A Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, 6-Week, In-Patient Study to Assess Efficacy and Safety of HP-3070 in Subjects Diagnosed With Schizophrenia
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Noven Pharmaceuticals, Inc.

Clinical Study Protocol 
 
Protocol Title: A Randomized, Double-Blind, Placebo-
Controlled, Fixed-Dose, 6-Week, In-
Patient Study to Assess Efficacy and 
Safety of HP-3070 in Subjects Diagnosed 
with Schizophrenia 
 
Date of Protocol: 20 January 2016 
 
NCT Number: NCT02876900 
 
 

Noven Pharmaceuticals, Inc. 
 
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HP-3070-GL-04 
HP-3070 
 
 
 
Protocol Version 2.0 Amendment 1: 20 January 2016 
Protocol Final Version: 16 November 2015  
 
 
   
Clinical Study Protocol 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Fixed-Dose, 6-Week, In-Patient Study to Assess Efficacy 
and Safety of HP-3070 in Subjects Diagnosed with 
Schizophrenia 
Protocol Number: 
HP-3070-GL-04 
Date of Protocol: 
   
20 January 2016 
Protocol Version: 
Version 2.0 Amendment 1 
Product: 
Asenapine Transdermal Patch 
Pre-IND No.: 
125707 
EudraCT No.: 
2015-005134-21 
Study Phase: 
3 
Sponsor: 
Noven Pharmaceuticals, Inc. 
Empire State Building, 350 Fifth Avenue, 37th Floor, 
New York, NY 10118 
Study Director (Medical): 
Susan Kozauer, MD  
Medical Director, Medical and Scientific Services 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, North Carolina 27703 
Susan.Kozauer@quintiles.com 
Study Director (Clinical Operations):  Dana Annunziato 
Senior Director, Clinical Research 
Noven Pharmaceuticals, Inc. 
Empire State Building, 350 Fifth Avenue, 37th Floor, 
New York, NY 10118 
dannunziato@noven.com 
Project Manager: 
Michael Smallwood 
Senior Clinical Project Manager 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, North Carolina 27703 
Michael.smallwood@quintiles.com 
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Protocol Version 2.0 Amendment 1: 20 January 2016 
Protocol Final Version: 16 November 2015  
 
 
Confidential 
 
 
Medical Advisor: 
Elena Vlad, MD, Psych, PhD 
 
Medical Director, Medical and Scientific Services 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, North Carolina 27703 
elena.vlad@quintiles.com 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee.  Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without 
written authorization from the Sponsor. 
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HP-3070-GL-04 
HP-3070 
Signatures 
PROTOCOL TITLE: 
A Randomized, Double-Blind, Placebo-Controlled, 
Fixed-Dose, 6-Week, In-Patient Study to Assess Efficacy and Safety of HP-3070 in Subjects 
Diagnosed with Schizophrenia 
PROTOCOL NO: 
HP-3070-GL-04 
Dana Annunziata 
Senior Director, Clinical Research 
Noven Pharmaceuticals, Inc. 
Elena Vlad, MD, Psych, PhD 
Medical Director 
Medical and Scientific Services 
Quintiles, Inc. 
Llk!.1Afi11-_tti 
Signature 
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Signature 
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I w 
Date 
3 
Protocol Version 2.0 Amendment I: 20 January 2016 
Protocol Final Version: 16 November 2015 
Confidential 
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Protocol Version 2.0 Amendment 1: 20 January 2016 
Protocol Final Version: 16 November 2015  
 
 
Confidential 
 
 
SYNOPSIS 
Name of Sponsor/Company: 
Noven Pharmaceuticals, Inc.  
Name of Finished Product: 
HP-3070 
Name of Active Ingredient: 
Asenapine 
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, 6-Week In-Patient 
Study to Assess Efficacy and Safety of HP-3070 in Subjects Diagnosed with 
Schizophrenia 
Protocol No: 
HP-3070-GL-04 
Investigators: 
TBD 
Study center(s): 
Approximately 70 centers 
Study duration: 
Screening/Run-in, Washout Period:  Maximum 14 days  
Double-blind Treatment Period:  6 weeks 
Follow-up Visit/Telephone call:  30 days after the last patch is removed 
Phase:  3 
Objectives: 
Primary Objective: 
The primary objective of the study is to evaluate efficacy of HP-3070 compared with placebo for the treatment 
of schizophrenia as evaluated by Positive and Negative Syndrome Scale (PANSS) total score. 
Secondary Efficacy Objectives: 
 Key Secondary Efficacy Objective: 
o Clinical Global Impression – Severity of Illness Scale (CGI-S) 
 Other Secondary Efficacy Objectives:  To evaluate the efficacy of HP-3070 using the following 
measures: 
o PANSS total score at each time point 
o Clinical Global Impression – Severity of Illness Scale (CGI-S) at each time point 
o Clinical Global Impression – Improvement Scale (CGI-I) at each time point 
o Proportion of CGI-I responders at each time point including Week6; CGI-I responders are 
defined as subjects who have a score of 1 (very much improved) or a score of 2 (much 
improved) 
o Positive, negative, and general pathology subscores of PANSS 
o Proportion of PANSS responders; PANSS responders are defined as subjects  who have a 
≥30% reduction in PANSS total score between Baseline and at each time point including 
Week 6 
o Calgary Depression Scale for Schizophrenia (CDSS) 
o Medication Satisfaction Questionnaire (MSQ) score 
Safety Objectives: 
 Adverse events (AEs), including treatment-emergent AEs (TEAEs), AEs leading to discontinuation 
from the study drug, serious adverse events (SAEs), and deaths 
 Change from Baseline in clinical laboratory results (including prolactin, fasting glucose, and lipids), 
ECG results, body weight, and vital signs 
 Results of C-SSRS, BARS, AIMS, and SAS 
 Dermal safety 
Exploratory Objective: 
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 To assess the impact of covariates on asenapine exposure using a model-based approach and to 
explore the exposure-response relationship with relevant endpoints. 
Methodology: 
This is a Phase 3, randomized, double-blind, placebo-controlled, in-patient, safety, and efficacy study to 
evaluate HP-3070 for the treatment of schizophrenia.  
This study will consist of a Screening/placebo Run-in Period of 3 to 14 days, a 6-week double-blind Treatment 
Period and a 30 day Follow-up Period. 
This study will enroll subjects who are in an acute exacerbation (i.e., have had an acute episode no longer than 
8 weeks prior to the Screening Visit), have a PANSS total score ≥80 with scores of 4 or higher on at least 
2 out of the 4 pre-defined PANSS positive subscale items, and have a CGI-S ≥4.  Subjects will be hospitalized 
at the Screening Visit and will remain hospitalized during the study.  The subject may leave the hospital for 
necessary personal business.  During this time, the subject must be supervised by study staff or a responsible 
caretaker.  Any subject who leaves the site must have an alcohol breathalyzer and urine drug and pregnancy 
tests when they return to the site.  Investigator should contact Medical Advisor to discuss specifics of subject 
off-site overnight travel to confirm appropriateness. 
The study will evaluate 9.0 mg (HP-3070-9.0) and 18.0 mg (HP-3070-18.0) of HP-3070 transdermal patches 
versus placebo transdermal patches. To maintain double-blind each subject will wear two patches.  Patches 
will be applied by site personnel at approximately the same time daily and site personnel will remove the 
patches at approximately 24 hours after patch application.  Each patch will be worn for 24 hours.  Every day, 
approximately 24 hours after patch application, site personnel will remove previous day’s patches and apply 
new patches.  Patch adhesion will be assessed at specified time points and prior to patch removal. 
In this study, efficacy will be evaluated using widely accepted, standard questionnaires.  These include the 
PANSS, CDSS, CGI-S, CGI-I, and MSQ. 
In addition to standard safety measures (AEs, clinical laboratory assessments, vital signs, weight, ECG 
results), this study will also include assessments of EPS symptoms using the Barnes Akathisia Rating Scale 
(BARS), Abnormal Involuntary Movement Scale (AIMS), and Simpson-Angus Scale (SAS).  Suicidality will 
be monitored using the Columbia-Suicide Severity Rating Scale (C-SSRS).  Dermal safety will be assessed by 
a review of any dermal reactions (such as irritation and discomfort due to the patch) reported as AEs. 
Screening/Run-In Period:  At the Screening Visit, subjects will be asked to sign the informed consent form 
(ICF).  No screening procedures may begin prior to obtaining informed consent.  Each subject will be assigned 
a unique subject number after signing the ICF. 
After obtaining informed consent, the subject will be enrolled and hospitalized for the duration of the study.  
The subject will stay in the unit throughout the study, except for supervised leave for personal business.  
While undergoing screening procedures and waiting for results of laboratory tests, electrocardiograms (ECGs), 
and other assessments, the subject will be enrolled in the Run-in Period and start treatment with the 
single-blind placebo patch.  Subjects will be blinded to the treatment during the Run-in Period.  The subject 
must have the single-blind placebo patch applied for a minimum of 3 days prior to entering the double-blind 
Treatment Period.  In addition, current antipsychotic and other prohibited medications will be washed out 
during this period and wash-out must be completed prior to randomization and entering the double-blind 
Treatment Period.  Subjects who do not meet the eligibility criteria at the Screening/Run-In Visit and the 
Baseline Visit will be discontinued from the study.  Subjects who are not compliant with wearing the run-in 
patches will also be discontinued from the study. 
Double-blind Treatment Period:  Subjects eligible for enrollment in the double-blind Treatment Period will 
be randomly assigned to HP-3070-9.0 or HP-3070-18.0, or placebo in a 1:1:1 ratio stratified by country.  All 
trial personnel and subjects will be blinded to the treatment for the duration of the trial.  Subjects will receive 
treatment with study medication daily for 6 weeks.  Patches will be applied by site personnel at approximately 
the same time every day and each patch will be worn for 24 hours.  Every day, approximately 24 hours after 
patch application, site personnel will remove previous day’s patches and apply new patches.  
In the event that the patches are detached completely, new patches should be applied immediately, provided 
that there are at least 6 hours of time remaining before the next dose. 
Blood samples will be collected at 2, 14, and 22 hours with ± 2 hour- window on Day 21 and 42 and analyzed 
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for asenapine and desmethyl asenapine concentrations.  Actual blood sampling time will be recorded.  A 
model-based approach will be used to assess the impact of covariates on asenapine exposure and to explore the 
exposure-response relationship of relevant endpoints.  Details on the methodology will be included in a 
standalone pharmacokinetic (PK) report. 
At discharge (Week 6 or early termination), the subject will be prescribed an approved antipsychotic treatment 
and returned to the care of their physician. 
Follow-up Period:  All subjects will have a follow-up contact (site visit or telephone call, at the discretion of 
the Investigator) 30 days after the last patch is removed.  This contact will be used to collect information about 
any AEs or SAEs that may have occurred since discharge and to follow-up on any AE that was on-going at 
discharge. 
Planned number of subjects: 
Sufficient number of subjects will be screened to randomize 
approximately 612 subjects (approximately 204 in each of the 
3 treatment arms). 
Diagnosis and 
main criteria for inclusion: 
The assessment and documentation of the subject’s eligibility is the 
responsibility of the Investigator.  The Sponsor/designee reserves the 
right to provide final approval of subject eligibility. 
Inclusion Criteria: 
Subjects must meet all of the following criteria to be considered eligible 
to participate in the study: 
1. Adult male or female subjects, ≥18 years of age 
2. Subject is able to undergo informed consent process and signs 
ICF.  
3. Subject has current diagnosis of schizophrenia as per Diagnostic 
and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5 Criteria, Mini International Neuropsychiatric Interview 
(MINI), and as confirmed by Investigator assessment. 
4. Subject has PANSS total score ≥80, AND score of 4 or more in 
at least 2 of the following PANSS items at Screening and at 
Baseline: 
a. Conceptual disorganization 
b. Delusions 
c. Hallucinatory behavior 
d. Unusual thought content 
5. Subject has CGI-S scale score of ≥4 (moderately ill) at 
Screening and Baseline.  
6. Subject has history of relapse and/or exacerbation of symptoms 
when they are not receiving antipsychotic treatment, excluding 
the current episode. 
7. Subject is confirmed by the Investigator to be experiencing an 
acute exacerbation of schizophrenia, as evidenced by ALL of 
the following: 
a. The duration of the current episode is no more than 
8 weeks. 
b. The subject’s current symptoms represent a marked 
and substantial exacerbation of schizophrenia 
compared with the subject’s symptomatic state prior to 
the emergence of the current episode. 
c. A corresponding functional deterioration to the 
symptomatic exacerbation is evident. 
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8. Subject has not been hospitalized for more than 21 days for the 
current episode by the day of the Screening Visit, not including 
social hospitalization (e.g., homelessness or need for shelter that 
is unrelated to the subject’s underlying psychiatric condition). 
9. Subject agrees not to begin formal, structured psychotherapy 
targeting the symptoms of schizophrenia from the time of the 
Screening Visit until the last dose of study drug.  
10. Subject would benefit from hospitalization or continued 
hospitalization for the treatment of schizophrenia (as determined 
by the Investigator).  
11. Subjects must not be treatment naïve or treatment resistant.  
Treatment resistance is defined as having little or no 
symptomatic response to at least 2 courses of antipsychotic 
treatment of an adequate duration (at least 6 weeks) and at a 
therapeutic dose (according to the drug’s package insert). 
12. Subject has had previous positive response to an antipsychotic 
medication other than clozapine in a prior episode. 
13. Subject has a stable living situation and caretaker support when 
not hospitalized. 
14. Subject is male, or a female who is not of childbearing potential 
(i.e., surgically sterile, postmenopausal for at least 1 year) or 
who is non-pregnant, non-lactating, and is using a medically 
accepted method of contraception.  Acceptable methods of 
contraception include condoms (male or female) with a 
spermicidal agent, diaphragm or cervical cap with spermicide, 
medically prescribed intrauterine device, and hormonal 
contraceptives.  A female of child-bearing potential who is not 
currently sexually active must agree to use a medically accepted 
method of contraception should she become sexually active 
while participating in the study.  Each sexually active female of 
child-bearing potential must also agree to use a medically 
accepted method of contraception for 1 month after the final 
dose of study medication. 
15. Subjects must agree that they will not donate sperm or eggs 
from the time of the Screening Visit until 3 months following 
administration of the last treatment or dose of study medication. 
16. Agrees not to use any other transdermal patch products (e.g., 
nicotine replacement patch, hormonal replacement patch, etc.) 
for the duration of the study. 
17. Subjects must be able to wear a transdermal patch for 24 hours. 
Exclusion Criteria 
The subject will be excluded from the study if any of the following 
exclusion criteria are met: 
1. Subject is presenting with a first episode of schizophrenia based 
on the clinical judgment of the Investigator. 
2. Subject has been diagnosed with schizophrenia less than 
6 months prior to Screening Visit. 
3. Subject has received electroconvulsive therapy, transcranial 
magnetic stimulation, vagal nerve stimulation, or other brain 
stimulation treatments within 90 days of Screening Visit. 
4. Subject has a current DSM-5 diagnosis other than schizophrenia 
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including (but not limited to) schizoaffective disorder, major 
depressive disorder, bipolar disorder, post-traumatic stress 
disorder, anxiety disorders, delirium, dementia, amnestic, or 
other cognitive disorders 
5. Subject has a diagnosis of mental retardation, history of 
traumatic brain injury causing ongoing cognitive difficulties, 
Alzheimer’s Disease or another form of dementia (or suspicion 
thereof), or any chronic organic disease of the central nervous 
system that would interfere with the efficacy or safety endpoints 
of the study. 
6. Subject has experienced acute depressive symptoms within 
30 days prior to Screening Visit that requires treatment with an 
antidepressant, as determined by the Investigator.  
7. Subject is a known non-responder to previous asenapine 
treatment, as per Investigator judgment. 
8. Subject is currently taking clozapine for the treatment of 
schizophrenia.  Subjects taking low doses of clozapine (up to 
100 mg/day) for sedative properties and not treatment resistance 
or suicidality may be acceptable as per Investigator judgment 
and as approved by the Sponsor/designee. 
9. Subject with schizophrenia who is considered 
resistant/refractory to antipsychotic treatment by history or who 
has a history of failure to respond to clozapine or response to 
clozapine treatment only.  Treatment resistance is defined as 
having little or no symptomatic response to at least 2 courses of 
antipsychotic treatment of an adequate duration (at least 
6 weeks) and at a therapeutic dose (according to the drug’s 
package insert). 
10. Subject who is unwilling to discontinue or, in the opinion of the 
Investigator, unable to discontinue any prohibited medication 
prior to the Baseline Visit without significant medical or 
psychiatric destabilization, or increased suicidality, as per the 
washout requirements.  Prohibited medications include: 
a. Antipsychotics, including depot or long-acting 
injectables 
b. Antidepressants 
c. Mood stabilizers 
d. Stimulants 
e. Nonpsychopharmacologic medications with 
psychotropic properties, per Investigator and approved 
by Sponsor/designee 
f. Herbal drugs/dietary supplements unless approved by 
Sponsor/designee  
11. Subjects taking drugs (current antipsychotic or other prohibited 
medication) that require >14 days for washout 
12. Subject who is involuntarily committed, incarcerated, or under 
legal compulsion to seek psychiatric treatment. 
13. Subject currently has clinically significant neurological, hepatic, 
renal, metabolic, hematological, immunological, cardiovascular, 
pulmonary, or gastrointestinal disorders such as any history of 
myocardial infarction, congestive heart failure, human 
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immunodeficiency virus seropositive status/acquired 
immunodeficiency syndrome.  Medical conditions that are 
minor or well-controlled may be considered acceptable if the 
condition does not expose the subject to an undue risk of a 
significant adverse event (AE) or interfere with assessments of 
safety or efficacy during the course of the study.  Subjects with 
chronic Hepatitis B or C may be included provided that their 
condition is stable and values for liver function tests and other 
laboratory test results meet the criteria specified in the protocol 
for entry into the study.  The Sponsor/designee should be 
contacted in any instance where the Investigator is uncertain 
regarding the stability of a subject’s medical condition(s) and 
the potential impact of the condition(s) on study participation. 
14. Subject has any other medical condition or laboratory result 
that, in the opinion of the Investigator, may make the subject 
unsuitable for the study. 
15. Subjects with the following laboratory test and ECG results are 
excluded: 
a. Platelets ≤75,000/mm3  
b. Hemoglobin ≤9 g/dL  
c. Neutrophils, absolute ≤1000/mm3  
d. Aspartate transaminase >2×upper limit of normal 
(ULN) 
e. Alanine transaminase >2×ULN 
f. Creatine phosphokinase >3×ULN, unless discussed 
with and approved by the Medical Advisor 
g. Creatinine ≥2 mg/dL or ≥176.8 µmol/L 
h. Hemoglobin A1c (HbA1c) ≥6.5% unless the subject 
has a diagnosis of stable diabetes 
i. QT interval corrected using Fridericia’s formula 
(QTcF) ≥450 msec (males), QTcF ≥470 msec 
(females) 
j. Prolactin.  The enrollment of subjects with prolactin 
levels equal or higher than 5 X ULN 
should be 
discussed with the Medical Advisor 
16. Subject with hypothyroidism or hyperthyroidism (unless 
condition has been stabilized with medications for at least the 
past 90 days); subjects with abnormal free T4 and thyroid 
stimulating hormone (TSH) levels. 
17. Subject is currently treated with insulin for diabetes.  Subjects 
being treated for diabetes with medications other than insulin 
are eligible for the study if their condition is stable as 
determined by satisfying ALL of the following criteria: 
a. HbA1c <7.0%, AND 
b. Screening glucose ≤125 mg/dL or ≤6.94 mmol/L 
(fasting) or <200 mg/dL or <11.1 mmol/L (nonfasting).  
Note:  If the nonfasting screening glucose is 
≥200 mg/dL or ≥11.1 mmol/L, subjects must be 
retested in a fasted state and the retest value must be 
≤125 mg/dL or ≤6.94 mmol/L, AND 
c. Subject has been maintained on a stable regimen of 
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oral anti-diabetic medication(s) for at least 28 days 
prior to Screening or diabetes has been well-controlled 
by diet for at least 28 days prior to Screening, AND 
d. Subject has not had any hospitalizations within the 
12 months prior to Screening due to diabetes or 
complications related to diabetes, AND 
e. Subject’s diabetes is not newly diagnosed during 
Screening. 
18. Subject has epilepsy or history of seizures, with the exception of 
a single seizure episode (e.g., childhood febrile, post traumatic). 
19. Subject has uncontrolled hypertension (diastolic blood pressure 
>95 mmHg in any position) or symptomatic hypotension, or 
orthostatic hypotension which is defined as a decrease of 
≥30 mmHg in systolic blood pressure and/or a decrease of 
≥20 mmHg in DBP after at least 3 minutes standing compared 
with the previous supine blood pressure, OR development of 
symptoms.  Note:  Blood pressure measurements may be 
repeated once to ensure reproducibility of the exclusionary 
result(s) before excluding a subject based on the criteria noted 
above. 
20. Subject has a history of neuroleptic malignant syndrome. 
21. Subject has a score of >2 (mild) on any item of the AIMS at 
Screening. 
22. Subject has a score of 5 (severe akathisia) on the Barnes 
Akathisia Rating Scale (BARS) global clinical assessment of 
akathisia at Screening. 
23. Subject has a history of pituitary adenoma or cancer <5 years 
prior to Screening.  Subjects currently being treated for cancer 
may not be enrolled in the study. 
24. Female subject who is breastfeeding. 
25. Female subject with a positive urine pregnancy test that is 
confirmed positive by serum pregnancy test at Screening or 
Baseline. 
26. Subject who currently (within the past 6 months) meets the 
DSM-5 criteria for substance use disorders (excluding nicotine 
and caffeine). 
27. Subject has positive urine drug/alcohol screen at the Screening 
Visit.  Positive results that are due to short-term prescription 
medications that can be safely discontinued (e.g., opioids for 
acute pain that has resolved) may continue at the discretion of 
the Investigator with the agreement of the Sponsor/designee.  
Subjects with positive cannabis results may be included, 
provided the Investigator does not feel the subject is a 
compliance risk, the subject does not fulfill the criteria for 
substance abuse or dependence as stated in Exclusion 
Criterion 26, the subject agrees to abstain for the duration of the 
study, and with concurrence with the Sponsor/designee. 
28. Subject is at imminent risk of self-harm or harm to others in the 
Investigator’s opinion based on clinical interview and responses 
provided on the Columbia Suicide Severity Rating Scale 
(C-SSRS).  Note that subjects will be excluded if they report 
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suicidal ideation meeting the description of C-SSRS Type 4 or 
5 (i.e., suicidal ideation with intent, with or without a plan) in 
the past 6 months or suicidal behavior (as described by the 
C-SSRS) in the past 12 months at Screening.  Subjects will also 
be excluded at Baseline if they report suicidal ideation of 
Type 4 or 5 or suicidal behavior, as measured by the C-SSRS 
between Screening and Baseline. 
29. Subject has a known allergy or hypersensitivity to asenapine. 
30. Subject has current or history of allergy or hypersensitivity to 
adhesive dressings. 
31. Subject has history of allergy to more than 2 distinct chemical 
