Clinical trial NCT02892422
Conditions: Schizophrenia
Sponsor: H. Lundbeck A/S
Start date: 2016-08-01; Completion date: 2019-10-10
Enrollment: 528 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the safety and tolerability of the long-term treatment with Lu AF35700.

Detailed description:
Safety study in patients with schizophrenia who have participated and completed a study investigating Lu AF35700 including Studies 16159A and 16323A. Or in patients with schizophrenia for whom a switch of antipsychotic treatment can be potentially beneficial according to the investigator's clinical judgement.

Arms: arm 1: None
Interventions: intervention 1: Lu AF35700
Intervention descriptions: intervention 1: Flexible-dose of Lu AF35700, 10 or 20 mg/day, tablets, orally.

From Day 8, the daily dose can be increased to 20mg. Thereafter, the daily dose can be adjusted (decreased to 10mg or following a decrease, increased to 20mg/day)

Patients who completed the 16159A study, only, can be switched to a weekly 70 mg Lu AF35700 dosing regimen (tablets, orally, once weekly) after 8 weeks in this study

Protocol documents:
Prot_000.pdf: 
H. Lundbeck A/S 
Confidential
Page 1 of 87
Clinical Study Protocol
Interventional, open-label, flexible-dose, long-term safety 
study of Lu AF35700 in adult patients with schizophrenia
Lu AF35700
Study No.:
16159B
EudraCT/IND No.:
2015-003284-11 (EU) / 116,335 (US)
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
1.0 
(the version No. in the footer is the system version No.)
Date of edition:
24-May-2016
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S is the holder of any and all 
related intellectual property rights, including, but not limited to, copyrights.  This document is 
confidential.  It is not to be copied or distributed to other parties without prior written authorisation 
from H. Lundbeck A/S.


H. Lundbeck A/S 
Confidential
Page 2 of 87
Synopsis – Study 16159B
Sponsor
H. Lundbeck A/S
Investigational Medicinal Product
Lu AF35700
EudraCT/IND No.
2015-003284-11 / 116,335
Title of Study
Interventional, open-label, flexible-dose long-term safety study of Lu AF35700 in adult patients with 
schizophrenia
Study Site(s) and Number of Patients Planned
120 sites are planned in approximately 15 countries (in-/out-patient clinics). The selected sites will be preferably 
the sites which participated in the study 16159A or in the study 16323A.
Approximately 400 patients with schizophrenia are planned to be enrolled with the following assumptions: 270 
patients who will have completed the study 16159A, 30 patients who will have completed the dosing period of 
the study 16323A and 100 additional patients with schizophrenia for whom a switch of antipsychotic treatment 
can be potentially beneficial. The distribution of the number of patients may be adjusted based upon the 
recruitment rate in each group.
Objectives
Primary objective:
to evaluate the safety and tolerability of the long-term treatment with Lu AF35700.
Exploratory objectives:
to evaluate the long-term safety and tolerability of daily and weekly doses of Lu AF35700 in patients with 
schizophrenia during the 52-week treatment period
to evaluate the therapeutic effectiveness of daily and weekly doses of Lu AF35700 in patients with 
schizophrenia over a period of 52 weeks on:
psychotic symptoms
negative symptoms 
global clinical impression
remission rate
quality of life and functioning
treatment satisfaction
health care resource utilisation
Study Methodology
This study is a multi-national, multi-site, open-label, flexible-dose, long-term (52-week) safety study in 
patients with schizophrenia who have participated and completed a study investigating Lu AF35700 including 
studies 16159A and 16323A, or in patients with schizophrenia for whom a switch of antipsychotic treatment 
can be potentially beneficial according to the investigator’s clinical judgement (either due to sub-optimal 
symptom control or lack of tolerability of their current antipsychotic treatment).
The recruitment of patients who need to change their antipsychotic treatment can start in a given site only after 
the recruitment of the patients in the study 16159A or in the study 16323A is completed.
The adjustment of Lu AF35700 dosing regimen (10 mg/day or 20 mg/day) during the course of the study will 
be left to the investigator’s clinical judgement. 
For patients who have completed the study 16159A, the daily dosing regimen (10 mg/day or 20 mg/day) can 
be switched to weekly dosing regimen (70 mg/week) according to the investigator’s clinical judgement. The 
number of patients under weekly dosing regimen will be limited to 50 patients by IVRS/IWRS.
For patients who completed study 16159A (16159A-patients)
The Baseline Visit of this long-term safety study (study 16159B) will take place at the same visit as the Visit 
12 (Primary Outcome Visit, end of Week 16) of the study 16159A.
After the baseline assessment, for eligible patients, the treatment with Lu AF35700 will be initiated at daily 


H. Lundbeck A/S 
Confidential
Page 3 of 87
dose of 10 mg at Day 1 of study 16159B. In addition, for 16159A-patients, the treatment (Lu AF35700, 
risperidone or olanzapine) received during study 16159A will be tapered down in a blinded fashion and will 
be completed in 7 days. 
At the end of the first week (Week 1 Visit), all patients will be treated with 10 mg/day Lu AF35700 only. 
From the Week 1 Visit, according to the investigator’s clinical judgement, the 10 mg/day dose can be 
increased to 20 mg/day based on the patient’s response. Thereafter, the 20 mg/day dose can be reduced to 
10 mg/day based on the patient’s tolerability to treatment. This can occur at scheduled or unscheduled visits.
From the Week 8 Visit, the switch from Lu AF35700 daily dosing regimen to Lu AF35700 weekly dosing 
regimen can be performed at any consecutive visit according to the investigator’s clinical judgment. The first 
weekly tablet will be taken 7 days after the last daily tablet. The Lu AF35700 weekly dosing regimen can be 
switched back to a daily dosing regimen of 10 mg/day for tolerability reasons or to 20 mg/day for worsening 
of the patient’s clinical status. This can occur at scheduled or unscheduled visits. The first daily tablet will be 
taken 7 days after the last weekly tablet.
For patients who completed the dosing period of the study 16323A (16323A-patients)
The Baseline Visit of study 16159B will take place at the same visit as the last day of the dosing period of 
study 16323A.
After the baseline assessment, for eligible patients, the treatment with Lu AF35700 will be initiated at daily 
dose of 10 mg at Day 1 of study 16159B. In addition, for 16323A-patients, the treatment (Lu AF35700 or 
quetiapine) received during study 16323A will be tapered down in a blinded fashion and will be completed in 
7 days.
At the end of the first week (Week 1 Visit), all patients will be treated with 10 mg/day Lu AF35700 only. 
At visits following the Week 1 Visit, according to the investigator’s clinical judgement, the 10 mg/day dose 
can be increased to 20 mg/day based on the patient’s response. Thereafter, the 20 mg/day dose can be reduced 
to 10 mg/day based on the patient’s tolerability to treatment. This can occur at scheduled or unscheduled 
visits.
For other patients who can potentially benefit from treatment with Lu AF35700 (Other Patients)
After the baseline assessment, for eligible patients, the current antipsychotic treatment will be tapered down 
and completed in 7 days, while the treatment with Lu AF35700 will be initiated at a 10 mg/day dose at Day 1.  
The 10 mg/day dose will be maintained during the first week of study 16159B.
At the end of the first week (Week 1 Visit), all patients will be treated with 10 mg/day Lu AF35700 only. 
At visits following the Week 1 Visit, according to the investigator’s clinical judgement, the 10 mg/day dose 
can be increased to 20 mg/day based on the patient’s response. Thereafter, the 20 mg/day dose can be reduced 
to 10 mg/day based on the patient’s tolerability to treatment. This can occur at scheduled or unscheduled 
visits.
For all patients 
Safety and effectiveness assessments will be performed at the end of Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48, and 52.
Patients who complete the 52-week Treatment Period will be contacted for a safety follow-up assessment 
6 weeks after the last dose taken.
If possible, patients who withdraw from the study will be seen for a Withdrawal Visit as soon as possible after 
they withdraw and will be contacted for a safety follow-up assessment 6 weeks after the last dose of IMP.
The total study duration per patient from screening to the end of follow-up will be up to 58 weeks for 
16159A-patients and 16323A-patients and up to 60 weeks for Other Patients.
The study design is presented in Panel 1, the scheduled assessments are summarised in Panel 2, and the 
treatment regimen is presented in Panel 3.


