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Michael Huss
Child and Adolescent Psychiatry, Johannes Gutenberg University Mainz, Mainz, Germany
Separating efficacy and sedative effects of guanfacine extended release in children and adolescents with ADHD from four randomized, controlled, phase 3 clinical trials
Research was funded by Shire Development LLC
DRAFT SLIDES
Co-authors
Keith McBurnett,1 Andrew J Cutler,2 Amaia Hervas,3 Joan Gu,4 Bryan Dirks,4 Jeffrey H Newcorn5
1Department of Psychiatry, University of California, San Francisco, CA, USA 2Florida Clinical Research Center, Bradenton, FL, USA 3Child and Adolescent Mental Health Unit, University Hospital Mútua de Terrassa, Barcelona, Spain 4Shire, Lexington, MA, USA 5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Disclosures
The following authors have received compensation for serving as consultants or speakers for, or they or the institutions they have worked for have received research support or royalties from, the companies or organizations indicated below
– M Huss: Actelion, Eli Lilly, Engelhard Arzneimittel, Janssen-Cilag, Medice, Novartis, Shire and Steiner Arzneimittel
– K McBurnett: Abbott Laboratories, Cephalon Inc., Eli Lilly and Company, Johnson & Johnson, Lexicon Pharmaceuticals Inc., McNeil Consumer Healthcare, National Institute of Mental Health, New River Pharmaceuticals Inc., Otsuka America Pharmaceutical Inc., Shire and Sigma-Tau Pharmaceuticals Inc.
– A J Cutler: AbbVie [Abbott], Akili Interactive, Arbor Pharmaceuticals, AstraZeneca, Eli Lilly, Euthymics, Janssen, Johnson & Johnson PRD, Lundbeck, Neos Therapeutics, Neurovance, Novartis, Noven, Otsuka, Pfizer [NextWave], Purdue, Rhodes Pharmaceuticals, Shire, Sunovion, Supernus and Teva
– A Hervas: Eli Lilly, Janssen and Shire
– J H Newcorn: Alcobra, Biobehavioral Diagnostics, Cerecor, Enzymotec, Ironshore, Neos, National Football League, Rhodes, Shire and Sunovion
J Gu and B Dirks are employees of Shire and own stocks or stock options
Guanfacine extended release (GXR)
Non-stimulant treatment approved for children and adolescents with ADHD
– USA and Canada: as monotherapy or an adjunct to stimulant therapy
– Europe: when stimulants are not suitable, not tolerated or have been shown to be ineffective
In pivotal GXR trials, common TEAEs were somnolence, fatigue and sedation
To investigate whether sedation may have confounded the efficacy outcomes (i.e. may have accounted for improvement in hyperactivity) in four RCTs in children and adolescents with ADHD, post hoc analyses were conducted to compare:
– time courses of sedative TEAEs and GXR response
– change in symptoms in individuals with and without sedative TEAEs
RCT, randomized controlled trial; TEAE, treatment-emergent adverse event
SPD503-301: randomization to GXR 2, 3 or 4 mg or placebo (1:1:1:1)
SPD503-304: randomization to GXR 1, 2, 3 or 4 mg or placebo (1:1:1:1:1)
Study designs: two fixed-dose studies
aGXR was initiated at 1 mg/day on day 1 and increased weekly by 1 mg until randomized dose was reached (2 mg at week 1, 3 mg at week 2 and 4 mg at week 3). GXR, guanfacine extended release; PBO, placebo
Study week
SPD503-301 (N = 345)
Children and adolescents (6–17 years)
SPD503-304 (N = 324)
Children and adolescents (6–17 years)
0 1 2 3 4 5 6 7 8 9 13 12
Escalationa