classes of drug (e.g., sulfas and penicillins). 
32. Subject has any skin abnormality present at the potential patch 
application site that is likely to be aggravated by the study drug 
(i.e., infection, rash, excessive fragility or dryness, any cut or 
abrasion), presence of tattoo, excessive hair or open sores, or 
scar tissue.  Presence of significant skin disorder such as 
atrophy, psoriasis, or vitiligo. 
33. Subject has participated in a previous HP-3070 study. 
34. Subject has participated in any other investigational trial or used 
investigational drugs within 30 days prior to the Screening Visit 
or has participated in more than 2 studies in the past 12 months. 
35. Any subject who, in the opinion of the Investigator or Medical 
Advisor, should not participate in the study. 
36. Subject is a Study Investigator, sub-Investigator, study 
coordinator, employees of a participating Investigator, or 
immediate family member of the aforementioned. 
Test product, dose and mode of 
administration: 
HP-3070 (Asenapine maleate, transdermal patch) : 
During the double-blind Treatment Period, subjects randomly assigned to 
the HP-3070 treatment arms will have the following 2 patches applied:  
 HP-3070 9.0 mg treatment arm:  one (1) 9.0 mg 20 cm2 patch 
and one (1) placebo patch, once daily  
or 
 HP-3070 18.0 mg treatment arm:  two (2) 9.0 mg 20 cm2 
patches, once daily 
Reference therapy, dose, and 
mode of administration: 
Matching placebo patch: During the double-blind Treatment Period, 
subjects randomly assigned to the placebo treatment arm will have 
2 placebo patches applied (0 mg, 20 cm
2), once daily. 
Patch application and removal 
During the double-blind treatment period, each subject will have 
2 patches applied once daily.  Patches will be removed after 
approximately 24 hours and new patches will be applied daily.  Patches 
will be applied and removed by site personnel. 
Both patches will be applied to one of the following application sites 
daily:  abdomen, hip, upper arm, upper back, and upper chest each day. 
Application sites will be rotated daily.  
In the event that a patch should detach completely, the time and activity 
at the time of patch detachment must be documented.   
If both patches are detached completely then 2 new patches from the 
subject’s kit should be applied immediately, provided that there are at 
least 6 hours of time remaining before the next dose. 
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If only one patch detaches completely, then the other patch should also 
be removed and two new patches from the subject’s kit should be applied 
immediately, provided that there are at least 6 hours of time remaining 
before the next dose. Regardless of what time the new patches are 
applied, patch removal time of the new patches will be approximately 
24-hours after the application of the original patches.  In other words, 
removal time of the new patches may not exceed 24 hours from the time 
the first patches were applied. 
Under no circumstances should the detached patch/patches be reapplied 
to the subject. Under no circumstances should the patches be reinforced 
or taped. 
Criteria for evaluation: 
Primary Efficacy Endpoint:  The primary efficacy endpoint is the change in Positive and Negative Syndrome 
Scale (PANSS) total score between Baseline and Week 6. 
Secondary Efficacy Endpoints: 
The key secondary endpoint is: 
 To evaluate the efficacy of HP-3070 compared with placebo for the treatment of schizophrenia as 
evaluated by change in Clinical Global Impression – Severity of Illness Scale (CGI-S) scores between 
Baseline and Week 6 
Other secondary efficacy endpoints include: 
 Change from Baseline in PANSS total score at each time point in addition to Week 6 
 Change from Baseline in CGI-S at each time point in addition to Week 6 
 CGI-I score at each time point  
 The proportion of CGI-I responders at each time point including Week 6; CGI-I responders are  
defined as subjects who have a score of 1 (very much improved) or a score of 2 (much improved) 
 Change from Baseline in positive, negative, and general pathology subscores of PANSS at each time 
point 
 Proportion of PANSS responders; PANSS responders are defined as subjects who have a  ≥30% 
reduction in PANSS total score between Baseline and at each time point including Week 6 
 Change from Baseline in CDSS score at each time point 
 MSQ score at each time point 
Safety Endpoints: 
 AEs, including TEAEs, AEs leading to discontinuation from the study drug, SAEs, and deaths 
 Change from Baseline in clinical laboratory results (including prolactin, fasting glucose, and lipids), 
ECG results, body weight and vital signs 
 Results of C-SSRS, BARS, AIMS, and SAS 
 Dermal safety 
Exploratory Endpoints 
 A model-based approach will be used to assess the impact of covariates on asenapine exposure and to 
explore the exposure-response relationship with relevant endpoints. 
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Statistical methods: 
Analysis Sets:  Four analysis sets will be used in analyzing the data obtained from this protocol: 
 Intent-to-Treat (ITT):  includes all consented and randomized subjects. Regardless of any protocol 
deviations, analyses performed on the ITT set will be based on the randomized treatment assignment 
and all available data. 
 Full Analysis Set (FAS):  includes all randomized subjects who have had at least 1 patch of double-
blind study medication applied and who have a Baseline PANSS total score and at least 
1  post-Baseline assessment of the primary efficacy measure (PANSS total score).  Evaluable subjects 
will be defined as those who meet the FAS definition.  The FAS will be used as the primary set for 
analysis of efficacy endpoints based on randomized treatment assignment. 
 Safety Analysis Set (SAF):  includes all subjects who have had at least 1 patch of double-blind study 
medication applied and who have at least 1 post-dose safety measurement during the double-blind 
treatment period.  In the unlikely event that errors may have occurred in treatment arm assignments, 
then analyses using the SAF will be based on treatment actually received.  The SAF will be used for 
the analysis of dermal evaluations and safety endpoints. 
 Pharmacokinetic Analysis Set (PAS):  includes all subjects who have received at least 1 dose of study 
medication during the double blind treatment period and have at least 1 blood sample for PK 
assessment.  Subjects may be excluded from the PAS set if they significantly violate inclusion or 
exclusion criteria, significantly violate the protocol in a way that may influence the PK analysis, if 
any unexpected error occurs during the study that may influence the PK analysis (e.g., early 
detachment of transdermal systems, apparent sample switching, etc.) or if their data are unavailable 
or incomplete.  The PAS will be used for the analysis with model based approach.  Excluded cases 
will be documented together with the reason for exclusion. 
Statistical Analyses: 
 Primary Efficacy Analysis:  The primary efficacy endpoint of this trial is the change from Baseline to 
Week 6 in the PANSS total score by dose; the primary analysis set is the FAS.  The comparisons of 
interest are: 
o HP-3070 9.0 mg versus placebo 
o HP-3070 18.0 mg versus placebo 
The p-values for the comparisons are adjusted for multiple comparisons using Hochberg procedure.  
The primary efficacy variable, change from Baseline to Week 6 in the PANSS total score for each of 
the 3 treatment arms, will be analyzed using a mixed model repeated measures (MMRM) analysis.  
The MMRM model will include change from Baseline in PANSS total score as the repeated 
dependent variable, with country, treatment (HP-3070-9.0 [9.0 mg], HP-3070-18.0 [18.0 mg], and 
placebo), visit, treatment by visit interaction, and the Baseline PANSS total score as covariates.  An 
unstructured covariance matrix will be assumed.  The MMRM model may be repeated on additional 
analysis sets as a sensitivity analysis.  If normality assumption is violated, ANCOVA analysis on 
rank-transformed data will be used as a supportive analysis.  
 Key Secondary Analysis: The key secondary endpoint is CGI-S.. If either or both doses are positive 
in the primary efficacy analysis, analysis for the key secondary efficacy endpoint will be carried out 
using Hochberg-based gatekeeping procedure to limit the overall Type I error rate to <0.05. 
In  summary,  
the  Hochberg-based  
tree-gatekeeping procedure  will  be  applied  
to  p-values  from  
the 
mixed models for repeated measurements (MMRM) analysis to control the family-wise Type I error 
rate at 5% by taking into account multiple doses and multiple primary and key secondary endpoints.  
 Additional Analyses of Primary and Key Secondary Endpoints:  Other sensitivity analyses may be 
performed on the primary and key secondary endpoints to assess the robustness of the results based 
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on the model used for primary analysis.  Details will be provided in the Statistical Analysis Plan.  The 
analyses will be performed according to the National Academy of Sciences (2010) guidelines. 
 Analysis  of  Other  Secondary  Efficacy  Endpoints:    Other  secondary  efficacy  endpoints  will  be 
summarized but will not be adjusted as part of the tree-gatekeeping procedure. 
 Analysis of Safety:  All safety summaries will be descriptive; no statistical significance tests will be 
performed on safety data. 
 Analysis of PK:  model based assessment including the population PK following HP-3070 
administration will be evaluated using asenapine concentrations in plasma and relevant endpoints.  
The methodology and results will be described in a standalone PK report. 
Sample Size Calculation: 
Assuming an effect size of 0.35 on the change in PANSS total score from baseline to Week 6 for the 
2 pairwise comparisons between each active HP-3070 treatment arm and placebo, the power for detecting a 
statistically significant HP-3070 advantage will be approximately 0.90 having 204 evaluable subjects per each 
treatment arm using a 2-side alpha level of 0.025 for each comparison.  A 2-sided overall Type I error is equal 
to 0.05.  Having 3 treatment arms, the total number of subjects randomized in the trial and included in the 
primary analysis set will be approximately 612.  A sufficient number of subjects will be screened to randomize 
the proposed sample size. 
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TABLE OF CONTENTS 
SIGNATURES .............................................................................................................................. 
3 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................... 
20 
2.0 
INTRODUCTION ......................................................................................................... 
23 
2.1 
Background Information ................................................................................. 
23 
2.2 
Rationale ............................................................................................................. 
26 
2.3 
Hypothesis........................................................................................................... 
26 
2.4 
Risk Assessment ................................................................................................. 
27 
2.5 
Study Compliance ............................................................................................. 
27 
3.0 
STUDY OBJECTIVES ................................................................................................. 
28 
3.1 
Primary Objective ............................................................................................. 
28 
3.2 
Secondary Objectives ........................................................................................ 
28 
3.3 
Safety Objectives ............................................................................................... 
28 
3.4 
Exploratory Objective ...................................................................................... 
28 
4.0 
INVESTIGATIONAL PLAN....................................................................................... 
29 
4.1 
Summary of Study Design................................................................................ 
29 
4.1.1 Screening/Run-in Period ...................................................................... 
30 
4.1.2 Double-blind Treatment Period ........................................................... 
30 
4.1.3 Follow-up Period .................................................................................. 
30 
4.2 
Discussion of Study Design .............................................................................. 
34 
4.3 
Selection of Study Population .......................................................................... 
35 
4.3.1 Inclusion Criteria 
.................................................................................. 
35 
4.3.2 Exclusion Criteria ................................................................................. 
37 
4.3.3 Subject Withdrawal .............................................................................. 
40 
5.0 
STUDY TREATMENTS .............................................................................................. 
41 
5.1 
Treatments Administered ................................................................................ 
42 
5.2 
Identity of Investigational Product 
................................................................. 
42 
5.3 
Packaging, Labelling and Storage .................................................................. 
42 
5.4 
Study Drug Accountability .............................................................................. 
42 
5.5 
Method of Assigning Subjects to Treatment ................................................. 
43 
5.6 
Selection of Doses in the Study ........................................................................ 
43 
5.7 
Dosing of Subjects ............................................................................................. 
45 
5.8 
Treatment Interruptions or Modifications.................................................... 
46 
5.9 
Blinding ............................................................................................................... 
46 
5.10 Prior and Concomitant Treatments ............................................................... 
46 
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5.10.1 Medications Prohibited during the Study ........................................... 
47 
5.10.2 Permitted Medications ......................................................................... 
47 
5.10.3 Concomitant Medication Cautions ...................................................... 
48 
5.10.4 Other Restrictions ................................................................................. 
49 
5.11 Medical Care of Subjects after End of Study ............................................... 
49 
5.12 Treatment Compliance ..................................................................................... 
49 
6.0 
EFFICACY, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS ............................................................................................................. 
49 
6.1 
Efficacy ................................................................................................................ 
49 
6.1.1 M.I.N.I. International Neuropsychiatric Interview (MINI) ............... 
50 
6.1.2 Positive and Negative Syndrome Scale (PANSS).............................. 
50 
6.1.3 Secondary Efficacy............................................................................... 
50 
6.1.3.1 Clinical Global Impression - Severity of 
Illness Scale (CGI-S) 
......................................................... 
50 
6.1.3.2 Clinical Global Impression - Improvement 
Scale (CGI-I) 
...................................................................... 
51 
6.1.3.3 Calgary Depression Scale for Schizophrenia 
(CDSS) ............................................................................... 
51 
6.1.3.4 Medication Satisfaction Questionnaire (MSQ)................ 
51 
6.2 
Safety ................................................................................................................... 
51 
6.2.1 Adverse Events and Serious Adverse Events ..................................... 
51 
6.2.1.1 Adverse Events .................................................................. 
51 
6.2.1.2 Serious Adverse Events ..................................................... 
52 
6.2.1.3 Categorization of Adverse Events .................................... 
53 
6.2.1.4 Reporting of Adverse Events ............................................ 
55 
6.2.1.5 Reporting of Serious Adverse Events............................... 
55 
6.2.1.6 Follow-up of Adverse Events ........................................... 
56 
6.2.1.7 Pregnancy and Contraception ........................................... 
56 
6.2.2 Clinical Laboratory Evaluations .......................................................... 
57 
6.2.2.1 Clinical Laboratory Assessments ..................................... 
57 
6.2.2.2 Monitoring of Selected Laboratory Values ...................... 
59 
6.2.3 Vital Signs, Physical Findings and Other Safety 
Assessments .......................................................................................... 
60 
6.2.4 Evaluation of Extrapyramidal Symptoms (EPS) ................................ 
60 
6.2.4.1 Simpson Angus Scale (SAS)............................................. 
60 
6.2.4.2 Abnormal Involuntary Movement Scale 
(AIMS) ............................................................................... 
61 
6.2.4.3 Barnes Akathisia Rating Scale (BARS) ........................... 
61 
6.2.5 Suicidality: Columbia-Suicide Severity Rating Scale 
(C-SSRS)............................................................................................... 
62 
6.2.6 Evaluations of Patch and Dermal Assessments .................................. 
62 
6.3 
Pharmacokinetics .............................................................................................. 
64 
6.3.1 Pharmacokinetic Blood Sampling ....................................................... 
64 
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6.3.2 Drug Concentration Measurements ..................................................... 
65 
6.4 
Appropriateness of Measurements ................................................................. 
65 
7.0 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 
65 
7.1 
Monitoring .......................................................................................................... 
66 
7.2 
Data Management/Coding ............................................................................... 
66 
7.3 
Quality Assurance Audit .................................................................................. 
67 
8.0 
STATISTICAL METHODS ........................................................................................ 
68 
8.1 
Determination of Sample Size ......................................................................... 
68 
8.2 
Sample Size Recalculation ............................................................................... 
68 
8.2.1 Procedures for Sample Size Recalculation ......................................... 
68 
8.3 
Study Endpoints ................................................................................................ 
69 
8.3.1 Primary Analyses Endpoint ................................................................. 
69 
8.3.2 Key Secondary Analysis Endpoint ...................................................... 
69 
8.3.3 Other Secondary Analyses Endpoints ................................................. 
69 
8.3.4 Exploratory Endpoint ........................................................................... 
69 
8.4 
Statistical Methods ............................................................................................ 
70 
8.4.1 Analysis Populations ............................................................................ 
70 
8.4.2 Primary Efficacy Analysis ................................................................... 
71 
8.4.3 Key Secondary Efficacy Analysis ....................................................... 
71 
8.4.4 Other Secondary Efficacy Analyses.................................................... 
72 
8.4.5 Subgroup Analyses ............................................................................... 
72 
8.4.6 Safety Analyses .................................................................................... 
72 
8.4.7 Data to be Analyzed ............................................................................. 
73 
8.4.8 Missing Data ......................................................................................... 
73 
8.5 
Subject Disposition and Characteristics 
........................................................ 
73 
8.6 
Safety ................................................................................................................... 
73 
8.6.1 Adverse Events ..................................................................................... 
74 
8.6.2 Clinical Laboratory Evaluations .......................................................... 
74 
8.6.3 Vital Signs Measurements, Physical Findings and Other 
Safety Evaluations ................................................................................ 
74 
8.6.4 Dermal Evaluations .............................................................................. 
74 
8.7 
Pharmacokinetic Analyses ............................................................................... 
74 
8.8 
Interim Analyses 
................................................................................................ 
74 
9.0 
ETHICS ........................................................................................................................... 
75 
9.1 
Institutional Review Board or Independent Ethics Committee 
................. 
75 
9.2 
Ethical Conduct of the Study........................................................................... 
75 
9.3 
Subject Information and Informed Consent ................................................. 
75 
9.4 
Study Administration ....................................................................................... 
76 
9.5 
Administrative Structure ................................................................................. 
76 
9.6 
Data Handling and Record Keeping .............................................................. 
77 
9.7 
Direct Access to Source Data/Documents ...................................................... 
78 
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9.8 
Investigator Information .................................................................................. 
78 
9.8.1 Investigator Obligations 
....................................................................... 
78 
9.8.2 Protocol Signatures .............................................................................. 
78 
9.8.3 Publication Policy................................................................................. 
78 
9.9 
Financing and Insurance .................................................................................. 
79 
10.0 REFERENCES ............................................................................................................... 
80 
11.0 APPENDIX 1: SIGNATURE OF INVESTIGATOR............................................... 
82 
12.0 APPENDIX 2: POSITIVE AND NEGATIVE SYNDROME SCALE 
(PANSS) 
........................................................................................................................... 
83 
13.0 APPENDIX 3: CLINICAL GLOBAL IMPRESSION - SEVERITY 
OF ILLNESS SCALE (CGI-S) 
.................................................................................. 
121 
14.0 APPENDIX 4: CLINICAL GLOBAL IMPRESSION - 
IMPROVEMENT SCALE (CGI-I) 
.......................................................................... 
123 
15.0 APPENDIX 5: CALGARY DEPRESSION SCALE FOR 
SCHIZOPHRENIA (CDSS) ....................................................................................... 
125 
16.0 APPENDIX 6: MEDICATION SATISFACTION QUESTIONNAIRE 
(MSQ) ............................................................................................................................ 
127 
17.0 APPENDIX 7: SIMPSON ANGUS SCALE (SAS)................................................. 
129 
18.0 APPENDIX 8: ABNORMAL INVOLUNTARY MOVEMENT 
SCALE (AIMS) ............................................................................................................ 
136 
19.0 APPENDIX 9: BARNES AKATHISIA RATING SCALE (BARS) .................... 
141 
20.0 APPENDIX 10: COLUMBIA-SUICIDE SEVERITY RATING 
SCALE (C-SSRS) ......................................................................................................... 
144 
21.0 APPENDIX 11: M.I.N.I. INTERNATIONAL 
NEUROPSYCHIATRIC INTERVIEW (MINI) ..................................................... 
151 
 
