Alessandro ZuddasChild & Adolescent Neuropsychiatry

Department of Biomedical Sciences, University of Cagliari,

& “A Cao” Paediatric Hospital, “G. Brotzu” Hospital Trust

Cagliari, Italy

The Clinical Global Impression score:a widely used instrument in psychiatry

A discussion of Benedetto Vitiello presentation

AO Brotzu

Financial Disclosure (2013-2017)

Research grants• Shire• Vifor• Roche• Lundbeck• Janssen• EU 7 Framework Program (PERS, STOP, ADDUCE, MATRICS), • Assessorato Sanità Regione Sardegna

RoyaltiesGiunti.OS, Oxford University Press

Speaker or advisory relationship with: Angelini, Lilly, Astra Zeneca, Servier, Shire, Takeda, Vifor.

Member of Data Safety Monitory BoardsOtsuka, Lundbek,

European rules forapproval of new ADHD medications

The EMA has developed the only formal guideline on ADHD clinical trial design – Guideline on clinical investigation of medicinal products for the treatment of attention deficit hyperactivity disorder1

Recommendations include: Three-arm studies (inclusion of an active comparator)

Both symptomatic and functional efficacy outcomes

Measures of clinical response

Monitoring of treatment-emergent adverse events (TEAEs), vital signs, ECG parameters and suicidal ideation and behaviours

Evidence of the maintenance of effect which may be assessed via randomized withdrawal design

1. EMA, 2010. Available from: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/08/WC500095686.pdf (Accessed 17 January 2014)ADHD, attention-deficit/hyperactivity disorder; EMA, European Medicines Agency

Defined in diagnostic criteria

• Hyperactivity/ impulsivity

• Inattention

The effects of ADHD on an individual’s life extend beyond symptoms

Functional impairment

Health-related quality of life

(HRQoL)

Also required for diagnosis

• Social

• Academic

• Occupational

Symptoms

The impact of disease on an individual’s quality of life in

multiple domains

Subject of next presentation (by César Soutullo)

Coghill D Eur Neuropsychopharmacol 2011;21:571-83.

Defined in diagnostic criteria

• Hyperactivity/ impulsivity

• Inattention

The effects of ADHD on an individual’s life extend beyond symptoms

Functional impairment

Health-related quality of life

(HRQoL)

Also required for diagnosis

• Social

• Academic

• Occupational

Symptoms

The impact of disease on an individual’s quality of life in

multiple domains

Symptoms do not capture the range of outcomes and impact of ADHD

Impact of behaviour on daily life is the

major motivation for seeking treatment

Coghill D Eur Neuropsychopharmacol 2011;21:571-83.

Questionnaire (76 items) completed by parents Five domains and 12 associated subdomains

Domain (number of items)

Subdomains (number of items)

Achievement (10) Academic Performance (5) Peer Relations (5)

Risk Avoidance (14) Individual Risk Avoidance (4) Threats to Achievement (10)

Resilience (19)Family

Involvement (8)Physical

Activity (6)Social

Problem-Solving (5)

Satisfaction (11) Satisfaction with Health (7) Satisfaction with Self (4)

Comfort (22)Physical

Comfort (9)Emotional

Comfort (9)RestrictedActivity (4)

Child Health and Illness Profile – Child Edition: Parent Report Form (CHIP-CE:PRF)

Interpreting T-scores: normal distribution, mean = 50 and standard deviation (SD) = 10

50.0%

15.9%

0.1%

84.1%

Cumulative frequency

50(Mean)

40(−1 SD)

30(−2 SD)

20(−3 SD)

60(+1 SD)

Representation in this talk

T-score

70(+2 SD)

80(+3 SD)

97.7%

99.9%

Black circle at 50

2.3% of normative reference population have a T-score ≤ 30

2.3%

20 50 6030 40

Pretreatment mean domain T-scores in three ADHD study populations and controls

30.2 30.2 30.5

32.3 29.9 30.2

36.8 36.0 36.0

35.5 32.8 34.4

44.5 42.5 43.7

49.7 48.6

50.0 50.5

45.3 44.6

45.5 42.8

50.8 53.5

Diabetes ControlLDX EU Studies n=262

ADOREStudy n=1477

Pooled ATX studies n=793

50

40

30

Achievement

Risk Avoidance

Resilience

Satisfaction

Comfort

No statistical comparisons between these studies have been performed ATX, atomoxetine