1–4 mg
Maintenance 2–4 mg
Taper
Escalationa 1–4 mg
Maintenance 1–4 mg
Taper
Follow-up
Follow-up
GX
R
PB
O
GX
R
PB
O
Study designs: two dose-optimization studies
SPD503-312: randomization to GXR or placebo (1:1) SPD503-316: randomization to GXR, placebo or ATX (reference) (1:1:1)
aGXR was initiated at 1 mg/day on day 1 and increased weekly by 1 mg until an ‘acceptable’ response (30% reduction from baseline in ADHD Rating Scale IV total score and a Clinical Global Impression-Improvement score of 1 or 2, with tolerable side effects) was achieved. bATX dose range was based on participants’ weight at baseline. ATX, atomoxetine; GXR, guanfacine extended release; PBO, placebo
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 G
XR
P
BO
Children and adolescents (6–17 years)
Optimizationa 1–7 mg
Maintenance 1–7 mg
Optimizationb 0.5–1.2 mg/kg (< 70 kg)
40–100 mg (≥ 70 kg)
Maintenance 0.5–1.2 mg/kg (< 70 kg)
40–100 mg (≥ 70 kg)
ATX
Follow-up Taper
Follow-up Taper
GX
R
PB
O
SPD503-312 (N = 314)
SPD503-316 (N = 338)
Optimizationa 1–7 mg
Maintenance 1–7 mg
Taper Follow-up
GX
R
PB
O
Optimizationa 1–4 mg
Maintenance 1–4 mg
Study week
Adolescents (13–17 years)
Adolescents (13–17 years)
Children (6–12 years)
Time courses of sedative TEAEs and response: pooled SPD503-301 and 304 data
Data are presented by randomized dose. aDefined as somnolence, sedation and hypersomnia. bDefined as having ≥ 30% reduction from baseline in ADHD Rating Scale IV total score; analysis based on last observation carried forward. GXR, guanfacine extended release; PBO, placebo; TEAE, treatment-emergent adverse event
0
5
10
15
20
Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8
Inci
den
ce o
f se
dat
ive
TEA
Es (
%)
PBO (n=149)
GXR 1 mg (n=61)
GXR 2 mg (n=150)
GXR 3 mg (n=151)
GXR 4 mg (n=151)
0
25
50
75
100
Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Endpoint
Pro
po
rtio
n o
f re
spo
nd
ers
(%) PBO (n=141)
GXR 1 mg (n=57)
GXR 2 mg (n=147)
GXR 3 mg (n=142)
GXR 4 mg (n=144)
GXR (all doses) PBO
Mean onset (days) 12.0 6.4
Mean duration (days) 17.8 27.0
Incidence of sedative TEAEsa
Cumulative treatment responseb
PBO (n = 149)
GXR 1 mg (n = 61)
GXR 2 mg (n = 150)
GXR 3 mg (n = 151)
GXR 4 mg (n = 151)
PBO (n = 141)
GXR 1 mg (n = 57)
GXR 2 mg (n = 147)
GXR 3 mg (n = 142)
GXR 4 mg (n = 144)
ADHD-RS-IV total score in patients with and without reported sedative TEAEs
GXR significantly reduced ADHD-RS-IV total score compared with placebo in the absence of sedative TEAEs
*p < 0.001. Data based on last observation carried forward. LS means, effect sizes and p values are based on type III sum of squares from an ANVOVA model for the change from baseline, including treatment group, age group, study, and pooled country (SPD503-312 and 316 only) as fixed effects, and baseline value as a covariate. Sedative events: somnolence, sedation and hypersomnia. aAll GXR doses combined. ADHD-RS-IV, ADHD Rating Scale IV; GXR, guanfacine extended release; LS, least-squares; NS, not significant; TEAE, treatment-emergent adverse event
−15
−10
−5
0
5
Pla
ceb
o-a
dju
sted
LS
mea
n
chan
ge f
rom
bas
elin
e to
en
dp
oin
t in
AD
HD
-RS-
IV t
ota
l sc
ore
(9
5%
CI)
Effect size 0.49 0.17 0.67 0.31
NS
*
NS
*
n = 297a n = 124
n = 132 n = 215
n = 193a n = 17
n = 134 n = 51
SPD503-301 and 304 SPD503-312 and 316
Without sedative