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LIST OF TABLES 
Table 1 
Schedule of Events 
...........................................................................................31 
Table 2 
Investigational Products 
...................................................................................42 
Table 3 
Steady-State Pharmacokinetics of HP-3070 Transdermal Patch 
.....................44
 
Table 4 
Prohibited/Restricted Medications and Washout Prior to Baseline 
.................47 
Table 5 
Medications Permitted for Specific Conditions 
...............................................48 
Table 6 
Other Restrictions 
............................................................................................49 
Table 7 
Clinical Laboratory Tests 
.................................................................................58 
Table 8 
Skin Irritation Descriptors................................................................................63 
Table 9 
Adhesive Residue Scale 
...................................................................................64 
Table 10 
Administrative Structure 
..................................................................................77 
 
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1.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Abbreviation  
Definition 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
AIMS 
Abnormal Involuntary Movement Scale 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
AR(1) 
Autoregressive (1) 
ARH(1) 
Heterogeneous autoregressive (1) 
AST 
Aspartate transaminase 
AUC 
Area under the concentration time curve 
BARS 
Barnes Akathisia Rating Scale 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
CDSS 
Calgary Depression Scale for Schizophrenia 
CGI-I 
Clinical Global Impression - Improvement scale 
CGI-S 
Clinical Global Impression - Severity of Illness scale 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
Cmax 
Maximum plasma concentration 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CS 
Compound symmetry 
CSH 
Heterogeneous compound symmetry 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
Diastolic blood pressure 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
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ECT 
Electroconvulsive therapy 
EDC 
Electronic data capture 
EPS 
Extrapyramidal symptoms 
ET 
Early termination 
EU 
European Union 
FA0 
No Diagonal Factor Analytic 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transaminase 
HbA1c 
Hemoglobin A1c 
HBAg 
Hepatitis B antigen 
HCV 
Hepatitis C 
HDL 
High-density lipoprotein 
HIV 
Human Immunodeficiency Virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-To-treat 
IUD 
Intrauterine device 
IVRS 
Interactive Voice-Activated Response System 
IWRS 
Interactive Web-based Response System 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last Observation Carried Forward   
MAR 
Missing at random 
MCAR 
Missing completely at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing not at random 
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MSQ 
Medication Satisfaction Questionnaire 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetic 
prn 
as needed 
QTcF 
QT interval corrected by Friderica’s formula 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Simpson Angus Scale 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SL 
Sublingual 
SOC 
Standard of care 
SOP 
Standard Operating Procedures 
SSR 
Sample size recalculation 
SUSARs 
Serious Unexpected Adverse Event Reactions 
t
1/2 
Elimination half life 
TEAE 
Treatment-Emergent Adverse Event 
TMS 
Transcranial magnetic stimulation 
TOEPH 
Heterogeneous Toeplitz structure 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
VNS 
Vagal nerve stimulation 
WBC 
White blood cell 
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2.0 INTRODUCTION 
2.1 Background Information 
Schizophrenia is a serious and chronic disabling disorder that affects approximately 1% of 
the world’s population.
1  It is characterized by positive symptoms (e.g., delusions, 
hallucinations, and disorganized speech), negative symptoms (e.g., affective flattening, 
alogia, avolition, and anhedonia social withdrawal), cognitive deficits, including attention, 
memory, and learning dysfunction.  Further, anxiety and depression are prominent features of 
schizophrenia.  These symptoms result in marked personal, familial, social, and occupational 
dysfunction.  These subjects are also at an increased risk of suicide, require extensive 
healthcare resource utilization, and have a poor prognosis.  The onset of the disorder occurs 
relatively early in life (adolescence to early adulthood).  Most schizophrenia patients have 
recurrent exacerbations of the positive symptoms and persistent negative and cognitive 
symptoms.  Schizophrenia patients require lifetime disease management and treatment. 
Asenapine is a second-generation antipsychotic agent, and the sublingual dosage form is 
marketed under the trade name of SAPHRIS® in the United States (US) and Sycrest
® in the 
European Union (EU).  Asenapine is a potent multireceptor antagonist with a high affinity 
for several serotonin, dopamine, noradrenaline, and histamine receptors.  In the United 
States, asenapine is indicated for the treatment of schizophrenia as well as for the acute 
treatment (as monotherapy or adjunctive therapy) of manic or mixed episodes associated with 
bipolar disorder.  In the EU it is approved for the treatment of moderate to severe manic 
episodes associated with bipolar I disorder in adults. 
Sublingual (SL) asenapine has to be administered twice daily.  The SL tablet should be 
placed under the tongue and left to dissolve completely and patients are advised to avoid 
eating or drinking for 10 minutes after administration. 
Asenapine can cause dysgeusia (distorted, altered, or unpleasant taste) or oral hypoesthesia 
(numbness) due to its local anesthetic effect and the oral hypoesthesia usually resolves within 
1 hour after dosing.  Across the 6-week schizophrenia trials and the 52-week schizophrenia 
trial with sublingual asenapine 5 or 10 mg administered twice daily, the rate of 
discontinuation due to oral hypoesthesia was 0.27%.  However, in a study that examined the 
effect of absorption site on the pharmacokinetics (PK) of asenapine in healthy male subjects, 
reported rates of oral paresthesias were 75.8%, 55.9%, and 45.7% for the SL, supralingual, 
and buccal absorption sites, respectively. 
Application site reactions, primarily in the SL area, have been reported during post-approval 
use of sublingual asenapine.  These application site reactions included oral ulcers, blisters, 
peeling/sloughing, and inflammation.  In many cases, the occurrence of these application site 
reactions led to discontinuation of therapy. 
Noven has developed HP-3070 (asenapine maleate transdermal drug delivery system), a 
transdermal patch which will be dosed once daily.  The transdermal route of application will 
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provide the patients with another treatment option that may have certain advantages over the 
sublingual (SL) formulation of asenapine, such as: 
 HP-3070 patch will mitigate oral hypoesthesia and/or dysgeusia that is commonly 
observed with SL asenapine; 
 HP-3070 patch may have less variability in asenapine absorption and a more gradual 
increase in plasma concentration compared to the SL route of administration; 
 HP3070 patch may potentially have  improved tolerability over the current SL route 
of administration for SAPHRIS®; because it has better PK characteristics; 
 HP-3070 patch may provide a means for physicians and caregivers to visually check a 
patient’s treatment compliance ; 
 HP-3070 patch has no restrictions related to eating and drinking 
In pre-clinical studies, HP-3070 transdermal patch has shown transdermal absorbability and 
dermal tolerability. 
To date, Noven has conducted a total of 4 Phase 1 clinical studies; 3 PK studies (HP-3070-
US-01, HP-3070-US-02 and HP-3070-US-03) in healthy volunteers and 1 PK study (HP-
3070-US-02b) in patients diagnosed with schizophrenia.  From these PK studies, it can be 
concluded that HP-3070 transdermal patch delivers steady plasma levels throughout the 24-
hour application period with low variability and has reproducible PK metrics across all 
studies. 
HP-3070 was first administered to healthy volunteers in HP-3070-US-01, the first-in-human 
patch application study designed to evaluate the single-dose PK, safety, and tolerability of 
the transdermal patch system HP-3070 compared with SL asenapine.  Eighteen healthy adults 
completed the study. 
After a single SL administration of Sycrest®, asenapine concentrations rose rapidly and 
exhibited single peak profiles, whereas following transdermal patch application, asenapine 
concentrations rose gradually and remained relatively constant over the dosing interval.  
A plateau in the plasma concentration was reached from 12 hours after patch application until 
removal of the patch 24 hours after patch application. 
The mean maximum plasma concentration (Cmax) following SL administration of 5 mg of 
Sycrest® was considerably higher than that attained with 3.6-mg and 4.8-mg patches and was 
attained much sooner.  The lower and more gradual progression to C
max observed with the 
transdermal patches has the potential to reduce the incidence of adverse events (AEs) in the 
immediate post dosing period.  Mean asenapine exposure area under the concentration curve 
(AUC
0-t) following use of the 4.8-mg transdermal patch was slightly higher than after the 
administration of the 5-mg SL tablet.  When the patch was removed, the plasma 
concentration of asenapine and its metabolite, desmethyl-asenapine, decreased at a rate 
similar to that seen after SL dosing (elimination half-life [t
1/2] of ~23 hours). 
HP-3070-US-02 was designed to evaluate the PK profile, dose proportionality, safety, and 
tolerability of HP-3070.  Part 1 evaluated single doses of 9.0 mg, 13.5 mg, and 18.0 mg in 
24 healthy volunteers.  The patch doses (sizes) were chosen based on the results obtained in 
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HP-3070-US-01.  In Part 2, healthy volunteers received 9-mg patches applied for 24-hours 
daily for 7 days. 
Single application of a 13.5-mg patch and multiple applications of a 9.0-mg patch resulted in 
a total of 115 AEs.  As a result, the 18.0-mg dose was not administered due to the 
unfavorable tolerability profile of 13.5 mg in healthy volunteers.  Further, only 3 subjects 
among the 11 subjects who started multiple applications of the 9-mg patch completed the 
7-day multiple applications.  No deaths or other serious adverse events (SAEs) occurred 
during this study.  As healthy volunteers were not able to tolerate higher doses and multiple 
doses of HP-3070, this study in healthy volunteers (HP-3070-US-02) was stopped early and a 
multiple dose PK study (HP-3070-US-02b) was conducted in patients diagnosed with 
schizophrenia. 
The statistical analysis of relative exposure for both asenapine and desmethyl-asenapine were 
within the 80% to 125% limits for both dose-normalized Cmax and AUC, confirming the 
dose-proportionality between the 9.0-mg and the 13.5-mg HP-3070 patches.  These similar 
desmethyl-asenapine/asenapine ratios and the percentage of the drug released between 
9.0 mg and 13.5 mg HP-3070 patches corresponded well to the dose-proportionality results 
for C
max and AUC. 
HP-3070-US-02b was an open-label, non-randomized, multiple-ascending dose study 
designed to evaluate the PK of asenapine and dopamine D2 receptor occupancy relative to 
steady state plasma levels in subjects with schizophrenia treated with HP-3070 patches 
(4.5 mg, 9.0 mg, 13.5 mg, and 18.0 mg) for 7 days. 
Plasma asenapine concentrations following multiple ascending doses 4.5 mg, 9.0 mg, 
13.5 mg, and 18.0 mg of HP-3070 patches increased with increasing dose.  The estimated 
slopes for the steady state C
max, C
min, and AUC
0-24 following multiple ascending doses of 
HP-3070 patches fell within the pre-defined criteria, confirming the dose-proportionality 
between 4.5 mg and 18.0 mg of HP-3070 patches.  These similar desmethyl- 
asenapine/asenapine ratios and percentage of drug released among all 4 dosages 
corresponded well to the dose-proportionality results.  Plasma asenapine concentration 
reached the steady state at around 72 hours after the first patch and showed sustained plasma 
concentrations at steady state. 
The D2/D
3 receptor occupancy in the caudate and putamen regions were increased between 
the doses of 4.5 and 9.0 mg followed by an observed plateau between the 9.0-mg and 
18.0-mg doses, with maximum occupancy of around 60% when 11C-PHNO was used as a 
radiolabeled ligand.  Receptor occupancy observed in this study is comparable to that 
obtained with other antipsychotics such as risperidone and olanzapine (at clinical dose) as 
measured with 11C-PHNO.
2 
Treatment with multiple doses of the HP-3070 patch for a total of 28 days was safe and well 
tolerated in patients with schizophrenia.  A total of 33 treatment-emergent adverse events 
(TEAEs) were observed in this study.  The most frequently reported TEAEs were 
somnolence (6 events), dizziness (4 events), and headache (3 events).  There were no deaths 
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or SAEs reported during the study.  No subjects were discontinued during the study due to 
AEs. 
HP-3070-US-03 was designed to examine the PK, safety, tolerability, adhesion and irritation 
potential of the 9.0-mg HP-3070 transdermal patch at 5 different application sites (upper arm, 
upper chest, upper back, abdomen, and hip area) in healthy Japanese (n = 20) and Caucasian 
(n = 20) subjects. 
All PK parameters assessed were similar among the 5 different application sites and 
asenapine exposure, measured as C
max and AUC, from all tested application sites (upper 
chest, upper back, abdomen, and hip area) was bioequivalent to that of the upper arm 
(reference application site) with the exception of C
max for the abdomen compared with the 
upper arm for which the lower boundary was slightly out of criteria.  The results of this study 
suggest that the 5 application sites evaluated in this study (abdomen, hip area, upper arm, 
upper back, and upper chest) can be used as application sites for the HP-3070 transdermal 
patch. 
Following 24-hour HP-3070 patch applications, no marked ethnic differences between 
Caucasian and Japanese subjects were found for all PK parameters assessed for both 
asenapine and desmethyl-asenapine. 
Treatment with the 9-mg patch applied for 24 hours was safe and well tolerated in healthy 
male and female Caucasian and Japanese subjects.  There were no deaths or SAEs reported 
during the study.  No subjects were discontinued during the study due to AEs.  The most 
frequently reported TEAEs were somnolence (25 events), insomnia (10 events), nausea (8 
events), fatigue (7 events), headache (6 events), influenza-like illness (6 events), irregular 
menstruation (5 events), and dizziness (4 events).  No difference in patch adhesion was seen 
between Caucasian and Japanese subjects and between the application sites of upper back, 
abdomen, upper chest, hip area, and upper arm. 
In all of the PK studies completed to date, adhesion of HP-3070 transdermal patch was good 
and treatment with HP-3070 transdermal patches was safe and well tolerated.  There were no 
difficulties associated with patch application and skin irritation and discomfort scores suggest 
good dermal tolerability of the transdermal patches. 
2.2 Rationale 
This study is designed to evaluate efficacy and safety of HP-3070 compared with placebo 
transdermal patch in subjects diagnosed with schizophrenia, who are in an acute exacerbation 
and to assess the impacts of covariates on asenapine exposure as delivered in a patch 
formulation, using a population-based approach. 
2.3 Hypothesis 
The null hypothesis of the primary endpoint is that there is no difference between treatment 
arms in the change from Baseline in Positive and Negative Syndrome Scale (PANSS) total 
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score at Week 6.  The alternative hypothesis is that the treatment arms differ in the change 
from Baseline in PANSS total score at Week 6. 
2.4 Risk Assessment 
Potential risks associated with participation in this study have been identified through the 
review of information available from marketed formulations containing asenapine 
(SAPHRIS
® and Sycrest
®).  These products have been marketed since 2009 and the safety 
profile of asenapine is well-established. 
The most common AE associated with SAPHRIS® and Sycrest
® have been anxiety and 
somnolence.  Less common AEs include nervous system disorders (as dystonia, akathisia, 
sedation, dizziness, and dyskinesia), oral hypoesthesia, muscle rigidity, and fatigue.  
Increases in liver transaminases have been reported, as well as increased appetite and weight 
increase.  The SAEs known to be associated with antipsychotics include tardive dyskinesia, 
suicidality, and neuroleptic malignant syndrome.  Other risks associated with this drug class 
include orthostatic hypotension, syncope, weight gain, metabolic imbalance, neutropenia, and 
allergic reactions.  More details are presented in the Investigator Brochure. 
The risks specific to the HP-3070 patch (as opposed to the molecule [asenapine] itself) are 
limited to potential dermal reactions to the patch.  A potential risk of the study is treatment 
failure (particularly in the placebo control group), which may result in worsening symptoms.  
Hospitalization of the subjects for the entire duration of the study will enable close 
observation of the subjects whereby the risk of treatment failure as well as potential dermal 
reactions can be addressed in real-time.  The subjects will be under observation and they will 
be monitored for changes in extrapyramidal symptoms (EPS) scores, electrocardiograms 
(ECGs), laboratory values, vital signs, and physical examination.  Psychotropic medications 
which can be used concomitantly to manage the patient’s symptoms are discussed in 
Section 5.10. 
2.5 Study Compliance 
This study will be performed in compliance with the protocol, International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and applicable regulatory 
requirements. 
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3.0 STUDY OBJECTIVES  
3.1 Primary Objective  
The primary objective of the study is to evaluate efficacy of HP-3070 compared with placebo 
for the treatment of schizophrenia as evaluated by PANSS total score. 
3.2 Secondary Objectives 
 Key Secondary Efficacy Objective: 
o Clinical Global Impression – Severity of Illness Scale (CGI-S) 
 Other Secondary Efficacy Objectives:  To evaluate the efficacy of HP-3070 using the 
following measures: 
o PANSS total score at each time point 
o Clinical Global Impression – Severity of Illness Scale (CGI-S) at each time 
point 
o Clinical Global Impression – Improvement Scale (CGI-I) at each time point 
o Proportion of CGI-I responders at each time point including Week6; CGI-I 
responders are defined as subjects who have a score of 1 (very much 
improved) or a score of 2 (much improved). 
o Positive, negative, and general pathology subscores of PANSS 
o Proportion of PANSS responders; PANSS responders are defined as subjects  
who have a  ≥30% reduction in PANSS total score between Baseline and at 
each time point including Week 6 
o Calgary Depression Scale for Schizophrenia (CDSS) 
o Medication Satisfaction Questionnaire (MSQ) score 
3.3 Safety Objectives 
 AEs, including TEAEs, AEs leading to discontinuation from the study drug, SAEs, 
and deaths 
 Change from Baseline in clinical laboratory results (including prolactin, fasting 
glucose, and lipids), ECG results, body weight and vital signs 
 Results of C-SSRS, BARS, AIMS, and SAS  
 Dermal Safety 
3.4 Exploratory Objective 
To assess the impact of covariates on asenapine exposure using a model-based approach and 
to explore the exposure-response relationship with relevant endpoints. 
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4.0 INVESTIGATIONAL PLAN 
4.1 Summary of Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, in-patient, safety, and 
efficacy study to evaluate HP-3070 for the treatment of schizophrenia. 
This study will enroll subjects who are in an acute exacerbation (i.e., have had an acute 
episode no longer than 8 weeks prior to the Screening Visit), have a PANSS total score 
≥80 with scores of 4 or higher on at least 2 out of the 4 pre-defined PANSS positive subscale 
items, and have a CGI-S ≥4.  Subjects will be hospitalized at the Screening Visit and will 
remain hospitalized during the study.  The subject may leave the hospital for necessary 
personal business.  During this time, the subject must be supervised by study staff or a 
responsible caretaker.  Any subject who leaves the site must have an alcohol breathalyzer and 
urine drug and pregnancy tests when they return to the site.  Investigator should contact 
Medical Advisor to discuss specifics of subject off-site overnight travel to confirm 
appropriateness. 
This study will consist of a Screening/placebo Run-in Period of 3 to 14 days (described in 
Section 4.1.1), a 6-week double-blind Treatment Period (described in Section 4.1.2) and a 
30 day Follow-up Period (described in Section 4.1.3). 
The study will evaluate 9.0 mg (HP-3070-9.0) and 18.0 mg (HP-3070-18.0) of HP-3070 
transdermal patches versus placebo transdermal patches.  Patches will be applied by site 
personnel at approximately the same time daily and each patch will be worn for 24 hours.  
Every day, approximately 24 hours after patch application, site personnel will remove 
previous day’s patches and apply new patches.  Patch adhesion will be assessed at specified 
time points. 
In this study, efficacy will be evaluated using widely accepted, standard questionnaires.  
These include the PANSS, CDSS, CGI-S, CGI-I, and MSQ.  Efficacy measures are described 
in Section 6.1.  The methods used for the analysis of efficacy data are presented in 
Section 8.3. 
In addition to standard safety measures (AEs, clinical laboratory assessments, vital signs, 
weight, ECG results), this study will also include assessments of EPS symptoms using the, 
Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), 
and Simpson-Angus Scale (SAS).  Suicidality will be monitored using the Columbia-Suicide 
Severity Rating Scale (C-SSRS).  Dermal safety will be assessed by daily evaluation of 
irritation at the site of patch application and by a review of any dermal reactions reported as 
AEs.  Safety measures are described in Section 6.2. 
The schedule of study procedures and assessments is presented in Table 1. 
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4.1.1 
Screening/Run-in Period 
Subjects will be asked to sign the informed consent form (ICF).  No screening procedures 
may begin prior to obtaining informed consent. 
After obtaining informed consent, each subject will be assigned a unique subject number.  
Eligible subjects will be hospitalized for the duration of the study.  While undergoing 
screening procedures, including the MINI, and waiting for results of laboratory tests, ECGs, 
and other assessments, the subject will start treatment with the single-blind placebo patch.  
Subjects will be blinded to the treatment during the Run-in Period.  The subject must have 
the single-blind placebo patch applied for a minimum of 3 days prior to being randomized 
into the double-blind Treatment Period.  In addition, current antipsychotic and other 
prohibited medications will be washed out during the run-in period and must be completed 
prior to randomization into the double-blind treatment period.  Subjects who have a decrease 
in PANSS total score ≥20% from Screening to Baseline or a PANSS total score <80 at 
Screening or Baseline will be discontinued from the study and will not enter the double-blind 
Treatment Period.  Subjects who are not compliant with wearing the run-in patches will also 
be discontinued from the study.  Subjects who are screened but discontinued before 
randomization will be considered screen failures. 
Rescreening of subjects will be considered on a case-by-case basis and must be approved by 
the medical monitor. 
4.1.2 
Double-blind Treatment Period 
Eligible subjects will be randomized at Baseline (Day 0) and randomly assigned to HP-3070 
(9.0 mg or 18.0 mg) or placebo in a 1:1:1 ratio.  Subjects will receive treatment with study 
medication daily starting on Day 1 and up to Day 42 for a total of 6 weeks. 
Efficacy and safety data will be collected in accordance with the Schedule of Events. 
Blood samples will be collected at pre-determined time points and analyzed for asenapine 
and desmethyl asenapine concentrations. 
At discharge (Week 6 or early termination [ET]), the subject will be prescribed an approved 
antipsychotic treatment and returned to the care of their physician. 
4.1.3 
Follow-up Period 
All subjects will have a follow-up contact (site visit or telephone call, at the discretion of the 
Investigator) 30 days after the last patch is removed.  This contact will be used to collect 
information about any AEs or SAEs that may have occurred since discharge and to follow-up 
on any AE that was on-going at discharge. 
The Schedule of Events is presented in Table 1. 
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Table 1  
Schedule of Events 
Study Period 
Screening/ 
Single-blind 
Placebo Run-
In Period [a] 
Double-Blind Treatment Period 
Safety 
Follow-up Visit or
Telephone Call [b] 
Week/Day 
3 to 14 days Baseline
Day 0 [c]
Day 7/ 
Wk 1 
Day 14/ 
Wk 2 
Day 21/  
Wk 3  
Day 28/ 
Wk 4 
Day 35/ 
Wk 5 
Day 42/  
Wk 6 or ET
30 days after 
removal of last patch
Visits 
1  
2  
3  
4  
5  
6  
7  
8 
8 
Informed consent 
X   
  
  
  
  
  
  
 
 
Pre-randomization form 
X 
  
  
  
  
  
  
 
 
Assign subject number from IWRS  
X 
  
  
  
  
  
  
 
 
Inclusion/exclusion criteria 
X  
X  
  
  
  
  
  
 
 
Demographics 
X 
  
  
  
  
  
  
 
 
Physical examination including skin 
examination 
X 
 
 
 
 
 
 
 
 
X 
 
Medical history including 
psychiatric history 
X 
 
 
 
 
 
 
 
 
 
 
MINI [d] 
X 
 
 
 
 
 
 
 
 
 
 
 
PANSS [d] 
X  
X   
X  
X  
X  
X  
X  
X 
 
CDSS [d] 
X  
X  
X  
X  
X  
X  
X  
X 
 
C-SSRS [d] 
X  
X  
X  
X  
X  
X  
X  
X 
 
CGI-S [d] 
X  
X  
X  
X  
X  
X  
X  
X 
 
CGI-I [d] 
 
  
X  
X  
X  
X  
X  
X 
 
AIMS [d] 
X  
X  
X  
X  
X  
X  
X  
X 
 
SAS and BARS [d] 
X  
X  
X  
X  
X  
X  
X  
X 
 
MSQ [d] 
X 
  
  
X  
  
X  
  
X 
 
Vital signs [e] 
X  
X  
X  
X  
X  
X  
X  
X 
 
Weight and height [f]  
X  
X  
X  
X  
X  
X  
X  
X 
 
Standard 12-lead ECG [g] 
X  
X  
X  
X  
X  
X  
X  
X 
 
Clinical laboratory testing (fasting)  
X  
X  
  
  
X  
  
  
X 
 
Urine drug screen/blood alcohol [h] 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum/urine pregnancy test [i] 
X  
X  
X  
X  
X  
X  
X  
X 
 
Serology   
(HIV, HBsAg, anti-HCV) [j] 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant therapies 
X  
X  
X  
X  
X  
X  
X  
X 
X 
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Study Period 
Screening/ 
Single-blind 
Placebo Run-
In Period [a] 
Double-Blind Treatment Period 
Safety 
Follow-up Visit or
Telephone Call [b] 
Week/Day 
3 to 14 days Baseline
Day 0 [c]
Day 7/ 
Wk 1 
Day 14/ 
Wk 2 
Day 21/  
Wk 3  
Day 28/ 
Wk 4 
Day 35/ 
Wk 5 
Day 42/  
Wk 6 or ET
30 days after 
removal of last patch
Visits 
1  
2  
3  
4  
5  
6  
7  
8 
8 
Adverse events 
X  
X  
X  
X  
X  
X  
X  
X 
X 
PK blood samples [k] 
 
  
  
  
X  
  
  
X 
 
Blood sample for prolactin level [l]  
 
X  
  
  
X  
  
  
X 
 
Dispense run-in kit 
X 
  
  
  
  
  
  
 
 
Randomization/ 
assign double-blind kit 
 
 
X 
 
 
 
 
 
 
 
 
Provide subject identification card  
X 
  
  
  
  
  
  
 
 
Dosing with single-blind patch 
(patch application and removal of 
previous patch, if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
Dosing with double-blind patch  
(patch application and removal of 
previous patch, if applicable) 
 
X  
X  
X  
X  
X  
X  
X 
 
Skin Irritation Assessment [m] 
X  
X  
X  
X  
X  
X  
X  
X 
 
Patch Adhesion Assessment [m]  
X   
X  
X  
X  
X  
X  
X  
X 
 
Patch Discomfort Assessment [m]  
X  
X  
X  
X  
X  
X  
X  
X 
 
Adhesive Residue Assessment [m]  
X  
X  
X  
X  
X  
X  
X  
X 
 
Drug accountability 
X  
X  
X  
X  
X  
X  
X  
X 
 
 
AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CDSS = Calgary Depression Scale for Schizophrenia; CGI-I = Clinical Global 
Impression - Improvement scale; CGI-S = Clinical Global Impression - Severity of Illness scale; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; 
ET = end of treatment; HBsAg = hepatitis B antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IWRS = Interactive Web-Based Response System; 
MINI = Mini International Neuropsychiatric Interview; MSQ = Medication Satisfaction Questionnaire; PANSS = Positive and Negative Syndrome Scale; PK = pharmacokinetics; 
SAS = Simpson Angus Scale; Wk = week 
 
a. The subject must use the single-blind placebo patch for a minimum of 3 days prior to entering the double-blind Treatment Period.  Washout of the subject’s current 
antipsychotic and other prohibited medications must be completed by the end of the Screening/Run-in Period.  Subjects who have a decrease in PANSS total score ≥20% from 
Screening to Baseline or a PANSS total score <80 at Screening or Baseline will be discontinued from the study. 
b. Subjects will have a follow-up contact (site visit or telephone call, at the discretion of the Investigator) 30 days after the last patch is removed. 
c. All baseline assessments and laboratory samples will be performed prior to randomization. 
d. It is suggested that assessment scales should be performed in the order they appear in the Schedule of Events 
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e. Blood pressures (sitting) and pulse rates should be measured after subject has rested (sitting quietly) for 5 minutes.  In addition, assessments for orthostatic hypotension will 
be performed at each visit.  Blood pressure readings and pulse rate will be obtained after the subject has been supine for 5 minutes.  These will be repeated after the subject 
has been standing up for approximately1 to 3 minutes. 
f. Height will be obtained at Screening, only. 
g. ECG recordings will be obtained after the subject has been supine and at rest for at least 5 minutes. 
h. Urine drug screen and alcohol breathalyzer test should be completed if the subject leaves the study site. 
i. All positive urine pregnancy test results must be confirmed by a serum test.  Subjects with positive urine and serum pregnancy test results at screening must not be enrolled.  
Subjects with positive urine and serum pregnancy test results during the trial must discontinue treatment.  Urine pregnancy test to be repeated if subject leaves the study site. 
j. Subjects with chronic Hepatitis B or C may be included provided that their condition is stable and that values for liver function tests and other laboratory tests results meet the 
criteria specified for entry into the study. 
k. At least 3 blood samples will be collected at 2, 14, and 22 hours after application of the patch with ± 2 hour- window on Day 21 and 42.  Actual blood sampling time will be 
recorded. 
l. The central laboratory will not report prolactin levels to the sites nor the Sponsor, because this could potentially result in unblinding the treatment.  The central laboratory will 
report prolactin levels as “masked” on the laboratory report (see Section 6.2.2.2.3 for more details).
 
m. Patch adhesion will be evaluated throughout the day including at the time points during which the site staff collects routine vital signs as per hospital policy/SOP; and 
immediately prior to removal of previous day’s patch. In addition, subjects will be asked to check patch adhesion throughout the day and report immediately to site personnel 
if the patch detaches completely or detaches partially (i.e., some edges of the patch are lifting off the skin). Irritation at the site of patch application will be assessed each day 
between 30 and 60 minutes after patch removal.  Subjects will be asked to report to the site staff any discomfort or skin irritation due to the patch.  Discomfort and skin 
irritation reported by the subjects will be recorded as AEs.  Patch application site will be assessed weekly for adhesive residue.  
 
