Table 1.
Summary of randomized, double-blind, placebo-controlled studies of guanfacine extended-release (GXR) monotherapy in children and adolescents with attention-deficit hyperactivity disorder (ADHD)
| Study | Study design – RCT | Sample | ADHD diagnosis (subtypes), n (%) | GXR dose | Study duration | Key findings – efficacy |
|---|---|---|---|---|---|---|
| Biederman et al24 | Multicenter (48 centers, USA), fixed-dose escalation study | n=345 (mean age 10.5 years, range 6–17 years) GXR 2 mg: n=87 GXR 3 mg: n=86 GXR 4 mg: n=86 PL: n=86 Male =257 (74.5%) |
ADHD-I: 90 (26.1) ADHD-H/I: 7 (2.0) ADHD-C: 248 (71.9) |
GXR 2, 3, or 4 mg/day | 8 weeks | • SI in ADHD-RS-IV scores in all groups of children taking GXR (−16.18 with 2 mg, −16.43 with 3 mg, and −18.87 with 4 mg) versus −8.48 for PL. ES: 0.64 (2 mg GXR), 0.66 (3 mg GXR), 0.86 (4 mg GXR). • All children taking GXR (versus PL) showed SI in ADHD-H/I and ADHD-I subscales of the ADHD-RS-IV. • At end point compared to PL, all groups on GXR showed SI on CGI-I, PGA, CPRS-R:SF, and CTRS-R. • Patients taking GXR were more likely to meet the responder criteria (30% decrease in ADHD-RS-IV and CGI-I ≤2) over time (P<0.05 for all GXR doses versus PL) from week 3 through study end. |
| Sallee et al25 | Multicenter (51 sites, USA), dose-ranging study | n=324 (mean age 11 years, range 6–17 years) GXR 1 mg: n=62 GXR 2 mg: n=65 GXR 3 mg: n=65 GXR 4 mg: n=66 PL: n=66 Male =233 (72.4%) |
ADHD-I: 82 (25.5) ADHD-H/I: 6 (1.9) ADHD-C: 234 (72.7) |
GXR 1, 2, 3, or 4 mg/day | 9 weeks | • At end point, all GXR dose groups showed significant decreases in ADHD-RS-IV total scores (mean −19.6) compared with PL (−12.2), with ES 0.43–0.62. Reductions in ADHD-I and ADHD-H/I subscale scores were also significant at all GXR doses compared with PL. • Significantly more subjects taking GXR 1, 3, and 4, but not 2 mg, showed clinical improvements in the CGI-I and PGA compared to PL. • Using parental assessments on the CPRS-R, the 1 and 2 mg GXR doses were considered to have a duration of 8 hours; the 3 and 4 mg/day doses had a 12-hour duration |
| Connor et al53 | Multicenter (33 sites, USA), flexible-dose, dose-optimization study | n=214 (mean age 9.4 years, range 6–12 years) GXR: n=136 PL: n=78 Male =147 (68.7%) |
ADHD-I: 27 (12.6) ADHD-H/I: 7 (3.3) ADHD-C: 180 (84.1) |
GXR 1–4 mg/day | 9 weeks | • LSMC from baseline in the oppositional subscale of the CPRS-R:L was −10.9 for GXR and -6.8 for PL (ES 0.59, P<0.001). • LSMC in ADHD-RS-IV total score from baseline was greater for GXR compared to PL (−23.8 versus −11.5, ES 0.92; P<0.001). |
| Kollins et al51 | Multicenter (nine sites in the USA), dose-optimization, noninferiority study | n=178 (mean age 12.6 years, range 6–17 years) GXR: n=121 PL: n=57 Male =124 (69.7%) |
ADHD-I: 42 (23.6) ADHD-H/I: 3 (1.7) ADHD-C: 133 (74.7) |