H. Lundbeck A/S 
Confidential
Page 4 of 87
Target Patient Population
Any patient with schizophrenia who has participated and completed a study investigating the Lu AF35700, can 
be included in this study, including:
Patients with treatment resistant schizophrenia (TRS) who completed study 16159A (16159A-patients);
Patients with schizophrenia who completed the dosing period of study 16323A (16323A-patients).
In addition, patients who are not experiencing an acute exacerbation, who are currently under antipsychotic 
treatment and who, according to the investigator’s clinical judgement, can potentially benefit from treatment 
with Lu AF35700 (Other Patients), can also be included in this study.
Key Inclusion Criteria 
For 16159A-patients
The patient has completed study 16159A.
The patient is able to read and understand the Informed Consent Form.
The patient has signed the Informed Consent Form specific for study 16159B.
The patient can potentially benefit from 52-week treatment with Lu AF35700 according to the investigator’s 
clinical judgement.
For 16323A-patients
The patient has completed the dosing period of study 16323A.
The patient is able to read and understand the Informed Consent Form.
The patient has signed the Informed Consent Form specific study 16159B.
The patient has a confirmed diagnosis of schizophrenia according to DSM-5™. 
The patient can potentially benefit from 52-week treatment with Lu AF35700 according to the investigator’s 
clinical judgement.
For Other Patients
The patient has schizophrenia, diagnosed according to DSM-5™. 
The patient is able to read and understand the Informed Consent Form.
The patient has signed the Informed Consent Form specific study 16159B.
The patient is a man or woman, aged ≥18 years.
The patient has been prescribed oral antipsychotic treatment at the recommended dose range as stated in the 
SmPC or equivalent document/label for 6 weeks prior to the Screening Visit.
The patient has a PANSS total score ≥60 and 90 at Screening and Baseline Visits.
The patient has a Clinical Global Impression – Severity of Illness (CGI-S) score 4.
The patient is in need of a change in the current antipsychotic treatment and, according to the investigator’s 
clinical judgement, the patient can potentially benefit from a switch to another treatment including, but not 
limited to, any of the following reasons:
lack of adequate response to his or her current antipsychotic medication;
poor tolerability to his or her current antipsychotic medication; 
unwillingness of the patient to adhere to his or her current antipsychotic medication.
Key Exclusion Criteria
For 16159A-patients
The patient has been diagnosed with a primary psychiatric disorder other than schizophrenia during 
study 16159A.
The patient, in the opinion of the investigator, is at significant risk of suicide, or:
Answers “Yes” to any question on the Suicidal Behaviour section of the C-SSRS, OR
Answers “Yes” to questions 4 and 5 on the Suicidal Ideation section of the C-SSRS


H. Lundbeck A/S 
Confidential
Page 5 of 87
For 16323A-patients
The patient has been diagnosed with a primary psychiatric disorder other than schizophrenia during 
study 16323A.
The patient, in the opinion of the investigator, is at significant risk of suicide, or:
Answers “Yes” to any question on the Suicidal Behaviour section of the C-SSRS, OR
Answers “Yes” to questions 4 and 5 on the Suicidal Ideation section of the C-SSRS
For Other Patients
The patient has any current psychiatric disorder (DSM-5™ criteria) other than schizophrenia established as the 
primary diagnosis.
The patient is experiencing acute exacerbation of psychotic symptoms at the Screening Visit, between the 
Screening and Baseline Visits or at the Baseline Visit. 
The patient is treated with clozapine at the time of the Screening Visit.
The patient has a substance use disorder which according to the investigator’s judgment may compromise the 
patient’s ability to comply with the study procedures, or preclude the benefits of the study medication.
The patient, in the opinion of the investigator, is at significant risk of suicide, or:
Answers “Yes” to any question on the Suicidal Behaviour section of the C-SSRS, OR
Answers “Yes” to questions 4 and 5 on the Suicidal Ideation section of the C-SSRS
Investigational Medicinal Products, Doses and Mode of Administration
Lu AF35700 – 10, 20 mg/day; tablets, orally, once daily
Lu AF35700 – 70 mg/week; tablets, orally, once weekly
Tablets will be taken in the morning or evening. 
For16159A-patients 
In addition, during the first week of study 16159B, 16159A-patients will receive (in a blinded fashion) a 
down-titration wallet from study 16159A.
For patients who were randomised to risperidone or olanzapine in study 16159A, the discontinuation of 
risperidone or olanzapine will be done according to the following scheme:
Risperidone: 4 mg/day for the first 3 days; 2 mg/day for the 4 subsequent days, encapsulated tablets, orally, 
once daily
Olanzapine: 10 mg/day for the first 3 days; 5 mg/day for the 4 subsequent days, encapsulated tablets, orally, 
once daily
For patients who were randomised to Lu AF35700 in study 16159A, the Lu AF35700 encapsulated tablets will 
be stopped and patients will receive placebo for 7 days, encapsulated tablets, orally, once daily.
For 16323A-patients 
In addition, during the first week of study 16159B, 16323A-patients will receive (in a blinded fashion) a 
down-titration wallet from study 16323A.
For patients who were randomised to quetiapine, the discontinuation of quetiapine will be done according to 
the following scheme:
Quetiapine: 600 mg/day for the first 3 days; 300 mg/day for the 4 subsequent days, encapsulated tablets, 
orally, once daily.
For patients who were randomised to Lu AF35700, the Lu AF35700 encapsulated tablets will be stopped and 
patients will receive placebo for 7 days, encapsulated tablets, orally, once daily.
For Other Patients
The treatment with Lu AF35700 tablets will be initiated at daily dose of 10 mg at Day 1 of study 16159B, 
while the discontinuation of the current oral antipsychotic medication will be gradually down-titrated 
according to the corresponding current SmPC or equivalent document/label and will be completed at Day 7.


