risperdaltrial.com · 2017-05-12 · multicenter . studies . of . risperidone . use in . children...

From: Pandina, Gahan [JANUS] Sena: Wednesday, November 20, 2002 8:39 PM To: Gharabawi, Georges [JANUS] Stable: C&A Prolactin Data

Ompor anca: High

:A.NAB.Prolactin. FINALppt (3...

Georges,

Attached is the prolactin presentation (MRC reviewed) that was given at the national advisory board last week.

Gahan

Gahan J. Pandina, Ph.D. Assistant Director, CNS Clinical Development Janssen Pharmaceutica Products, L.P. 1125 Trenton -Harbourton Rd " Titusville, NJ 08560 OFFICE: (609) 730 2324 ° FAX: (609) 730 3125 EMAIL: gpandina @janus.jnj.com

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Date:

M.L. GRAY, CSR, RPR

Exhibit Pm¢udiaom -20

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Long -term Risperidone Treatment vs Prolactin

Levels

Carin Binder, MBA Director, Clinical Affairs

Janssen -Ortho, Inc.

Questions From June Advisory Board

How do prolactin values change over time? Is there as relationship between prolactin level and:

Duration of treatment Age Gender Weight SHAP Motor effects Clinical response Comorbid ADHD and PSTIM

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Multicenter Studies of Risperidone Use in Children With Disruptive Behavior Disorders Study ID Design Duration

(weeks)

RIS -CAN -19 Double- blind, placebo -controlled 6

RIS -CAN -20* Open -label follow -up to RIS -CAN -19 48

RIS- USA -93 Double- blind, placebo -controlled 6

RIS -USA -97* Open -label follow -up to RIS -USA -93 48

RIS- INT -41 Separate open -label trial to collect safety data 48

Eligibility limited to children with at least 2 weeks of treatment during the preceding double -blind trial

REFERENCES

Aman, M., DeSmedt, G., Derivan, A., Lyons, B., Findling, R. (2002). Double- blind, placebo controlled, study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry, 159,1337 -1346.

Snyder, R., Turgay, A., Aman, M., Binder, C., Fisman, S., Carroll A. (2002). Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. JAACAP, 41:9, 1026-1036.

Turgay, A., et al (2002). Long -term safety and efficacy of risperidone for the treatment of disruptive behavior disorders in children with subaverage IQs. Pediatrics, 110 (3), pp:e34.

Data on file: Johnson & Johnson PRD, LLP

Analysis Populations

ITT population Patients who received at least 1 dose of risperidone

Primary analysis population (PAP) Subset of the ITT population with pre -dose and at least 1 post -dose PRL observation at or after 4 weeks

Data on file: Johnson & Johnson PRD, LLC

Number of Patients With Prolactin Measurements at Each Time Point

(PAP -as observed) 700 -

600 -

500 -

400 -

300 -

200 -

100 -

0

n-550

n=499

7

n=441

1f'ia

9

n=394 n=358

u11l Girls miI Boys

Pro -dose 4 to 7 8 to 12 16 to 24 28 to 36 40 to 48

Treatment Duration (weeks)


n=42 $

52 to 55

Patient Demographics

Characteristic ITT

Population N =700

Primary Analysis Population (PAP)

N =592

Non -PAP

N =108

Age, years Mean ( ±SD) 9.9 ±2.4 9.9 ± 2.5 9.7 ±2.3 Median (range) 9.9 (5.0 -15.0) 9.9 (5.1 -15.0) 9.8 (5.0 -14.7)

Gender, n ( %) Boys 574 (82.0) 489 (82.6) 85 (78.7) Girls 126 (18.0) 103 (17.4) 23 (21.3)

Race, n ( %) Black 78 (11.2) 57 (9.6) 21 (19.6) White 550 (78.7) 475 (80.2) 75 (70.1) Other 72 (10.1) 60 (10.2) 12 (11.2)


Pre -dose Characteristics

Characteristic ITT Population Primary Analysis Population (PAP)