GXR 1–3 mg/day | 6 weeks | • Reductions at end point in mean ADHD-RS-IV total scores were significantly greater with GXR (−18.0) than with PL (−11.9) (LSMC 6.3, P=0.001). • Significantly more subjects taking GXR versus PL showed a CGI-I ≤2 (56.8% versus 35.1%, P=0.007). • GXR treatment did not impair measures of psychomotor functioning or alertness (CRT, SWM, DSST/Coding, and PERMP), compared with PL. |
| Newcorn et al52 | Multicenter (47 sites, USA and Canada), dose-optimization study | n=333 (mean age 9.1 years, range 6–12 years) GXR-AM: n=107 GXR-PM: n=114 PL: n=112 Male =235 (70.6%) |
ADHD-I: 7 (2.1) ADHD-H/I: 6 (1.8) ADHD-C: 320 (96.1) |
GXR 1–4 mg/day | 8 weeks | • Mean changes from baseline to week 8 (visit 10 or last observation carried forward) in ADHD-RS-IV total scores were significant for both GXR-treatment groups combined (GXR all-active −20.0) and separately (GXR-AM −19.8, GXR-PM −20.1) compared with PL (−11.0). Treatment-effect size 0.77 (all-active), 0.75 (GXR-AM), and 0.78 (GXR-PM). • Subjects on GXR showed significantly greater reductions in ADHD-H/I and ADHD-I subscale scores compared to PL, regardless of time of GXR administration. • Mean weight-adjusted optimal dose for GXR was 0.084 (0.03) mg/kg. |
| Hervas et al49 | Multicenter (58 centers in eleven European countries, the USA, and Canada), dose-optimization study | n=337 (mean age 10.8 years, range 6–17 years) GXR: n=114 ATX: n=112 PL: n=111 Male =249 (73.9%) |
ADHD-I: 36 (10.7) ADHD-H/I: 14 (4.1) ADHD-C: 287 (85.2) |
GXR: 0.05–0.12 mg/kg/day (6–12 years, 1–4 mg/day; 13–17 years, 1–7 mg/day) ATX: 10–100 mg/day/ |
Children: 4 weeks Adolescents: 7 weeks | • LSMC in ADHD-RS-IV total score from baseline was greater for GXR and ATX compared to PL (PL-adjusted differences): GXR -8.9, ES 0.76, P<0.001; ATX -3.8, ES 0.32, P<0.05. Similar differences were reported in ADHD-H/I and ADHD-I subscales of the ADHD-RS-IV. • SI was observed in the CGI-I and the WFIRS-P learning and school and family domains with GXR and ATX compared to PL. • Mean weight-adjusted optimal doses were 0.084 (0.03) mg/kg for GXR and 1.03 (0.21) mg/kg for ATX. |
Abbreviations: RCT, randomized controlled trial (double-blind placebo-controlled); PL, placebo; ATX, atomoxetine; GXR-AM, GXR given in the morning; GXR-PM, GXR given in the evening; ADHD, Attention-deficit hyperactivity disorder; ADHD-C, ADHD combined subtype (Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV-TR); ADHD-H/I, ADHD hyperactive/impulsive subtype (DSM-IV-TR); ADHD-I, ADHD inattentive subtype (DSM-IV-TR); SI, significant improvement; ES, effect size; LSMC, least-squares mean change; ADHD-RS-IV, ADHD Rating Scale IV; CGI-I, Clinical Global Impression – improvement; CPRS-R:LF, Conners Parent Rating Scale – revised: long form; CPRS-R, Conners Parent Rating Scale – revised; CPRS-R:SF, Conners Parent Rating Scale – revised: short form; CTRS-R, Conners Teacher Rating Scale – revised; PGA, Parent Global Assessment; WFIRS-P, Weiss Functional Impairment Rating Scale – parent report; CRT, choice-reaction time; DSST/Coding, Digit Symbol Substitution Task/Coding Test; PERMP, Permanent Product Measurement of Performance; SWM, spatial working memory.