H. Lundbeck A/S 
Confidential
Page 6 of 87
For all patients
Dose adjustments for efficacy or tolerability are allowed according to the investigator’s clinical judgement 
based on the patient’s response and tolerability to treatment.
Effectiveness Assessments
Positive and Negative Syndrome Scale (PANSS)
4-item Negative Symptom Assessment (NSA-4)
Clinical Global Impression – Severity of Illness Scale (CGI-S)
Quality of Life scale in Schizophrenia (QLS)
Tolerability and Quality of Life scale (TooL)
The Readiness for Work Questionnaire (WoRQ)
Personal and Social Performance scale (PSP)
Medication Satisfaction Questionnaire (MSQ)
Health Economics Assessment (HEA)
Pharmacokinetic Assessments and Biobanking
Blood samples will be collected during the study for pharmacokinetic analysis of Lu AF35700 and its 
metabolite.
Biobanking blood samples will be collected for long term storage and possible future exploratory biomarker 
research including gene expression profiling, pharmacogenetics, metabolomics/proteomics.
Safety and Tolerabilty Assessments
Adverse events (AEs)
Clinical safety laboratory tests
Vital signs
Weight/BMI/waist circumference
Electrocardiograms (ECGs)
Physical examinations
Modified Simpson Angus Scale (mSAS), Abnormal Involuntary Movement Scale (AIMS),  Barnes Akathisia 
Scale (BARS)
Columbia Suicide Severity Rating Scale (C-SSRS)
Serum prolactin, HBA1c, and blood lipid profile
Endpoints
Primary safety and tolerability endpoints:
Adverse events
Absolute values, changes values from baseline and potentially clinically significant values in: 
Clinical safety laboratory tests
Body weight, BMI, and waist circumference
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse)
ECG parameters (ventricular rate, RR, PR, QRS, QT, and QTcF)
Exploratory safety and tolerability endpoints:
Mean change from baseline in AIMS, BARS and mSAS total scores
C-SSRS categorisation 


H. Lundbeck A/S 
Confidential
Page 7 of 87
Endpoints – continued
Exploratory effectiveness endpoints:
Psychotic symptoms 
Mean change from baseline in PANSS total score
Mean change from baseline in PANSS subscale scores (PANSS Negative Symptoms subscale, PANSS 
Positive Symptoms subscale, PANSS General Psychopathology subscale)
Negative symptoms
Mean change from baseline in NSA-4 total score
Global clinical impression
Mean change from baseline in CGI-S score
Andreason symptoms remission rate
Binary variable (Y/N) of remission rate (simultaneous ratings of mild or less on PANSS specific items: 
P1, G9, P3, P2, G5, N1, N4, and N6) at Week 52 Visit
Quality of life and functioning
Mean change from baseline in QLS score
Mean change from baseline in TooL score
Mean change from baseline in WorQ score
Mean change from baseline in PSP total score
Treatment satisfaction:
Mean change from baseline in MSQ score
Health care resource utilisation
Health care resource used during 52-week study period
Statistical Methodology
Safety and effectiveness assessments will be summarised descriptively.
For 16159A-patients, summaries will be prepared with respect to 2 baselines: Baseline 2 just prior to 
randomisation in study 16159A and Baseline in study 16159B. Summaries will be prepared overall and by the 
previous treatment (treatment group in the studies feeding into this extension study or previous treatment for 
patients not included in any Lu AF35700 study before). 
Specific tables of adverse events seen shortly after initiation of the weekly dosing regimen will be prepared.
The statistical methodology will be detailed in a Statistical Analysis Plan.
Sample Size Considerations
No formal sample size calculation has been performed for the present study. 
Approximately 400 patients with schizophrenia are planned to be enrolled in total in order to provide relevant 
long-term safety data. It is assumed that about 270 patients will come from study 16159A, 30 patients from 
study 16323A, and an additional 100 patients who need to change their antipsychotic treatment will be 
included. The distribution of the number of patients may be adjusted based upon the recruitment rate in each 
group. With approximately 400 patients included, it will be possible to obtain solid information on long-term 
safety of treatment with Lu AF35700. 
To ensure sufficient exposure to the daily dosing regimen, the number of patients who completed 
study 16159A and who can be treated with the weekly dosing regimen will be limited to 50 patients.


H. Lundbeck A/S 
Confidential
Page 8 of 87
Ethical Rationale for Study and Study Design
This open-label long-term study will provide long-term data of Lu AF35700 for the treatment of patients with 
schizophrenia who have completed studies 16159A or 16323A or for treatment of patients for whom a switch 
to an antipsychotic treatment with Lu AF35700 can be beneficial according to the investigator’s clinical 
judgement (either due to sub-optimal symptom control or lack of tolerability). 
The design of the study is in accordance with the Declaration of Helsinki (ethical principles for medical 
research involving human subjects).
The following aspects of the current study design will serve as safeguards for the safety and well-being of the 
enrolled patients:
At each visit, the investigator will evaluate safety, tolerability, and benefit of treatment, and decide whether 
the patient will continue in the study.
Safety follow-up contact will be performed 6 weeks after the last dose of Lu AF35700 (whether it will be a 
Primary Outcome or Withdrawal Visit) to ensure a proper follow-up of the enrolled patients.
The patient may withdraw from the study at any time, for any reason, specified or unspecified and without 
penalty or loss of benefits to which the patient is otherwise entitled. Unscheduled visits can be made and 
immediate withdrawal is possible if his/her condition worsens.
The patient will be fully informed about the study including the risks and benefits of his/her participation in 
the study.
Panel 1
Study Design


H. Lundbeck A/S 
Confidential
Page 9 of 87
Panel 2
Study Procedures and Assessments
Visit
Screeninga
Baselineb
Treatment Period
Primary 
Outcome or 
Withdrawalc
Safety 
Follow-Upd
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
End of Week
-
0
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52
Day
-14/-7
0
7
14
28
56
84
112 140 168 196 224 252 280 308 336
364
Visit Window (days)e
3
3
3
6
7
7
7
7
7
7
7
7
7
7
7
+3
Baseline Procedures and Assessments
Signed informed consent
a