Non -PAP

Tanner Stage, n ( %) n =700 n =592 n =108 0 6 (0.9) 4 (0.7) 2 (2.1) 1 487 (72.6) 420 (73.0) 67 (69.8) 2 96 (14.3) 83 (14.4) 13 (13.5) 3 44 (6.6) 36 (6.3) 8 (8.3) 4 29 (4.3) 23 (4.0) 6 (6.3) 5 9 (1.3) 9 (1.6) 0

NA 29 17 12

Weight, kg ( ±SD) n =698 n =591 n =107 35.1 ±13.2 35.3 ±13.4 33.6 ±11.7

Height, cm ( ±SD) n =679 n =573 n =106 137.5±15.6 137.8 ±15.9 135.9 ±14.3

IQ, mean ( ±SD) n =699 n =591 n =108 65.1 ± 13.4 65.1 ± 13.3 65.4 ± 14.0

DSM -IV Axis II, n ( %) n =700 n =592 n =108 Borderline mental retardation 288 (41.2) 236 (39.9) 52 (48.1) Mild mental retardation 282 (40.3) 248 (42.0) 34 (31.5) Moderate mental retardation 129 (18.5) 107 (18.1) 22 (20.4) NA 1 1 0


Risperidone Dosing

ITT Population

N =700

Primary Analysis Population (PAP)

N =592

Non -PAP

N =108

Duration of risperidone exposure (days)

Mean ± SD 308 ± 116.1 319 ± 101.3 245 ± 163.4 Median (range) 359 (1 to 505) 361 (28 to 505) 336 (1 to 498)

Average daily dose (mg)

Mean ± SD 1.23 ± 0.72 1.26 ± 0.70 1.05 ± 0.77 Median (range) 1.20 (0 to 4.17) 1.22 (0 to 4.17) 0.96 (0.02 to

3.48)


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Prolactin Levels by Exposure: All Patients

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Prre-dose 4 to 7 8 to 12 16 to 6 tc? 35 40 to 48 52 to 55

Treatment Duration (weeks) rri ©F,V [ry= 550 n=499 nw,, q `û rm394 n=358 n=42

Data on Me; Johnson 89a Johnson PRO, LLC

Prolactin Levels vs Dose Weeks 4 to 7 (PAP -as Observed): Log Scale

1000

r::

0.0001 0.001 0.01

Risperidone Dose [mglkg]

*Log scale used due to large range of individual values for PRL and risperidone dose


0.1

Prolactin Levels vs Dose Weeks 40 to 48 (PAP -as Observed): Log Scale

1000 -

1

O o o O O

o oc6 o

o a o ----- -----------------p- --------- o 0°óco

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0.0001 0.001 0.01

Risperidone Dose [mg/kg]

0.1

*Log scale used due to large range of individual values for PRL and risperidone dose


Correlation Between Risperidone Dose and PRL Level


n Variance (Percent)*

Weeks 4 to 7 550 0.30

Weeks 8 to 12 499 0.01

Weeks 16 to 24 441 0.11

Weeks 28 to 36 394 0.25

Weeks 40 to 48 358 0.78

*Percent of variation in prolactin level that can be attributed to risperidone dose; R2 x 100


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Incidence of Prolactin Levels: Normal and Above Upper Limit of Normal

100% -

90% -

80% -

70% -

60% -

50% -

40% -

30% -

20% -

10%-

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ULN

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Pre -dose 4 to 7 8 to 12 16 to 24 28 to 36 40 to 48 52 to 55

Treatment Duration (weeks) n =592 n =550 n =499 n =441 n =394 n =358 n =42


Prolactin Levels by Exposure

35

30

25

20

15

10

5

o

PAP Fixed -n Subsets

Pre -dose

-Q- Predose to week 4 to 7 (n © M0)

-Q- Predose to vusah 12 (n 466)

Predose to week i6 t 24 (o 365)

Predose to week 20 to 3C Qo ° MG)

G°'rredose to week 40 to 60 (n ° 200)