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4.2 Discussion of Study Design 
This is a Phase 3, multi-center, placebo-controlled, randomized, double-blind, in-patient 
study designed to demonstrate the efficacy and safety of HP-3070 transdermal patches when 
used in subjects diagnosed with schizophrenia. 
A parallel-group design was selected because it is free of the assumptions underlying 
competing designs (for example, crossover).  A parallel group approach is considered the 
optimal study design to evaluate efficacy. 
The use of a randomized double-blind design will minimize bias by randomly assigning the 
subjects to treatment arms, and ensuring that the subjects, the Investigators and site 
personnel, and the Sponsor/designee are blinded to the treatment allocations. 
A placebo control will be used to allow for an unbiased assessment of treatment effects and 
safety data.  The comparison with placebo is justified as this is an in-patient study and 
subjects will be closely monitored and study treatment will be discontinued and the subject 
will be returned to standard of care (SOC) treatment if their mental status deteriorates. 
The study population will include male and female subjects, ≥18 years of age with a 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of 
schizophrenia who are in an acute exacerbation.  These subjects represent an appropriate 
population in which to evaluate the efficacy of the HP-3070 patch. 
The rationale for dose selection is described in Section 5.6. 
The 6-week duration is considered to be sufficient for achieving a steady state condition of 
HP-3070.  This time period is also sufficient to evaluate changes in the primary and 
secondary outcome measures. 
Subjects will be hospitalized throughout the study to ensure proper medical care, and to 
allow for the close monitoring of mental status and any potential negative effects of 
treatment. 
Severity of illness and psychopathology will be measured using the PANSS and CDSS.  
The CGI-S and the CGI-I will be used to confirm clinical relevance of changes in the 
efficacy assessment scales.  The efficacy measurements chosen for this study are standard 
validated instruments and these are commonly used to evaluate efficacy endpoints in subjects 
with schizophrenia who are in an acute exacerbation. 
The primary efficacy endpoint is change from baseline to Week 6 in Positive and Negative 
Syndrome Scale (PANSS) total score. The PANSS scale is a standard validated instrument 
that is a gold standard in acute schizophrenia studies and is an appropriate instrument to 
evaluate efficacy in patients diagnosed with schizophrenia who are in acute exacerbation.   
This instrument is the primary efficacy endpoint that has been used for pivotal trials for 
several products such as SAPHRIS
®, Latuda
®, and Vraylar
®.   
The key secondary endpoint is change from baseline to week 6 in the CGI-S score. 
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The Clinical Global Impression – Severity (CGI-S) scale is an accepted, standard efficacy 
rating scale in acute schizophrenia trials. CGI-S is an acceptable key secondary variable: (i) 
based on precedence (SAPHRIS® and other approved antipsychotics); (ii) CGI-S assesses a 
domain of the illness other than that assessed by the primary efficacy variable, therefore, 
there is no redundancy with the primary efficacy variable (PANSS total score). 
While the PANSS is the cornerstone for evaluation of efficacy of antipsychotic drugs in 
patients with schizophrenia who are in an acute exacerbation and is a useful clinical research 
tool, clinical implications of PANSS scores are not very well defined and the PANSS scores 
are not intuitively understood by clinicians; whereas, scores from the Clinical Global 
Impression (CGI) scale are better understood by clinicians and are better translated into 
clinical practice as they inform the clinician of the subject’s overall clinical status.  
The CGI-S is a valid and reliable clinician administered scale and has widespread use in 
psychiatry clinical trials. The CGI-S scale measures the clinician’s global impression of the 
severity of illness at each time point taking into account the reported and observed symptoms 
in the past 7 days.  In the HP-3070-GL-04 study, the CGI-S will be analyzed as change from 
baseline to Week 6. Inclusion of the CGI-S as key secondary endpoint in the HP-3070-GL-04 
will facilitate replication of SAPHRIS® data. 
The safety measures used in this study are standard safety measures which include AEs, 
concomitant therapy, clinical laboratory results, medical history, physical examination, vital 
signs, weight gain and ECGs.  In addition, the AIMS, BARS, and SAS will be used to assess 
EPS.  The C-SSRS will be used to assess suicidality.  The C-SSRS facilitates prospective, 
systematic monitoring for emergence of suicidality within clinical trials and it is a low-
burden, clinician-administered tool that covers the wide spectrum of suicidality from ideation 
to behavior.  Skin irritation and discomfort reported by the subjects will be recorded as AEs.  
Skin irritation and discomfort at the patch application site is an important assessment because 
the condition of the skin may influence the absorption of the drug from the transdermal 
patch. 
This study also includes assessment of patch adhesion and evaluation of amount of adhesive 
residue at the patch application site.  Adhesion of transdermal patch to the skin is a critical 
factor and one of the most important functional properties directly related to drug delivery 
and therapeutic effect.  Patch adhesion must be satisfactory in order for requirement for any 
clinical conclusions to be valid. 
4.3 Selection of Study Population 
The assessment and documentation of the subject’s eligibility is the responsibility of the 
Investigator.  The Sponsor/designee reserves the right to provide final approval of subject 
eligibility. 
4.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Adult male or female subjects, ≥18 years of age 
2. Subject is able to undergo informed consent process and signs ICF. 
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3. Subject has current diagnosis of schizophrenia as per DSM-5 Criteria, Mini 
International Neuropsychiatric Interview (MINI), and as confirmed by Investigator 
assessment. 
4. Subject has PANSS total score ≥80, AND score of 4 or more in at least 2 of the 
following PANSS items at Screening and at Baseline: 
a. Conceptual disorganization 
b. Delusions 
c. Hallucinatory behavior 
d. Unusual thought content 
5. Subject has CGI-S scale score of ≥4 (moderately ill) at Screening and Baseline. 
6. Subject has history of relapse and/or exacerbation of symptoms when they are not 
receiving antipsychotic treatment, excluding the current episode. 
7. Subject is confirmed by the Investigator to be experiencing an acute exacerbation of 
schizophrenia, as evidenced by ALL of the following: 
a. The duration of the current episode is no more than 8 weeks. 
b. The subject’s current symptoms represent a marked and substantial 
exacerbation of schizophrenia compared with the subject’s symptomatic state 
prior to the emergence of the current episode. 
c. A
 corresponding functional deterioration to the symptomatic exacerbation is 
evident. 
8. Subject has not been hospitalized for more than 21 days for the current episode by the 
day of the Screening Visit, not including social hospitalization (e.g., homelessness or 
need for shelter that is unrelated to the subject’s underlying psychiatric condition). 
9. Subject agrees not to begin formal, structured psychotherapy targeting the symptoms 
of schizophrenia from the time of the Screening Visit until the last dose of study drug. 
10. Subject would benefit from hospitalization or continued hospitalization for the 
treatment of schizophrenia (as determined by the Investigator). 
11. Subjects must not be treatment naïve or treatment resistant.  Treatment resistance is 
defined as having little or no symptomatic response to at least 2 courses of 
antipsychotic treatment of an adequate duration (at least 6 weeks) and at a therapeutic 
dose (according to the drug’s package insert). 
12. Subject has had previous positive response to an antipsychotic medication other than 
clozapine in a prior episode. 
13. Subject has a stable living situation and caretaker support when not hospitalized. 
14. Subject is male, or a female who is not of childbearing potential (i.e., surgically 
sterile, postmenopausal for at least 1 year) or who is non-pregnant, non-lactating, and 
is using a medically accepted method of contraception.  Acceptable methods of 
contraception include condoms (male or female) with a spermicidal agent, diaphragm 
or cervical cap with spermicide, medically prescribed intrauterine device (IUD), and 
hormonal contraceptives.  A
 female of child-bearing potential who is not currently 
sexually active must agree to use a medically accepted method of contraception 
should she become sexually active while participating in the study
.  Each sexually 
active female of child-bearing potential must also agree to use a medically accepted 
method of contraception for 1 month after the final dose of study medication. 
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15. Subjects must agree that they will not donate sperm or eggs from the time of the 
Screening Visit until 3 months following administration of the last treatment or dose 
of study medication. 
16. Agrees not to use any other transdermal patch products (e.g., nicotine replacement 
patch, hormonal replacement patch, etc.) for the duration of the study. 
17. Subject must be able to wear a transdermal patch for 24 hours. 
4.3.2 
Exclusion Criteria 
The subject will be excluded from the study if any of the following exclusion criteria are 
met: 
1. Subject is presenting with a first episode of schizophrenia based on the clinical 
judgment of the Investigator. 
2. Subject has been diagnosed with schizophrenia less than 6 months prior to Screening 
Visit. 
3. Subject has received electroconvulsive therapy (ECT), transcranial magnetic 
stimulation (TMS), vagal nerve stimulation (VNS), or other brain stimulation 
treatments within 90 days of Screening Visit. 
4. Subject has a current DSM-5 diagnosis other than schizophrenia including (but not 
limited to) schizoaffective disorder, major depressive disorder, bipolar disorder, post-
traumatic stress disorder, anxiety disorders, delirium, dementia, amnestic, or other 
cognitive disorders. 
5. Subject has a diagnosis of mental retardation, history of traumatic brain injury 
causing ongoing cognitive difficulties, Alzheimer’s Disease or another form of 
dementia (or suspicion thereof), or any chronic organic disease of the central nervous 
system that would interfere with the efficacy or safety endpoints of the study
. 
6. Subject has experienced acute depressive symptoms within 30 days prior to Screening 
Visit that requires treatment with an antidepressant, as determined by the Investigator. 
7. Subject is a known non-responder to previous asenapine treatment, as per Investigator 
judgment. 
8. Subject is currently taking clozapine for the treatment of schizophrenia.  Subjects 
taking low doses of clozapine (up to 100 mg/day) for sedative properties and not 
treatment resistance or suicidality may be acceptable as per Investigator judgment and 
as approved by the Sponsor/designee. 
9. Subject with schizophrenia who is considered resistant/refractory to antipsychotic 
treatment by history or who has a history of failure to respond to clozapine or 
response to clozapine treatment only.  Treatment resistance is defined as having little 
or no symptomatic response to at least 2 courses of antipsychotic treatment of an 
adequate duration (at least 6 weeks) and at a therapeutic dose (according to the drug’s 
package insert). 
10. Subject who is unwilling to discontinue or, in the opinion of the Investigator, unable 
to discontinue any prohibited medication prior to the Baseline Visit without 
significant medical or psychiatric destabilization, or increased suicidality
, as per the 
washout requirements.  Prohibited medications include: 
a. Antipsychotics, including depot or long-acting injectables 
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b. Antidepressants 
c. Mood stabilizers 
d. Stimulants 
e. Non-psychopharmacologic medications with psychotropic properties, per 
Investigator and approved by Sponsor/designee 
f. Herbal drugs/dietary supplements unless approved by Sponsor/designee 
11. Subjects taking drugs (current antipsychotic or other prohibited medication) that 
require >14 days for washout 
12. Subject who is involuntarily committed, incarcerated, or under legal compulsion to 
seek psychiatric treatment. 
13. Subject currently has clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary
, or gastrointestinal 
disorders such as any history of myocardial infarction, congestive heart failure, 
human immunodeficiency virus (HIV) seropositive status/acquired immunodeficiency 
syndrome (AIDS).  Medical conditions that are minor or well-controlled may be 
considered acceptable if the condition does not expose the subject to an undue risk of 
a significant AE or interfere with assessments of safety or efficacy during the course 
of the study
.  Subjects with chronic Hepatitis B or C may be included provided that 
their condition is stable and values for liver function tests and other laboratory test 
results meet the criteria specified in the protocol for entry into the study.  The 
Sponsor/designee should be contacted in any instance where the Investigator is 
uncertain regarding the stability of a subject’s medical condition(s) and the potential 
impact of the condition(s) on study participation. 
14. Subject has any other medical condition or laboratory result that, in the opinion of the 
Investigator, may make the subject unsuitable for the study
. 
15. Subjects with the following laboratory test and ECG results are excluded: 
a. Platelets ≤75,000/mm3  
b. Hemoglobin ≤9 g/dL  
c. Neutrophils, absolute ≤1000/mm3  
d. Aspartate transaminase (AST) >2×upper limit of normal (ULN) 
e. Alanine transaminase (ALT) >2×ULN 
f. Creatine phosphokinase (CPK) >3×ULN, unless discussed with and approved 
by the Medical Advisor 
g. Creatinine ≥2 mg/dL or ≥176.8 µmol/L 
h. Hemoglobin A1c (HbA1c) ≥6.5% unless the subject has a diagnosis of stable 
diabetes 
i. QT interval corrected using Fridericia’s formula (QTcF) ≥450 msec (males), 
QTcF ≥470 msec (females) 
j. Prolactin.  The enrollment of subjects with prolactin levels equal or higher 
than 5 X ULN should be discussed with the Medical Advisor 
16. Subject with hypothyroidism or hyperthyroidism (unless condition has been stabilized 
with medications for at least the past 90 days); subjects with abnormal free T4 and 
thyroid stimulating hormone (TSH) levels. 
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17. Subject is currently treated with insulin for diabetes.  Subjects being treated for 
diabetes with medications other than insulin are eligible for the study if their 
condition is stable as determined by satisfying ALL of the following criteria: 
a. HbA1c <7.0%, AND 
b. Screening glucose ≤125 mg/dL or ≤6.94 mmol/L (fasting) or <200 mg/dL or 
<11.1 mmol/L (nonfasting).  Note:  If the nonfasting screening glucose is 
≥200 mg/dL or ≥11.1 mmol/L, subjects must be retested in a fasted state and 
the retest value must be ≤125 mg/dL or ≤6.94 mmol/L, AND 
c. Subject has been maintained on a stable regimen of oral anti-diabetic 
medication(s) for at least 28 days prior to Screening or diabetes has been well-
controlled by diet for at least 28 days prior to Screening, AND 
d. Subject has not had any hospitalizations within the 12 months prior to 
Screening due to diabetes or complications related to diabetes, AND 
e. Subject’s diabetes is not newly diagnosed during Screening 
18. Subject has epilepsy or history of seizures, with the exception of a single seizure 
episode (e.g., childhood febrile, post traumatic). 
19. Subject has uncontrolled hypertension (diastolic blood pressure [DBP] >95 mmHg in 
any position) or symptomatic hypotension, or orthostatic hypotension which is 
defined as a decrease of ≥30 mmHg in systolic blood pressure (SBP) and/or a 
decrease of ≥20 mmHg in DBP after at least 3 minutes standing compared with the 
previous supine blood pressure, OR development of symptoms.  Note:  Blood 
pressure measurements may be repeated once to ensure reproducibility of the 
exclusionary result(s) before excluding a subject based on the criteria noted above. 
20. Subject has a history of neuroleptic malignant syndrome. 
21. Subject has a score of >2 (mild) on any item of the AIMS at Screening. 
22. Subject has a score of 5 (severe akathisia) on BARS global clinical assessment of 
akathisia at Screening. 
23. Subject has a history of pituitary adenoma or cancer <5 years prior to Screening.  
Subjects currently being treated for cancer may not be enrolled in the study. 
24. Female subject who is breastfeeding. 
25. Female subject with a positive urine pregnancy test that is confirmed positive by 
serum pregnancy test at Screening or Baseline. 
26. Subject who currently (within the past 6 months) meets the DSM-5 criteria for 
substance use disorders (excluding nicotine and caffeine). 
27. Subject has positive urine drug/alcohol screen at the Screening Visit.  Positive results 
that are due to short-term prescription medications that can be safely discontinued 
(e.g., opioids for acute pain that has resolved) may continue at the discretion of the 
Investigator with the agreement of the Sponsor/designee.  Subjects with positive 
cannabis results may be included, provided the Investigator does not feel the subject 
is a compliance risk and the subject does not fulfill the criteria for substance abuse or 
dependence as stated in Exclusion Criterion 26 above, the subject agrees to abstain 
for the duration of the study
, and with the concurrence with the Sponsor/designee. 
28. Subject is at imminent risk of self-harm or harm to others, in the Investigator’s 
opinion based on clinical interview and responses provided on the C-SSRS.  Note that 
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subjects will be excluded if they report suicidal ideation meeting the description of 
C-SSRS Type 4 or 5 (i.e., suicidal ideation with intent, with or without a plan) in the 
past 6 months or suicidal behavior (as described by the C-SSRS) in the past 
12 months at Screening.  Subjects will also be excluded at Baseline if they report 
suicidal ideation of Type 4 or 5 or suicidal behavior, as measured by the C-SSRS 
between Screening and Baseline. 
29. Subject has a known allergy or hypersensitivity to asenapine. 
30. Subject has current or history of allergy or hypersensitivity to adhesive dressings. 
31. Subject has history of allergy to more than 2 distinct chemical classes of drug (e.g., 
sulfas and penicillins). 
32. Subject has any skin abnormality present at the potential patch application site that is 
likely to be aggravated by the study drug (i.e., infection, rash, excessive fragility or 
dryness, any cut or abrasion), presence of tattoo, excessive hair or open sores, or scar 
tissue.  Presence of significant skin disorder such as atrophy
, psoriasis, or vitiligo. 
33. Subject has participated in a previous HP-3070 study
. 
34. Subject has participated in any other investigational trial or used investigational drugs 
within 30 days prior to the Screening Visit or has participated in more than 2 studies 
in the past 12 months. 
35. Any subject who, in the opinion of the Investigator or Medical Advisor, should not 
participate in the study
. 
36. Subject is a Study Investigator, sub-Investigator, study coordinator, employees of a 
participating Investigator, or immediate family member of the aforementioned. 
4.3.3 
Subject Withdrawal 
All subjects are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice to further treatment.  The criteria for 
enrollment are to be followed explicitly.  If a subject who does not meet enrollment criteria is 
inadvertently enrolled, that subject should be withdrawn from the study and the Sponsor or 
Quintiles must be contacted.  An exception may be granted in rare circumstances where there 
is a compelling reason to allow the subject to continue.  In these rare cases, the Investigator 
must obtain documented approval from the Sponsor/designee to allow the subject to continue 
in the study. 
In addition, subjects will be withdrawn from study drug and from the study in the following 
circumstances: 
 The Investigator decides that the subject should be withdrawn.  Subjects may be 
withdrawn if continuing in the study is not in the subject’s best interest, their condition 
worsens during the study or for safety reasons, as determined by the Investigator. 
o If this decision is made because of an AE or a clinically significant laboratory value, 
the study drug is to be discontinued and appropriate measures are to be taken.  The 
Sponsor/designee is to be notified immediately. 
 The subject is unwilling to continue in the study. 
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 Subject requires treatment with a prohibited concomitant medication 
 The subject becomes pregnant.  All pregnancies must be followed to conclusion to 
determine their outcome.  
 The subject has one of the following elevated liver enzyme conditions, confirmed by 
repeat testing: 
o ALT or AST >3×ULN and total bilirubin >2×ULN 
o ALT or AST >8×ULN 
o ALT or AST >5×ULN for more than 2 weeks 
o ALT or AST >3×ULN with the appearance of jaundice, worsening of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia 
 The subject has an absolute neutrophil count of <1000 per mm3, and after repeat testing 
in the subsequent 48 hours, the values fail to normalize. 
 Lack of compliance with protocol. 
 The Investigator or the Sponsor, for any reason, stops the study. 
Subjects who discontinue the study early will have ET procedures performed as shown in the 
Schedule of Events (see Table 1).  Randomized subjects who discontinue the study early will 
be considered dropouts.  Subjects who withdraw from the study may remain hospitalized as 
needed for safety while they transition to SOC treatment and into the care of their personal 
physician. 
A follow-up phone call will be made to the subject 30 days (±2 days) after the ET visit. 
Subjects who are withdrawn from the study will not be replaced. 
In all cases, the reason for withdrawal must be recorded.  If the reason for subject withdrawal 
is not known, considerable efforts must be made to establish whether the reason for 
withdrawal was an AE.  Subjects, for whom the study drug is discontinued, will be 
encouraged to continue to complete all the scheduled procedures. 
5.0 STUDY TREATMENTS 
5.1 Treatments Administered 
Subjects will receive treatment with HP-3070 (asenapine maleate, transdermal patch) 9.0 mg 
or 18.0 mg or placebo.  Information concerning the application and removal of the patches is 
available in Section 5.7. 
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5.2 Identity of Investigational Product 
HP-3070 contains asenapine maleate (trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-
dibenz[2,3:6,7] oxepino[4,5-c]pyrrolidine maleate) as a white crystalline powder.  It is 
supplied as a dermal patch consisting of a plastic film, adhesive matrix and backing film. 
The investigational product and placebo comparator used in this study are described in 
Table 2. 
Table 2  
Investigational Products 
Investigational 
Product 
Dosage Form and Strength  
Dosage Form 
Shape/Size 
HP-3070-9.0  
One patch contains 9.0 mg 
asenapine maleate (0.45 mg 
of asenapine maleate per 
1.0 cm2) 
Transdermal patch  
square with an area of 
20 cm2 
HP-3070-9.0 Placebo  
One patch contains 0 mg 
asenapine maleate 
Transdermal patch  
square with an area of 
20 cm2 
 
5.3 Packaging, Labelling and Storage 
Each patch is packed in an aluminum foil sachet with light shading capacity.  The sachet is 
air tight, and sealed by a heat sealer.  The appropriate number and sizes of sachets are 
provided in a box. 
The study drug will be labeled in accordance with all regulatory requirements.  The 
Investigator/designee will complete the blank spaces on the label for the subject number, site 
number, and date dispensed. 
The Sponsor will be responsible for ensuring that the quality of the study drug is adequate for 
the duration of the trial.  Study drug is to be stored at room temperature in a secure area 
according to local regulations.  The study drug must be dispensed only from official study 
sites by authorized personnel according to local regulations. 
All study drug supplies that will be used in the study must be maintained securely under the 
direct responsibility of the Investigator or delegated by the Investigator to the hospital 
pharmacist, or other personnel licensed to store and dispense drugs.  All drugs shall be 
dispensed in accordance with the Investigator’s prescription, and it is the Investigator’s 
responsibility to ensure that an accurate record of drugs issued and returned is maintained.  
Under no circumstances will the Investigator allow the study drug to be used other than as 
directed by the protocol.  Storage conditions should be monitored by the site personnel for 
adherence to label specifications. 
5.4 Study Drug Accountability 
The Investigator, a member of the investigational staff, or a hospital pharmacist must 
maintain an adequate record of the receipt and distribution of all study medication using a 
drug accountability form.  These forms must be available for inspection at any time. 
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Used, partially used, the aluminum foil sachet of used and partially used patches, and unused 
study drug products should be retained until the Clinical Research Associate (CRA) has been 
able to complete drug accountability and reconciliation. 
All study medication supplies should be accounted for at the termination of the study and a 
written explanation provided for discrepancies.  All used, partially used, and unused study 
medication supplies and packaging materials are to be inventoried and returned to 
Sponsor/designee by the Investigator.  The Investigator is not permitted to return or destroy 
used, partially used, or unused clinical drug supplies or packaging materials unless 
authorized by the Sponsor/designee. 
5.5 Method of Assigning Subjects to Treatment 
Subjects will be randomly assigned to treatment using a 1:1:1 ratio to 1 of 3 treatment arms 
(HP-3070-9.0, HP-3070-18.0, or placebo) stratified by country. 
Once the subject meets all the eligibility criteria for randomization in the double-blind 
Treatment Period, the study center will request the study medication assignment using the 
Interactive Voice Activated Response System (IVRS) or Interactive Web-based Response 
System (IWRS).  All randomized subjects will be managed by IVRS/IWRS.  Detailed 
information will be provided in the Study Manual. 
5.6 Selection of Doses in the Study 
The results of placebo-controlled clinical trials of SL asenapine have demonstrated a similar 
efficacy of the 5.0 mg and 10.0 mg twice daily (BID) doses in reducing the total PANSS 
score.  The exposure response relationship of the effect of asenapine on the time course of 
PANSS total score using data from the Phase 2 and Phase 3 studies of SL asenapine has been 
characterized and published.
4  Based on this analysis, asenapine effect was best described by 
an inhibitory E
max model and the area under the concentration time curve (AUC) was a better 
predictor of response than dose. 
The rationale supporting the selection of the 2 doses (9.0 mg and 18.0 mg) to be studied in 
Study HP-3070-GL-04 is based on (a) the comparison of exposure (AUC
0-24) between 
approved doses of SAPHRIS
® and selected doses for HP-3070 in the target population and 
(b) safety assessment for HP-3070. 
In Study HP-3070-US-02b, the steady-state PK of HP-3070 transdermal patch at the doses of 
4.5 mg, 9.0 mg, 13.5 mg and 18.0 mg were evaluated in a multiple ascending-dose study in 
patients diagnosed with schizophrenia.  As shown in Table 3, the doses selected to be 
investigated in this study are expected to provide an exposure which is within the range of 
exposure provided by the approved doses of SAPHRIS
®.  The mean AUC
0-24 following the 
9.0  mg of once daily HP-3070 patch is similar to the mean AUC0-24 obtained by the 
administration of SAPHRIS
® 5.0 mg BID while mean exposure following 18.0 mg of once 
daily HP-3070 patch is similar to that following the administration of SAPHRIS® 
10.0 mg BID.
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Table 3  
Steady-State Pharmacokinetics of HP-3070 Transdermal Patch  
Formulation  
Dose  
Population 
Mean Body 
Weight (kg) 
Mean Cmax 
ng/mL (%CV) 
Mean AUC0-24 
ng.h/mL (%CV) 
Data source 
HP-3070 
4.5 mg 
(n=22) 
Schizophrenia patient 
(Mostly Caucasian) 
86.6  
1.14 (30%)  
22.3 (28%) 
HP-3070-US-02b 
9.0 mg 
(n=21) 
Schizophrenia patient 
(Mostly Caucasian) 
87.0  
2.26 (24%)  
45.8 (25%) 
13.5 mg 
(n=20) 
Schizophrenia patient 
(Mostly Caucasian) 
87.0  
3.40 (19%)  
69.3 (20%) 
18.0 mg 
(n=20) 
Schizophrenia patient 
(Mostly Caucasian) 
87.0  
4.68 (17%)  
96.2 (19%) 
SAPHRIS® 
5.0 mg BID 
(n=28) 
Schizophrenia patient 
(Caucasian, Black, Other) 82.1  
4.23 (45%)  
53.0 (38%) 
NDA 22-117 (Study 
A7501001)5  
10.0 mg BID 
(n=25) 
Schizophrenia patient 
(Caucasian, Black, Other) 82.1  
6.56 (51%)  
86.8 (53%) 
AUC = area under the plasma concentration time curve; BID = twice daily; Cmax = maximum plasma concentration. 
Note:  AUC0-24 is indicated as arithmetic mean (%CV). 
For SAPHRIS®, mean AUC
0-24 was calculated as double of mean AUC
0-12 
 
