Clinical trial NCT01711021
Conditions: Attention Deficit Hyperactivity Disorder
Keywords: ADHD
Sponsor: Noven Pharmaceuticals, Inc.
Start date: 2012-10-01; Completion date: 2013-03-01
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate safety and efficacy of d-Amphetamine Transdermal System for the treatment of Attention Deficit Hyperactivity Disorder in children and adolescents.

Detailed description:
The study will consist of a four-week screening period, a 3-day wash-out period (if applicable), a five-week open-label, step-wise dose optimization period and two-week double blind randomized crossover treatment period with weekly classroom assessments and a safety follow-up by telephone 7 - 10 days after last dose of study drug.

Arms: arm 1: The study was conducted in 2 parts: a 5-week, open-label, step-wise Dose Optimization Period and a 2-week, randomized, cross-over Double-Blind Treatment Period.

Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment.

Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment.

d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied. arm 2: The study was conducted in 2 parts: a 5-week, open-label, step-wise Dose Optimization Period and a 2-week, randomized, cross-over Double-Blind Treatment Period.

Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment.

Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment.

Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.
Interventions: intervention 1: d-Amphetamine Transdermal Patch intervention 2: Placebo patch
Intervention descriptions: intervention 1: The study was conducted in 2 parts: a 5 week, open-label, step-wise Dose Optimization Period and a 2-week, randomized, cross-over Double-Blind Treatment Period.

Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied. intervention 2: The study was conducted in 2 parts: a 5 week, open-label, step-wise Dose Optimization Period and a 2-week, randomized, cross-over Double-Blind Treatment Period.

Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.

Protocol documents:
Prot_000.pdf: 

































































































































































SAP_001.pdf: 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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TABLE OF CONTENTS 
Approvals .............................................................................................................................. 1 
Table of Contents .................................................................................................................. 2 
1. 
Introduction ................................................................................................................... 4 
1.1 
Changes from Protocol ..................................................................................................... 4 
2. 
Study Objectives ............................................................................................................. 4 
3. 
Study Design .................................................................................................................. 5 
3.1 
Sample Size Considerations ............................................................................................. 6 
3.2 
Randomization ................................................................................................................. 6 
4. 
Study Variables and Covariates ....................................................................................... 6 
4.1 
Primary Variable ............................................................................................................... 6 
4.2 
Secondary Variables ......................................................................................................... 6 
4.2.1 
SKAMP ......................................................................................................................... 6 
4.2.2 
PERMP ......................................................................................................................... 7 
4.2.3 
ADHD-RS-IV ................................................................................................................. 7 
4.2.4 
CPRS-R:S ...................................................................................................................... 8 
4.2.5 
CGI ............................................................................................................................... 8 
4.2.6 
Safety .......................................................................................................................... 9 
4.3 
Predetermined Covariates and Prognostic Factors ......................................................... 9 
5. 
Definitions .................................................................................................................... 10 
6. 
Analysis Populations ..................................................................................................... 11 
6.1 
Full Analysis Set .............................................................................................................. 11 
6.2 
Completers ..................................................................................................................... 11 
6.3 
Safety .............................................................................................................................. 12 
7. 
Statistical Methods ....................................................................................................... 12 
7.1 
Efficacy Analyses ............................................................................................................ 13 
7.1.1 
Primary Variable ....................................................................................................... 13 
7.1.2 
Missing Data .............................................................................................................. 15 
7.1.3 
Secondary Variables .................................................................................................. 17 
7.1.3.1 SKAMP ................................................................................................................. 17 
7.1.3.2 PERMP ................................................................................................................. 19 
7.1.3.3 ADHD-RS-IV ......................................................................................................... 20 
7.1.3.4 CPRS-R:S .............................................................................................................. 20 
7.1.3.5 CGI ....................................................................................................................... 20 
7.2 
Subject Disposition ......................................................................................................... 21 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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7.3 
Protocol Deviations and Violations ................................................................................ 21 
7.4 
Treatments ..................................................................................................................... 21 
7.4.1 
Extent of Study Drug Exposure ................................................................................. 21 
7.4.2 
Concomitant Medications ......................................................................................... 22 
7.5 
Demographic and Baseline Characteristics .................................................................... 22 
7.6 
Dermal Evaluations ........................................................................................................ 22 
7.6.1.1 Adhesions ............................................................................................................ 23 
7.6.1.2 Irritation .............................................................................................................. 23 
7.6.1.3 Discomfort ........................................................................................................... 23 
7.6.1.4 Adhesive Residue ................................................................................................ 24 
7.7 
Safety Analyses ............................................................................................................... 24 
7.7.1 
Adverse Events .......................................................................................................... 24 
7.7.2 
Deaths and Serious Adverse Events .......................................................................... 25 
7.7.3 
Laboratory Data ........................................................................................................ 25 
7.7.4 
Vital Signs .................................................................................................................. 26 
7.7.5 
Columbia Suicide Severity Rating Scale (Children’s Version) ................................... 26 
7.7.6 
Physical Examinations, ECGs, and Other Observations Related to Safety ............... 27 
8. 
Interim Analyses ........................................................................................................... 27 
9. 
Data Review ................................................................................................................. 28 
9.1 
Data Handling and Transfer ........................................................................................... 28 
9.2 
Data Screening ............................................................................................................... 28 
10. 
Validation ................................................................................................................. 28 
Appendix 1 
Glossary of Abbreviations ............................................................................ 30 
Appendix 2 
Normal Ranges for Vital Signs ...................................................................... 32 
Appendix 3  
List of In-Text Tables, Figures, and Listings ................................................... 32 
Appendix 4 
List of Post-Text Tables, Figures, Listings, and Supportive SAS Output 
Appendices 
32 
Appendix 5  
List of Additional Protocol Violation/ Protocol Deviation Identification Listings
 