4 to 7 8 to 12 16 to 24 28 to 36 40 to 48


To be included ki a subset, patients had to have PRL measurements at all time points Data on St: Johnson Johnson PRD, LLC

Prolactin Levels by Exposure

80

70- Z u) J 60-

a) : 50- á. > 4- a) 40 - o -J

4E' 30-

a. 20- a) - 10-

0

PAP Fixed -n Subsets Total n

-0- Predose to week 4 to 7 (n = 550)

--0- Predose to week 8 to 12 (n = 466)

-A- Predose to week 16 to 24 (n = 385)

-Q- Predose to week 28 to 36 (n = 318)

---0- Predose to week 40 to 48 (n = 269)

Pre -dose 4to7 8to12 16to 24 28 to 36 40 to 48

Treatment Duration (weeks) To be included in a subset, patients had to have PRL measurements at all time points


55 -

50 -

45 -

40 -

35 -

30 -

25 -

20 -

15- 10-

5-

0-

Prolactin Observations by Continuation Status

PAP Fixed -n Subsets

TT

C: n=466 D: n=84

Patients Continuing Patients Discontinuing

11

TT TT TT TT C: n=385 C: n=318 C: n=269 C: n=22 D: n=81 D: n=67 D: n=49 D: n=247

Weeks 4 -7 Weeks 8 -12 Weeks 16 -24 Weeks 28 -36 Weeks 40-48

Treatment Duration (weeks) Data on file: Johnson & Johnson PRD, LLC

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Pre -dose Prolactin Level by Gender

PAP --as Observed

1

n=489

T

n=103

Boys Girls


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Prolactn Levels by Age

Weeks 40 to 48 (PAP -as Observed)

*

Data ®n Me: Johnson Johns ti n PRO, LLC

i 10 11

App, rYearaj

12 13 14 15

Prolactin Levels by Gender

60

50

40

30

2©

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--0- Boys -0- Girls

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Pre- dose

4 to 7 8 to 12 16 to 24 28 to 36 40 to 48 52 to 55


Boys n =489 n =457 n =417 uw369 n =323 n =303 n =34 Girls n103 n =93 n =82 no7? n =71 n =55 n =8

Data on fDDea Johnson & Johnson PRD, LLC

Prolactin Levels in Boys >_10 vs <10 Years of Age

50 -

45 -

40 -

35 -

30 -

25 -

20 -

15- 10- 5- 0

-o- Boys ?10 years -0- Boys <10 years



Boys X10 n =234 n =222 n =209 n =191 n =156 n =149 n =16

Boys <10 n =255 n =235 n =208 n =178 n =167 n =154 n =18

Data on file: Johnson & Johnson PRO, LLC

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Prolactin Levels in Girls >_9 vs <9 Years of Age

- 60 E

50 . > 40 a)

© 11

11- 10

co a) 2

-0- Girh L-9 ye8irs -0- Girls <9 years



Girls z9 [n*M n=54 n=48 n=43 n=46 nnal n=2 Girls <9 ril°Zn',i n=39 n=34 ui=29 n=25 nmM n=6

n filo: Johnson & Johnson P ®o LLC

Prolactin Levels by Age Group: All Patients

50

6,0

60

30

20

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35

30

25

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-1:1- 12 to 15

1 ? 6 5 o o 1/4o

ti 9

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Data on halo: Johnson & Johnson PRD, LLC

Correlation Between PRL Level and Age

Exposure n Variance (Percent)*

Pre -dose 592 0.01

Weeks 4 to 7 550 0.19

Weeks 8 to 12 499 1.24

Weeks 16 to 24 441 1.48

Weeks 28 to 36 394 1.32

Weeks 40 to 48 358 1.76

*Percent of variation in PRL level that can be attributed to age; R2 x loo


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Change in Weight at Endpoint From Expected Weight: All Patients

12.0

10.0-

+ 8.0 -

6.0

4.0-

2.0

IIM

n=129

PRL

PRL

n=22

,

ng/mL >50 ngimL

n=158 n=18

.. I!