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Study HP-3070-US-02b also demonstrated that daily application of HP-3070 transdermal 
patches for 7 days at doses of 4.5 to 18.0 mg was safe and well tolerated.  After dosing with 
HP-3070, there were no clinically significant findings with respect to vital signs, 24-hour 
cardiac Holter, 12-lead ECG, clinical laboratory, or C-SSRS assessments. 
Based on safety assessments and comparison of exposure between approved doses of 
SAPHRIS® and 9.0 mg and 18.0 mg of HP-3070, patches are considered to be appropriate 
doses to be studied in this trial. 
5.7 Dosing of Subjects 
During the single-blind Run-in Period, site personnel will apply 2 placebo patches to subjects 
once daily.  The subject must use the single-blind placebo patch for a minimum of 3 days 
prior to being randomized into the double-blind Treatment Period.  Subjects will be blinded 
regarding the placebo status of the patches. 
During the double-blind Treatment Period (Day 1 through Day 42) site personnel will apply 
2 patches to subjects per the randomization code.  The treatment received by each subject 
will be: 
 HP-3070 9.0-mg treatment arm:  one (1) 9.0-mg 20 cm2 patch and one (1) placebo patch 
(0-mg, 20 cm
2), once daily; 
 HP-3070 18.0-mg treatment arm:  two (2) 9.0-mg 20 cm2 patches, once daily; and 
 Placebo treatment arm:  two (2) placebo patches (0 mg, 20 cm2) once daily. 
Patch Application and Removal 
There are no special requirements related to food and beverage or other medications in regard 
to the timing of patch application. 
The application area should be clean, dry, non-oily, non-hairy, and not irritated.  Patches will 
be applied by site personnel at approximately the same time every day and each patch will be 
worn for 24 hours.  Every day, approximately 24 hours after patch application, site personnel 
will remove previous day’s patches and apply 2 new patches. 
Both patches will be applied in close proximity without overlapping to 1 of the following 
application sites:  abdomen, hip, upper arm, upper back, and upper chest.  Patch application 
site will be rotated daily. 
In the event that a patch should detach completely, the time, activity and reason at the time of 
patch detachment must be documented.  Under no circumstances should the detached 
patch/patches be reapplied to the subject.  Under no circumstances should the detached patch 
be reinforced with tape. 
If both patches are detached completely then 2 new patches from the subject’s kit should be 
applied immediately, provided that there are at least 6 hours of time remaining before the 
next dose.  If only one patch detaches completely, then the other patch should also be 
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removed and 2 new patches from the subject’s kit should be applied immediately, provided 
that there are at least 6 hours of time remaining before the next dose. 
Regardless of the time when the new patches are applied, patch removal time of the new 
patches will be approximately 24 hours after the application of the original patches.  In other 
words, removal time of the new patches may not exceed 24 hours from the time the first 
patches were applied. 
The time of patch application, removal, and detachment will be recorded.  If a patch is 
removed prior to the scheduled removal time, the time and reason for early patch removal 
will be recorded.  
Detailed information regarding patch application and removal will be provided in the Study 
Manual. 
5.8 Treatment Interruptions or Modifications 
Dose modifications are not permitted.  If the patient misses a dose or receives an extra dose 
for any reason, this should be recorded and discussed with the Medical Advisor. 
5.9 Blinding 
This is a randomized, double-blind, placebo-controlled study with limited access to the 
randomization code.  The HP-3070 patches and placebo patches will be identical in physical 
appearance; subjects treated with active drug and placebo will receive the same number of 
patches. 
The treatment each subject will receive will not be disclosed to the Investigator, study center 
staff, subject, or Sponsor/designee.  The treatment codes will be held by the IVRS/IWRS 
vendor. 
The process for breaking the blind will be handled through the IVRS/IWRS. 
Investigators are strongly discouraged from requesting that the blind be broken for an 
individual subject, unless there is an emergency and the Investigator determines that 
unblinding and identification of the study drug is necessary for the purpose of providing 
urgent patient care and knowledge of the subject’s treatment assignment will alter subsequent 
care.  The reason for unblinding should be discussed with the Medical Advisor prior to 
unblinding, if possible.  If the subject’s condition requires unblinding prior to contact with 
the Medical Advisor or if the subject and/or Investigator are inadvertently unblinded during 
the course of the study, then the Medical Advisor should be contacted within 24 hours after 
the unblinding. 
Pertinent information regarding the circumstances of unblinding a subject’s treatment code 
must be documented. 
5.10 Prior and Concomitant Treatments 
Medications taken from 6 months prior to the Screening visit through the End of Study 
(including the 30 day Follow-up Period) must be recorded.  The Investigator should instruct 
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the subject to notify the site about any new medication he or she takes after the start of the 
study. 
5.10.1 
Medications Prohibited during the Study 
Prohibited/restricted medications and washout periods for specific drugs are presented in 
Table 4. 
Table 4 
Prohibited/Restricted Medications and Washout Prior to Baseline 
Prohibited/Restricted Medication  
Washout/Other Conditions  
Antipsychotics, oral or immediate release IM 
Antipsychotics, depot or long acting injectable  
Washout:  3 days, 7 days for aripiprazole 
One full cycle plus ½ cycle as per prescribing labela 
Antidepressants 
Fluoxetine 
Monoamine oxidase inhibitors 
All other antidepressants 
Washout: 
28 Days 
14 days 
7 days 
Prohibited during the study 
Mood stabilizers 
Lithium 
Anticonvulsants 
Washout: 
3 days 
3 days 
Prohibited during the study 
Varenicline 
Washout:  5 days 
Prohibited during the study 
Benzodiazepines other than the ones used as per 
protocol specifications 
Washout:  3 days 
Prohibited during the study 
Ramelteon or Tasimelteon 
Prohibited during the study starting at Screening Visit 
Antihistamines  
Diphenhydramine and hydroxyzine prohibited during 
the study.  Only non-sedating antihistamines are 
allowed for the treatment of allergy during the study 
Narcotic Analgesics 
Subject must have a negative urine drug screen prior to 
Baseline.  Prohibited during the study starting at 
Screening Visit.  Exception:  during study, these drugs 
may be allowed for acute pain conditions (e.g., tooth 
extraction) for a maximum of 3 days. 
Vitamins, non-prescription herbal preparations, 
other supplementsb 
Washout:  7 days, 
(14 days for St. John’s Wort) 
Prohibited during the study 
Antiemetic drugs containing dopamine antagonists  
Prohibited during the study starting at Screening Visit 
Stimulants 
Prohibited during the study starting at Screening Visit 
Other medications with psychotropic properties  
Prohibited during the study, starting at the Screening 
Visit 
Note:  Subjects taking drugs that require a washout-out period >14 days are not eligible for the study. 
Note:  The Investigator should contact the Medical Advisor with any concerns about the acceptability of any medication. 
a. Concerns about label interpretation should be discussed with Medical Advisor. 
b. Supplements for general health and other non-psychiatric purposes, such as daily vitamins may be allowed with the 
approval of the Medical Advisor.  Supplements for established medical conditions, such as iron for iron deficiency 
anemia, are not exclusionary. 
 
5.10.2 
Permitted Medications 
Medications used for chronic non-psychiatric medical conditions (e.g., antihypertensives, 
oral hypoglycemic, etc.) are allowed if the condition and treatment regimen are stable before 
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Screening.  Initiation or adjustments of therapies for non-psychiatric concurrent conditions 
will be left to the Investigator’s discretion.  If necessary, the Medical Advisor may be 
contacted. 
Psychotropic medication, other than the study medication, may be initiated during the study.  
Conditions for the use of psychotropic concomitant medications are presented in  Table 5. 
 Table 5  
Medications Permitted for Specific Conditions 
Medication 
Use 
Lorazepam 
Oral medication allowed as needed (prn use only) for the treatment of insomnia, 
agitation, and or anxiety only.  Maximum 6 mg/day during Screening and for the 
first 2 weeks of treatment, 4 mg/day during weeks 3 to 4 of treatment, and 2 
mg/day for the remainder of the study.  If lorazepam is not available in certain 
regions, another locally available benzodiazepine at equivalent doses may be 
approved by the Medical Advisor.
a,b,c 
Benztropine 
Allowed for the use of treatment-emergent EPS, up to 4 mg/day or equivalent 
anticholinergic dose if benztropine is not available in certain countries.
b 
The EPS scales are to be administered before medication is given (except in case of 
dystonia), to ensure documentation of the decision to administer the treatment. 
Not permitted within 12 hours of EPS scale administration. 
Zolpidem 
Allowed on an as needed basis (prn use only) for the treatment of insomnia as per 
prescribing label. If zolpidem is not available in specific regions, another hypnotic 
may be approved by the Medical Advisor.b,c 
Not permitted within 12 hours of EPS scale administration. 
Propranolol 
Not permitted within 12 hours of EPS scale administration. 
Allowed up to 60 mg/day in 20-mg doses for the treatment of akathisia.b 
a. If a subject requires greater than then maximum allowances, then the Investigator must discuss the suitability of the 
subject to continue with the  Medical Advisor 
b. Not to be given within 12 hours prior to efficacy or safety assessments 
c. Recommend reduced dosages for subjects older than 65 years of age 
 
5.10.3 
Concomitant Medication Cautions 
Investigator’s clinical judgment will be used in the following situations (the Medical Advisor 
for the study may be contacted if necessary): 
 Caution should be used with co-administration with agents/conditions that induce 
CYP1A2 (e.g., smoking, rifampin) or inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin, 
ketoconazole); 
 Paroxetine (CYP2D6 substrate and inhibitor) dose should be reduced by half when used 
in combination with HP-3070; 
 Potential additive effect on QT-interval prolongation; avoid concomitant use of other 
drugs known to prolong QTc intervals including Class 1A antiarrhythmics (e.g., 
quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), 
antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and 
antibiotics (e.g., gatifloxacin, moxifloxacin); and 
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 May enhance hypotensive effects of certain antihypertensive agents and other drugs that 
can cause hypotension or bradycardia.  Use concomitantly with caution; consider 
monitoring orthostatic vital signs in such subjects. 
5.10.4 
Other Restrictions 
Other restrictions are summarized in Table 6. 
Table 6  
Other Restrictions 
Restriction 
Timeframe 
ECT, TMS, VNS, or other brain stimulation 
treatment 
90 days prior to Screening and for the duration of 
study participation 
Formal, structured psychotherapy targeting the 
symptoms of schizophrenia 
For duration of study participation 
Transdermal medical patches other than study drug  For the duration of study participation. 
ECT = electroconvulsive therapy; TMS = transcranial magnetic stimulation; VNS = vagal nerve stimulation 
 
Note:  If a subject is a smoker and the hospital does not allow smoking, they may use 
nicotine replacement options, but the use of a nicotine transdermal patch is not permitted. 
5.11 Medical Care of Subjects after End of Study 
After the end of the study, subjects may remain hospitalized as needed for safety while they 
transition to standard of care (SOC) treatment and into the care of their personal physician. 
5.12 Treatment Compliance 
To ensure treatment compliance, patches will be applied and removed by designated 
qualified staff.  The exact times of patch application and removal will be recorded.  In 
addition, patch adhesion will be assessed throughout the day (during routine check of vital 
signs as per hospital policy/SOP and before removal of previous day’s patch).  
Noncompliance is defined as using less than 80% or more than 120% of study medication 
during any evaluation period (visit to visit).  If the subject is noncompliant, the Medical 
Advisor should be contacted to discuss the subject’s eligibility to continue in the study. 
6.0 EFFICACY, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS 
6.1 Efficacy 
The raters administering the efficacy assessments must be qualified and experienced.  All 
assessment scales should be performed in the order they appear in the Schedule of Events 
(Table 1).  Raters will be trained to administer these scales.  Raters must be certified to 
administer the PANSS.  Qualified personnel, who are approved by the Sponsor/designee to 
administer the efficacy assessments, will be participating in initial and ongoing training 
sessions.  Details of the training will be provided in the Rater Qualification Methodology.  
The number of raters within each study site should be kept to a minimum.  All efforts will be 
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made to ensure that the same clinician administers the scales for a given subject.  Notations 
in the subject’s trial records should substantiate the ratings. 
6.1.1 
M.I.N.I. International Neuropsychiatric Interview (MINI) 
The MINI. International Neuropsychiatric Interview (MINI 6.0) for Schizophrenia and 
Psychotic Disorders is a short, structured, diagnostic interview developed by psychiatrists 
and clinicians in the United States and Europe for DSM-IV and ICD-10 diagnoses of 
schizophrenia and other psychotic disorders.
6  The MINI is the most widely used psychiatric 
structured diagnostic interview instrument in the world, employed by mental health 
professionals and health organizations in more than 100 countries. The questions on the 
MINI are designed to be answered generally with just “Yes” or “No.”  The MINI has been 
shown to be valid, reliable, and more time-efficient than other, lengthier diagnostic 
interviews. 
6.1.2 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS7 consists of 3 subscales containing a total of 30 items.  For each item, severity is 
rated on an anchored 7-point scale, with a score of 1 indicating the absence of symptoms and 
a score of 7 indicating extremely severe symptoms.  The items for each subscale are as 
follows: 
1)  Positive Subscale (7 positive items:  delusions, conceptual disorganization, 
hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and 
hostility), 
2)  Negative Subscale (7 negative items:  blunted affect, emotional withdrawal, poor 
rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of 
spontaneity and flow of conversation, stereotyped thinking), and 
3)  General Psychopathology Subscale (16 items:  somatic concern, anxiety, guilt feelings, 
tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, 
unusual thought content, disorientation, poor attention, lack of judgment and insight, 
disturbance of volition, poor impulse control, preoccupation, and active social 
avoidance). 
A copy of the PANSS is provided in Appendix 2 (Section 12.0). 
6.1.3 
Secondary Efficacy 
6.1.3.1 Clinical Global Impression - Severity of Illness Scale (CGI-S) 
The severity of illness for each subject will be rated using the CGI-S.
8  To perform this 
assessment, the rater or Investigator will answer the following question:  “Considering your 
total clinical experience with this particular population, how mentally ill is the subject at this 
time?”  Response choices include:  0 = not assessed; 1 = normal, not at all ill, 2 = borderline 
mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 
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7 = among the most extremely ill subjects.  A sample of the CGI-S is provided in Appendix 3 
(Section 13.0). 
6.1.3.2 Clinical Global Impression - Improvement Scale (CGI-I) 
The efficacy of trial medication will be rated for each subject using the CGI-I.
7  The rater or 
Investigator will rate the subject’s total improvement whether or not it is due entirely to drug 
treatment.  All responses will be compared with the subject’s condition at Baseline prior to 
the first dose of double-blind study drug.  Response choices include:  0 = not assessed, 
1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 
5 = minimally worse, 6 = much worse, and 7 = very much worse.  A sample of the CGI-I is 
provided in Appendix 4 (Section 14.0). 
6.1.3.3 Calgary Depression Scale for Schizophrenia (CDSS) 
The CDSS is a nine-item scale designed for assessment of the level of depression in patients 
with schizophrenia.9  Each of the 9 items is rated on a 4-point scale, scored from 0 to 3.  
The first 8 items are rated on the basis of responses during a semi-structured interview 
conducted by a qualified clinician.  The ninth item (Observed Depression) is rated by 
evaluating signs and symptoms over the course of the interview.  The total score is derived 
by adding each of the 9 items together.  Totals scores of 6 or more identifies the presence of 
treatment-emergent depression predictive of major depressive episodes.  A sample is 
included in Appendix 5 (Section 15.0). 
6.1.3.4 Medication Satisfaction Questionnaire (MSQ) 
The Medication Satisfaction Questionnaire (MSQ) includes one simple question to ask 
patients about their satisfaction with their medication.  Vernon et al. evaluated the 
psychometric properties in psychotic populations of the MSQ and found that responses to 
this one question were able to separate patients receiving active drug from those receiving 
placebo and was a good proxy for efficacy.10  As such, it was determined that a 1-point 
change on the MSQ may be considered clinically meaningful.  A sample is provided in 
Appendix 6 (Section 16.0). 
6.2 Safety 
Safety variables included in this study are:  AEs, physical examinations, vital signs, body 
weight, clinical laboratory tests (including prolactin levels, fasting glucose, and lipids), 
ECGs, C-SSRS, evaluations of EPS (BARS, AIMS, and SAS), and dermal adverse events. 
6.2.1 
Adverse Events and Serious Adverse Events 
6.2.1.1 Adverse Events 
An AE is any untoward medical occurrence in a subject given study drug.  The event does 
not necessarily have to have a causal relationship with this treatment.  The recording of AEs 
will begin when the subject signs the ICF and will continue up to the 30 day follow-up 
period.  AEs that are ongoing at discharge will be followed until resolution or for 30 days 
after the last dose of study drug, whichever comes first. 
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An AE can be: 
 Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
 Any new disease or exacerbation of an existing disease. 
 Any deterioration in non-protocol-required measurements of laboratory values or other 
clinical tests (e.g., ECG or X-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug. 
 Recurrence of an intermittent medical condition (e.g., headache) not present at Baseline. 
For the purpose of this study, in addition to the AE definitions described above the following 
definitions will also be used. 
 Treatment-emergent depression defined a priori as a CDSS score ≥6. 
 Abnormalities in physical examination findings that require clinical intervention or 
further investigation (beyond ordering a repeat [confirmatory] test) 
 Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with a clinical 
event that has already been reported. 
 Worsening in the subject’s symptoms of schizophrenia or new symptoms will be 
considered AEs. 
 Symptoms of other psychiatric disorders will be considered AEs if they are new (not part 
of the subject’s medical history) or if their severity and/or frequency are greater than 
those noted in the subject’s medical history. 
 Overdose:  An overdose is defined as the ingestion of study drug beyond the dosing 
regimen defined in the study protocol and/or an overdose of any other product.  An 
overdose, and any symptoms resulting from the overdose, are considered AEs and should 
be recorded.  An overdose will be considered an SAE if it meets the definition of an SAE 
described in Section 6.2.1.2. 
 Spontaneous complaints of dermal reactions (skin irritation, discomfort) will be recorded 
as AEs (see Section 6.2.6 for details).  Spontaneous reports might include but are not 
limited to the following: initial dermal response and exacerbation of an existing response. 
6.2.1.2 Serious Adverse Events 
Definition of SAE:  An SAE, experience or reaction, is any untoward medical occurrence 
(whether considered to be related to study drug or not) that at any dose: 
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 Results in death 
 Is life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital abnormality/birth defect 
 Is an important medical event 
Note:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at immediate risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe (ICH E2A 
Guideline:  Clinical Safety Data Management:  Definitions and Standards for Expedited 
Reporting, Oct 1994).  It should be noted that hospitalization for a pre-planned procedure or 
diagnostic tests is not considered an AE or SAE. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse. 
Potential Hy’s Law cases should be reported via the SAE process.  This is defined as: 
 ALT or AST >3×ULN AND 
 ALP <2×ULN AND 
 Increase in bilirubin ≥2×ULN 
The process for reporting SAEs is described in Section 6.2.1.5. 
6.2.1.3 Categorization of Adverse Events 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug.  The action taken and the outcome must also be recorded. 
6.2.1.3.1 Severity 
 
The severity of the AE will be characterized as “mild, moderate or severe” according to the 
following definitions: 
 Mild events are usually transient and do not interfere with the subject’s daily activities. 
 Moderate events introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities. 
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 Severe events interrupt the subject’s usual daily activity. 
6.2.1.3.2 Relationship 
All efforts should be made to categorize an AE by its relationship to drug.  The Investigator 
will determine the relationship of the AE to the study drug by using the following definitions. 
Probable (must meet first 3 criteria):  This category applies to those AEs which are 
considered, with a high degree of certainty, to be related to the test drug.  An AE may be 
considered probable, if: 
 It follows a reasonable temporal sequence from administration of the drug; 
 It cannot be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the 
subject; 
 It disappears or decreases on cessation or reduction in dose.  (There are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists; e.g., (1) bone marrow depression, (2) tardive dyskinesias); 
 It follows a known pattern of response to the suspected drug; and 
 It reappears upon rechallenge. 
Possible (must meet the first 2 criteria):  This category applies to those AEs in which the 
connection with the test drug administration appears unlikely but cannot be ruled out with 
certainty.  An AE may be considered possible if, or when: 
 It follows a reasonable temporal sequence from administration of the drug; 
 It may have been produced by the subject’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject; and 
 It follows a known pattern of response to the suspected drug. 
Unlikely (must meet the first two criteria):  In general, this category is applicable to an 
adverse event which meets the following criteria: 
 It does not follow a reasonable temporal sequence from administration of the drug; 
 It may readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; 
 It does not follow a known pattern of response to the suspected drug; and 
 It does not reappear or worsen when the drug is readministered. 
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Unrelated:  This category is applicable to those AEs which are judged to be clearly and 
incontrovertibly due only to extraneous causes (disease, environment, etc.) and do not meet 
the criteria for drug relationship listed under unlikely, possible or probable. 
6.2.1.4 Reporting of Adverse Events 
All AEs, regardless of severity and when they occurred (any time after the ICF is signed and 
through the Follow-up Period), are to be recorded.  The Investigator should complete all the 
details requested including dates of onset, severity, action taken, outcome, relationship to 
study drug.  Each event should be recorded separately. 
6.2.1.5 Reporting of Serious Adverse Events 
All SAEs will be recorded using the electronic data capture (EDC) system.  The Investigator 
will be instructed to contact the Sponsor/designee for any questions on SAE reporting.  
Contact details will be provided per country, and per region (please refer to Study Manual for 
the appropriate information).   
Urgent safety queries issued in EDC must be followed up and addressed within 1 business 
day.  Follow-up information and response to non-urgent safety queries should be combined 
for reporting to provide the most complete data possible within each follow-up.  In the event 
that the EDC system is unavailable, SAEs are to be reported by faxing/emailing the paper 
SAE Form to Quintiles using the appropriate fax number provided for each country or project 
safety mailbox. 
6.2.1.5.1  
Notification of Regulatory Authorities, Investigators, and Institutional 
Review Board/Independent Ethics Committee 
Any SAE, including death due to any cause, which occurs during this study, whether or not 
related to the study drug, must be reported immediately (within 24 hours of the site’s 
knowledge of the event).  Additional information will be available in the Study Manual. 
The report will contain as much available information concerning the SAE to enable the 
Sponsor (or an authorized representative) to file a report, which satisfies regulatory reporting 
requirements.  These timelines apply to initial reports of SAEs and to all follow-up reports. 
All SAEs during the 30 day follow-up period will be collected and reported as previously 
described. 
6.2.1.5.2  
Reporting of Serious Adverse Events to Regulatory Authorities and 
Investigators 
Investigators will be notified by the Sponsor or Quintiles of all Serious Unexpected Adverse 
Event Reactions (SUSARs) that require prompt submission to their Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC).  Investigators should provide written 
documentation of IRB/IEC notification for each report to the Sponsor or Quintiles.  
The Sponsor or Quintiles will ensure that all SUSARs are reported to the appropriate 
regulatory authorities. 
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6.2.1.6 Follow-up of Adverse Events 
All AEs will be followed up to resolution.  However, AEs and SAEs that are ongoing at the 
subject’s last study visit (i.e., discharge from the clinic at the end of the double-blind 
treatment period or early termination) will be followed until resolution or for 30 days after 
last dose of study drug, whichever comes first.  Resolution means that the subject has 
returned to a baseline state of health or the Investigator does not expect any further 
improvement or worsening of the AE.  All AEs and SAEs that occur during the 30 day 
follow-up period should be reported to the Sponsor or Quintiles. 
6.2.1.7 Pregnancy and Contraception 
It is important that female subjects and the partners of male subjects do not become pregnant 
during the study. 
Instructions for Male Subjects 
All male subjects should avoid fathering a child by the use of an effective means of 
contraception (see below), unless their partner is not of childbearing potential, i.e. 
postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy). 
Male subjects (including men who have had vasectomies) whose partners are currently 
pregnant should use a condom for the duration of the study and for 1 month after the last 
patch is removed.  This is to ensure that the fetus is not exposed to the drug product via the 
ejaculate. 
Male subjects must not donate sperm for 3 months following the removal of the last patch.  
Males should continue using contraception for 1 month after the last patch is removed. 
Instructions for Female Subjects 
Female subjects must use contraception unless they are not of childbearing potential, i.e. 
postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy).  Sexually active females of child-bearing potential must agree to use a 
medically accepted method of contraception during the study and for 1 month after the final 
dose of study medication.  Female subjects must not donate eggs for 3 months after the last 
patch is removed. 
Acceptable forms of contraception 
 Condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository; 
 Established use of oral, injected or implanted hormonal methods of contraception; 
 Established use of medically prescribed topically-applied transdermal contraceptive 
patch; 
 Documented placement of an IUD or intra-uterine system (by female partner); and 
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 Male sterilization (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). 
The Sponsor/designee must be notified within 24 hours of the site’s knowledge of any 
subject who becomes pregnant while participating in a clinical study.  It is the responsibility 
of the Investigator, or designee, to report any pregnancy in a subject which occurs during the 
study by using the Pregnancy form. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion 
to determine their outcome.  This information is important for both drug safety and public 
health concerns.  The Investigator should make every effort to follow the subject until 
completion of the pregnancy.  If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., post-partum complications, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly, including that in an aborted fetus), the 
Investigator should follow the procedures for reporting SAEs. 
6.2.2  
Clinical Laboratory Evaluations 
6.2.2.1 Clinical Laboratory Assessments 
A central laboratory designated by the Sponsor will be used for all laboratory assessments 
during the trial.  If an immediate result is required, a sample should be sent to both the local 
and central laboratory. 
Urine samples and fasting blood samples will be collected from each subject as presented in 
Table 1 (Schedule of Events).  The clinical laboratory parameters evaluated in this study are 
presented in Table 7. 
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Table 7  
Clinical Laboratory Tests 
Hematology: 
WBC count with differential 
RBC count 
Hematocrit 
Hemoglobin 
Platelet count 
 
Urinalysis: 
pH 
Specific gravity 
Protein 
Ketones 
Glucose 
Blood 
Microscopic exam (performed only if any part of 
the urinalysis is not negative) 
 
Urine Drug Screens: a 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Marijuana 
Methadone 
Opiates 
Phencyclidine 
Propoxyphene 
 
Additional Tests (screening only): 
HIV 
HbsAgd 
Anti-HCVd 
Blood alcohole 
Serum Chemistry: 
ALP 
ALT  
AST  
BUN 
CPKf 
Creatinine 
LDH 
Total bilirubin 
Triglycerides  
Cholesterol (total, LDL, and HDL) 
Calcium 
Chloride 
Glucose 
Insulin 
Magnesium 
Bicarbonate 
Inorganic phosphorus 
Sodium 
 
Potassium 
Total protein 
Uric acid 
GGT 
Prolactinb 
Albumin 
 
Additional Tests: 
Urine pregnancy (women of child-bearing capacity)c 
TSH (free T4,
 if TSH is abnormal) 
HbA1c 
Alcohol breathalyzer testg 
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood urea nitrogen; 
CPK = creatine phosphokinase; GGT = gamma glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = Hepatitis B 
antigen; HCV = Hepatitis C Virus; HDL = high density lipoprotein; HIV = human immunodeficiency virus; LDH = lactic 
dehydrogenase; LDL = low density lipoprotein; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white 
blood cell count. 
a. Urine drug screens may be done at the Investigator’s discretion.  If the subject is allowed to leave the unit, a urine drug 
screen must be done when the subject returns. 
b. The central laboratory will not report prolactin levels to the sites nor the Sponsor, because this could potentially result 
in unblinding the treatment.  The central laboratory will report prolactin levels as “masked” on the laboratory report. 
See Section 6.2.2.2.3 for additional information. 
c. All positive urine pregnancy test results must be confirmed by a serum test.  Subjects with positive urine and serum 
pregnancy test results at Screening must not be enrolled.  Subjects with positive urine and serum pregnancy test results 
during the trial must discontinue treatment and be withdrawn from the trial. If the subject is allowed to leave the unit, a 
urine pregnancy test must be done when the subject returns. 
d. Subjects with chronic Hepatitis B or C may be included in the study provided that their condition is stable and that 
values for liver function tests and other laboratory tests results meet the criteria specified for entry into the study. 
e. A serum blood sample will be collected to test blood alcohol level at the screening visit.      
f. Reflex testing for urine myoglobin will be done in cases where CPK > 1000 U/L. 
g. If the subject is allowed to leave the unit, an alcohol breathalyzer test must be done when the subject returns. 
 