Diagnosis (DSM-5TM)
a
f
Demographics (age, sex, 
race)
a
f
Relevant social, medical 
and psychiatric history
a
f
Height
a
f
Inclusion/exclusion criteria


Effectiveness Assessments
PANSS

g















CGI-S

g















PSP

g



NSA-4
g



QLS
g



WoRQ
g



TooL
g



MSQ
g



HEA
h

Pharmacokinetic Assessments
Blood sampling for 
Lu AF35700 and 
metabolite assay
g



Translational Medicines Assessmentsi
Blood sampling for gene 
expression profiling 
(RNA)j
i
i
Blood sampling for 
metabolomics/proteomics 
(plasma) j
i
i
Blood sampling for 
pharmacogenetics 
(optional) k
i


H. Lundbeck A/S 
Confidential
Page 10 of 87
Visit
Screeninga
Baselineb
Treatment Period
Primary 
Outcome or 
Withdrawalc
Safety 
Follow-Upd
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
End of Week
-
0
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52
Day
-14/-7
0
7
14
28
56
84
112 140 168 196 224 252 280 308 336
364
Visit Window (days)e
3
3
3
6
7
7
7
7
7
7
7
7
7
7
7
+3
Safety Assessments
Adverse events

l















m
Blood and urine sampling for 
clinical safety laboratory 
tests
a
g



n
Serum prolactino
a
g



HBA1c (fasting)
a
g



Fasting blood glucose (P-
glucose) and lipid profile 
(S-cholesterol,  
S-triglycerides, S-low 
density lipoprotein (LDL), S-
high density lipoprotein 
(HDL))
a
g



Vital signs

g















ECGs p

g





Body weight

g



Waist circumference

g



Physical Examination
a
g

Abnormal movements 
rating scales
(AIMS, BARS, mSAS)
g



C-SSRS

g















Other Study Procedures
IMP dispensedq















Possible change in IMP 
doseq














IMP returned and 
accountability















Recent and concomitant 
medication

s
















Urine drug screen
a
t

Pregnancy testu
a
g



a.
Screening Visit will be performed only for newly recruited patients and screening assessments marketed with an “a” 
will not be repeated at Baseline Visit. 16159A-patients and 16323A-patients will proceed from their lead-in study 
directly to the Baseline Visit. The ICF must be signed before any study related activities take place.
b.
For 16159A-patients, the Baseline Visit will be performed the same day as the Primary Outcome Visit of 
study 16159A. For 16323A-patients, the Baseline Visit will be performed the same day as the last day of the dosing 
period of study 16323A. The inclusion/exclusion criteria are confirmed based on the evaluation of the latest data 
available in the study 16323A or 16159A as applicable.
c.
This visit should take place as soon as possible after the patient withdraws from the study treatment. 
d.
The Safety Follow-up Visit will be done 6 weeks (+3 days) after the last dose of IMP. This visit can be a telephone 
contact, unless an SAE has occurred since last visit or unless there was a clinically significant abnormal safety 
laboratory test value at the last visit. In such cases, safety follow-up(s) must be scheduled to allow for a medical 
examination and/or blood sampling. Further Safety Follow-up Visits beyond 6 weeks may be needed as judged by the 


H. Lundbeck A/S 
Confidential
Page 11 of 87
investigator (if further Safety Follow-up Visits are performed, these must be recorded in the patient’s medical record, 
and not in the CRF).
e.
If the date of a patient visit does not conform to the study plan, subsequent visits should be planned to maintain the visit 
schedule relative to the Baseline Visit. The number of days between 2 visits should not exceed the number of days for 
which the patient has been dispensed IMP.
f.
For 16159A-patients and 16323A-patients, the data will be linked respectively from the Screening Visit in the study
16159A eCRF or from the Screening Visit in the study 16323A eCRF, when applicable.
g.
For 16159A-patients and 16323A-patients, results from effectiveness/safety assessments and blood/urine samples 
performed respectively at the Primary Outcome Visit (Visit 12) in study 16159A or at the last day of the dosing period 
(Day 42) in study 16323A (when available) will be linked to the Baseline Visit (Visit 1) in study 16159B, when 
applicable.
h.
For 16159A-patients, HEA data will be linked from the Baseline A Visit in the study 16159A eCRF.
i.
To be performed only for newly recruited patients not previously participating in a study investigating Lu F35700.
j.
Exploratory gene expression profiling (RNA) and metabolomics/proteomics are covered by the main Patient 
Information Sheet. 
k.
Sampling for pharmacogenetics is optional and a separate Patient Information Sheet covers this analysis. This sampling 
should preferably be at the Baseline Visit, but may be collected at any visit that includes a clinical safety laboratory 
sample. 
l.
For 16159A-patients and 16323A-patients, ongoing adverse events from study 16159A and 16323A, respectively, are 
to be transferred by the investigator to the eCRF, when applicable.
m. Only for adverse events ongoing at the Primary Outcome/Withdrawal Visit and new SAEs.
n.
Only to be taken if the laboratory test was clinically significantly abnormal at the Primary Outcome/Withdrawal Visit.
o.
Prolactin results will remain blinded throughout the study.
p.
For 16159A-patients, additional ECGs will be done; 1 ECG recording before the daily dose is switched to weekly 
dosing (preferably on the day the decision of switching from daily to weekly dosing is taken) and 1 ECG recording the 
day after the first weekly dose is taken.
q.
The first dose of IMP should be taken after the Baseline Visit is completed. All treatment assignment and subsequent 
IMP assignment is done via the IVRS/IWRS. The IVRS/IWRS will be assessed at the unscheduled visit only if the dose 
adjustment requires dispensing of IMP.
r.
The dose of IMP can be increased for efficacy or decreased for tolerability at scheduled or unscheduled visits from 
Week 1 Visit.
s.
For 16159A-patients and 16323A-patients, ongoing concomitant medication in study 16159A and 16323A, 
respectively, must be transferred by the investigators to the 16159B eCRF. All prescription, non-prescription 
medications, and herbal medications taken during study 16159B will be recorded as concomitant medications. 
t.
Urine drug screen tests can be repeated any time during the study at the discretion of the investigator.
u.
S-βhCG pregnancy test should be performed at the Screening Visit (Only for Other-patients), Visit 5, Visit 10 and the 
Primary Outcome/Withdrawal Visit for women of childbearing potential. Urine pregnancy tests can be performed at 
any time during the study at the discretion of the investigator.