n=149

n=23 n=126

4 IE

n=22

T

ill

1

111

S! 0.0

5 to 7


8to9 1Otoll

Age Group

12 to 15

Analysis of Change in Weight at Endpoint From Expected Weight

<_50 vs >50 Both genders All age groups

Factor P- values

Age group 0.02 Gender 0.24

Age group x gender interaction 0.56 PRL 0.05

Age group x PRL interaction 0.92 Gender x PRL interaction 0.13

Age group x gender x PRL interaction 0.90


Change in Weight at Endpoint From Expected Weight

14 PRL _50 ng/mL PRL >50 ng/mL

n=465 n-65

n=20

2

Q

Boys


Girls

Change in Weight at Endpoint From Expected Weight in Boys

PRL s50 ng/mL PRL >50 ng/mL

n=19

6 -i n=103

0

n=132 - n=16

n=20 n=105

n=125

i I

ih

n=10

11

5to7 8to9 10to11 12to15

Age Group (years)


Analysis of Change in Weight at Endpoint From Expected Weight

4_50 vs >50

Boys only All age groups

Factor P- values

Age group 0.16 PRL 0.60

Age group x PRL interaction 0.93


Change in Weight at Endpoint From Expected Weight in Girls

14 PRL <_5Q ng/mL

12 PRL >50 ng/mL

n=26 -- n=3

5 to 7


n=2

ßto9

n=12

10 to 11

Age Group (years)

12 to 15

CO L N O N a CO o

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. n Analyss of Change Weight at Endpoint Expected From C

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<_50 vs >50 0' ...3.

Girls only ,,

All age groups ° n_

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I Side Effects Hypothetically g

Attributable to Prolactin (SHAP) i

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Gahan Pandina, PhD ° U

Assistant Director, Medical Affairs Janssen Pharmaceutica Products, LP

SHAP by Baseline Tanner Stage

Number ( %) of Patients

ITT PA Non-PA

Total number of patients 700 592 108

Number of patients with at least one SHAP, n ( %)

14 (2.0) 13 (2.2) 1 (0.9)

Tanner stage, n 1 4 2 2

3 4 4 3

5 0

In the PA population, mean onset of the first SHAP was 98.8 days (minimum 1 day and maximum 254 days)


Definitions

Preferred terms excluded from analysis per pediatric endocrinologists:

Dysmenorrhea Growth hormone excess Hyperprolactinemia Penis disorder Sexual function abnormal Testis disorder Vaginitis atrophic

Patients with >_1 week of amenorrhea, girls with >_31 days of gynecomastia and boys <10 years of age with gynecomastia are included


Individual SHAP

Number ( %) of Patients

ITT PA Non -PA

Endocrine disorders 5 (0.7) 5 (0.8) 0 (0.0)

Gynecomastia 5 (0.7) 5 (0.8) 0 (0.0)

Reproductive disorders, female 9 (1.3) 8 (1.4) 1 (0.9) Amenorrhea 4 (0.6) 3 (0.5) 1 (0.9)

Menorrhagia 3 (0.4) 3 (0.5) 0 (0.0)

Breast enlargement 1 (0.1) 1 (0.2) 0 (0.0)

Lactation nonpuerperal 1 (0.1) 1 (0.2) 0 (0.0) Menstrual disorder 1 (0.1) 1 (0.2) 0 (0.0)

Vaginal hemorrhage 1 (0.1) 1 (0.2) 0 (0.0)


Risperidone Dosing Information in Patients With and Without SHAP

PAP - as Observed Patients with SHAP at

any thTli0,

0 r c 3)

Patients without SHAP

(n=579) Duration (days)

Mean (±SD) 3,50 (31.2) 318 ( i 02o 1 )

Median (range) 365 (28 0 to 4`,1,) 360 (20 to 505)

Average daily dose (ingBciay4) Mean (±SD)

` .29 (KM) 126 (0a71 )

Median (range) /e20 (0e12 to 2.29) 1,23 (0,001 to 4.17)