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Clinical laboratory tests will be reviewed for results of potential clinical significance at each 
time point during the study.  The Investigator will evaluate any change in laboratory values.  
If the Investigator determines a laboratory abnormality to be clinically significant, it is 
considered a laboratory AE; however, if the abnormal laboratory value is consistent with a 
current diagnosis, it may be documented accordingly. 
6.2.2.2 Monitoring of Selected Laboratory Values 
6.2.2.2.1 Liver  
Enzymes 
Subjects should be closely observed if they meet the definition of Hy’s Law cases, defined 
as: 
 ALT or AST >3×ULN AND 
 Alkaline phosphatase (ALP) <2×ULN AND 
 increase in bilirubin ≥2×ULN 
If the subject’s laboratory results meet these criteria, the subject should be evaluated and 
repeat or additional testing should be performed.  Elevations in liver enzymes that require 
discontinuation of the subject are presented in Section 4.3.3.  Potential Hy’s Law cases 
should be reported as SAEs. 
6.2.2.2.2 Neutrophil  
Counts 
Subjects with an absolute neutrophil count of <1000 per mm3 should have an additional test 
within 24 hours.  If the values are not within normal limits or increasing, the subject will be 
discontinued from the study. 
6.2.2.2.3 Prolactin 
The central laboratory will not report the prolactin levels after baseline to the sites or 
Sponsor/designee, as this value could unblind the subject’s treatment.  The central laboratory 
will report prolactin levels as “masked” on the laboratory report.  If an Investigator suspects 
hyperprolactinemia (due to symptoms or signs that could be attributed to a high prolactin 
level), a blood sample should be taken and sent to the central laboratory.  Blood samples for 
prolactin levels should not be sent to the local laboratory. 
If a subject’s serum prolactin level is >10×ULN, the site will be notified by the central 
laboratory and the Investigator will do a repeat blood draw within 3 days.  If the subject’s 
prolactin level is still >10×ULN, the Investigator should consider other possible causes of 
hyperprolactinemia (e.g., primary hypothyroidism, chronic renal failure, cirrhosis, use of 
drugs [opiates, estrogens, cimetidine, etc.], pregnancy for female subjects). 
If the laboratory requests a prolactin re-test, a “dummy” request will be sent for another 
subject at the same clinical site and the subject will be selected randomly in order to preserve 
the blind.  Such cases will be discussed with the study Medical Advisor. 
The Medical Advisor and site will remain blinded to the subject’s treatment allocation. 
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6.2.3 
Vital Signs, Physical Findings and Other Safety Assessments 
Height will be recorded at Screening, only.  Weight will be recorded at each visit.  
A complete physical examination including examination of the head, neck, ears and throat, 
thorax, abdomen, urogenital, extremities, neurological, and skin and mucosae will be 
performed at Screening and at end of study.  Abnormal physical examination findings at the 
Screening will be recorded as medical history and abnormal physical examinations findings 
at subsequent visits will be recorded as AEs.   
Vital sign measurements will include temperature, systolic blood pressure (SBP), diastolic 
blood pressure (DBP), and heart rate.  Blood pressures (sitting) and pulse rates should be 
measured after subject has rested (sitting quietly) for 5 minutes. 
In addition, assessments for orthostatic hypotension will be performed.  Blood pressure 
readings and pulse rate will be obtained after the subject has been supine for 5 minutes.  
These will be repeated after the subject has been standing up for approximately 1 to 
3 minutes. 
Subjects with a decrease of ≥30 mmHg in SBP and/or a decrease of ≥20 mmHg in DBP after 
≥3 minutes standing compared with the previous supine blood pressure, OR development of 
symptoms are considered to have orthostatic hypotension. 
Twelve-lead ECGs will be recorded at Screening and at the visits specified in Table 1.  
An ECG recordings will be obtained after the subject has been supine and at rest for at least 
5 minutes.  Additional 12-lead ECGs may be obtained at the Investigator’s discretion and 
should always be obtained if the subject discontinues the study.  A central ECG service will 
be utilized for reading all ECGs in order to standardize interpretations for the safety analysis.  
In addition, ECG results will be evaluated at the investigational site to monitor safety during 
the trial.  The Investigator or designee will review, sign, and date each ECG reading, noting 
whether or not any abnormal results are of clinical significance.  The ECG will be repeated if 
any results are considered by the Investigator to be clinically significant. 
6.2.4 
Evaluation of Extrapyramidal Symptoms (EPS) 
The rater who administers the EPS scales must be trained and experienced.  Raters will be 
trained to administer these scales.  The number of raters should be kept to a minimum and all 
efforts should be made to ensure that the same clinician administers the scales for a given 
subject.  Notations in the subject’s trial records should substantiate the ratings. 
6.2.4.1 Simpson Angus Scale (SAS) 
The SAS11 consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder 
shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and 
akathisia).  Each item will be rated on a 5-point scale, with a score of 0 representing absence 
of symptoms, and a score of 4 representing a severe condition.  The SAS Total Score is the 
sum of the scores for all 10 items.  Anticholinergics, propranolol, benzodiazepines, and non-
benzodiazepine sleep aids are not permitted within 12 hours of scale administration (see  
Table 5).  Investigators are encouraged to delay scale administration until 12 hours have 
elapsed, if at all possible.  However, if delaying administration of the scale is not feasible, the 
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SAS should still be administered and the use of the medication documented, including a 
notation of the drug name, dose, and time of administration.  A copy of the scale is included 
in Appendix 7 (Section 17.0). 
6.2.4.2 Abnormal Involuntary Movement Scale (AIMS) 
The AIMS8 assessment consists of 10 items describing symptoms of dyskinesia.  Facial and 
oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk 
movements (item 7) will be observed unobtrusively while the subject is at rest (e.g., in the 
waiting room), and the Investigator will also make global judgments on the subject’s 
dyskinesias (items 8 through 10).  Each item will be rated on a 5-point scale, with a score of 
0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating 
a severe condition (for item 10, awareness, severe distress).  For this scale, the subject is to 
be sitting on a hard, firm chair.  In addition, the AIMS includes 2 yes/no questions that 
address the subject’s dental status.  Anticholinergics, propranolol, benzodiazepines, and non-
benzodiazepine sleep aids are not permitted within 12 hours of scale administration (see  
Table 5).  Investigators are encouraged to delay scale administration until 12 hours have 
elapsed, if at all possible.  However, if delaying administration of the scale is not feasible, the 
AIMS should still be administered and the use of the medication documented, including a 
notation of the drug name, dose, and time of administration.  The AIMS Movement Rating 
Score is defined as the sum of items 1 through 7 (i.e., items 1 through 4, facial and oral 
movements; items 5 and 6, extremity movements; and item 7, trunk movements).  A copy of 
the scale is presented in Appendix 8 (Section 18.0). 
6.2.4.3 Barnes Akathisia Rating Scale (BARS) 
The BARS12 consists of 4 items related to akathisia.  These include objective observation of 
akathisia by the Investigator, subjective feelings of restlessness by the subject, subjective 
distress due to akathisia, and global clinical assessment of akathisia.  The first 3 items will be 
rated on a 4-point scale, with a score of 0 representing absence of symptoms and a score of 
3 representing a severe condition.  The global clinical evaluation will be made on a 6-point 
scale, with 0 representing absence of symptoms and a score of 5 representing severe 
akathisia.  To complete this scale, subjects will be observed while they are seated and then 
standing for a minimum of 2 minutes in each position.  Symptoms observed in other 
situations (e.g., while engaged in neutral conversation or engaged in activity on the ward) 
may also be rated.  Subjective phenomena are to be elicited by direct questioning.  
Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids are not 
permitted within 12 hours of scale administration (see  Table 5).  Investigators are 
encouraged to delay scale administration until 12 hours have elapsed, if at all possible.  
However, if delaying administration of the scale is not feasible, the BARS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration.  The BARS Global Score is defined as the global 
clinical assessment of akathisia.  A copy of the scale is presented in Appendix 9 (Section 
19.0). 
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6.2.5 
Suicidality: Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the trial using the C-SSRS.
13  The C-SSRS facilitates 
prospective, systematic monitoring for emergence of suicidality within clinical trials and it is 
a low-burden, clinician-administered tool that covers the wide spectrum of suicidality from 
ideation to behavior.  A training tool will be supplied to the site by the Sponsor for use by 
staff members that have not had C-SSRS training within the past 2 years. The site will 
document training of selected staff members and file the training certificates in the trial 
master file. 
This trial will use the “Baseline/Screening” and “Since Last Visit” versions of the scale.  
The “Baseline/Screening” version, which assesses the lifetime experience of the subject with 
suicide events and suicidal ideation and the occurrence of suicide events and/or ideation 
within a specified time period prior to entry into the trial, will be completed for all subjects at 
the Screening and Baseline visits to determine eligibility (prior to the first dose).  Any subject 
with suicidal ideation within the last 6 months or suicidal behavior within the past 12 months 
or who in the clinical judgment of the Investigator presents a serious risk of suicide should be 
excluded from the study. Subjects will also be excluded if they report suicidal ideation or 
suicidal behavior at Baseline. The “Since Last Visit” C-SSRS form will be completed at all 
post-Screening visits.  A copy of the scale is presented in Appendix 10 (Section 20.0). 
6.2.6 
Evaluations of Patch and Dermal Assessments 
Each subject will wear 2 patches simultaneously; both patches will be applied in close 
proximity without overlapping to 1 application site.  Dermal assessments for both patches 
will be assessed but only the worse of the 2 scores will be recorded.  Dermal assessments will 
be conducted as follows:  
 Patch adhesion will be evaluated throughout the day including at the time points during 
which the site staff collects routine vital signs as per hospital policy/SOP; and 
immediately prior to removal of previous day’s patch. In addition, subjects will be asked 
to check patch adhesion throughout the day and report immediately to site personnel if 
the patch detaches completely or detaches partially (i.e., some edges of the patch are 
lifting off the skin). 
 Irritation at the site of patch application will be assessed each day between 30 and 60 
minutes after patch removal. 
 Subjects will be asked to report to the site staff any discomfort or skin irritation due to 
patch.  Discomfort and skin irritation reported by the subjects will be recorded as AEs. 
 Once a week, after removal of the patch, site personnel will assess patch application sites 
for adhesive residue. 
Spontaneous complaints of dermal reactions will be recorded as AEs.  Spontaneous reports 
might include but are not limited to the following:  initial dermal response and exacerbation 
of an existing response. 
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The actual time of all scheduled and unscheduled evaluations will be recorded. 
Skin irritation at patch application site  
Thirty to 60 minutes after patch removal site personnel will conduct a visual inspection of the 
skin at the patch application site and will record any irritation observed using the descriptors 
provided in the Berger and Bowman scale14 presented in Table 8. The investigator will assess 
any irritation observed at the patch application site as clinically significant or not clinically 
significant.     
In addition, spontaneous reports of skin irritation by the subject will be recorded as an AE. If 
a subject reports skin irritation, then site personnel will conduct visual inspection of the skin 
at the application site and will record the description of the observed skin irritation using the 
descriptors provided in the Berger and Bowman scale14 presented in Table 8.  
Table 8  
Skin Irritation Descriptors 
Observation 
No evidence of irritation  
Minimal erythema (barely perceptible) 
Definite erythema, readily visible; minimal edema, or minimal papular response 
Erythema and papules 
Definite edema 
Erythema, edema, and papules 
Vesicular eruption 
Strong reaction spreading beyond test (application) site 
Slightly glazed appearance  
Marked glazed appearance  
Glazing with peeling and cracking  
Glazing with fissures  
Film of dried serous exudates covering all or part of the patch site  
Small petechial erosions and/or scabs  
 
Discomfort at patch application site 
Report of discomfort at the patch application site will be recorded as an AE.  If a subject 
reports discomfort at the patch application site, the site personnel will ask the subject to rate 
the discomfort as mild, moderate, or severe, and will ask the subject to describe the 
discomfort.  The description of discomfort as reported by the subject should be recorded 
verbatim. 
Patch adhesion 
Patch adhesion will be assessed by site personnel at the time points defined in the Schedule 
of Events (Table 1).  Adhesion will be evaluated according to Yes/No questions as follows:  
1. Is the patch fully attached to the skin? Yes/No 
2. If ‘No’, did the patch detach completely? Yes/No 
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 If “Yes” and the patch/patches are completely detached, the time and activity at the 
time of patch detachment will be documented. 
o If both patches are detached completely, then two new patches from the 
subject’s kit should be applied immediately, provided that there is at least 
6 hours of time remaining before the next dose; 
o If only one patch detaches completely, then the other patch should also be 
removed and two new patches from the subject’s kit should be applied 
immediately, provided that there is at least 6 hours of time remaining before 
the next dose; 
o Under no circumstances should the detached patches be reapplied to the 
subject; and 
o Regardless of what time the new patches are applied, patch removal time of the 
new patches will be approximately 24 hours after the application of the original 
patches.  In other words, removal time of the new patches may not exceed 
24 hours from the time the first patches were applied. 
 If “No” and partial patch detachment (i.e., some edges of the patch are lifting off the 
skin) is observed then the site personnel/subject should smooth the patch down such that 
the complete patch is in contact with the skin again.   
In addition to patch adhesion assessments by site personnel at specified time points, subjects 
should be instructed to should check adhesion of the patch throughout the day and report to 
site personnel immediately if patch detaches completely or if partial patch detachment is 
observed. 
Adhesive Residue 
Once a week, immediately after the removal of a patch, the amount of adhesive residue 
remaining at the application site will be examined by site personnel and graded as described 
in Table 9. 
Table 9  
Adhesive Residue Scale 
Adhesive Residue 
Score  
Definition 
0  
None 
1  
Light  
2  
Medium   
3  
Heavy  
4  
Patch not present 
 