H. Lundbeck A/S 
Confidential
Page 12 of 87
Table of Contents
Synopsis – Study 16159B .......................................................................................................................2
List of Panels.........................................................................................................................................17
List of Abbreviations and Definitions of Terms ................................................................................18
1
Introduction................................................................................................................................21
1.1
Background........................................................................................................................21
1.1.1
Overview............................................................................................................21
1.1.2
Nonclinical Pharmacology Data.........................................................................21
1.1.3
Pharmacokinetics and Metabolism in Animals..................................................22
1.1.4
Nonclinical Safety Studies .................................................................................23
1.1.5
Clinical Data.......................................................................................................24
1.1.5.1
Overview of Studies.........................................................................24
1.1.5.2
Pharmacokinetics.............................................................................25
1.1.5.3
Safety...............................................................................................25
1.1.6
Target Occupancy ..............................................................................................27
1.2
Rationale for the Study......................................................................................................27
2
Objectives....................................................................................................................................27
3
Study Design...............................................................................................................................28
3.1
Overview of the Study Design...........................................................................................28
3.2
Rationale for the Study Design..........................................................................................29
4
Ethics...........................................................................................................................................31
4.1
Ethical Rationale................................................................................................................31
4.2
Informed Consent ..............................................................................................................32
4.3
Personal Data Protection....................................................................................................33
4.4
Independent Ethics Committee(s) (IEC(s)) and Institutional Review Board(s) 
(IRB(s))..............................................................................................................................33
4.5
Regulatory Approval/Notification Requirements..............................................................34
5
Study Population........................................................................................................................34
5.1
Numbers of Patients and Sites ...........................................................................................34
5.2
Recruitment of patients who can potentially benefit from treatment with Lu 
AF35700 ............................................................................................................................34
5.3
Selection Criteria ...............................................................................................................35
5.4
Withdrawal Criteria ...........................................................................................................45
6
Investigational Medicinal Products..........................................................................................45
6.1
Treatment Regimen ...........................................................................................................45
6.2
IMPs, Formulations, and Strengths....................................................................................48
6.3
Manufacturing, Packaging, Labelling, and Storage of IMPs.............................................48
6.4
Method of Assigning Patients to Treatment ......................................................................49
6.5
IMP Accountability ...........................................................................................................49
6.6
Post -study Access to IMP.................................................................................................49
7
Concomitant Medication...........................................................................................................50
8
Study Visit Plan..........................................................................................................................50


H. Lundbeck A/S 
Confidential
Page 13 of 87
8.1
Overview............................................................................................................................50
8.2
Screening Visit (Visit 1)....................................................................................................50
8.2.1
Pre-screening......................................................................................................51
8.2.2
Patient Identification Card .................................................................................51
8.2.3
Re-screening.......................................................................................................51
8.3
Baseline Visit (Visit 2) ......................................................................................................51
8.4
Withdrawal Visit................................................................................................................51
8.5
Safety Follow-up Visit/Contact (Visit 18).........................................................................52
8.6
End-of-study Definition.....................................................................................................53
9
Assessments ................................................................................................................................53
9.1
Screening and Baseline Procedures and Assessments.......................................................53
9.1.1
Demographics and Other Baseline Characteristics ............................................53
9.1.2
Drug Screen........................................................................................................53
9.2
Effectiveness Assessments ................................................................................................54
9.2.1
Clinician-rated scales .........................................................................................54
9.2.1.1
Use of clinician-rated scales ............................................................54
9.2.1.2
Positive and Negative Syndrome Scale (PANSS) ...........................54
9.2.1.3
Personal and Social Performance Scale (PSP).................................54
9.2.1.4
Clinical Global Impression Scale- Severity (CGI-S).......................55
9.2.1.5
4-Item Negative Symptom Assessment (NSA-4)............................55
9.2.1.6
Quality of Life Scale (QLS).............................................................55
9.2.1.7
Readiness for work questionnaire (WoRQ).....................................56
9.2.2
Patient Reported Outcomes (PROs)...................................................................56
9.2.2.1
Use of patient reported outcomes ....................................................56
9.2.2.2
Medication Satisfaction Questionnaire (MSQ)................................57
9.2.2.3
Tolerability and Quality of Life questionnaire (TooL)....................57
9.2.3
Health Care Resource Utilisation.......................................................................57
9.3
Pharmacokinetic Assessments...........................................................................................58
9.4
Translational Medicines Assessments (For Other Patients only)......................................58
9.4.1
General Considerations ......................................................................................58
9.4.2
Blood Sampling for Gene Expression Profiling.................................................59
9.4.3
Blood Sampling for Metabolomic/Proteomic Biomarkers.................................59
9.4.4
Blood Sampling for Pharmacogenetics..............................................................59
9.5
Safety Assessments............................................................................................................60
9.5.1
Adverse Events...................................................................................................60
9.5.2
Clinical Safety Laboratory Tests........................................................................60
9.5.3
Vital Signs..........................................................................................................62
9.5.4
Weight and Waist Circumference ......................................................................62
9.5.5
Electrocardiograms (ECGs) ...............................................................................63
9.5.6
Physical Examination.........................................................................................63


H. Lundbeck A/S 
Confidential
Page 14 of 87
9.5.7
Safety Assessment Tools....................................................................................63
9.5.7.1
Columbia-Suicide Severity Rating Scale (C-SSRS)........................64
9.5.7.2
Abnormal Involuntary Movement Scale (AIMS)............................64
9.5.7.3
Barnes Akathisia Scale (BARS) ......................................................64
9.5.7.4
Modified Simpson Angus Scale (mSAS) ........................................65
9.5.7.5
Rater Qualification and Certification...............................................65
9.6
Order of Assessments ........................................................................................................65
9.7
Treatment Compliance.......................................................................................................66
9.8
Total Volume of Blood Drawn and Destruction of Biological Material ...........................66
10
Adverse Events...........................................................................................................................67
10.1
Definitions .........................................................................................................................67
10.1.1
Adverse Event Definitions .................................................................................67
10.1.2
Adverse Event Assessment Definitions .............................................................68
10.1.3
Study-specific Adverse Event Definitions .........................................................69
10.2
Pregnancy ..........................................................................................................................69
10.3
Recording Adverse Events ................................................................................................69
10.4
Reporting Serious Adverse Events ....................................................................................70
10.5
Treatment and Follow-up of Adverse Events....................................................................70
11
Data Handling and Record Keeping ........................................................................................71
11.1
Data Collection..................................................................................................................71
11.1.1
Electronic Case Report Forms (eCRFs).............................................................71
11.1.2
Patient Binders ...................................................................................................72
11.1.2.1
Use of Patient Binders .....................................................................72
11.1.2.2
Rating Scales and Patient-reported Outcomes (PROs)....................72
11.1.2.3
Serious Adverse Event Fallback Forms...........................................72
11.1.3
External Data......................................................................................................72
11.2
Retention of Study Documents at the Site.........................................................................72
11.2.1
eCRF Data..........................................................................................................72
11.2.2
Other Study Documents .....................................................................................73
12
Monitoring Procedures..............................................................................................................73
13
Audits and Inspections ..............................................................................................................74
14
Protocol Compliance..................................................................................................................74
15
Study Termination.....................................................................................................................74
16
Endpoints....................................................................................................................................75
16.1
Primary Endpoint(s)...........................................................................................................75
16.2
Exploratory Endpoint(s) ....................................................................................................75
17
Statistical Methodology .............................................................................................................76
17.1
Responsibilities..................................................................................................................76
17.2
Analysis Sets......................................................................................................................76
17.3
Descriptive Statistics .........................................................................................................76
17.4
Patient Disposition.............................................................................................................77
17.5
Demographics and Other Baseline Characteristics............................................................77
17.6
Recent and Concomitant Medication.................................................................................77
17.7
Exposure and Compliance.................................................................................................77
17.8
Effectiveness Analyses......................................................................................................77
17.9
Safety Analyses .................................................................................................................78