39 
Appendix 6  
Shells for In-Text Tables, Figures, and Listings .............................................. 40 
Appendix 7  
Shells for Post-Text Tables, Figures, and Listings ........................................... 41 
Appendix 8  
Shells for Additional Protocol Violation/Deviation Identification Listings .... 163 
 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Noven Pharmaceuticals, Inc. Protocol: N25-006. 
The format and content of this SAP are structured to provide sufficient detail to meet the 
requirements specified by the International Conference on Harmonization (ICH) E9: Guidance 
on Statistical Principles in Clinical Trials.  
This SAP should be read in conjunction with the study protocol and case report form (CRF). 
This version of the plan has been developed using the protocol amendment 4 dated 08MAY2013 
and version 2.0 of the CRF dated 05MAR2013. Any further changes to the protocol or CRF may 
necessitate updates to the SAP. 
The SAP is to be developed in two stages. The purpose is to “finalize” a SAP so that 
programming can be started early in the process. Versions of the SAP up to initial sponsor 
approval will be known as SAP1. Changes following approval of SAP1 will be tracked in the 
SAP Change Log and a final version of the SAP, known as SAP2, will be issued for sponsor 
approval prior to database lock. 
1.1 
CHANGES FROM PROTOCOL 
There are no changes from protocol amendment 4, dated 08 May 2013. 
2. STUDY OBJECTIVES 
The primary objective is to assess efficacy of d-Amphetamine Transdermal Drug Delivery 
System (d-ATS) compared to placebo, as measured by the Swanson, Kotkin, Agler, M-Flynn and 
Pelham Scale (SKAMP) total score. An additional primary objective is to assess the safety and 
tolerability of d-ATS. 
The secondary objectives are: 
 To assess onset of efficacy of d-ATS compared to placebo as measured by the SKAMP 
total score 
 To assess duration of efficacy of d-ATS compared to placebo as measured by the 
SKAMP total score 
 To assess additional efficacy assessments including: 
o Permanent Product Measure of Performance (PERMP) 
o Attention-Deficit/Hyperactivity Disorder Rating Scale, Version IV 
(ADHD-RS-IV) 
o Conners' Parent Rating Scale-Revised Short Form (CPRS-R:S) 
o Clinical Global Impression (CGI) scale. 
 To assess the skin irritation, discomfort, adhesion and adhesive residue of d-ATS 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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3. STUDY DESIGN 
This is a randomized, double-blind, cross-over, placebo controlled study to evaluate the safety 
and efficacy of d-ATS in children and adolescents 6 to 17 years of age with Attention Deficit 
Hyperactivity Disorder (ADHD). 
The study will consist of a four-week screening period, a 72-hour wash-out period (if 
applicable), a five-week open-label, step-wise dose optimization period and two-week double 
blind randomized crossover treatment period with weekly classroom assessments and a safety 
follow-up by telephone 7 - 10 days after last dose of study drug.  Approximately 90 subjects will 
be randomized at 3 sites. 
Screening Period (Visit -1): Screening procedures may be performed within four weeks prior to 
the Dose Optimization Period of the study. 
Washout Period: Eligible subjects will undergo a 72 hour wash-out period if applicable. 
Baseline Visit (Day 0, Visit 0): Eligible subjects will return to the clinic on Day 0 for baseline 
assessments. Subjects who continue to meet the eligibility criteria will be entered into the 
open-label Dose Optimization period. 
Dose-Optimization Period [Day 1 to Day 35; Visit 1 (Day 7), Visit 2 (Day 14), Visit 3 (Day 
21), Visit 4 (Day 28) and Visit 5 (Day 35)]: Following Screening Period and Washout Period (if 
applicable), eligible subjects will enter the open-label Dose-Optimization Period. Optimal dose 
will be defined as the dose that will produce a reduction in ADHD RS-IV score ≥ 30% and 
CGI-Improvement (CGI-I) score of 1 or 2 and has tolerable side effects. Tolerability will be 
determined by the investigator. The Investigator can increase the current dose to provide 
additional symptom control. One dose reduction will be permitted if the subject experiences 
unacceptable tolerability of the current dose.  
Subjects will be discontinued if they are unable to tolerate d-ATS or cannot reach their optimal 
dose by Week 5. If the subject has reached their optimal dose, then at the discretion of a 
medically qualified investigator, one dose reduction per participant may occur during the dose 
optimization period for safety reasons. However if the current dose is intolerable and the subject 
has never reached their optimal dose, the subject would be discontinued from the study. A dose 
increase may occur at visit 4 if no prior dose has met criteria for optimal response and the current 
dose is well tolerated as deemed by a medically qualified investigator. The dose used during the 
week 5 visit will be the dose that the subject is randomized to during the Double-Blind 
Treatment Period. During Visit 5, subjects will attend a half-day practice laboratory school with 
analog classroom sessions to become familiar with classroom schedules and procedures. Three 
SKAMP assessments will be performed, and 3 practice PERMP tests will be given during the 
practice session. 
Double-Blind Treatment Period [Day 36 to Day 49; Visit 6 (Day 42) and Visit 7 (Day 49)]: 
Subjects who have reached an optimal dose will enter the two-week double-blind treatment 
period. Subjects will be randomized to receive daily d-ATS treatment (at the optimized dose) for 
one week followed by daily placebo patched (identical in appearance to d-ATS) for one week, or 
vice versa. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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During Week 6 subjects will receive study patches in accordance with the randomization 
schedule and during Week 7 subjects will cross-over to receive the other study treatment per the 
randomization schedule. 
Follow-Up: A safety follow-up will be conducted by telephone 7-10 days (Visit 8, Day 56) after 
last dose of study drug. 
The duration of the study will be approximately 56 days for each individual subjects (not 
including screening and washout). 
3.1 SAMPLE SIZE CONSIDERATIONS 
Assuming a standard deviation (SD) of
 
and based on an average difference in total SKAMP scores between Placebo and d-ATS of 
, 74 subjects would need to complete the study to detect a true difference of 
 
in mean total SKAMP scores between placebo and d-ATS at 80% power when testing at a 
significance level of α = 0.05 (2-sided). Assuming a dropout rate of 20%, 90 subjects will be 
randomized and it is expected that 74 subjects will complete the study. A subject will be 
considered to have completed the study if the subject received both treatments during the double-
blind Treatment Period and have completed both 12-hour classroom sessions during the double-
blind Treatment Period. 
3.2 RANDOMIZATION 
Randomization will occur prior to the start of the double-blind study period. Subjects will be 
randomized to one of the two treatment sequences (d-ATS then Placebo or Placebo then d-ATS) 
in a 1:1 ratio. Each eligible subject will be randomized to group assignment by a centralized 
Interactive Voice Response System (IVRS) /Interactive Web Response System (IWRS). 
Randomization will be applied centrally, without any stratification factors, across all sites to 
ensure even distribution of subjects across each treatment sequence. 
4. STUDY VARIABLES AND COVARIATES 
4.1 PRIMARY VARIABLE 
The primary efficacy measure is the mean SKAMP total score. The SKAMP scale is a validated 
rating scale that assesses manifestations of ADHD in a classroom setting through several 
subscales, including deportment (behavior) and attention. Multiple SKAMP assessments will be 
completed at the end of individual classroom sessions across the day by observers who rated 
each subject on 13 items, using a 7-point impairment scale (0=normal, 6=maximal impairment). 
4.2 SECONDARY VARIABLES 
4.2.1 
SKAMP  
The SKAMP total score at each assessment time point will also be used to assess the secondary 
measures of onset and duration of efficacy. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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4.2.2 
PERMP 
The PERMP, a 5-page math test consisting of 80 problems per page (total of 400 problems), will 
be used in this study to evaluate effortful performance in the classroom as a measure of efficacy. 
Subjects will be instructed to work at their seats and to complete as many problems as possible in 
10 minutes. The appropriate level of difficulty for each student will be determined based on 
results of a math pretest administered at screening. Performance will be evaluated using two 
scores: PERMP-A (number of problems attempted) and PERMP-C (number of problems 
correct). In order to prevent the subjects from taking the same test more than once during the 
study, subjects will receive randomized problems in a different version of the test at each 
assessment. 
4.2.3 
ADHD-RS-IV 
The ADHD-RS-IV is a clinician-rated scale that reflects current symptoms of ADHD based on 
Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition, Text Revision 
(DSM-IV-TR) criteria; it is a global assessment that measures the severity of symptoms from 
visit to visit, but is not utilized to assess symptoms of ADHD over the course of the day. The 
ADHD-RS-IV consists of 18 items that are grouped into 2 subscales (hyperactivity/impulsivity 
and inattention). Each item is scored on a 4-point scale from 0 (no symptoms) to 3 (severe 
symptoms), yielding a total score of 0 to 54. 
ADHD-RS-IV Hyperactivity-Impulsivity Subscale includes the following question scores: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADHD-RS-IV Inattention Subscale includes the scores for the following questions: 
 
 
 
 
 
 
 
 
 
 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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 
 
  
 
 
 
 
 
. 
4.2.4 
CPRS-R:S 
The CPRS-R:S is a standard instrument for the assessment of ADHD in children and 
adolescents. It evaluates problem behaviors as reported by the parent or alternative caregivers. 
The CPRS-R:S contains 27 items and covers a subset of the subscales and items on the long 
parent form. Scales include: oppositional, cognitive problems/inattention, hyperactivity, and 
ADHD index.  
4.2.5 
CGI 
The CGI provides a global evaluation of baseline severity and improvement over time, and, like 
the ADHD-RS-IV scale, measures global impressions of severity from visit to visit but not over 
the course of the day. At baseline, the investigator will use the CGI-Severity (CGI-S) to rate 
severity on a scale that ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill 
subjects) plus a not assessed option. At each visit thereafter, the clinician will use the CGI-I to 
rate improvement relative to baseline on a scale ranging from 1 (very much improved) to 7 (very 
much worse) plus a not assessed option. For analysis, CGI-I and CGI-S scores will be 
dichotomized.  
For CGI-S: 
The non-severe illness is defined as subjects achieving a score of 
1: Normal, not at all ill or 
2: Borderline mentally ill or 
3: Mildly ill. 
The severe illness is defined as subjects achieving a score of 
4: Moderately ill or 
5: Markedly ill or 
6: Severely ill 
7: Among the most extremely ill patients. 
Subjects achieving a score of 0: Not assessed will be considered as missing data. The number 
and percentage of subjects with severe illness and non-severe illness at each time point will be 
summarized. 
 