TEAEs
Without sedative
TEAEs
With sedative
TEAEs
With sedative
TEAEs
GXR Placebo
Summary and conclusions
The results presented suggest that:
– the time-courses of sedative TEAEs and treatment response with GXR were independent in these studies (i.e. sedation occurred early and typically preceded response)
– GXR significantly reduces ADHD symptoms in patients without sedative TEAEs
These findings from group analytic approaches are relevant for the majority of patients, but may not fully explain trajectories of response and tolerability in individual patients
Overall, these findings suggest that sedation does not account for the symptomatic improvement associated with GXR
GXR, guanfacine extended release; TEAE, treatment-emergent adverse event
Acknowledgements
Under the direction of the authors, David Gothard and Isabelle Kaufmann, employees of Oxford PharmaGenesis, provided writing assistance for this presentation. Editorial assistance in fact checking, copy editing, formatting and proofreading was also provided by Oxford PharmaGenesis
Caleb Bliss from Shire Development LLC reviewed and edited the presentation for scientific accuracy
Shire International GmbH provided funding to Oxford PharmaGenesis for support in writing and editing this presentation
ADHD-RS-IV subscale scores
ADHD-RS-IV total score by ADHD subtype
Back-up
-15
-10
-5
0
ADHD-RS-IV subscale scores
GXR improved ADHD symptoms of both inattention and hyperactivity-impulsivity
*p < 0.001. Data based on last observation carried forward. LS means, effect sizes and p values are based on type III sum of squares from an ANCOVA model for the change from baseline, including treatment group, age group, study, and pooled country (SPD503-312 and 316 only) as fixed effects, and baseline value as a covariate. aAll GXR doses combined. ADHD-RS-IV, ADHD Rating Scale IV; GXR, guanfacine extended release; LS, least-squares
Effect size 0.63 0.50 0.67
n = 266 n = 266
n = 490a n = 141
Pla
ceb
o-a
dju
sted
LS
mea
n c
han
ge
fro
m b
asel
ine
to e
nd
po
int
in
AD
HD
-RS-
IV s
core
(9
5%
CI)
Total Inattention subscale
Hyperactivity- Impulsivity
subscale
Total
*
* *
Hyperactivity- Impulsivity
subscale
Inattention subscale
SPD503-301 and 304 SPD503-312 and 316
GXR Placebo
0.61 0.54 0.61
*
* * –5
–10
–15
-15
-10
-5
0
ADHD-RS-IV total score by ADHD subtype
GXR significantly improved core ADHD symptoms across the inattentive and combined/hyperactive-impulsive subtypes
***p < 0.001; **p < 0.01; *p < 0.05. Data based on last observation carried forward. LS means, effect sizes and p values are based on type III sum of squares from an ANCOVA model for the change from baseline, including treatment group, age group, study, and pooled country (SPD503-312 and 316 only) as fixed effects, and baseline value as a covariate. aAll GXR doses combined. ADHD-RS-IV, ADHD Rating Scale IV; GXR, guanfacine extended release; LS, least-squares
Inattentive subtype
Effect size 0.50 0.64 0.64 0.52
Combined/ hyperactive-
impulsive subtype
Inattentive subtype
Combined/ hyperactive-
impulsive subtype
Pla
ceb
o-a
dju
sted
LS
mea
n c
han
ge
fro
m b
asel
ine
to e
nd
po
int
in
AD
HD
-RS-
IV t
ota
l sco
re (
95
% C
I)
n = 61 n = 56
n = 205 n = 210
GXR Placebo
n = 127a n = 363a
n = 38 n = 103
–5
–10
–15
**
*** *** *
SPD503-301 and 304 SPD503-312 and 316