6.3 Pharmacokinetics 
6.3.1 
Pharmacokinetic Blood Sampling 
At least 3 blood samples will be collected at 2, 14, and 22 hours after application of the patch 
with ± 2 hour window on Day 21 and 42.  Actual blood sampling time will be recorded.  
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Blood will be obtained for the determination of asenapine and selected metabolites in human 
plasma as per the instructions provided by the laboratory. 
The samples obtained for PK analysis may be used for analysis of other metabolites in the 
future.  The potential future analysis will be limited to the analysis of study drug metabolites. 
A model-based approach including population PK analysis will be used to assess the impact 
of covariates on asenapine exposure and to explore the exposure-response relationship of 
relevant endpoints.  The detailed methodologies and results will be presented in a separate 
PK analysis report. 
6.3.2 
Drug Concentration Measurements 
The bioanalysis of asenapine and desmethyl-asenapine in plasma samples will be performed 
using a liquid chromatography tandem mass spectrometry method.  The bioanalytical 
methodology and procedures will be documented in a Bioanalytical Study Plan.  The 
Bioanalytical Report will be included in a separate PK analysis report. 
Other asenapine metabolites might be assessed using remaining plasma samples in a separate 
analysis study if deemed necessary. 
6.4 Appropriateness of Measurements 
The efficacy assessments used in this study are standard and validated instruments in this 
population.  The safety assessments include standard measures (hematology, clinical 
chemistry [including prolactin levels], and urinalysis), vital signs, ECGs and physical 
examination findings and dermal adverse events. 
7.0 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the 
Sponsor/designee is responsible for implementing and maintaining quality assurance and 
quality control systems with written Standard Operating Procedures (SOPs).  This study will 
be conducted following Quintiles SOPs. 
Quality control will be applied to each stage of data handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
 Investigator meeting(s); 
 Central laboratories for clinical laboratory parameters and ECGs; 
 Center Initiation visit; 
 Early center visits post-enrollment; 
 Routine center monitoring; 
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 Ongoing center communication and training; 
 Data management quality control checks; 
 Continuous data acquisition and cleaning;  
 Internal review of data; and 
 Quality control check of the final clinical study report. 
In addition, Sponsor and/or Quintiles Clinical Quality Assurance Department may conduct 
periodic audits of the study processes, including, but not limited to study center, center visits, 
central laboratories, vendors, clinical database, and final clinical study report.  When audits 
are conducted, access must be granted for all study-related documents including medical 
history and concomitant medication documentation to authorized Sponsor’s representatives 
and regulatory authorities. 
7.1 Monitoring 
The Sponsor has engaged the services of a contract research organization (CRO), Quintiles, 
to perform all monitoring functions within this clinical study.  Noven representatives, or their 
designees, will conduct visits to the clinical sites to monitor the various aspects of the study.  
The Investigator agrees to allow these monitors and other authorized Noven personnel, 
including quality assurance monitors, access to the clinical supplies, dispensing and storage 
area, and clinical files of the study subjects, and agrees to assist the Noven personnel in their 
activities, if requested.  Study sites are also subject to inspection by Food and Drug 
Administration (FDA) representatives or other regulatory authorities.  The Investigator 
agrees to assist such inspectors in their duties. 
Prior to each monitoring visit, the Investigator or designee should record all data generated 
since the last visit on the electronic case report forms (eCRFs).  The Investigator and site 
staff will be expected to cooperate with the monitor, and to be available during at least a 
portion of the monitoring visit to sign eCRFs, answer questions, and to provide any missing 
information. 
7.2 Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of 
the Data Management and Biostatistics departments of Quintiles. 
Subjects will be enrolled in the study and randomized to a study treatment using the 
IVRS/IWRS.  The IVRS/IWRS and eCRF are validated real-time systems and are compliant 
with Guidance for Industry, Part 11, electronic records; Electronic Signatures – Scope and 
Application; Computerized Systems Used in Clinical Investigations; General Principles of 
Software Validation; Final Guidance for Industry and FDA Staff. 
Electronic Data Capture will be used for this study, meaning that all eCRF data will be 
entered in electronic forms at the study center.  Data collection will be completed by 
authorized study center staff designated by the Investigator.  Appropriate training and 
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security measures will be completed with the Investigator and all authorized study center 
staff prior to the study being initiated and any data being entered into the system for any 
study subjects.  Data management will be conducted under Quintiles SOPs. 
All data must be entered in English.  The eCRFs should always reflect the latest 
observations. 
The eCRF is considered a data entry form and should not constitute the original (or source) 
medical records unless otherwise specified.  Any data captured electronically will be 
pre-specified in the data management plan.  Source documents are all documents used by the 
Investigator or hospital that relate to the subject’s medical history, that verify the existence of 
the subject, the inclusion and exclusion criteria and all records covering the subject’s 
participation in the study.  They include laboratory notes, ECG results, memoranda, 
pharmacy dispensing records, subject files, etc. 
The Investigator is responsible for maintaining source documents.  These will be made 
available for inspection by the Study Monitor at each monitoring visit.  The Investigator must 
submit a completed eCRF for each subject who receives study medication, regardless of 
duration.  All supportive documentation submitted with the eCRF, such as laboratory or 
hospital records, should be clearly identified with the study and subject number.  Any 
personal information, including subject name, should be removed or rendered illegible to 
preserve individual confidentiality. 
Electronic case report form records will be automatically appended with the identification of 
the creator, by means of their unique User ID.  Specified records will be electronically signed 
by the Investigator to document his/her review of the data and acknowledgement that the data 
are accurate.  This will be facilitated by means of the Investigator’s unique User ID and 
password; date and time stamps will be added automatically at time of electronic signature.  
If an entry on an eCRF requires change, the correction should be made in accordance with 
the relevant software procedures.  All changes will be fully recorded in a protected audit trail, 
and a reason for the change will be required. 
Adverse events, medical history, and concomitant diseases will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary.  Concomitant medications will 
be coded using the World Health Organization drug dictionary. 
7.3 Quality Assurance Audit 
Study centers, the study database, and study documentation may be subject to Quality 
Assurance audit during the course of the study by the Sponsor or Quintiles.  In addition, 
inspections may be conducted by regulatory bodies at their discretion. 
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8.0 STATISTICAL METHODS 
8.1 Determination of Sample Size 
Assuming an effect size of 0.35 on the change in PANSS total score from baseline to Week 6 
for the 2 pairwise comparisons between each active HP-3070 treatment arm and placebo, the 
power for detecting a statistically significant HP-3070 advantage will be approximately 0.90 
having 204 evaluable subjects per each treatment arm using a 2-side alpha level of 0.025 for 
each comparison.  A 2-sided overall Type I error is equal to 0.05.  Having 3 treatment arms, 
the total number of subjects randomized in the trial and included in primary analysis set will 
be approximately 612.  A sufficient number of subjects will be screened to randomize the 
proposed sample size. 
The effect size of 0.35 was chosen based on the lowest effect size observed in results from 
the studies conducted with SL asenapine and approved by FDA (Sycrest
®/SAPHRIS
® 
[Study 041004, and Study 041023]). 
8.2 Sample Size Recalculation 
Sample size recalculation (SSR) will be conducted on the blinded data after approximately 
50% of the desired number of patients have been randomized and completed up to 6 weeks of 
study treatment.  This SSR will be directed and conducted by an independent statistician 
from Quintiles, who is not involved in the trial conduct other than this SSR.   
The purpose of this SSR is to assess the assumption made regarding the sample size 
calculation for the primary endpoint.  No other information will be generated. 
This SSR will NOT be conducted with an intention of decreasing the original sample size or 
stopping the trial early.  There will be no Type I error adjustment due to this SSR. 
8.2.1 
Procedures for Sample Size Recalculation 
The expected common (pooled) standard deviation is 20, which corresponds to a difference 
in means of 7 for our assumed effect size of 0.35.  Using the transferred blinded data, the 
independent statistician will calculate the following metrics for the primary endpoint 
(PANSS Total Score): 
 The common (pooled) SD 
Using these metrics and the original assumptions of mean difference in reduction of PANSS 
scores from Baseline to Week 6, between treatment arms Type I error rate (0.025) and 
90% power of the new sample size will be recalculated.  More details, including decision 
rules and maximum increase in sample size, are available in the Statistical Analysis Plan 
(SAP).  The independent statistician will provide a report which will include the following: 
 Re-estimation of sample size 
 The common SD for the primary endpoint  
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Based on the documented SSR and the observed dropout rate, the independent statistician 
may recommend a new sample size to be sent to the Sponsor for final decision. 
8.3 Study Endpoints 
8.3.1 
Primary Analyses Endpoint 
The primary efficacy endpoint is the change in PANSS total score between Baseline and 
Week 6. 
8.3.2 
Key Secondary Analysis Endpoint 
The key secondary endpoints is: 
 To evaluate the efficacy of HP-3070 compared with placebo for the treatment of 
schizophrenia as evaluated by change in Clinical Global Impression – Severity of Illness 
Scale (CGI-S) scores between Baseline and Week 6 
8.3.3 
Other Secondary Analyses Endpoints 
The other secondary endpoints include: 
 Change from Baseline in PANSS total score at each time point in addition to Week 6; 
 Change from Baseline in CGI-S at each time point in addition to Week 6; 
 CGI-I score at each time point;  
 The proportion of CGI-I responders at each time point including Week 6; CGI-I 
responders are  defined as subjects who have a score of 1 (very much improved) or a 
score of 2 (much improved); 
 Change from Baseline in positive, negative, and general pathology subscores of PANSS 
at each time point; 
 Proportion of PANSS responders; PANSS responders are defined as subjects who have a 
≥30% reduction in PANSS total score between Baseline and at each time point including 
Week 6; 
 Change from Baseline in CDSS score at each time point; and 
 MSQ score at each time point. 
8.3.4 
Exploratory Endpoint 
A model-based approach will be used to assess the impact of covariates on asenapine 
exposure and to explore the exposure-response relationship with relevant endpoints. 
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8.4 Statistical Methods 
All analyses, summaries, and listings will be performed using SAS® software (Version 9.2 or 
higher). 
Baseline characteristics, efficacy and safety data will be summarized using the appropriate 
descriptive statistics. 
For the efficacy variables, descriptive statistics (including n, SD, mean, minimum, 
maximum, and 95% CI) for the changes from Baseline during the 6-week treatment period 
will be presented. 
Continuous variables will be summarized by descriptive statistics (sample size [n], mean, 
SD, median, minimum, and maximum).  Categorical variables will be summarized in 
frequency tables (n, frequencies, and percentages).  Individual subject data will be presented 
in listings. 
All statistical tests of treatment effects will be performed at a 2-sided significance level of 
0.05, unless otherwise stated. 
Additional details concerning statistical methods are presented in the SAP. 
All references to study medication refer only to the double-blind treatment period. 
8.4.1 
Analysis Populations 
Four analysis sets will be used in analyzing the data obtained from this protocol: 
Intent-to-Treat (ITT):  includes all consented and randomized subjects.  Regardless of any 
protocol deviations, analyses performed on the ITT set will be based on the randomized 
treatment assignment and all available data. 
Full Analysis Set (FAS):  includes all consented and randomized subjects who have had at 
least 1 patch of double-blind study medication applied and who have a Baseline PANSS total 
score and at least 1 post-Baseline assessment of the primary efficacy measure (PANSS total 
score).  Evaluable subjects will be defined as those who meet the FAS definition.  The FAS 
will be used as the primary set for analysis of efficacy endpoints based on randomized 
treatment assignment. 
Safety Analysis Set (SAF):  includes all subjects who have had at least 1 patch of 
double-blind study medication applied and who have at least 1 post-dose safety measurement 
during the double-blind treatment period.  In the unlikely event that errors may have occurred 
in treatment arm assignments, then analyses using the SAF will be based on treatment 
actually received.  The SAF will be used for the analysis of dermal evaluations and safety 
endpoints. 
Pharmacokinetic Analysis Set (PAS):  includes all subjects who have received at least 1 dose 
of study medication during the double blind treatment period and have at least 1 blood 
sample for PK assessment.  Subjects may be excluded from the PAS set if they significantly 
violate inclusion or exclusion criteria, significantly violate the protocol in a way that may 
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influence the PK analysis, if any unexpected error occurs during the study that may influence 
the PK analysis (e.g., early detachment of transdermal systems, apparent sample switching, 
etc.) or if their data are unavailable or incomplete.  The PAS will be used for the analysis 
with model based approach.  Excluded cases will be documented together with the reason for 
exclusion. 
8.4.2 
Primary Efficacy Analysis 
The primary efficacy analysis (the analysis of the primary variable) will be performed on the 
Full Analysis Set (FAS). 
The primary efficacy variable, change from Baseline to Week 6 in the PANSS total score for 
each of the 3 treatment arms, will be analyzed using a mixed model repeated measures 
(MMRM) analysis.  The MMRM model will include change from Baseline in PANSS total 
score as the repeated dependent variable, with country, treatment (HP-3070-9.0 [9.0 mg], 
HP-3070-18.0 [18.0 mg], and placebo), visit, treatment by visit interaction, and the Baseline 
PANSS total score as covariates.  An unstructured covariance matrix will be assumed.  In the 
event the convergence cannot be attained with the unstructured correlation matrix, the 
following alternative structures will be attempted in the specified order (from least to most 
restrictive):  heterogeneous Toeplitz structure (TOEPH), heterogeneous autoregressive (1) 
(ARH[1]), heterogeneous compound symmetry (CSH), No Diagonal Factor Analytic 
(FA0[q], with q equal to the number of time points), Toeplitz structure (TOEP), 
autoregressive (1) (AR[1]), and compound symmetry (CS).  If either ARH(1) or AR(1) 
structure is used, a random subject intercept will also be included in the model.  
The MMRM model may be repeated on additional analysis sets as a sensitivity analysis. 
If the normality assumption is violated, ANCOVA analysis on rank-transformed data will be 
used as a supportive analysis. 
8.4.3 
Key Secondary Efficacy Analysis 
Change from Baseline to Week 6 in the CGI-S scores will be assessed using the same 
MMRM model used for the change in PANSS scores.   
Each study drug dose will be compared with placebo and model-based point estimates for the 
treatment effects, 95% confidence intervals (CIs), and p-values will be calculated.  The 
analysis set will be the FAS. 
In order to control the family-wise Type I error rate, the Hochberg-based matched parallel 
gatekeeping procedure will be used to account for multiple doses and multiple primary and 
key secondary endpoints.   
The primary and key secondary efficacy hypotheses will be grouped into 2 hierarchical 
families.  Family 1 is the HP-3070-9.0 versus placebo (Hypothesis 1) and HP-3070-18.0 
versus placebo (Hypothesis 2), based on the primary endpoint of change from baseline in 
PANSS total score at Week 6.  Family 2 is HP-3070-9.0 versus placebo (Hypothesis 3) and 
HP3070-18 versus placebo (Hypothesis 4), based on the key secondary endpoint of change 
from Baseline in CGI-S at Week 6.  
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The matched parallel gatekeeping procedure performs multiplicity adjustments as follows: 
1. The comparisons for the primary endpoint (Hypotheses 1 and 2) are performed using 
a truncated Hochberg procedure (gamma = 0.9). 
2. The comparisons for CGI-S (Hypotheses 3 and 4) corresponding to the doses that 
were significant in Step 1 are performed, using a regular Hochberg procedure. 
Further details are provided in the SAP. 
8.4.4 
Other Secondary Efficacy Analyses 
The same statistical model will be used for the analysis for the change from Baseline in the 
PANSS subscales, CDSS, CGI-S, and the scores for CGI-I, and MSQ at each assessment.  
The differences in proportions of CGI-I, and PANSS responders will be analyzed using the 
Cochran-Mantel-Haenszel Test.  
Details are provided in the SAP. 
8.4.5 
Subgroup Analyses 
Details of subgroup analyses for primary and key secondary objectives are described in the 
SAP. 
8.4.6 
Safety Analyses 
Safety analyses will be performed on the Safety Analysis Set (SAF). 
Scores for C-SSRS, SAS, BARS, and AIMS will be summarized for each treatment arm 
using descriptive statistics at each visit for raw numbers and change from baseline values. 
Adverse events will be coded using MedDRA.  The collection of AEs will begin after the 
subject has signed the ICF.  The TEAEs during the double-blind treatment period are defined 
as AEs with onset date on or after the start of study medication through the 30 day follow-up 
period, or AEs with onset prior to the first dose of study medication and with an increase in 
severity after the start of study medication through the 30 days follow-up period.  The same 
rule applies for Run-in Period. 
For each study treatment, numbers of events and incidence rates will be tabulated by 
preferred term and system organ class.  Adverse events will be summarized separately for the 
Screening/Run-in Period and Double-blind Treatment Period.  Adverse events will be 
summarized by severity and relationship to drug.  If the subject has the same AE on multiple 
occasions, the summary will reflect the maximum severity or closest relationship reported. 
The SAEs, including death as an outcome, and AEs leading to withdrawal of subjects will be 
tabulated for each treatment arm.  Commonly occurring AEs, i.e., those which occur in 5% or 
more of the subjects in any treatment arm will be summarized using descriptive statistics. 
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All laboratory test results, vital signs measurements, ECG results, weight, and body mass 
index will be summarized for each treatment arm using descriptive statistics at each visit for 
raw numbers and change from baseline values. 
Patch adhesion and adhesive residue assessment results will be summarized at each visit by 
treatment arm, and by treatment arm overall. 
The results of the PK analyses will be presented in a stand-alone report. 
8.4.7 
Data to be Analyzed 
Data handling will be the responsibility of Quintiles.  The data will be inspected for 
inconsistencies by performing validation checks. 
All details regarding the statistical analysis and the preparation of tables, listings and figures 
will be described in the SAP prepared by Quintiles and approved by the Sponsor before 
database lock. 
The statistical analysis will be performed by Quintiles.  After database lock, the final SAS 
data sets in SDTM and ADaMs formats will be transferred to Noven with SAS programs and 
all supportive documentation. 
8.4.8 
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 dropout rate performance of sensitivity analysis is critical.  The purpose of sensitivity 
analysis is to explore whether different analyses under different sets of missingness 
assumptions provide robust efficacy results.  The sensitivity analysis will be performed on 
primary endpoints.  The extent to which efficacy results are stable across such an 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).  Details are provided in the SAP.  
8.5 Subject Disposition and Characteristics 
The disposition summary will include all enrolled subjects.  Subject characteristics will be 
obtained at Screening and will be summarized for all subjects.  Summaries will include 
descriptive statistics for continuous variables (sample size, mean, and SD, median, minimum, 
and maximum) and for categorical variables (sample size, frequency and percent).  Subject 
characteristics may include, but are not limited to:  age, gender, race/ethnicity, height, 
weight, and body mass index. 
8.6 Safety 
Safety variables will be summarized based on the SAF. 
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8.6.1 
Adverse Events 
The TEAEs are defined as AEs that first occurred or worsened in severity after the first 
administration of the study drug.  Adverse event summaries will include incidence of TEAEs 
by MedDRA preferred term and system organ class, SAEs (including deaths), AEs that led to 
study drug discontinuation, AEs by severity, and AEs by relationship to study drug. 
8.6.2 
Clinical Laboratory Evaluations 
Laboratory assessments will be presented as mean changes from Baseline and incidence of 
abnormal values.  Shift tables will be presented for selected parameters.  Of special interest 
are prolactin levels, fasting glucose, and lipids. 
8.6.3 
Vital Signs Measurements, Physical Findings and Other Safety Evaluations 
Descriptive statistics for the change from Baseline will be summarized at each visit for 
C-SSRS, SAS, BARS, and AIMS. 
Mean changes from Baseline and incidence of treatment-emergent abnormal vital signs, 
weight, and ECG results will be summarized.  The number and proportion of subjects with 
orthostatic hypotension will also be summarized. 
8.6.4 
Dermal Evaluations 
Data for patch adhesion and adhesive residue assessment will be presented and summarized 
at each visit by treatment arm, and by treatment arm overall.  Data for skin irritation and 
discomfort will be presented as TEAEs. 
8.7 Pharmacokinetic Analyses 
Plasma asenapine and desmethyl asenapine concentrations will be analyzed and listed. 
A model-based approach will be used to assess the impact of covariates on asenapine 
exposure and to explore the exposure-response relationship of relevant endpoints.  Details on 
the methodology of population PK model development, exposure-response analysis and 
model-based simulations will be included in a standalone PK report. 
8.8 Interim Analyses 
No interim analysis for efficacy is planned. 
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9.0 ETHICS 
9.1 Institutional Review Board or Independent Ethics Committee 
An Ethics Committee should approve the final protocol, including the final version of the 
ICF and any other written information and/or materials to be provided to the subjects.  
The Investigator will provide the Sponsor or Quintiles with documentation of IRB/IEC 
approval of the protocol and informed consent before the study may begin at the study 
center(s).  The Investigator should submit the written approval to the Sponsor/designee 
before enrollment of any subject into the study. 
Sponsor/designee should approve any modifications to the ICF that are needed to meet local 
requirements. 
The Investigator will supply documentation to the Sponsor or Quintiles of required 
IRB/IEC’s annual renewal of the protocol, and any approvals of revisions to the informed 
consent document or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC any new information that may 
adversely affect the safety of subjects or the conduct of the study.  Similarly, the Investigator 
will submit written summaries of the study status to the IRB/IEC annually, or more 
frequently if requested by the IRB/IEC.  Upon completion of the study, the Investigator will 
provide the Ethics Committee with a brief report of the outcome of the study, if required. 
9.2 Ethical Conduct of the Study 
This study will be conducted and the informed consent will be obtained according to the 
ethical principles stated in the Declaration of Helsinki (48th General Assembly, Somerset 
West, Republic of South Africa, October 2008 [or current version]), the applicable guidelines 
for GCP (CPMP/ICH/135/95), or the applicable drug and data protection laws and 
regulations of the countries where the study will be conducted. 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects.  The study will be conducted in compliance with GCP and the applicable 
national regulations so as to assure that the rights, safety, and well-being of the participating 
study subjects are protected consistent with the ethical principles that have their origin in the 
Declaration of Helsinki. 
9.3 Subject Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the subject in 
simple terms before the subject will be entered into the study.  The ICF contains a statement 
that the consent is freely given, that the subject is aware of the risks and benefits of entering 
the study, and that the subject is free to withdraw from the study at any time.  Written 
consent must be given by the subject and/or legal representative, after the receipt of detailed 
information on the study. 
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The Investigator is responsible for ensuring that informed consent is obtained from each 
subject or legal representative and for obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to 
the administration of study medication.  The Investigator will provide each subject with a 
copy of the signed and dated consent form. 
9.4 Study Administration 
9.5 Administrative Structure 
Central organizations used for the conduct, monitoring, and/or evaluation of this trial are 
provided on the Contact List. 
A Medical Advisor will be made available to every Investigator as designated by the 
Sponsor.  The central and regional Medical Advisors will consult with sites on general 
eligibility questions, subject safety, protocol conduct, compliance, as well as additional tasks 
specified in the protocol.  The Medical Advisor will also work closely with the local clinical 
and safety teams designated by the Sponsor.  The administrative structure is presented in 
Table 10. 
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Table 10  
Administrative Structure 
Data Management 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, NC 27703  
Biostatistics 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, NC 27703 
Medical Writing 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, NC 27703 
Clinical Manager 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, NC 27703 
Medical Advisor 
Elena Vlad, MD, Psych, PhD 
Medical Director, Medical and Scientific Services
Quintiles, Inc. 
4820 Emperor Drive 
Durham, NC 27703 
Clinical Safety 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, NC 27703 
Electronic Data Capture  
Oracle 
Health Sciences Global Business Unit 
77 Fourth Avenue 
Waltham, MA 02451 
 
ERT (eResearch Technology) 
1818 Market Street, Suite 1000 
Philadelphia, PA 19103 
Clinical Research Organization 
Quintiles, Inc. 
4820 Emperor Drive 
Durham, NC 27703 
Scale Management and Training 
ProPhase, LLC. 
3 Park Avenue, 28th & 37th Floor 
New York, NY 10016 
 
ERT (eResearch Technology) 
1818 Market Street, Suite 1000 
Philadelphia, PA 19103 
Central ECG reading 
Quintiles Data processing Centre (India) Pvt. Ltd. 
502-A, Leela Business Park, 
M.V.Road, Andheri-(East), 
Mumbai-400059 
India 
 
Quintiles Data processing Centre (India) Pvt. Ltd. 
Third Floor, Etamin Block, Prestige Technology Park II, 
Bellandur, Sarjapur-Marathahalli outer Ring road, 
Banglore-560103, Karnataka 
India 
IVRS/IWRS 
Cenduit, LLC 
4825 Creekstone Drive 
Suite 400  
Durham, NC 27703 
Central Laboratory 
Q2 Solutions 
27027 Tourney RoadSuite 2E 
Valencia, CA 91355 
Model Based Analysis 
Metrum Research Group, LLC 
2 Tunxis Rd., Suite 112,  
Tariffville, CT 06081 
Bioanalytic Lab 
Q2 Solutions 
19 Brown Rd 
Ithaca, NY 14850 
 
9.6 Data Handling and Record Keeping 
It is the Investigator’s responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other 
supporting documentation).  The study site should plan on retaining such documents for 
approximately 15 years after study completion.  The study site should retain such documents 
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until at least 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years after the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period if required by the 
applicable regulatory requirements or the hospital, institution, or private practice in which the 
study is being conducted.  Subject identification codes (subject names and corresponding 
study numbers) will be retained for this same period of time.  These documents may be 
transferred to another responsible party, acceptable to Sponsor, who agrees to abide by the 
retention policies.  Written notification of transfer must be submitted to Sponsor.  
The Investigator must contact Sponsor prior to disposing of any study records. 
9.7 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each subject randomized into the study. 
The Investigator will allow the Sponsor, Quintiles, and authorized regulatory authorities to 
have direct access to all documents pertaining to the study, including individual subject 
medical records, as appropriate. 
9.8 Investigator Information 
9.8.1 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline 
for GCP (GCP, 1997; the US CFR Title 21 parts 50, 56, and 312; and European Legislation); 
and the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator agrees to conduct the clinical study in compliance with this protocol after 
the approval of the protocol by the IEC/IRB in compliance with local regulatory 
requirements.  The Investigator and the Sponsor will sign the protocol to confirm this 
agreement. 
9.8.2 
Protocol Signatures 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative.  By signing the protocol, the 
Investigator confirms in writing that he/she has read, understands and will strictly adhere to 
the study protocol and will conduct the study in accordance with ICH Tripartite Guidelines 
for Good Clinical Practice and applicable regulatory requirements.  The study will not be 
able to start at any center where the Investigator has not signed the protocol. 
9.8.3 
Publication Policy  
The data generated by this study are confidential information of the Sponsor.  The Sponsor 
will make the results of the study publicly available.  The publication policy with respect to 
the Investigator and study center will be set forth in the Clinical Trial Agreement. 
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9.9 Financing and Insurance  
The Sponsor has obtained liability insurance, which covers this study as required by local 
law and/or national regulations and/or ICH guidelines whichever is applicable.  The terms of 
the insurance will be kept in the study files. 
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10.0 REFERENCES 
1. http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml.  Accessed May 14, 
2015. 
2. Graff-Guerrero A, Mamo D, Shammi CM, Mizrahi R, Marcon H, Barsoum P, et al. 
The effect of antipsychotics on the high-affinity state of D2 and D3 receptors positron 
emission tomography study with [
11C]-PHNOArch. Gen Psychiatry. 
2009;66(6):606-615. 
3. SAPHRIS® Summary Basis of Approval. 
4. Friberg, L.E., de Greef, R., Kerbusch, T. and Karlsson, M.O. Modeling and 
simulation of the time course of asenapine exposure response and dropout patterns in 
acute schizophrenia. Clin Pharmacol Ther.  2009(86):84-91. 
5. Chapel S, Hutmacher M, Haig G, et al.  Exposure-response analysis in patients with 
schizophrenia to assess the effect of asenapine on QTc prolongation.  Journal of 
Clinical Pharm, 2009;49:1297-1308. 
6. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, 
Hergueta T, Baker R, Dunbar G. The M.I.N.I. International Neuropsychiatric 
Interview (M.I.N.I.): The Development and Validation of a Structured Diagnostic 
Psychiatric Interview. J Clin Psychiatry. 1998;59(suppl 20):22-33. 
7. Kay SR, Opler LA, Fiszbein A.  Positive and negative syndrome scale (PANSS) 
rating criteria. Schizophr Bull. 1987;13(2):261-76. 
8. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of 
Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National 
Institute of Mental Health; 1976. 
9. Addington D, Addington J, Maticka-Tyndale E. Assessing depression in 
schizophrenia: The Calgary Depression Scale. Br J Psychiatry Suppl. 
1993;(22):39-44. 
10. Vernon MK, Revicki DA, Awad AG, et al. Psychometric evaluation of the 
Medication Satisfaction Questionnaire (MSQ) to assess satisfaction with 
antipsychotic medication among schizophrenia patients. Schizophr Res. 
2010;118(1-3):271-278. 
11. Simpson GN, Angus JWS.  A rating scale for extrapyramidal side effects. 
Acta Psychiatr Scand. 1970;212 (Suppl 44): S11-S19. 
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Protocol Version 2.0 Amendment 1: 20 January 2016 
Protocol Final Version: 16 November 2015  
 
 
Confidential 
 
12. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 
1989;154(5):672-6. 
13. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA et al. The 
columbia-suicide severity rating scale. Initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-1277.  
14. Berger, RS, Bowman, JP. A reappraisal of the 21-day cumulative irritation test in 
man. J. Toxicol. Ot. & Ocular Toxicol. 1982;1(2);109-115. 
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HP-3070-GL-04 
HP-3070 
Protocol Version 2.0 Amendment 1: 20 January 2016 
Protocol Final Version: 16 November 2015  
 
 
Confidential 
 
11.0 APPENDIX 1: SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE:  A Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, 
6-Week, In-Patient Study to Assess Efficacy and Safety of HP-3070 
in Subjects Diagnosed with Schizophrenia 
PROTOCOL NO:  
HP-3070-GL-04 
This protocol is a confidential communication of Noven.  I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol.  I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki 
and that are consistent with good clinical practices and the applicable laws and regulations.  
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from Noven 
Pharmaceuticals, Inc. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, title, and the 
name of the center in which the study will be conducted.  Return the signed copy to Quintiles, Inc. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:    
___________________________  Date: ______ 
Printed Name:   
  
  
___________________________ 
Investigator Title:    
  
___________________________ 
 
Name/Address of Center:    
___________________________ 
  
  
  
  
  
___________________________ 
  
  
  
  
  
___________________________ 
 
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HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
12.0 APPENDIX 2: POSITIVE AND NEGATIVE SYNDROME 
SCALE (PANSS) 
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P
 A
 N
 S
 S
Po
s
i
t
ive
 and
 Nega
t
ive
 Syndrome
 Sca
le
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P1. Delusions
P2. Conceptual disorganization
P3. Hallucinatory behavior
P4. Excitement
P5. Grandiosity
P6. Suspiciousness/persecution
P7. Hostility
N1. Blunted affect
N2. Emotional withdrawal
N3. Poor rapport
N4. Passive/apathetic social withdrawal
N5. Difficulty in abstract thinking
N6. Lack of spontaneity and flow of conversation
N7. Stereotyped thinking
G1. Somatic concerns
G2. Anxiety
G3. Guilt feelings
G4. Tension
G5. Mannerisms and posturing
G6. Depression
G7. Motor retardation
G8. Uncooperativeness
G9. Unusual thought content
G10. Disorientation
G11. Poor attention
G12. Lack of judgment and insight
G13. Disturbance of volition
G14. Poor impulse control
G15. Preoccupation
G16. Active social avoidance
S1. Anger
S2. Difficulty in delaying gratification
S3. Affective lability
PANSS
QuikScore™
Form
1 = Absent
2 = Minimal
3 = Mild
4 = Moderate
5 = Moderate/ Severe
6 = Severe
7 = Extreme
Use this scale for all items:
Patient Name or ID: ______________________________      Rater: ________________      Date: ___ / ___ / ___
Copyright © 1992, 2000 Multi-Health Systems Inc.
All  
rights  
reserved.
 In the U.S.A., P
.O. Box 950, North Tonawanda, NY 14120-0950, (800) 456-3003.
In Canada, 3770 Victoria Park Avenue, Toronto, ON M2H 3M6,  (800) 268-6011.
Internationally
,  +1-416-492-2627.
Fax, +1-416-492-3343 or (888) 540-4484.
For Reference Only
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P1
P2
P3
P4
P5
P6
P7
N1
N2
N3
N4
N5
N6
N7
G1
G2
G3
G4
G5
G6
G7
G8
G9
G10
G11
G12
G13
G14
G15
G16
S1
S2
S3
SUMS
Positive
Negative
Positive minus
Negative
COMPOSITE
General
Anergia
Thought
Disturbance
Activation
Paranoid/
Belligerence
Depression
Supplemental
Thought
Paranoid/
Positive 
Negative 
General 
Anergia  Disturbance Activation 
Belligerence Depression Supplemental
Thought
Paranoid/
Positive 
Negative 
General 
Anergia  Disturbance Activation 
Belligerence Depression Supplemental
SUMS
PANSS
QuikScore™
Form
Patient Name or ID: ______________________________      Rater: ________________      Date: ___ / ___ / ___
Copyright  ©  1992,  1999,  Multi-Health  Systems  Inc. All  rights  reserved.  In  the  U.S.A.,  P
.O.  Box  950,  North  Tonawanda,  NY  14120-0950,  (800)  456-3003.
In  Canada,  3770  Victoria  Park Avenue,  Toronto,  ON  M2H  3M6,  (800)  268-6011.  Internationally,  +1-416-492-26270.  Fax,  +1-416-492-3343  or  (888)  540-4484.
For Reference Only
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General
Thought
Paranoid/
Positive 
Negative 
Composite Psychopath. 
Anergia  Disturbance Activation Belligerence Depression
99 100+
37+ 
87+
27+
20+
27+ 
100+ 99
99 99
36
86
99 
99
99 98
35
85
26
19
26 
98 
99
99 97
84
97 
99
99 96 
49
34
83
21
96 
99
99 95 
48
33
82
25
25 
95 
99
99 94
49
32
81
18
94 
99
99 93 
47
80
20
93 
99
99 92 
46
48
31
24
24 
92 
99
99 91
47
30
79
91 
99
99 90 
45
29
78
17
90 
99
99 89 
44
46
28
77
23
19
23 
89 
99
99 88
76
88 
99
99 87 
43
45
27
75
16
22 
87 
99
99 86
44
26
74
22
18
86 
99
99 85 
42
25
73
85 
99
99 84 
41
43
72
28
21 
84 
99
99 83
42
24
71
21
15
17
83 
99
99 82 
40
23
70
27
82 
99
99 81 
39
41
22
69
20 
81 
99
99 80
21
68
20
26
80 
99
99 79 
38
40
67
14
16
79 
99
99 78
39
20
66
19 
78 
99
99 77 
37
19
65
19
25
77 
99
99 76 
36
38
18
64
15
76 
99
99 75
37
63
24
13
18 
75 
99
99 74 
35
17
62
18
74 
99
99 73 
34
36
16
23
73 
99
99 72
15
61
14
17 
72 
99
99 71 
33
35
14
60
17
22
12
71 
99
98 70
34
59
70 
98
97 69 
32
13
58
21
13
16 
69 
97
96 68 
31
33
12
57
16
68 
96
96 67
32
11
56
20
11
15 
67 
96
95 66 
30
55
12
66 
95
93 65 
29
31
10
54
15
65 
93
92 64
9
53
19
14 
64 
92
90 63 
28
30
8
52
10
63 
90
89 62
29
51
14
18
11
62 
89
86 61 
27
7
50
13 
61 
86
84 60 
26
28
6
49
17
9
60 
84
82 59
5
48
13
10
59 
82
79 58 
25
27
4
47
16
12 
58 
79
76 57 
24
26
46
57 
76
73 56
3
45
12
15
8
56 
73
69 55 
23
25
2
44
9
11 
55 
69
66 54
24
1
43
14
54 
66
62 53 
22
11
53 
62
58 52 
21
23
0
42
7
8
10 
52 
58
54 51
-1
41
13
51 
54
50 50 
20
22
-2
40
10
50 
50
46 49 
19
21
-3
39
12
7
9 
49 
46
42 48
38
6
48 
42
38 47 
18
20
-4
37
9
11
47 
38
35 46
19
-5
36
8
46
35
31 45 
17
-6
35
10
6
45 
31
27 44 
16
18
34
8
5
7 
44 
27
24 43
-7
33
9
43 
24
21 42 
15
17
-8
32
5
42 
21
18 41 
14
16
-9
31
7
8
6 
41 
18
16 40
-10
30
4
40 
16
14 39 
13
15
29
4
39 
14
12 38
14
-11
28
6
7
5 
38 
12
10 37 
12
-12
27
3
37 
10
8
36  
11  
13 
-13  
26
6
36  8
7
35
25  
5
3  
4  
35  7
6
34  
10  
12 
-14
5
34  6
5
33  
9  
11 
-15  
24
33 
5
4
32
-16
Ô23
4
4
32 
4
3
31
Ô8
Ô10
31 
3
2
30
Ô-17
30 
2
Patient Name or ID: ______________________________      Rater: ________________      Date: ___ / ___ / ___
Positive and Negative Syndrome Scale (PANSS) Profile Form
%ile
%ile
T
T
Copyright  ©  1992,  1999,  Multi-Health  Systems  Inc. All  rights  reserved.  In  the  U.S.A.,  P
.O.  Box  950,  North  Tonawanda,  NY  14120-0950,  (800)  456-3003.
In  Canada,  3770  Victoria  Park Avenue,  Toronto,  ON  M2H  3M6,  (800)  268-6011.  Internationally,  +1-416-492-26270.  Fax,  +1-416-492-3343  or  (888)  540-4484.
For Reference Only
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HP-3070-GL-04 
HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
13.0 APPENDIX 3: CLINICAL GLOBAL IMPRESSION - 
SEVERITY OF ILLNESS SCALE (CGI-S) 
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Clinical Global Impression- Severity of Illness Scale
Considering your total clinical experience with this particular population, how mentally ill is the 
patient at this time? 
0 = Not assessed  
  