For CGI-I 
The responders are defined as subjects achieving a score of 
1: Very much improved or 
2: Much improved or 
3: Minimally improved on the clinician-rated CGI global improvement item. 
The non-responders are defined as subjects achieving a score of 
4: No change or 
5: Minimally worse or 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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6: Much worse or 
7: Very much worse. 
Subjects achieving a score of 0: Not assessed will be considered as missing data. The number 
and percentage of responder and non-responders at each time point will be summarized. 
 
The actual values of each question of CGI-S, and CGI-I, severity (severe or non-severe), and 
responder (yes/no) will be listed. 
4.2.6 
Safety 
Safety will be assessed by evaluating: 
 Adverse events (AEs) 
 Suicidality [assessed using Columbia Suicide Severity Rating Scale (C-SSRS)] 
 Concomitant medications 
 Clinical laboratory tests 
 Vital signs 
 Physical examinations 
 Electrocardiograms (ECGs) 
4.3 PREDETERMINED COVARIATES AND PROGNOSTIC FACTORS 
Demographic and baseline characteristics known to be related to treatment response may be 
considered for inclusion as covariates in exploratory statistical analysis models. 
The effect of the following factors on the primary efficacy analysis (FAS population) will be 
considered: 
 Investigator site 
 Optimized dose 
 Gender 
 ADHD type (inattentive, hyperactive/impulsive, combined, not otherwise specified) 
 Baseline ADHD severity (defined as the pre-dose ADHD-RS-IV rating scale at baseline, 
Visit 0)  
 Age group  
To ensure summaries from the subgroups are informative, these will only be performed where 
subgroups include 5 or more subjects in each.Where subgroups have less than 5 subjects the 
small group will be combined with the next group, if there is a consecutive order to the 
groupings or with the next smallest group if there is no order. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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5. DEFINITIONS 
SKAMP Total Score 
The SKAMP total score will be the sum of the 13 individual item scores at each timepoint. 
Missing data will not be handled at an item level, if any of the 13 items are missing for a 
timepoint then the SKAMP total score will be missing for that timepoint. 
Mean SKAMP Total Score 
The mean SKAMP total score will be the average of all SKAMP total scores collected over the 
course of a laboratory assessment day, with the exception of the score from the session prior to 
dosing.  
Onset of efficacy 
The onset of efficacy, based on the SKAMP total scores, will be defined as the time of the first 
assessment time showing statistical significance between d-ATS and placebo. If no significant 
difference is found at any time point for the onset of efficacy, no onset of efficacy will be 
deemed to have occurred, and the onset of efficacy will be defined as ‘none’. 
Duration of efficacy 
The duration of efficacy, based on the SKAMP total scores, will be defined as the difference 
between the time point that indicates that the effect has ended and the onset of efficacy, as 
defined above. The time point that indicates that the effect has ended will be defined as the first 
time point at which there is a non-significant difference between the two treatment groups after a 
time point in which there is a significant difference between the two treatment groups. If there is 
no time point at which there is a non-significant difference between the two treatment groups 
after a time point in which there is a significant difference between the two treatment groups, 
then the end of effect will be defined as 12 hours post-dose. 
Onset of effect (50% reduction in SKAMP total score)  
Onset of effect of 50% reduction in SKAMP total score is defined for each subject as the first 
time point at which there is a 50% reduction in SKAMP total score from the pre-dose 
observation on the same classroom day. 
Duration of effect (50% reduction in SKAMP total score)  
Duration of effect of 50% reduction in SKAMP total score will be determined by persistence of 
the 50% reduction from the pre-dose observation in SKAMP total score level. The end of effect 
will be determined as the first timepoint after onset of effect at which 50% reduction from the 
pre-dose observation in SKAMP total score is not observed. The duration of effect will be 
calculated as the difference between the end of effect and onset of effect, in hours.  
Age 
Age will be calculated as (date of informed consent – date of birth + 1) / 365.25. 
Baseline 
Baseline is defined as data collected at Visit 0 (Day 0).  If data was not collected at Visit 0, the 
last data available prior to Visit 0 will be used as the baseline data. However during the double 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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blind crossover phase change from baseline analyses will be performed taking the pre-dose data 
at the same classroom visit to be the baseline. 
Body Mass Index 
Body Mass Index (BMI) will be calculated as weight in kg / (screening height in m)2. 
Prior and Concomitant Medications 
Prior medications are defined as those taken prior to the date of first dose of study medication.  
Concomitant medications are defined as those on or after the date of first dose of study 
medication  through and including the day of the safety follow-up visit. Medications with a 
missing or incomplete start date will be assumed to be concomitant. 
Concomitant medications will be assigned to either the Dose-Optimization Period or the 
double-blind Treatment Period of the study according to the start date, and will be summarized 
separately. Concomitant medications for which a missing or incomplete start date makes it 
impossible to determine which period of the study they started in will be counted as starting in 
the Dose-Optimization Period. 
Treatment-emergent adverse event 
A treatment-emergent adverse event (TEAE) is one which first occurs or worsens in severity 
after the first patch application and not later than 30 days following last patch removal. Adverse 
events are collected through the last study visit.  Those AEs with a start date equal to the date of 
first patch application will be considered as TEAEs. 
Adverse events for which a missing or incomplete start date makes it impossible to determine 
whether or not they were treatment-emergent will be counted as being treatment-emergent. 
Adverse events will be assigned to either the Dose-Optimization Period or the double-blind 
Treatment Period of the study according to the start date, and will be summarized separately. 
Adverse events for which a missing or incomplete start date makes it impossible to determine 
which period of the study it started in will be counted as starting in the Dose-Optimization Period 
6. ANALYSIS POPULATIONS 
6.1 FULL ANALYSIS SET  
The full analysis set (FAS) includes all consented and randomized subjects who have taken at 
least one dose of study medication. The FAS population will be used as the primary population 
for analysis of efficacy endpoints. 
6.2 COMPLETERS 
The completers population includes all consented and randomized subjects who  
 received full prescribed dose of the double-blind study medication at both test laboratory 
classroom sessions 
 completed the full classroom tests on both test classroom sessions 
 did not miss more than four consecutive days of therapy during the double blind 
treatment period 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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 
 did not use prohibited concomitant medications during the double blind treatment period 
The Completers population will be used for supportive analyses of efficacy endpoints. 
6.3 SAFETY 
The safety (SP) population includes all subjects who have taken at least one dose of the study 
medication and have at least one post dose safety measurement (including dermal assessments). 
In the unlikely event that errors may have occurred in treatment arm assignments, analyses using 
the Safety population will be based on treatment actually received. The SP population will be 
used for the analysis of dermal evaluations and safety endpoints. 
7. STATISTICAL METHODS 
Summaries will be presented for the SP population for all subjects combined during the Dose-
Optimization Period of the study. During the double-blind Treatment Period of the study, 
summaries will be presented for the FAS, Completers, and SP populations by treatment (i.e, 
d-ATS and placebo, with all d-ATS dose levels combined), and some tables by treatment and 
treatment sequence. Subjects are intended to receive both treatments during the double-blind 
cross-over period of the study, so summaries for Visits 6 and 7 will be combined, with subjects 
contributing data to both treatment columns for the combined time point.  As a result, the 
numbers of subjects in each treatment arm in the header of these summaries will reflect the total 
number of subjects receiving the treatment, and the number of subjects contributing data for each 
visit will be presented in the body of the table. 
Early termination visits will be mapped to the next scheduled visit for inclusion in summary 
tables, where appropriate. For example, a subject who terminates after Visit 3 (e.g., has 
assessments at Visits 1 - 3 and early termination assessments) would have assessments from 
early termination mapped to the next scheduled visit for each assessment. Different assessments 
may be mapped to different visits; in this example, most assessments would be mapped to Visit 
4, ECG would be mapped to Visit 5 as no ECG assessments are scheduled to be performed at 
Visit 4. This mapping is considered part of the observed values, and will be conducted before 
any summaries or analyses are performed on observed values. Similarly, it will be conducted 
before any scoring algorithm is applied. Listings will present early termination data as the 
mapped visit, as well as under ‘ET’ Visit as well. 
Unless otherwise noted, categorical variables will be summarized using counts and percentages. 
Percentages will be rounded to one decimal place, except 0% and 100% will be displayed 
without any decimal places. Continuous variables will be summarized using the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. All analyses 
will use SAS® version 9.1 or higher.  
All raw data will be presented to the original number of decimal places.  The means and medians 
will be presented to 1 more decimal place than the raw data.  The standard deviations will be 
presented to 2 more decimal places than the raw data. 
To preserve the Type I error rate in analyzing the secondary endpoints of onset and duration of 
efficacy, a closed test procedure will be used. The closed test principle states that the trial-wise 
error rate can be controlled by the ordered testing of each hypothesis in the closed family using a 
suitable α level significance. A condition of the Closed Test procedure is that the order of testing 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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of the endpoints in a family matters. Thus hypotheses in a family must be ordered and the testing 
of each subsequent hypothesis in the order can only proceed if the testing of the prior hypothesis 
achieves a significant p-value with Type I error rate of predetermined α level, which will be set 
at α= 0.05 for this study. Testing of the hypotheses in the family proceeds until a hypothesis fails 
to achieve a significant p-value. If/when a hypothesis in the family fails to achieve significance, 
then significant p-values cannot be claimed for all subsequent hypotheses in that family, i.e., 
once one hypothesis fails to achieve significance, testing should cease.   
If the primary efficacy endpoint, difference between d-ATS and placebo in mean SKAMP total 
score for the double-blind phase, is statistically significant (i.e., p<0.05), the secondary variables 
of onset and duration of efficacy will be tested using a closed testing procedure. The closed 
testing procedure starts from the time-point of 1 hour post-morning dose, then 2, 3, 4.5, 6, 7, 9, 
10 and 12 hours post-dose. At each timepoint the order of testing will be onset of efficacy 
followed by duration of efficacy, before moving to the next timepoint. Duration of efficacy will 
not be considered until onset of efficacy has been determined.  
All data collected will be presented in data listings, and the listings will be sorted by 
investigator/site, subject, and time point. 
7.1 EFFICACY ANALYSES 
The primary population for efficacy assessments will be the FAS population. The Completers 
population will be used to conduct sensitivity analyses. Efficacy summaries will be presented by 
visit by treatment arm. Variables that are collected in both the Dose-Optimization and double-
blind Treatment Periods will be combined on the same table, but no summaries will be presented 
in the placebo column for the Dose-Optimization Period.  
7.1.1 Primary Variable 
Data Summaries 
Continuous summary statistics will be presented for the mean SKAMP total score for Visits 6 
and 7 for the FAS. Similar summaries will be presented for the Completers population.  
Primary Efficacy Analysis 
A likelihood-based Mixed-effect Model Repeated Measures (MMRM) will be used to assess the 
primary objective.  
In the model, the SKAMP total score for each timepoint will be analyzed with the fixed effects 
of sequence (two levels), period (two levels), treatment (two levels) and time (10 levels, one for 
each of 30 minutes prior and 1, 2, 3, 4.5, 6, 7, 9, 10, and 12 hours post dosing) while the repeated 
measures effect of timepoint will be defined for subject within sequence and “Variance 
Components (VC)’ covariance structure. An example of the SAS procedure to be used is 
presented below.  
proc glimmix data=<dataset>; 
  class <treatment sequence period timepoint subject>; 
  model <SKAMP> = <treatment>  
<sequence>  
<period>  
<timepoint>  