Coghill & Hodgkins ECAP 2016

Placebo(n = 106)

LDX(n = 104)

OROS-MPH(n = 107)

−20

Baseline (mean ± SD)

Endpoint (mean ± SD)

LS mean change (± SE)

AD

HD

-RS-

IV t

ota

l sco

re

40.7 41.0 40.534.8 21.716.0

−5.7

−30

−10

0

10

20

30

40

50

−24.3 −18.7

p < 0.001Effect size: 1.80

p < 0.001Effect size: 1.26

Full analysis set

N = 317

p < 0.001Effect size: 0.54

(LDX vs OROS-MPH post hoc analysis)

p-values and effect sizes from an ANCOVA:change in ADHD-RS-IV total score from baseline to endpoint

Proportion (%) of CGI-I score of 1 or 2

30.9 40.3 30.1

34.7 44.6 31.6

37.5 42.2 36.6

35.2 39.5 34.4

44.0 46.8 43.0

31.2 37.7

31.4 40.6

35.5 40.1

36.2 40.2

44.5 48.1

29.3

32.8

37.3

36.1

46.5

LDX (n = 104) Placebo (n = 106) OROS-MPH (n = 107)

EndpointBaseline EndpointBaseline EndpointBaseline

***p < 0.001; **p < 0.01; *p < 0.05, change from baseline to endpoint (not adjusted for multiplicity)

***

***

**

**

*

***

***

*

*

*****

50

40

30

Achievement

Risk Avoidance

Resilience

Satisfaction

Comfort

***p < 0.001; **p < 0.01;

*p < 0.05,

change from baseline to endpoint

3R 9R

Follow-up

Studyvisit 1

Open-labelbaseline

Fixed dose

Randomized-withdrawal period (6 weeks)

2 3 4 5 6

V10

7 8 9 1R 2R 4R 5R 6R 7R 8R

V11 V12 V13 V14 V15 V16 V17

0 1 2 3 4 8 12 16 20 24 25 26 27 28 29 30 31 32

W24 W28 W32 W36 W40 W44 W48 W52

Dose maintenance

Dose optimization

Open-label period(≥ 26 weeks)

Studyweek

Original study designRandomized-withdrawal

baseline

LDX

30 mg

50 mg

70 mg

Placebo

Assigned LDX dose

Screening

33

0

0

SPD

48

9-3

25

ADHD-RS-IV total score during the open-label period

• At open-label endpoint,a the mean change (SD) from baseline in ADHD-RS-IV total score was –26.6 (11.4)

Open-label full analysis set N = 262Baseline n = 261V1R n = 181Endpoint n = 258

45

40

35

30

25

0

Mea

n A

DH

D-R

S-IV

to

tal s

core

(±

SD)

20

15

10

5

Baselin

e

V1W0

V2W1

V3W2

V4W3

V5W4

V6W8

V7W12

V8W16

V9W20

V1RW≥24

V2RW≥25

V3RW≥26

End

po

int

VisitWeek

aDefined as the last valid assessment obtained while on investigational product, after visit 1 and up to and including visit 3R (or up to and including visit 17 for patients who continued past visit 9 but did not enter the fixed-dose period)

***p < 0.001 active drug versus placebo≥ 50% increase in ADHD-RS-IV total score and a ≥ 2 point increase in Clinical Global Impressions-Severity rating relative to visit 3R. Endpoint was the last on-treatment, post-baseline visit of the randomized-withdrawal period (V4R–V9R) with a non-missing assessment

Randomized full analysis set

LDX (n = 76)

Placebo (n = 77)

Cu

mu

lati

ve p

rop

ort

ion

of

trea

tmen

t fa

ilure

s (%

)

***

V4R V5R V6R V7R V8R V9R EndpointW27 W28 W29 W30 W31 W32

0

20

40

60

80

100

30.2 38.9 39.6

32.3 44.1 45.8

36.8 40.5 42.0

35.5 40.3 41.9

44.5 49.4 51.0

41.2 35.3

46.8 41.3

42.6 40.2

43.3 39.3

51.1 48.5

40.1

47.5

43.3

44.9

51.1

LDX (n = 76)

EndpointBaseline EndpointBaseline EndpointBaseline

LDX (n = 262)

Open label (≤ 26 weeks) Randomized withdrawal (6 weeks)50

40

30

Achievement

Risk Avoidance

Resilience

Satisfaction

Comfort

Placebo (n = 77)

Domande?

azuddas@unica.it