Mean (iSD) age of pasúents with SNAP

Boys 7,t, ! (1.7) NA

Girls 12,0 (`.8) ----- NA

a'a on file; Johnson 81 Johnson PRO, LE_,C

Prolactin Levels in Patients With and Without SNAP

90

80 -

70 -

60 -

50 -

40 -

30 -

20 -

10-

0

-0- Patients with SHAP at any time -a- Patients without SHAP

Pre-dose 4 to 7 8 to 12 16 to 24 28 to 36 40 to 48 52 to 55

Treatment Duration (weeks) +SHAP n=13 n=11 n=12 n=12 n=11 n=9 n=0

-SHAP n=579 n=539 n=487 n=429 n=383 n=349 n=42


4-

0

Percent of Patients with SHAP: Normal Versus Above ULN

3.4

2.1

ï(

3.5

{

1.2

2.3

in Above ULN

[IA Normal

2.7 2.8

1.8

2.8

Pre-dose 4 to 7 8 to 12 16 to 24 28 to 36 40 to 48


n 12/563 31162 3/242 8/265 7/246 7/248 Normal

1/29 8/388 9/257 4/176 4/148 2/110 > U LN

P- values .64 .87 .09 .64 .93 .58 Data on file: Johnson & Johnson PRD. LLC

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Incidence of Motor Effects Number ( %) of Patients

rtrî (1,1° 0)

PA (n =592)

Non -PA '

(n =108) Number of patients with at least one EPS 147 (21.0) 129 (21.8) 18 (16.7)

CNS and PNS disorders 147 (21.0) 129 (21.8) 18 (16.7)

Hypertonia 37 (5.3) 34 (5.7) 3 (2.8)

Tremor 33 (4.7) 27 (4.6) 6 (5.6)

Extrapyramidal disorder 29 (4.1) 28 (4.7) 1 (0.9)

Hyperkinesia 24 (3.4) 22 (3.7) 2 (1.9)

Hypokinesia 22 (3.1) 19 (3.2) 3 (2.8)

Involuntary muscle contractions 21 (3.0) 20 (3.4) 1 (0.9)

Bradykinesia 14 (2.0) 12 (2.0) 2 (1.9)

Dystonia 11 (1.6) 9 (1.5) 2 (1.9)

Oculogyric crisis 6 (0.9) 4 (0.7) 2 (1.9)

Tardive dyskinesia 2 (0.3) 2 (0.3) 0

Hypotonia 1 (0.1) 1 (0.2) 0

In the PA population, mean onset of first EPS was 64.3 days (minimum '1 day and maximum 369 days)

Data on file: Johnson & Johnson PR J LLC

Prolactin Levels in Patients With and Without EPS

60

40

30

0 20

2 ro_

- Patients \NH- EPS - Patients withut EPS

Pve-dose 4 to 7 8 to 12 'd0 ta 28 to 38 40 .to 40 52 to 55

Treatment Duration (week) -re' E P13 wû12 9 n=110 n=116

-0'8 ri=463 n=432 vt=383

Data on file: J hnson & Johnson PR LLC

n=104 n=94 n=82 mi i n=337 n=300 n=276 w-A31

Percent of Patients with EPS by PRL Level: Normal vs Above ULN

30 - 27.6

25 -

21.5

20

i5-

10-

Q

21 6 21.0 1

-, {...

23.7 22.7

t I

ni

22 2

24.5

a+

On Above ULN uili Normal

24.3 23.6

k

i;

20.9

23.8

{

Pre -dose 4 to 7

n 1211563

8/29

8 to 12 16 to 24 28 to 36


40 to 48

34/162 55/242 65/265 58/246 59/248 Normal 84/388 61/257 39/176 36/148 23/110 >ULN

P- values .44 .86 .79 .57 .87 .55 Data on file: Johnson & Johnson PRD, LLC

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Responders on the Conduct Problem Subscale of the NCBRF Versus PRL Level

Response criteria: X25% Above ULN

Eli Normal 90- 80 - 80

83 81 80 85

[,

75

84

77 IfIlflfltli'i

79 82

Tr,_ l

70 -

60- 50 -

40 - ;.