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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<treatment * timepoint>  
/solution ddfm=kr; 
 
 random <timepoint>  / type=vc subject=<subject * period> residual; 
 lsmeans <treatment> / pdiff cl alpha=0.05; 
 
 estimate 'd-ATS - Placebo' <treatment> -1 1 / cl;  
run; 
 
Note: <italics> identifies where actual variable name substitutions are required. 
<sequence> will be required to be defined as <treatment * period> to ensure estimates are 
obtainable.The two treatment levels will be: d-ATS (5, 10, 15, 20 mg doses combined) and 
placebo. The treatment * time interaction is included in the model to allow the form of the 
relationship to be modeled. The purpose of including the interaction term is not to test it for 
significance and so p-value will not be presented. Raw means, least-squares (LS) means, 
differences in LS means, and 95% confidence interval (CI) for the difference between treatment 
arms, and p-values will be calculated for SKAMP total score over the treatment day for the FAS 
(primary), and Completers populations. 
Scaled residual and random effects plots will be considered to check the assumptions behind the 
mixed model. 
Assessment of Carryover 
The sequence effect (treatment x period interaction) will be tested at the significance level of 
0.10. If significant differences are detected between sequences, data will be reviewed and 
strength of evidence indicating a crossover effect will be considered. In this case data from Visit 
6 only will be presented to aid in assessment of the treatment effect. When only one period of 
data is used then the efficiencies gained from conducting a crossover trial design may be lost and 
there is concern associated with treating data as a parallel study due to the sample size being 
based up on the assumed efficiencies and may no longer be large enough to provide sufficient 
power. In this case, permutation test will be used to validate the results. Sampling without 
replacement (i.e. duplicate samples are not allowed) will be performed for 5000 permutations. 
The average mean treatment difference will be presented along with the associated 95% 
confidence interval and p-value for the permutation test. This will be compared against a 
significance level of 0.05. 
Effect Modification Analyses 
The primary efficacy analysis on the FAS population will also be conducted for the following 
subgroups: 
 Investigator site 
 Optimized dose 
 Gender 
 ADHD type (inattentive, hyperactive/impulsive, combined, not otherwise specified) 
 Baseline ADHD severity (defined as the pre-dose ADHD-RS-IV rating scale for 
Baseline, Visit 0)  