H. Lundbeck A/S 
Confidential
Page 15 of 87
17.9.1
Analysis of Adverse Events ...............................................................................78
17.9.2
Analysis of Other Safety Endpoints...................................................................78
17.10 Interim Analyses................................................................................................................78
17.11 Sample Size and Power .....................................................................................................78
17.12 Statistical Analysis Plan ....................................................................................................79
18
Clinical Study Report and Publications...................................................................................79
18.1
Clinical Study Report ........................................................................................................79
18.2
Data Ownership .................................................................................................................79
18.3
Publications........................................................................................................................79
19
Indemnity and Insurance ..........................................................................................................79
20
Finance........................................................................................................................................80
20.1
Site Agreement ..................................................................................................................80
20.2
Financial Disclosure ..........................................................................................................80
20.3
Equipment..........................................................................................................................80
References.............................................................................................................................................81


H. Lundbeck A/S 
Confidential
Page 16 of 87
Appendices
Appendix I
Clinical Study Protocol Authentication and Authorisation..........................83
Appendix II
Recent and Concomitant Medication: Disallowed or Allowed with 
Restrictions .......................................................................................................85


H. Lundbeck A/S 
Confidential
Page 17 of 87
List of Panels
Panel 1
Study Design........................................................................................................................8
Panel 2
Study Procedures and Assessments.....................................................................................9
Panel 3
Treatment regimen.............................................................................................................48
Panel 4
Clinical Safety Laboratory Tests .......................................................................................61


H. Lundbeck A/S 
Confidential
Page 18 of 87
List of Abbreviations and Definitions of Terms
AE
Adverse event
AIMS  
Abnormal involuntary movement scale
ALT
alanine aminotransferase
AME
absorption metabolism and excretion
AP
alkaline phosphatase
APTS
all-patients-treated set
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
AUC
area under curve
BARS
Barnes Akathisia Rating Scale
BUN
blood urea nitrogen
CAR
conditioned avoidance responding
CGI-S
Clinical Global Impression – Severity of Illness
CIOMS
Council for international Organizations of Medical Sciences
Cmax
maximum observed concentration
CNV
copy number variation
CPK
creatine phosphokinase
CRA
clinical research associate
CRF
case report form
CRO
Contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale 
DSM-5™
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form
EMA
European Medicines Agency
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
full-analysis set
FDA
United States Food and Drug Administration
HBA1c
Glycated haemoglobin, Type A1c
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
HEA
Health economic assessment 
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors


H. Lundbeck A/S 
Confidential
Page 19 of 87
IEC
independent ethics committee
IMP
investigational medicinal product
IND
Investigational New Drug Application
INR
international normalised ratio of prothrombin time
IRB
institutional review board
ISM
international study manager
I-TMF
investigator trial master file
IVRS
interactive voice response system
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LOCF
last observation carried forward
Lu
Lundbeck
MAD
Multiple ascending dose
MMRM
mixed model for repeated measurements
mSAS
Simpson Angus Scale
MSQ
Medication Satisfaction Questionnaire 
NOAEL
no-observed-adverse-effect level
NSA-4
4-item Negative Symptom Assesment 
PANSS
Positive and Negative Symptom Scale
PCS
potentially clinically significant
PD
pharmacodynamic(s)
PET
positron emission tomography
PK
pharmacokinetic(s)
popPK
Population pharmacokinetics
PR
specific ECG interval describing atrioventricular conduction 
PRO
patient-reported outcome
PSP
Personal and Social Performance Scale
QLS 
Quality of Life Scale
QP
qualified person
QRS
specific ECG interval describing ventricular depolarisation
QT
specific ECG interval describing ventricular depolarisation/repolarisation
QTc
heart-rate corrected QT interval
QTcF
heart-rate corrected QT interval using Fridericia’s correction formula
RR
specific ECG interval describing the ventricular depolarisation/repolarisation cycle
SAE
serious adverse event
SD
standard deviation
SmPC
Summary of Product Characteristics
SNP
single-nucleotide polymorphism
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction


H. Lundbeck A/S 
Confidential
Page 20 of 87
TEAE
treatment-emergent adverse event
tmax
time to maximum observed concentration
TMF
trial master file
TooL
Tolerability and Quality of Life
TRS
Treatment-resistant schizophrenia
WoRQ
Readiness for Work Questionnaire


H. Lundbeck A/S 
Confidential
Page 21 of 87
1
Introduction
1.1
Background
1.1.1
Overview
Schizophrenia is a severe, complex, chronic, and disabling psychiatric disorder with a lifetime 
prevalence of around 1%.1 Schizophrenia is characterised by profound disturbances in 
thinking, perception, and emotion and the clinical manifestation of the disease encompasses a 
wide range of symptoms such as positive symptoms (for example, delusions, hallucinations, 
and disorganised behaviour), negative symptoms (for example, affective flattening, social 
withdrawal, anhedonia, and poverty of speech), and symptoms of cognitive impairment (for 
example, impaired executive functioning, working memory, and attention deficits). 
Numerous antipsychotics have been developed which all rely on the same underlying 
mechanism, namely interfering with dopamine receptors, and more specifically, dopamine D2
receptor antagonism. Therapies with phenothiazines, such as haloperidol and thiothixene, are 
effective but induce extra pyramidal symptoms (EPS) such as dystonia, muscle rigidity, 
tremor, and akathisia.2 Long-term effects, which develop after months to years of therapy, 
also include tardive dyskinesia. The above-mentioned drugs are referred to as typical or 
conventional antipsychotics and the adverse effects appear to be directly related to the 
dopamine D2 receptor blockade in the basal ganglia,3 whereas the antipsychotic effect of these 
compounds is dependent on reducing dopamine D2 mediated neurotransmission in the 
mesolimbic tracts (including the nucleus accumbens, stria terminalis, and the olfactory 
tubercle).
Lu AF35700 is a novel deuterated compound with affinity for dopaminergic, serotonergic, 
and α-adrenergic receptors. The receptor binding profile and the pharmacological properties 
derived from animal experiments indicate that Lu AF35700 possesses antipsychotic activity 
combined with a benign tolerability profile.
The following sections 1.1.2 to 1.1.6 provide an overview of the nonclinical and clinical data 
currently available for Lu AF35700. Refer to the Investigator’s Brochure4 for more detailed 
information.
1.1.2
Nonclinical Pharmacology Data
Lu AF35700 is a novel deuterated compound with affinity for serotonergic, dopaminergic, 
and α-adrenergic receptors, and acts as an antagonist of those receptor types.  The multi-
receptor profile of Lu AF35700 is believed to have an antipsychotic effect.
Lu AF35700 has similar high affinity for the human serotonergic 5-HT2A and 5-HT6 receptors.  
Like “atypical antipsychotics”, the affinity for the human 5-HT2A receptor is substantially 


