
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| |[[File:INTUNIV11.jpg|thumb|800px]]
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| |}
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| <SMALL><SMALL><SMALL>LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted)</small></small></small>
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| <SMALL><SMALL><SMALL>a Treatment was given in combination with a psychostimulant. </small></small></small>
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| <SMALL><SMALL><SMALL>b Doses were shown to be statistically significantly superior to placebo. </small></small></small>
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| <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = INTUNIV (GUANFACINE) TABLET, EXTENDED RELEASE INTUNIV (GUANFACINE) KIT [SHIRE US MANUFACTURING INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b972af81-3a37-40be-9fe1-3ddf59852528#section-12.1 | publisher = | date = | accessdate = 25 February 2014 }}</ref>
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| ==References==
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| {{reflist|2}}
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| {{Antihypertensives and diuretics}}
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| {{Antihyperkinetics}}
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| {{Adrenergics}}
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| [[Category:Antihypertensive agents]]
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| [[Category:Guanidines]]
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| [[Category:Alpha-adrenergic agonists]]
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| [[Category:Acetamides]]
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| [[Category:Organochlorides]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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