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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 
 Age group  
To ensure summaries from the subgroups are informative, these will only be performed where 
subgroups include 5 or more subjects in each. Where subgroups have less than 5 subjects the 
small group will be combined with the next group, if there is a consecutive order to the 
groupings or with the next smallest group if there is no order. Baseline ADHD-RS-IV total score 
will be categorized into the following groups: 0-18; 19-36; and 37-54. Age will be categorized 
into groups for 6-12 years and 13-17 years. 
7.1.2 Missing Data 
MMRM is the best method to control type I error rate and minimize bias in the presence of 
missing data, although this does not fully overcome the issues and assumptions are still required 
to be made regarding the missing data mechanisms. Nevertheless, in the presence of a high drop 
out rate performance of sensitivity analysis is critical. The purpose of sensitivity analysis is to 
explore whether different analyses under different set of missingness assumptions provide robust 
efficacy results. The extent to which efficacy results are stable across such analysis provides 
confidence in the statistical conclusions.  
Missing data can be considered to be missing completely at random (MCAR), missing at random 
(MAR), or missing not at random (MNAR) according to the National Academy of Sciences 
(2010).  
To explore the effect of missing data the following sensitivity analyses will be conducted for the 
primary efficacy analysis for the FAS population. Under the assumption that missing data is 
missing at random and the analyses require the assumption of MAR to hold: 
 Imputation based analysis   
o Multiple Imputation  
Subjects with missing SKAMP total scores at any timepoint during Visits 6 and 7 will 
have these individual SKAMP total score values imputed.  
Step 1: Imputation 
For each missing SKAMP total score 20 imputations will be made using SAS PROC 
MI on the unimputed SKAMP total score efficacy data. All imputed data will be non-
negative. For intermittent missing data the Markov Chain Monte Carlo (MCMC) 
simulation will be used, the number of burn in iterations will be set at 200, or higher 
if required for convergence.  The thinning option will be set to select one out of every 
100 iterations to ensure sufficient separation from previous iterations.   
Once intermittent missing data has been imputed monotone missing data will be 
imputed using a regression model including factors for treatment and period and the 
SKAMP total score in the VAR statement.  
The number of multiple imputations will be 20, leading to 20 completed data sets. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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Step 2: Analysis of completed data sets 
The imputed data for the primary endpoint will be analyzed as per the method 
described in section 7.1.1. This will lead to 20 estimates for the comparison of d-ATS 
with placebo. 
Step 3: Inference 
The estimates will be averaged and the associated standard errors will be summarized 
based on within-imputation and between-imputation variance, as is customarily done 
in multiple imputation. In other words, PROC MIANALYZE will summarize the 20 
model estimates yielding a final estimate with associated 95% CI and p-value. 
o LOCF  
Subjects who started a classroom day but did not complete all the assessments will 
have their last observation within the same classroom day carried forward. Data from 
one classroom day will not be used to impute values for another test classroom day.   
The completed LOCF data will be analyzed as per the method described in section 
7.1.1.    
The following sensitivity analyses will be conducted for the primary efficacy analysis for the 
FAS population under the assumption of some data MNAR: 
 Worst-case scenario analyses 
o Scenario One  
Subjects with missing data which is considered due to a defined ‘poor outcome’ will 
have the worst case (largest) SKAMP total score for that subject within the same 
classroom day imputed. If no SKAMP total score is available for a subject in a 
classroom day the overall observed worst case (largest) SKAMP total score for the 
same treatment will be imputed. For subjects with missing data which is not 
considered due to the defined ‘poor outcome’ reasons the mean SKAMP total score 
per treatment will be imputed. 
Poor outcome reasons are defined as missing data due to poor tolerability and 
withdrawal due to lack of efficacy, AE or death.  
Poor outcome reasons will be reviewed on blinded data and defined prior to database 
lock.  
o Scenario Two 
Results of two analyses will be presented for comparison. The first will assign the 
best possible outcome to missing values in the placebo group and the second will 
assign the worst possible outcome to those of the d-ATS group. 
Sensitivity analysis using different methods of handling missing data will provide useful 
information about effectiveness of the study drug and confidence in the reliability of the 
conclusions drawn. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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7.1.3 Secondary Variables 
7.1.3.1 SKAMP  
The onset of efficacy, based on the SKAMP total scores, will be defined as the time of the first 
assessment time showing statistical significance between d-ATS and placebo. If no significant 
difference is found at any time point for the onset of efficacy, no onset of efficacy will be 
deemed to have occurred, and the onset of efficacy will be defined as ‘none’. 
Onset of efficacy as measured by the SKAMP total score (defined in Section 5) will be analyzed 
using the same MMRM model as for the primary analysis. In the model, the SKAMP total scores 
for each timepoint will be analyzed with the fixed effects of sequence (two levels), period (two 
levels), treatment (two levels) and time (10 levels, one for each of 30 minutes prior and 1, 2, 3, 
4.5, 6, 7, 9, 10, and 12 hours post dosing) while the repeated effect will be defined for subject-
within-sequence. The interaction term for treatment * time will be included in the model, but not 
tested for significance. The example SAS code shown in section 7.1.1 may be used for this 
analysis, substituting the estimate statement given (mean estimates across timepoints) for the 
following set of statements (mean estimates at each timepint): 
 
estimate 'd-ATS – Placebo 1hr post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 -1 0 0 0 0 0 0 0 0   0 1 0 0 0 0 0 0 0 0  
/ cl;  
 
estimate 'd-ATS – Placebo 2hrs post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 0 -1 0 0 0 0 0 0 0   0 0 1 0 0 0 0 0 0 0  
/ cl;  
 
estimate 'd-ATS – Placebo 3hrs post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 0 0 -1 0 0 0 0 0 0   0 0 0 1 0 0 0 0 0 0  
/ cl;  
 
estimate 'd-ATS – Placebo 4.5hrs post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 0 0 0 -1 0 0 0 0 0   0 0 0 0 1 0 0 0 0 0  
/ cl;  
 
estimate 'd-ATS – Placebo 6hrs post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 0 0 0 0 -1 0 0 0 0   0 0 0 0 0 1 0 0 0 0  
/ cl;  
 
estimate 'd-ATS – Placebo 7hrs post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 0 0 0 0 0 -1 0 0 0   0 0 0 0 0 0 1 0 0 0  
/ cl;  
 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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estimate 'd-ATS – Placebo 9hrs post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 0 0 0 0 0 0 -1 0 0   0 0 0 0 0 0 0 1 0 0  
/ cl;  
 
estimate 'd-ATS – Placebo 10hrs post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 0 0 0 0 0 0 0 -1 0   0 0 0 0 0 0 0 0 1 0  
/ cl;  
 
estimate 'd-ATS – Placebo 12hrs post dose'  
<treatment> -1 1  
<treatment*timepoint> 0 0 0 0 0 0 0 0 0 -1   0 0 0 0 0 0 0 0 0 1  
/ cl;  
 
The two treatment levels will be: d-ATS (5, 10, 15, 20 mg doses combined) and placebo. 
Continuous summary statistics will be presented for the SKAMP total score at each time point 
for Visits 6 and 7 for the FAS population. Raw means, LS means, differences in LS means, and 
95% CI for the difference between treatment arms, and p-values will be calculated for each post-
dose time point and for mean score over the treatment day for the FAS population. 
The SKAMP total scores will also be plotted by time point for the FAS population. 
Scaled residual and random effects plots will be considered to check the assumptions behind the 
mixed model. 
The assessment of treatment differences will follow the closed testing procedure described in 
Section 7. The closed testing procedure starts from the time-point of 1 hour post-morning dose, 
then 2, 3, 4.5, 6, 7, 9, 10 and 12 hours post-dose. At each timepoint the order of testing will be 
onset of efficacy followed by duration of efficacy, before moving to the next timepoint. Duration 
of efficacy will not be considered until onset of efficacy has been determined. 
 The onset time of efficacy action will be determined as the first post-dose time where the 
difference between the two treatments is statistically significant (i.e., p≤0.05). .  
 If the difference between the two treatments is statistically significant (i.e., p≤0.05) at the 
1 hours post-dose time point, the duration of efficacy will be claimed as the difference in 
hours between the end of efficacy; the last consecutive time point at which the difference 
is still statistically significant (i.e., p≤0.05) and onset of efficacy. If there is no time point 
at which there is a non-significant difference between the two treatment groups after a 
time point in which there is a significant difference between the two treatment groups, 
then the end of efficacy will be defined as 12 hours post-dose.  
For example, if a statistically significant difference in mean SKAMP total scores for d-ATS vs. 
placebo was determined at 1 hour post-dose and statistical significance was measured at all time-
points up to and including 10 hours post-dose, but statistical significance was not reached at 12 
hours post-dose, onset of clinical efficacy and end of clinical efficacy would be defined as 1 
hours post-dose and 10 hours post-dose, respectively, with duration of efficacy being 9 hours. 
Supportive analysis of onset of efficacy and duration of efficacy will be conducted using the 
same model for the Completers population.  