H. Lundbeck A/S 
Confidential
Page 22 of 87
higher than for the dopamine D2 receptor.  Distinctively, Lu AF35700 has higher affinity for 
the human dopamine D1 receptor than it has for the human dopamine D2 receptor.
The in vitro receptor profile of high affinity for 5-HT2A and 5-HT6 receptors and low affinity 
for dopamine D2 receptors was confirmed by in vivo occupancy studies.  The predicted 
steady-state concentration resulting in 50% target occupancy (EC50) was calculated based on 
in vivo occupancy and pharmacokinetic (PK) data from rats.  The EC50 for 5-HT6 (12 ng/mL) 
and 5-HT2A (20 ng/mL) receptors is equipotent and much lower than for dopamine D1
(115 ng/mL) and dopamine D2 (255 ng/mL) receptors.
The potent binding to dopamine D1 receptors combined with a lower affinity for the dopamine 
D2 receptors is believed to result in a beneficial efficacy profile and a tolerability profile 
without the troublesome adverse effects associated with extensive dopamine D2 receptor 
blockade, such as extrapyramidal symptoms (EPS), hyperprolactinaemia, sexual dysfunction, 
and dysphoria/anhedonia.  Furthermore, given the lack of muscarinic receptor blockade, it is 
expected that Lu AF35700 will not have a negative impact on cognitive performance related 
to muscarinic receptor inhibition.
In animal models, Lu AF35700 inhibited conditioned avoidance responding (CAR), 
amphetamine-induced hyperactivity, and phencyclidine (PCP)-induced hyperactivity at doses 
having no sedative or motor inhibiting effects, indicative of antipsychotic potential combined 
with few side effects.
Lu AF36152 is the major metabolite of Lu AF35700 and has a pharmacological in vitro and 
in vivo profile which is similar to that of Lu AF35700 although it is less potent in vivo.
1.1.3
Pharmacokinetics and Metabolism in Animals
The absorption, distribution, metabolism, and excretion (ADME) properties of Lu AF35700 
have been characterised in the animal species used for safety assessment:  Lu AF35700 is well 
absorbed from the gastrointestinal tract (94% in the rat) and the time to maximum observed 
concentration (tmax) is 0.5 to 1 hour post-dose in rats and dogs.  It is distributed throughout all 
tissues, including the brain.  The protein binding of Lu AF35700 is high (95% to 98%) in 
plasma from mice, rats, rabbits, dogs, and humans.  The main route of excretion in rats and 
dog is via the faeces.
Overall, the metabolic pathways across species are similar and all metabolites observed in 
humans were observed in at least one animal species used for safety evaluation. Relative 
abundance measurements in plasma following multiple oral administrations showed that the 
potential relevant human metabolites have been adequately safety tested in the animal toxicity 
studies in line with the regulatory recommendations.
  
 


H. Lundbeck A/S 
Confidential
Page 23 of 87
 
 
 
1.1.4
Nonclinical Safety Studies
Safety pharmacology studies were conducted with Lu AF35700 to examine the effect on the 
major physiological functions (central nervous system [CNS], cardiovascular, and respiratory 
systems) in rats and dogs.  The tolerability and toxicity of Lu AF35700 was evaluated by oral 
treatment for up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in dogs.  The potential 
genotoxicity of Lu AF35700 was evaluated in vitro and in vivo.  The effect of Lu AF35700 on 
fertility and early embryonic development was assessed in the rat, and foetal developmental 
toxicity was assessed in rats and rabbits. 
Both Lu AF35700 and its major metabolite Lu AF36152 show high affinity to cardiac ion 
channels in in vitro systems.  In a manual patch clamp assay, both compounds inhibited the 
human ether-à-go-go-related gene (hERG) ion channel with concentrations resulting in 50% 
inhibition (IC50) of 0.060 µM and 0.177 µM for Lu AF35700 and Lu AF36152, respectively.
In dogs, electrocardiogram (ECG) waveform morphology changes (ventricular ectopic beats) 
were observed in the cardiovascular safety pharmacology study and in the 4-week oral 
toxicity study but ventricular ectopic beats were not seen in dogs after 13 and 39 weeks of 
dosing.  An increase in QTc interval was observed at the highest dose during Weeks 6 and 13 
in the 13-week oral toxicity study, but QTc prolongation was not observed in the 39-week 
toxicity study; although these ECG changes could not be clearly attributed to treatment, a 
drug-related effect cannot be excluded.
The principal target organs identified in the repeated dose toxicity studies were the central 
nervous system (clinical observations in mice, rats, and dogs), the rodent mammary gland 
(prolactin-mediated effects in female mice, male, and female rats), the rodent female 
reproductive organs (prolactin-mediated effects on uterus in rats, and vagina in mice and rats), 
the lungs (phospholipidosis in rats), and the heart (ECG changes in dogs). 
Lu AF35700 was not genotoxic in standard regulatory in vitro and in vivo genotoxicity tests. 
The no-observed-adverse-effect levels (NOAELs) established in the toxicity studies were 
20 (males)/30 (females) mg/kg/day in the mouse, 40 (males)/80 (females) mg/kg/day in the 
rat, and 3 mg/kg/day in the dog.  The overall NOAEL at 3 mg/kg/day Lu AF35700 was 
established based on a reduced weight gain and an effect on the ECG (QTc prolongation and 
ventricular ectopic beats) at the highest dose in dogs. 
The behavioural and clinical observations in the animals and the toxicological target organs 
defined were as predicted from the pharmacological and chemical properties of Lu AF35700.  
Apart from the potential risk of ECG changes, no other effects of Lu AF35700 are considered 
relevant for humans at exposure levels corresponding to those achieved the highest dose 