 
4 = Moderately ill
1 = Normal, not at all ill  
  
5 = Markedly ill
2 = Borderline mentally ill    
6 = Severely ill
3 = Mildly ill   
  
  
7 = Among the most extremely ill patients
Reference:  Guy W. ECDEU Assessment Manual For Psychopharmacology. US Department of Health, Education, 
and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health; 1976.
For Reference Only
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HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
14.0 APPENDIX 4: CLINICAL GLOBAL IMPRESSION - 
IMPROVEMENT SCALE (CGI-I) 
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Clinical Global Impression - Improvement Scale 
Reference:
For Reference Only
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HP-3070-GL-04 
HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
15.0 APPENDIX 5: CALGARY DEPRESSION SCALE FOR 
SCHIZOPHRENIA (CDSS) 
 
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Interviewer:  
  
  Ask  
the  
first  question  as  written.  Use  
follow  up  probes  or  qualifiers  at  your  discretion.  Time  
frame 
refers to last two weeks unless stipulated. N.B.The last item, #9, is based on observations of the entire interview. 
1. DEPRESSION: How would you describe your mood over the last two 
weeks? Do you keep reasonably cheerful or have you been very 
depressed or low spirited recently? In the last two weeks how often 
have you (own words) every day? All day? 
0. Absent 
1. Mild  
Expresses some sadness or discouragement on questioning. 
2. Moderate  
Distinct depressed mood persisting up to half the time over last 
2 weeks: present daily. 
3. Severe  
Markedly depressed mood persisting daily over half the time 
interfering with normal motor and social functioning. 
2. HOPELESSNESS: How do you see the future for yourself? Can you 
see any future? - or has life seemed quite hopeless? Have you given 
up or does there still seem some reason for trying? 
0. Absent 
1. Mild  
Has at times felt hopeless over the last two weeks but still has 
some degree of hope for the future. 
2. Moderate  Persistent, moderate sense of hopelessness over last week. Can 
be persuaded to acknowledge possibility of things being better. 
3. Severe  
Persisting and distressing sense of hopelessness. 
3. SELF D
EPRECIATION: What is your opinion of your self compared 
to other people? Do you feel better, not as good, or about the same 
as others? Do you feel inferior or even worthless? 
0. Absent 
1. Mild  
Some inferiority; not amounting to feeling of worthlessness. 
2. Moderate  Subject feels worthless, but less than 50% of the time. 
3. Severe  
Subject feels worthless more than 50% of the time. May be 
challenged to acknowledge otherwise. 
4. GUILTY I
DEAS O
F R
EFERENCE: Do you have the feeling that you  
are being blamed for something or even wrongly accused? What  
about? (Do not include justifiable blame or accusation. Exclude  
delusions of guilt.) 
0. Absent 
1. Mild  
Subject feels blamed but not accused less than 50% of the time. 
2. Moderate  Persisting sense of being blamed, and/or occasional sense of 
being accused. 
3. Severe  
Persistent sense of being accused. When challenged, 
acknowledges that it is not so. 
5. PATHOLOGICAL G
UILT: Do you tend to blame yourself for little 
things you may have done in the past? Do you think that you deserve  
to be so concerned about this? 
0. Absent 
1. Mild  
Subject sometimes feels over guilty about some minor 
peccadillo, but less than 50% of time. 
2. Moderate  Subject usually (over 50% of time) feels guilty about past 
actions the significance of which he exaggerates. 
3. Severe  
Subject usually feels s/he is to blame for everything that has 
gone wrong, even when not his/her fault. 
6. MORNING D
EPRESSION: When you have felt depressed over the last  
2 weeks have you noticed the depression being worse at any  
particular time of day? 
0. Absent  
No depression. 
1. Mild  
Depression present but no diurnal variation. 
2. Moderate  
Depression spontaneously mentioned to be worse in a.m. 
3. Severe  
Depression markedly worse in a.m., with impaired functioning 
which improves in p.m. 
7. EARLY W
AKENING: Do you wake earlier in the morning than is  
normal for you? How many times a week does this happen? 
0. Absent  
No early wakening. 
1. Mild  
Occasionally wakes (up to twice weekly) 1 hour or more before 
normal time to wake or alarm time. 
2. Moderate  
Often wakes early (up to 5 times weekly) 1 hour or more before 
normal time to wake or alarm. 
3. Severe  
Daily wakes 1 hour or more before normal time. 
8. SUICIDE: Have you felt that life wasn’t worth living? Did you ever  
feel like ending it all? What did you think you might do? Did you  
actually try? 
0. Absent 
1. Mild  
Frequent thoughts of being better off dead, or occasional 
thoughts of suicide. 
2. Moderate  
Deliberately considered suicide with a plan, but made no 
attempt. 
3. Severe  
Suicidal attempt apparently designed to end in death (i.e.: 
accidental discovery or inefficient means). 
9. OBSERVED D
EPRESSION: Based on interviewer’s observations  
during the entire interview. The question “Do you feel like crying?”  
used at appropriate points in the interview, may elicit information  
useful to this observation. 
0. Absent 
1. Mild  
Subject appears sad and mournful even during parts of the 
interview, involving affectively neutral discussion. 
2. Moderate 
Subject appears sad and mournful throughout the interview, with 
gloomy monotonous voice and is tearful or close to tears at times. 
3. Severe  
Subject chokes on distressing topics, frequently sighs deeply 
and cries openly, or is persistently in a state of frozen misery if 
examiner is sure that this is present. 
© Dr. Donald Addington and Dr. Jean Addington.  
For Reference Only
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HP-3070-GL-04 
HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
16.0 APPENDIX 6: MEDICATION SATISFACTION 
QUESTIONNAIRE (MSQ) 
 
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MEDICATION SATISFACTION QUESTIONNAIRE 
Overall, how satisfied are you with your current medication? 
Extremely 
Very 
Somewhat 
Neither 
Somewhat 
Very satisfied 
Extremely 
dissatisfied 
dissatisfied 
dissatisfied 
dissatisfied 
satisfied 
satisfied 
nor satisfied 
0 1  0 2  0 3  0 4 
O s 
0 6  0 7 
"Spanish Medication Satisfaction Questionnaire", translated 
from English lo Spanish by Edith Grandiccelli de Talamo, on September 
3, 2007 from "Medication Satisfaction Questionnaire", . 
© 2010 International Society for 
CNS Drug Development 
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HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
17.0 APPENDIX 7: SIMPSON ANGUS SCALE (SAS) 
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SIMPSON-ANGUS SCALE (SAS) 
Copyright © Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects.  
Acta Psychiatrica Scandinavica 212:11–19, 1970. Reproduced with permission of Blackwell Publishing Ltd 
 
SAS - United States/English - Mapi. 
ID7808 / SAS_AU1.0_eng-USori.doc 
1
SIMPSON-ANGUS SCALE 
 
(SAS) 
 
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SIMPSON-ANGUS SCALE (SAS) 
Copyright © Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects.  
Acta Psychiatrica Scandinavica 212:11–19, 1970. Reproduced with permission of Blackwell Publishing Ltd 
 
SAS - United States/English - Mapi. 
ID7808 / SAS_AU1.0_eng-USori.doc 
2
 
 
1. GAIT:  
The patient is examined as he walks into the examining room, his gait, the swing of his arms, his general 
posture, all form the basis for an overall score for this item. This is rated as follows:  
 
 
 
0 = Normal  
 
 
 
1 = Diminution in swing while the patient is walking  
 
 
 
2 = Marked diminution in swing with obvious rigidity in the arm  
 
 
 
3 = Stiff gait with arms held rigidly before the abdomen  
 
 
 
4 = Stooped shuffling gait with propulsion and retropulsion  
 
 
 
 
 
 
2. ARM DROPPING:  
The patient and the examiner both raise their arms to shoulder height and let them fall to their sides. In 
a normal subject a stout slap is heard as the arms hit the sides. In the patient with extreme Parkinson's 
syndrome the arms fall very slowly:  
 
 
 
0 = Normal, free fall with loud slap and rebound  
 
 
 
1 = Fall slowed slightly with less audible contact and little rebound  
 
 
 
2 = Fall slowed, no rebound  
 
 
 
3 = Marked slowing, no slap at all  
 
 
 
4 = Arms fall as though against resistance; as though through glue  
 
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SIMPSON-ANGUS SCALE (SAS) 
Copyright © Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects.  
Acta Psychiatrica Scandinavica 212:11–19, 1970. Reproduced with permission of Blackwell Publishing Ltd 
 
SAS - United States/English - Mapi. 
ID7808 / SAS_AU1.0_eng-USori.doc 
3
 
 
 
 
 
3. SHOULDER SHAKING:  
The subject's arms are bent at a right angle at the elbow and are taken one at a time by the examiner 
who grasps one hand and also clasps the other around the patient's elbow. The subject's upper arm is 
pushed to and fro and the humerus is externally rotated. The degree of resistance from normal to 
extreme rigidity is scored as follows: 
 
 
 
0 = Normal  
 
 
 
1 = Slight stiffness and resistance  
 
 
 
2 = Moderate stiffness and resistance  
 
 
 
3 = Marked rigidity with difficulty in passive movement  
 
 
 
4 = Extreme stiffness and rigidity with almost a frozen shoulder  
 
 
 
 
 
 
4. ELBOW RIGIDITY:  
The elbow joints are separately bent at right angles and passively extended and flexed, with the subject's 
biceps observed and simultaneously palpated. The resistance to this procedure is rated. (The presence of 
cogwheel rigidity is noted separately.)  
 
 
 
0 = Normal  
 
 
 
1 = Slight stiffness and resistance  
 
 
 
2 = Moderate stiffness and resistance  
 
 
 
3 = Marked rigidity with difficulty in passive movement  
 
 
 
4 = Extreme stiffness and rigidity with almost a frozen shoulder  
 
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SIMPSON-ANGUS SCALE (SAS) 
Copyright © Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects.  
Acta Psychiatrica Scandinavica 212:11–19, 1970. Reproduced with permission of Blackwell Publishing Ltd 
 
SAS - United States/English - Mapi. 
ID7808 / SAS_AU1.0_eng-USori.doc 
4
 
 
 
 
 
5. FIXATION OF POSITION or Wrist Rigidity:  
The wrist is held in one hand and the fingers held by the examiner's other hand, with the wrist moved to 
extension, flexion and both ulner and radial deviation:  
 
 
 
0 = Normal  
 
 
 
1 = Slight stiffness and resistance  
 
 
 
2 = Moderate stiffness and resistance  
 
 
 
3 = Marked rigidity with difficulty in passive movement  
 
 
 
4 = Extreme stiffness and rigidity with almost a frozen shoulder  
 
 
 
 
 
 
6. LEG PENDULOUSNESS:  
The patient sits on a table with his legs hanging down and swinging free. The ankle is grasped by the 
examiner and raised until the knee is partially extended. It is then allowed to fall. The resistance to falling 
and the lack of swinging form the basis for the score on this item: 
 
 
 
0 = The legs swing freely  
 
 
 
1 = Slight diminution in the swing of the legs  
 
 
 
2 = Moderate resistance to swing  
 
 
 
3 = Marked resistance and damping of swing  
 
 
 
4 = Complete absence of swing 
 
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SIMPSON-ANGUS SCALE (SAS) 
Copyright © Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects.  
Acta Psychiatrica Scandinavica 212:11–19, 1970. Reproduced with permission of Blackwell Publishing Ltd 
 
SAS - United States/English - Mapi. 
ID7808 / SAS_AU1.0_eng-USori.doc 
5
 
 
 
7. HEAD DROPPING:  
The patient lies on a well-padded examining table and his head is raised by the examiner's hand. The 
hand is then withdrawn and the head allowed to drop. In the normal subject the head will fall upon the 
table. The movement is delayed in extrapyramidal system disorder, and in extreme parkinsonism it is 
absent. The neck muscles are rigid and the head does not reach the examining table. Scoring is as 
follows:  
 
 
 
0 = The head falls completely with a good thump as it hits the table  
 
 
 
1 = Slight slowing in fall, mainly noted by lack of slap as head meets the table  
 
 
 
2 = Moderate slowing in the fall quite noticeable to the eye  
 
 
 
3 = Head falls stiffly and slowly  
 
 
 
4 = Head does not reach the examining table  
 
 
 
 
 
8. GLABELLA TAP:  
Subject is told to open his eyes wide and not to blink. The glabella region is tapped at a steady, rapid 
speed. The number of times patient blinks in succession is noted:  
 
 
 
0 = 0 - 5 blinks  
 
 
 
1 = 6 – 10 blinks  
 
 
 
2 = 11 – 15 blinks  
 
 
 
3 = 16 - 20 blinks  
 
 
 
4 = 21 and more blinks  
 
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SIMPSON-ANGUS SCALE (SAS) 
Copyright © Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects.  
Acta Psychiatrica Scandinavica 212:11–19, 1970. Reproduced with permission of Blackwell Publishing Ltd 
 
SAS - United States/English - Mapi. 
ID7808 / SAS_AU1.0_eng-USori.doc 
6
 
 
 
9. TREMOR:  
Patient is observed walking into examining room and is then reexamined for this item:  
 
 
 
0 = Normal  
 
 
 
1 = Mild finger tremor, obvious to sight and touch  
 
 
 
2 = Tremor of hand or arm occurring spasmodically  
 
 
 
3 = Persistent tremor of one or more limbs  
 
 
 
4 = Whole body tremor  
 
 
 
 
 
10. SALIVATION:  
Patient is observed while talking and then asked to open his mouth and elevate his tongue. The following 
ratings are given:  
 
 
 
0 = Normal  
 
 
 
1 = Excess salivation to the extent that pooling takes place if the mouth is open and the tongue 
raised.  
 
 
 
2 = When excess salivation is present and might occasionally result in difficulty in speaking  
 
 
 
3 = Speaking with difficulty because of excess salivation  
 
 
 
4 = Frank drooling  
 
 
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Noven Pharmaceuticals, Inc. 
 
HP-3070-GL-04 
HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
18.0 APPENDIX 8: ABNORMAL INVOLUNTARY 
MOVEMENT SCALE (AIMS) 
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For Reference Only
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For Reference Only
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141

Noven Pharmaceuticals, Inc. 
 
HP-3070-GL-04 
HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
19.0 APPENDIX 9: BARNES AKATHISIA RATING SCALE 
(BARS) 
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Rating scale for drug-induced akathisia (Barnes 
Akathisia Rating Scale) 
Patient name: 
Patient research no.: 
Hospital No.: 
Ward:
Rater:
Instructions 
Patient should be observed while they are seated, and then standing while 
engaged in neutral conversation (for a minimum of two minutes in each 
position). Symptoms observed in other situations, for example while engaged in 
activity on the ward, may also be rated. Subsequently, the subjective 
phenomena should be elicited by direct questioning. 
Objective
0
Normal, occasional fidgety movements of the limbs 
1
Presence of characteristic restless movements: shuffling or tramping 
movements of the legs/feet, or swinging of one leg while sitting, and/or 
rocking from foot to foot or “walking on the spot” when standing, but
movements present for less than half the time observed 
2
Observed phenomena, as described in (1) above, which are present for at 
least half the observation period 
3
Patient is constantly engaged in characteristic restless movements, and/or 
has the inability to remain seated or standing without walking or pacing, 
during the time observed 
Subjective 
Awareness of restlessness 
0
Absence of inner restlessness 
1
Non-specific sense of inner restlessness 
2
The patient is aware of an inability to keep the legs still, or a desire to 
move the legs, and/or complains of inner restlessness aggravated 
specifically by being required to stand still 
3
Awareness of intense compulsion to move most of the time and/or reports 
strong desire to walk or pace most of the time 
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Distress related to restlessness
0
No distress 
1
Mild 
2
Moderate 
3
Severe
Global clinical assessment of akathisia 
0
Absent. No evidence of awareness of restlessness. Observation of 
characteristic movements of akathisia in the absence of a subjective report 
of inner restlessness or compulsive desire to move the legs should be 
classified as pseudoakathisia 
1
Questionable. Non-specific inner tension and fidgety movements 
2
Mild akathisia. Awareness of restlessness in the legs and/or inner
restlessness worse when required to stand still. Fidgety movements 
present, but characteristic restless movements of akathisia not necessarily 
observed. Condition causes little or no distress 
3
Moderate akathisia. Awareness of restlessness as described for mild 
akathisia above, combined with characteristic restless movements such as 
rocking from foot to foot when standing. Patient finds the condition 
distressing 
4
Marked akathisia. Subjective experience of restlessness includes a 
compulsive desire to walk or pace. However, the patient is able to remain 
seated for at least five minutes. The condition is obviously distressing 
5
Severe akathisia. The patient reports a strong compulsion to pace up and 
down most of the time. Unable to sit or lie down for more than a few 
minutes. Constant restlessness which is associated with intense distress 
and insomnia 
Reproduced from: A rating scale for drug-induced akathisia. T.R.E. Barnes, 
British Journal of Psychiatry (1989), 154, 672-676. 
© 1989 The Royal College of Psychiatrists. 
For Reference Only
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Noven Pharmaceuticals, Inc. 
 
HP-3070-GL-04 
HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
20.0 APPENDIX 10: COLUMBIA-SUICIDE SEVERITY 
RATING SCALE (C-SSRS) 
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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS) 
 
 
D
isc
la
imer
: 
Th
is sca
le 
is 
intended to be used by 
ind
iv
idua
ls who have rece
ived tra
in
ing 
in 
its adm
in
istrat
ion. The quest
ions conta
ined 
in the Co
lumb
ia-Su
i
c
ide Sever
ity Rat
ing Sca
le are suggested probes
. U
lt
imate
ly
, the determ
inat
ion of the presence of 
su
ic
ida
l 
ideat
ion or behav
ior depends on the 
judgment of the 
ind
iv
idua
l adm
in
ister
ing the sca
le. 
Def
in
it
ions of behav
iora
l su
ic
ida
l events 
in th
is sca
le are based on those used 
in The Columbia Suicide History 
Form, deve
loped by John Mann
, MD and Mar
ia Oquendo
, MD
, Conte Center for the Neurosc
ience of Menta
l D
isorders 
(CCNMD)
, New York State Psych
iatr
ic Inst
itute
, 1051 R
ivers
ide Dr
ive
, New York
, NY
, 10032
. (Oquendo M
. A
.
, 
Ha
lberstam B
. & Mann J
. J
.
, R
isk factors for su
ic
ida
l behav
ior
: uti
l
ity and 
l
im
itat
ions of researc
h 
instruments
. In M
.B
. F
irst 
[Ed
.] Standardized Evaluation in Clinical Practice, pp
. 103 -130
, 2003
.) 
 
For repr
ints of the C-SSRS contact Ke
l
ly Posner
, Ph
.D.
, New York State Psych
iatr
ic Inst
itute
, 1051 R
ivers
ide Dr
ive
, New 
York
, New York
, 10032
; 
inqu
ir
ies and tra
in
ing requ
irements contact posnerk@nysp
i
.co
lumb
ia
.edu
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
d by 
ind
iv
id
d by 
ind
iv
i
ver
ity Rat
in
ver
ity Rat
ion or beha
ion or beha
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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
D
isc
la
imer
: 
Th
is sca
le 
is 
intended to be used by 
ind
iv
idua
ls who have rece
ived tra
in
ing in 
its adm
in
istrat
ion. The quest
ions conta
ined 
in 
the Co
lumb
ia-Su
ic
ide Sever
ity Rat
ing Sca
le are suggested probes
. U
lt
imate
ly
, the determ
inat
ion of the presence of su
ic
ida
l 
ideat
ion or behav
ior depends on the 
judgment of the 
ind
iv
idua
l adm
in
ister
ing the sca
le. 
Def
in
it
ions of behav
iora
l su
ic
ida
l events 
in th
is sca
le are based on those used 
in The Columbia Suicide History Form, 
deve
loped by John Mann
, MD and Mar
ia Oquendo
, MD
, Conte Center for the Neurosc
ience of Menta
l D
isorders 
(CCNMD)
, New York State Psych
iatr
ic Inst
itute
, 1051 R
ivers
ide Dr
ive
, New York
, NY
, 10032
. (Oquendo M
. A
.
, 
Ha
lberstam B
. & Mann J
. J
., R
isk factors for su
ic
ida
l behav
ior
: uti
l
ity and 
l
im
itat
ions of researc
h 
instruments
. In M
.B
. F
irst 
[Ed
.] Standardized Evaluation in Clinical Practice, pp
. 103 -130
, 2003
.) 
 
For repr
ints of the C-SSRS contact Ke
l
ly Posner
, Ph
.D.
, New York State Psych
iatr
ic Inst
itute
, 1051 R
ivers
ide Dr
ive
, New 
York
, New York
, 10032
; 
inqu
ir
ies and tra
in
ing requ
irements contact posnerk@nysp
i
.co
lumb
ia
.edu
© 2008 The Research Foundation for Mental Hygiene, Inc. 
D
isc
l
D
isc
ua
ls who ha
ua
ls who ha
a
le are sugg
a
le are sug
r depends o
r depends o
a
l su
ic
id
a
l su
i
M
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Noven Pharmaceuticals, Inc. 
 
HP-3070-GL-04 
HP-3070 
Protocol
 Version 2.0 Amendment 1:
 20 January 2016 
Protocol
 Final
 Version:
 16 November 2015  
 
 
Confidential 
 
21.0 APPENDIX 11: M.I.N.I. INTERNATIONAL 
NEUROPSYCHIATRIC INTERVIEW (MINI) 
 
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O 
        
  
 
 
 
  
 
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.  
 
 
  
  
                
 
 
 
         
      
              
      
               
         
                         
           
 
  
 
 
 
 
 
 
 
 
 
    
  
  
  
      
  
  
  
                                           
    
 
   
   
 
 
   
 
 
 
 
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. 
 
 
 
  
 
 
  
 
 
  
 
 
 
     
 
  
 
    
 
 
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a) 
   
 
b) 
   
 
c) 
    
 
 
 
            
 
 
 
                   
                          
 
 
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.  
 
 
 
 
 
  
 
 
  
 
 
b
 
 
 
 
 
 
  
 
 
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.  
 
 
 
 
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.  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
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• 
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G5
 
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.  
 
 
 
 
 
   
  
 
 
 
 
 
 
           
 
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__________________________________ 
            
 
 
 
   
 
 
       
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c 
               
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.  
  
 
 
 
 
 
 
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↓ 
 
  
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≥
<
≥
≥
<
≥
<
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>
<
≥
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• 
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MOOD DISORDER DUE TO A GENERAL MEDICAL CONDITION
 
 
  
SUBSTANCE INDUCED MOOD DISORDER
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
MANIC EPISODE DUE TO A GENERAL MEDICAL CONDITION
 
 
  
HYPOMANIC EPISODE DUE TO A GENERAL MEDICAL CONDITION
 
 
  
SUBSTANCE INDUCED MANIC EPISODE
 
 
 
 
 
 
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SUBSTANCE INDUCED HYPOMANIC EPISODE
 
 
 
 
 
  
ANXIETY DISORDER WIITH PANIC ATTACKS DUE TO
A GENERAL MEDICAL CONDITION
 
 
  
SUBSTANCE INDUCED ANXIETY DISORDER WITH PANIC ATTACKS
 
 
 
  
 
 
 
  
OCD DUE TO A GENERAL MEDICAL CONDITION
  
SUBSTANCE INDUCED OCD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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GAD DUE TO A GENERAL MEDICAL CONDITION
 
  
SUBSTANCE INDUCED GAD
   
 
  
 
 
 
 
   
 
  
 
 
 
 
   
 
  
 
 
 
 
 
   
 
  
 
 
 
 
   
 
  
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
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