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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Onset and duration of effect as measured by the SKAMP total score (defined in Section 5) will 
be analyzed using two methods, firstly an MMRM model approach will be considered for the 
analysis of Onset and Duration of efficacy. Secondly a summary measures and survival analysis 
approach for onset and duration of effect for 50% reduction in SKAMP total score will be 
conducted.  
Onset of effect for 50% reduction in SKAMP total score is defined for each subject as the first 
time point at which there is a 50% reduction in SKAMP total score from the pre-dose 
observation on the same classroom day. 
Continuous summary statistics will be presented for the SKAMP total score at each time point 
for Visits 6 and 7, for the time of effect onset and for the duration of effect (hours) for the FAS. 
Time of onset of effect for 50% reduction in SKAMP total score will be summarized 
descriptively and displayed graphically using the Kaplan-Meier approach for the FAS. The upper 
and lower quartiles (and CI) as well as the 50th percentile (and CI) will be used to estimate 
median time of onset of effect in each treatment arm. The difference between treatment arms, d-
ATS and placebo, will be assessed using the Log-Rank test. Subjects that do not record a 50% 
reduction in SKAMP total score from the baseline value will be deemed to be censored at the last 
timepoint a SKAMP total score is recorded, for each classroom day.  
Duration of effect for 50% reduction in SKAMP total score will be determined by persistence of 
the reduction of 50% from the pre-dose observation in SKAMP total score. The end of effect will 
be determined as the first timepoint after onset of effect at which the 50% reduction in SKAMP 
total score is not observed. The duration of effect will be calculated as the difference between the 
end of effect and onset of effect, in hours. Duration of effect will be analyzed using the same 
methodology as the onset of effect. Subjects that record a 50% reduction in the SKAMP total 
score from the baseline value such that duration of effect continues at their final assessment time 
for that classroom day will be censored at that time. Subjects without an onset of effect will be 
excluded from the analysis of duration of effect. A sensitivity analysis will be performed where 
subjects without an onset of effect will be imputed to have duration of effect of 0 hours. 
Supportive analysis of onset of efficacy and duration of efficacy will be conducted using the 
same approach for the Completers population.  
Once onset and duration of efficacy are estimated (using the MMRM approach analysis for the 
FAS, as described above), the sensitivity analysis will be conducted for primary variable as 
specified in section 7.1.1 by excluding data from time points before onset and after the last time 
point included into the duration of efficacy. 
All data, including derived values, will be listed. 
7.1.3.2 PERMP 
Continuous summary statistics will be presented for PERMP-A and PERMP-C scores on the 
PERMP math test at screening and at each protocol-specified time point during the double blind 
period for the FAS. The PERMP-A and PERMP-C scores will also be plotted by time point for 
the FAS. 
The number of items attempted and the number of items correct at each time point after dosing 
for Visits 6 and 7 will be analyzed in the same way as for the SKAMP primary efficacy analysis. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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Raw means, LS means, differences in LS means, and 95% CI for the difference between 
treatment arms, p-values, and model results will be presented for each variable at each time point 
after dosing. 
Change from pre-dose for PERMP-A and PERMP-C will be examined. Each post-dose 
PERMP-A and PERMP-C score will be analyzed by t-test on the change from pre-dose within 
group.  
7.1.3.3 ADHD-RS-IV 
Continuous summary statistics will be presented for the ADHD-RS-IV Total, Inattention, and 
Hyperactivity-Impulsivity scores at each visit from baseline through Visit 7 and for the change 
from baseline to each subsequent visit for the FAS. The ADHD-RS-IV Total and subscale scores 
will also be plotted by visit for the FAS.  
The ADHD-RS-IV Total and subscale scores at Visits 6 and 7 will be analyzed in a similar way 
to the primary efficacy analysis, with the exclusion of timepoint from the model. Raw means, LS 
means, differences in LS means, and 95% CI for the difference between treatment groups, p-
values, and model results will be presented for each variable. 
7.1.3.4 CPRS-R:S 
Continuous summary statistics will be presented for the CPRS-R:S Total, Oppositional, 
Cognitive Problems/Inattention, Hyperactivity, and ADHD Index scores at each visit from Visit 
1 through Visit 7 for the FAS. The CPRS-R:S Total and subscale scores will also be plotted by 
visit for the FAS.  
The CPRS-R:S Total, Oppositional, Cognitive Problems/Inattention, Hyperactivity, and ADHD 
Index scores at Visits 6 and 7 will be analyzed in a similar way to the primary efficacy analysis, 
with the exclusion of timepoint from the model. Raw means, LS means, differences in LS means, 
and 95% CI for the difference between treatment arms, p-values, and model results will be 
presented for each variable. 
7.1.3.5 CGI 
Categorical summary statistics will be presented for the CGI-S scores at baseline for the FAS. 
Categorical summary statistics will also be presented for the CGI-I scores at each visit after 
baseline for the FAS. The categorical CGI-I summaries will be presented both for all categories 
of the scale and for the dichotomized version of the scale defined in Section 4.2.5. The 
percentages of subjects who improved according to the dichotomized version of the scale will 
also be plotted by visit for the FAS. 
Differences between the treatment arms in the dichotomized versions of the CGI-I scores at 
Visits 6 and 7 will be analyzed by using McNemar’s test. In order to adjust for a potential period 
effect, the Mainland-Gart test, which is a test of sequence versus period preference, will also be 
performed. Finally, Prescott’s test, which extends the Mainland-Gart test by including subjects 
who show no preference between the two periods, will also be conducted. Test statistics and p-
values for the difference between the treatment arms will be presented for each test. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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7.2 SUBJECT DISPOSITION 
There will be a clear accounting of all subjects who are enrolled onto dose optimization. The 
following will be summarized by treatment sequence group for all enrolled subjects: 
 The number of subjects who are enrolled onto dose optimization 
 The number of subjects who receive study medication 
 The number of subjects in Safety population 
 The number of subjects who are randomized into double-blind 
 The number of subjects in FAS population 
 The number of subjects in Completers population 
 The number of subjects who complete the study 
 The number of subjects who discontinued the study and reason for discontinuation 
The reasons for all study discontinuations will be summarized by treatment sequence, by 
treatment arm and study period, and will also be provided as a by-subject listing. The number 
and percentage of randomized subjects in each of the three efficacy study populations will be 
summarized for all subjects combined and for each treatment sequence.  
7.3 PROTOCOL DEVIATIONS AND VIOLATIONS 
All major protocol deviations or violations (PDVs) for each subject will be reviewed on blinded 
data prior to database lock to evaluate whether the subject has been protocol compliant.  Major 
PDVs will be assessed as to whether or not they have a significant impact on the assessment of 
efficacy. 
Major protocol violations will include, but are not limited to the following: 
 Dosing non-compliance 
 Deviation from visit window during the double-blind phase 
 Non-permitted concomitant medications 
 Violation of Inclusion/Exclusion Criteria 
The number of subjects with each type of major PDV will be tabulated by category and by 
deviation type for all subjects in the SP population.  A listing of all PDVs including deviation 
date, deviation type, deviation description and any relevant comments will be generated. 
7.4 TREATMENTS 
7.4.1 Extent of Study Drug Exposure 
The duration (days) of study drug dosing will be determined as follows for each subject and 
summarized by treatment arm and overall for both SP and Completers populations: 
Duration of study drug dosing overall for the double blind period (days) = date of last dose – date 
of first dose of double blind treatment + 1. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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The date of first dose of double blind treatment will be Visit 5 + 1 day according to the protocol.   
Duration of study drug dosing per visit (days) = date of last dose at that visit – previous visit date 
The percent compliance with study medication will be calculated at each visit and for the overall 
double-blind Treatment Period.   
Percent compliance = {[(Total number of patches dispensed) – (Total number of patches 
returned unused)]/ number of days in the interval} * 100% 
The duration of study drug dosing and percent compliance will be summarized by visit and 
overall for both Safety and Completers populations.  
Treatment dose at each visit during the dose-optimization phase will be summarized for the 
Safety population. A summary table for treatment dose for each treatment and period for the 
double-blind phase will be also presented. 
All dosing and compliance data also will be provided as data listings. 
7.4.2 Concomitant Medications 
All prior and concomitant medications recorded in the electronic case report form (eCRF) will be 
coded to generic term and all matching Anatomic Therapeutic Classification (ATC) codes using 
the current version of WHO Drug. Summaries will be prepared using the coded generic term.  
The number and percentage of subjects who had prior medications will be provided by preferred 
drug name for the SP population. The numbers and percentages of subjects who had concomitant 
medications during the Dose-Optimization Period and during the double-blind Treatment Period 
will be presented separately for the SP population. 
All prior and concomitant medications recorded in the eCRF will be listed. 
7.5 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographics and baseline characteristic data will be summarized by treatment arm for both the 
SP population and FAS. Demographic and baseline characteristics include, but are not limited to, 
age, age group, gender, race, ethnicity, weight, height, BMI, ADHD subtype, ADHD-RS-IV total 
(continuous and group) and subscale scores at baseline. Age will be calculated based on the date 
of informed consent, and the weight and height measurements will be those measured at 
screening. A category of ‘Multiple’ will be defined for race to summarize those subjects 
selecting more than one; all selections will be listed. 
7.6 DERMAL EVALUATIONS 
Summaries of dermal evaluations will be based on the SP population. Summary statistics will be 
presented separately for the SP population on all subjects combined during the 
Dose-Optimization Period and by treatment arm during the double-blind Treatment Period.  
No statistical analyses will be performed for the dermal evaluation data. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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7.6.1.1 ADHESIONS 
The source data are the adhesion scores of the patches. Data from the in-clinic assessments will 
be summarized for each treatment arm. 
 Frequency table showing the number of patches with each adhesion score at each 
evaluation time point. 
 The number of patches that detached will be summarized. 
 For detached patches, the duration of patch wear before patch detachment will be 
summarized (time of patch detachment will be subtracted from time of application). 
7.6.1.2 IRRITATION 
The source data will be the actual irritation scores recorded following visual evaluation of the 
application sites. If a patch is removed due to irritation, Last Observation carried Forward 
(LOCF) will be applied for all remaining time points.  LOCF is defined as the highest irritation 
score observed prior to discontinuation of the patch due to irritation. 
The letter grades will be converted to numerical equivalents in the following way: N (none)=0, 
A=0, B=1, C=2, and F, G, and H=3. For each subject, a combined score will be derived by 
adding the numerical grade and the numerical equivalent of the letter grade at each evaluation 
time point (e.g., 2C=2+2=4). Missing values for ‘Other Effects” when the applicable numerical 
value is “0” will be calculated as a score of “N” with a numerical value of “0”. Analyses for this 
data will be identified as combined scores. 
The following data from the in-clinic assessments will be provided for each treatment arm: 
 Frequency table with each combined “Dermal Response” and “Other Effect” score using 
worst case for all subjects. 
 Frequency table with each combined “Dermal Response” and “Other Effect” score using 
worst case for subjects who discontinued due to irritation. 
 Summary of number of patches that were removed due to irritation and number of 
patches that were removed due to irritation split by irritation combined score assessed at 
30 minutes after detachment/removal 
All irritation scores will be listed, including those captured in the dermal evaluation diary. 
7.6.1.3 DISCOMFORT 
The source data will be the discomfort scores of the patches. A summary of discomfort Scores 
recorded in clinic will present the discomfort scores and a summary of Description of Discomfort 
with the number and percent of subjects by each treatment and time point.  
The Wong Baker Faces Scores (WBS) and Visual Analog Scale (VAS) scores will be presented 
separately and combined, by treatment for each timepoint.  For the separate analyses the WBS 
and VAS will each be summarized by presenting mean, SD, median, minimum, maximum and 
IQR. For the combined analyses the numerical value of the scales will be taken and used to 
present combined continuous summary statistics. Additionally the WBS and VAS scores will be 
converted to the Numeric Rating Scale (NRS-11) and presented in combination under the Pain 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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Level with the number and percentage of subjects falling into each category. Subjects that do not 
provide a WBS or VAS score due to the discomfort assessment being 0 (no discomfort) will be 
include in the Rating level 0 and Pain Level of No Pain. 
 