30 -

20 -

10- 0

4 to 7

Total n

Normal 92 147 >ULN 243 183

8to12 16to24 28 to 36 40 to 48


P- values .62 .68 Data on file: Johnson & Johnson PRD, LLC

193 195 245 126 121 109

.04 .16 .43


90 -

80 -

70 -

60 -

50

40 -

30 -

20 -

10- 0

Total n Normal 92 147

>ULN 243 183

71 73

Response criteria: >_35%

72 71 17 T°

4to7 8to12

77

; 66

16 to 24

73 71 -

,r

28 to 36


P- values .77 .78 Data on file: Johnson & Johnson PRD, LLC

Above ULN

FIE Normal

40 to 48

193 195 245 126 121 109

.04 .71 .42


90- 80 -

70 61

60 - 8 1

50 -

40 -

30 -

20 -

10 -

o

Total n

Normal 92 147 >ULN 243 183

Response criteria: >_50Q/o

60 59 60 1TrTr

4to7 8to12 16 to 24

E Above ULN

E Normal

62 60 56

7-. 7

28 to 36 40 to 48


P-values .54 .85


193 195 245 126 121 109

.24 .50 .57

PRL Levels In Responders on the Conduct Problem Subscale of the NCBRF Versus Non -responders

50 -

45 -

40 -

35 -

30 -

25 -

20 -

15- 10- 5- 0


-0- Responders -0-- Non -responders

n

Responders Non -responders

4 to 7 8 to 12 16 to 24 28 to 36 40 to 48


271 266 252 251 288

64 64 67 65 66


PRL Levels In Responders on the Conduct Problem Subscale of the NCBRF Versus Non -responders

50 -

45 -

40 -

35 -

30 -

25 -

20 -

15- 10- 5- 0

n

Responders Non -responders


-0- Responders -o- Non -responders

4to7 8to12 16to24 28to36 40to48


240 236 225 226 257 95 94 94 90 97

'Data on file: Johnson & Johnson PRD, LLC

PRL Levels In Responders on the Conduct Problem Subscale of the NCBRF Versus Non- responders

50 -

.-. 45 - J E 40 -

Zo 35 -

a 30 - .. c 25 -

-Cis)

20 -

15- Ó L 10- `---'

5 -

0


-0-- Responders -O- Non -responders

4 to 7 8 to 12 16 to 24 28 to 36 40 to 48

Treatment Duration (weeks) n

Responders 202 195 177 185 213 Non -responders 133 135 142 131 141


Conduct Problem Subscale Score vs Prolactin Levels

Weeks 4 to 7 (PA - as Observed)

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Conduct Problem Subscale Score vs Prolactin Levels

50

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Weeks 40 to 48 (PA - as Observed)

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100 251

Correlation Between PRL Level and NCBRF Conduct Problem Subscale Score

Exposure n Variance (Percent)*

Pre -dose 592 0.03

Weeks 4 to 7 547 0.93

Weeks 8 to 12 496 0.29

Weeks 16 to 24 438 0.19

Weeks 28 to 36 392 0.24

Weeks 40 to 48 355 0.14

*Percent of variation in subscale score that can be attributed to prolactin level; R2 x 100

-Data on file: Johnson & Johnson PRD, LLC

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Age group x gender x ADHD interaction 0.61


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n 48 43 58 42 38 67 38 64 30 48 39 13


Analysis of Median Prolactin Level: Effect of ADHD Groups


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Boys Girls

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Analysis of Change in Weight at Endpoint From Expected Weight: Effect of Prolactin

X60 vs >60

Both genders All age groups

Factor P- values

Age group 0.06 Gender 0.12

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Age group x PRL interaction 0.63 Gender x PRL interaction 0.05

Age group x gender x PRL interaction 0.86



<_60 vs >60


Factor P- values





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Factor P- values




Prolactin Levels vs Age

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