Numeric Rating Scale (NRS-11): 
Rating 
Pain Level 
0 
No Pain 
1-3 
Mild Pain  
4-6 
Moderate Pain 
7-10 
Severe Pain 
 
All discomfort scores, including the WBS and VAS scores, will be listed, including those 
captured in the dermal evaluation diary. 
7.6.1.4 ADHESIVE RESIDUE 
The source data will be the adhesive residue scores of the patches. A summary of Adhesive 
Residue Scores recorded in clinic will present the adhesive residue scores with the number and 
percent of subjects by each treatment and time point. All adhesive residue data will be listed, 
including those captured in the dermal evaluation diary. 
7.7 SAFETY ANALYSES 
Safety data for the Dose-Optimization Period will be summarized using combined data from all 
subjects in the SP population. 
Safety data from the double-blind Treatment Period will be summarized using data from each 
treatment arm where applicable in the SP population. 
No inferential statistics are planned.  
7.7.1 Adverse Events 
Treatment-emergent adverse events will be assigned to either the open-label Dose-Optimization 
Period or the double-blind Treatment Period. TEAEs occurring in the safety follow up after the 
double blind Treatment Period will be reported under the double blind Treatment Period for the 
last treatment they received. TEAEs for which a missing or incomplete start and/or stop date 
makes it impossible to determine which period of the study they started in will be counted as 
starting in the Dose-Optimization Period. The subject’s dose of study drug at the onset of the 
event will be determined for all TEAEs. If a missing or incomplete start date makes it impossible 
to determine the dose at onset, then the dose at onset will be set to the lowest dose in the study 
(i.e., 5 mg/ 4.76 cm2). Adverse events that start before the first patch application will be 
summarized separately. For summaries, TEAEs with missing severity are assumed to be severe, 
and TEAEs with missing relationship to study drug are assumed to be related. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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Summary statistics for TEAEs will be presented separately for the SP population on all subjects 
combined during the Dose-Optimization Period and by treatment arm during the double-blind 
Treatment Period. All summaries of adverse events will consist of the number of events and the 
numbers and percentages of subjects who had the events being summarized. 
All TEAEs will be classified by SOC and PT using the latest version of MedDRA dictionary. All 
TEAEs that occur after first patch application up to 30 days following last patch application will 
be summarized. Subjects may have more than one TEAE per SOC or PT. Unless otherwise 
specified, at each level of subject summarization in reporting the incidence of the AE, a subject 
will be counted once if the subject reported one or more events.  
The following summaries will be presented separately for the Dose-Optimization Period and the 
double-blind Treatment Period by the dose being taken at the onset of the events and by 
MedDRA SOC, and preferred term:  
 Overall summary of TEAEs 
 TEAEs 
 Treatment-related TEAEs 
 TEAEs leading to premature discontinuation of study drug  
 TEAEs by intensity. 
7.7.2 Deaths and Serious Adverse Events 
The following summaries will be presented separately for the Dose-Optimization Period and the 
double-blind Treatment Period by the dose being taken at the onset of the events and by 
MedDRA SOC, and preferred term: 
 Serious adverse events (SAEs) 
 Treatment-related SAEs 
All data for serious adverse events and deaths will be listed  
7.7.3 Laboratory Data 
A central laboratory will be used to analyze all blood and urine samples with the exception of the 
urine pregnancy tests. Laboratory data is only collected at Screening and Visit 7/End of Study (or 
Early Termination visit).  For analyses of laboratory data, ‘baseline’ refers to the data collected 
at screening. The clinical laboratory assessment will consist of the following: 
Hematology: hemoglobin, hematocrit, white blood cell count, red blood cell count, 
platelet count, basophils, neutrophils, bands, lymphocytes, monocytes, and eosinophils. 
Serum Chemistry: total bilirubin, alkaline phosphatase, alanine transaminase, aspartate 
transaminase, creatine phosphokinase, lactate dehydrogenase, blood urea nitrogen, 
creatinine, glucose, total protein, albumin, sodium, potassium, chloride, calcium, 
inorganic phosphorus, and Hemoglobin A1c. 
Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, and blood. 
Urine drug screen and cotinine (screening only) 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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Summary statistics of raw data and change from baseline to End of Study values for each 
laboratory parameter will be presented by treatment arm. Data will be summarized as appropriate 
to the variable type.  
For change from baseline summaries, subjects with an undefined change from baseline, because 
of missing baseline data, will be excluded. Individual Subject Changes will be identified through 
shift tables. Shift tables will be presented for each laboratory parameter with counts and 
percentages of subjects, by treatment arm, for shift (change) from baseline, using the normal 
ranges from the central laboratory. 
Where multiple results are provided for a parameter the first set of observations will be included 
in the summaries, all data will be listed. Similarly, if both automated and manual differential 
results are provided for a visit then the automated differentials will be summarized, all will be 
listed. 
Laboratory data from unscheduled visits will be listed but will not be included in any summaries. 
Results of urine pregnancy results will be listed but will not be included in any summaries. 
7.7.4 Vital Signs 
Vital signs, including pulse, systolic blood pressure, diastolic blood pressure, temperature, and 
respiratory rate will be summarized. Summary statistics of raw data and change from baseline 
values for each vital signs parameter will be presented by treatment arm and time point. Data 
will be summarized as appropriate to the variable type. For change from baseline summaries, the 
results collected at baseline (visit 0) will be used in these calculations or the last data available 
prior to Visit 0 as per Section 5 definitions. Subjects with an undefined change from baseline, 
because of missing baseline data, will be excluded. Shift tables will be presented for each vital 
sign parameter with counts and percentages of subjects, by treatment arm and time point, for 
shift (change) from baseline, using the normal ranges for vital signs parameters. Normal ranges 
for vital signs data are defined in Appendix 2. 
Vital signs data from unscheduled visits will be listed but will not be included in any summaries. 
7.7.5 Columbia Suicide Severity Rating Scale (Children’s Version) 
Summaries will be presented for each of the subscales (i.e. Suicidal Ideation and Suicidal 
Behavior). 
Suicidal Ideation will be summarized for each of the following 5 ideation categories: 
1. Wish to be dead 
2. Non-specific active thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent. 
Descriptive summary of the number and percentages of subjects with the responses of “Yes” for 
each of the five categories will be presented by treatment arms and visit. The intensity and 
frequency for ideation will also be summarized descriptively by treatment arm and visit. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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Suicidal Behavior will be summarized for each of the following 5 behavior categories: 
1. Actual attempt 
2. Interrupted intent 
3. Aborted attempt 
4. Preparatory Acts or Behavior  
5. Suicidal behavior present during assessment period. 
Descriptive summary of the number and percentages of subjects with the responses of “Yes” for 
each of the five categories will be presented by treatment arms and visit.  
Additionally, the number of subjects who reported at least one occurrence of suicidal ideation 
and at least one occurrence of suicidal behavior, and subjects who reported at least one 
occurrence of suicidal ideation or at least one occurrence of suicidal behavior will be 
summarized by treatment arm and visit. For these summaries a subject will only be counted once 
in each in each sub-category. 
7.7.6 Physical Examinations, ECGs, and Other Observations Related to 
Safety 
There will be no separate physical examination listings since screening physical examination 
abnormalities were recorded as Medical History and post-randomization physical examination 
abnormalities were recorded as AEs. 
All quantitative 12-lead ECG interval measurements (QRS, QT, QTc, etc.) will be summarized 
with descriptive statistics by visit, and treatment arm. Summary statistics of raw data and change 
from baseline values will be presented by treatment arm and time point. Data will be summarized 
as appropriate to the variable type. For change from baseline summaries, subjects with an 
undefined change from baseline, because of missing baseline data, will be excluded. 
ECG assessments at each study visit will be evaluated to determine whether the ECG findings 
are: 1) Normal; 2) Abnormal, Not Clinically Significant and 3) Abnormal, Clinically Significant. 
Descriptive statistics (numbers and percentages of subjects in each of the three categories) will 
be presented by treatment arms for each visit. In addition shift tables will be also presented based 
on the above three categories of ECG interpretations, by treatment arm and time point. 
ECG data from unscheduled visits will be listed but will not be included in any summaries. 
Screening results from the Wechsler Abbreviated Scale of Intelligence - Second Edition 
(WASI-II) and M.I.N.I. International Neuropsychiatric Interview (M.I.N.I. 6.0) are used as to 
assess inclusion/exclusion criteria and are not recorded. These data will not be listed or included 
in any summaries. 
8. INTERIM ANALYSES 
No interim analysis is planned for this study. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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9. DATA REVIEW 
Final data for analysis will be cleaned prior to receipt for statistical programming. The purpose 
of this section is to indicate the history of the data and the process used to ensure that the data are 
acceptable for statistical analysis prior to database lock. 
9.1 DATA HANDLING AND TRANSFER 
All of the data will come from the 
 data management group in SAS® dataset format (SAS 
version 9.1 or later).  Coexistent diseases and AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), version 15.0 or later, to assign a system organ class (SOC) 
and preferred term (PT) to each AE.  Prior and concomitant medications will be coded to 
preferred drug names using the latest available World Health Organization Drug Dictionary 
(WHODD). 
More details about the data handling can be found in the Data Management Plan. 
9.2 DATA SCREENING 
Beyond the data screening built into the Data Management Plan, the programming of analysis 
datasets, tables, figures, and listings (TFL) provides additional data screening. Presumed data 
issues will be output into SAS logs identified by the word “Problem” and extracted from the logs 
by a SAS macro and sent to Data Management. 
Prior to database lock and unblinding, the database will be frozen for a period of time during 
which no changes will be made to the database. A review of pre-freeze TFLs run on clean 
subjects and post-freeze, blinded TFLs run on the frozen database allow for further data 
screening prior to lock. The post-freeze blinded TFLs will be discussed with the sponsor in a 
data review meeting to identify any final data issues and seek corrections prior to database lock. 
The 
 statistician and the sponsor must approve database lock. 
10. VALIDATION 
 goal is to ensure that each TFL delivery is submitted to the highest level of quality. 
Quality control procedures will be documented separately in the study-specific quality control 
plan. The following describes the procedure typically followed at 
. 
Derived datasets will be independently reprogrammed by a second programmer and the separate 
datasets produced must match 100%. 
Tables will be independently reprogrammed by a second programmer for numeric results.  
Statisticians will be involved in the process of programming and validating tables that include 
inferential statistical results. 
Figures will be checked for consistency against corresponding tables and listings, or 
independently reprogrammed if there are no corresponding tables or listings. 
Listings will be checked for consistency against corresponding tables, figures, and derived 
datasets. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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The entire set of TFLs will be checked for completeness and consistency prior to its delivery to 
the client by the lead analysis programmer, the lead statistician, and a senior level statistician, or 
above, who is not a member of the project team. 
The validation process will be repeated any time TFLs are redelivered using different data.  
Execution of this validation process will be documented through the study Table of Programs 
which is provided to the client at study conclusion. 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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APPENDIX 1 GLOSSARY OF ABBREVIATIONS 
Glossary of Abbreviations: 
ADHD 
Attention Deficit Hyperactivity Disorder 
ADHD-RS-IV 
Attention-Deficit/Hyperactivity Disorder Rating Scale, Version IV 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Classification 
BMI 
Body Mass Index 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CGI 
Clinical Global Impression  
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CI 
Confidence Interval 
CPRS-R:S 
Conners' Parent Rating Scale-Revised Short Form 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSR 
Clinical Study Report 
d-ATS 
d-Amphetamine Transdermal Drug Delivery System 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition, Text Revision 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FAS 
Full analysis set 
ICH 
International Conference on Harmonization 
ITT 
Intent-To-Treat 
IVRS 
Interactive Voice Response System 
LOCF 
Last Observation carried Forward 
LS 
Least squares 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNAR 
Missing not at random 
NRS-11 
Numeric Rating Scale (11 point scale) 
PDV 
Protocol Deviation or Violation 
PERMP 
Permanent Product Measure of Performance  
PERMP-A 
Permanent Product Measure of Performance , Number of Problems Attempted 


 
Sponsor:  Noven Pharmaceuticals, Inc.                                                                      Statistical Analysis Plan 
    Protocol:  N25-006                                                                                                  26 June 2013/ Version 2.0 
 
 
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Glossary of Abbreviations: 
PERMP-C 
Permanent Product Measure of Performance , Number of Problems Correct 
PT 
Preferred term 
SA 
Safety  
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SKAMP 
Swanson, Kotkin, Agler, M-Flynn and Pelham Scale 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Tables, Figures, and Listings 
VAS 
Visual Analog Scale 
WASI-II 
Wechsler Abbreviated Scale of Intelligence - Second Edition 
WBS 
Wong Baker Faces Scale 
WHODD 
World Health Organization Drug Dictionary