H. Lundbeck A/S 
Confidential
Page 24 of 87
tested in the mouse, rat and dog.  Please refer to the Investigator’s Brochure4 for the exposure 
ratios.
It is concluded that the toxicological effects of Lu AF35700 were well characterised in the 
toxicology, genotoxicity, and reproductive toxicology studies and the results support that 
Lu AF35700 can safely be administered to humans at the proposed dose levels.
1.1.5
Clinical Data
1.1.5.1
Overview of Studies
Currently, three studies with Lu AF35700 have been completed in healthy subjects 
(studies 14198A, 15867A, and 15868A).  One study in patients has been completed 
experimentally (study 14754A).  Finally, two studies are ongoing (studies 15859A and 
16156A).  As of August 2015, a total of 74 healthy subjects and 84 patients with 
schizophrenia have been exposed to Lu AF35700.
The completed studies in healthy subjects (all men) comprise the first-in-human (FIH) study, 
an AME study, and a PET study.  In the FIH study, 6 subjects received a single 10 mg dose 
and 20 subjects received 3 mg Lu AF35700 together with 3 mg of a non-deuterated 
Lu AF35700 analogue once daily for 18 days.  In each of the AME and PET studies, 
6 subjects received a single dose of 30 mg Lu AF35700.  Based on these studies, Lu AF35700 
was safe and well tolerated.
A multiple-ascending-dose (MAD) study in 96 patients with schizophrenia has been 
completed experimentally and preliminary unblinded data are included in this document.  The 
study was a double-blind, placebo-controlled study with 10 cohorts of up to 10 patients each.  
The treatment duration was 21 days in all cohorts.  In Cohorts 1 to 7, collectively referred to 
as Part A, male patients received daily doses of 5, 7.5, 11, 16, 20, or 30 mg/day.  In Cohorts 1 
to 6, the patients were randomised (7 to 3, respectively) to receive oral solutions of 
Lu AF35700 or placebo, and in Cohort 7, all patients received a 20 mg Lu AF35700 tablet 
(one-half of the patients in this cohort received the tablet in a fasted state and the other half 
received the tablet in a fed state).  In Cohort 8, the sole cohort in Part B, women with 
schizophrenia were randomised (7 to 3, respectively) to receive an oral solution of 
Lu AF35700 or placebo.  In Cohorts 9 and 10, collectively referred to as Part C, male and 
female patients were randomised (7 to 3, respectively) to receive oral solutions of 45 mg 
(Cohort 9) or 75 mg (Cohort 10) Lu AF35700 or placebo once weekly.  In all cohorts, patients 
who received doses ≥20 mg were up-titrated; refer to the Investigator Brochure4 for detailed 
information about the titration schedules used in each cohort.
Study 15859A is an ongoing open-label PET study investigating the occupancy-plasma-
concentration relationship of the D1, D2, and 5-HT6 receptors in men with schizophrenia. The 
occupancy-plasma-concentration relationship for each of the D1, D2, and 5-HT6 receptors is 
investigated in a separate group.  In each of the D1, D2, and 5-HT6 groups, up to four 
sequential cohorts of 2 patients each, receive Lu AF35700 doses for up to 21 days starting at 


H. Lundbeck A/S 
Confidential
Page 25 of 87
10, 20, and 10 mg/day, respectively, in the first cohort.  The doses in subsequent cohorts are 
adjusted based on the occupancy data.
Study 16156A is an ongoing randomised, double-blind, parallel-group, placebo-controlled 
single- and multiple-dose study investigating the safety, tolerability, and PK properties of 
Lu AF35700 in healthy Japanese and Caucasian men.  The study consist of three parts:  
Part A, in which Japanese and Caucasian men receive a single dose of 5 mg Lu AF35700; 
Part B, in which Japanese men receive a single dose of 10 mg Lu AF35700; and Part C, in 
which Japanese and Caucasian men receive a dose of 10 mg/day Lu AF35700 for 5 days.
1.1.5.2
Pharmacokinetics
A preliminary integrated popPK analysis was performed on data from studies 14198A, 
14754A, 15867A, and 15868A.  
In the popPK model, the absorption phase was adequately described by first-order absorption 
(absorption rate constant [ka] = 0.27 L/h) with lag-time (1 h).  The distribution profiles of both 
Lu AF35700 and Lu AF36152 were best described by two-compartment models with central 
and peripheral compartments.  The population volume of distribution of Lu AF35700 and 
Lu AF36152 was estimated to 5442 and 4933 L, respectively. Plasma protein binding was 
investigated in vitro in human plasma and, overall, Lu AF35700 was classified as “highly” 
protein bound (95% to 99%).  The apparent oral clearance of Lu AF35700 and Lu AF36152 
was estimated to 29 L/h and 15 L/h, respectively.  From the population estimates, the 
elimination half-life for Lu AF35700 and Lu AF36152 was estimated to 143 hours and 
250 hours, respectively.
Preliminary results from the MAD study indicate that for the patients receiving 
therapeutically relevant doses of Lu AF35700, the parent compound at Day 21/24 had a 
median tmax of 8 hours, mean Cmax ranging from 24.6 to 43.8 ng/mL, and mean area under the 
curve from zero to 24 hours (AUC0-24h) ranging from 455 to 759 ng·h/mL.  For the major 
metabolite Lu AF36152, the corresponding values were a median tmax ranging from 9 to 
14 hours, mean Cmax ranging from 25.2 to 43.8 ng/mL, and mean AUC0-24h ranging from 475 
to 685 ng·h/mL.
Please refer to the Investigator’s Brochure4 for a summary of PK parameters.
1.1.5.3
Safety
The main body of safety data in patients with schizophrenia comes from the MAD study 
(study 14754A) which has been completed.  The other study in patients with schizophrenia, 
the ongoing PET study (study 15859A), is still blinded. 
In the MAD study, the adverse events with the highest incidence (>10%) in the Lu AF35700 
groups in the daily dosing cohorts were:  somnolence (33%), anxiety (23%), headache (21%, 
placebo level), orthostatic hypotension (19%), dizziness (16%), psychotic disorder (14%), and 
akathisia (11%).  In the once-weekly dosing cohorts the adverse events occurring in 


H. Lundbeck A/S 
Confidential
Page 26 of 87
≥2 patients in the Lu AF35700 groups were (number of patients out of 12): somnolence (5), 
constipation (4), insomnia (3), anxiety (2), and musculoskeletal pain (2).  In total there was 
1 serious adverse event, increased psychosis, which necessitated hospitalisation of the patient.  
The patient recovered after 9 days after treatment with paliperidone.  The investigator 
assessed the causality as not related to the investigational medicinal product (IMP).  All non-
serious adverse events were of mild to moderate intensity, with the exception of one event of 
severe somnolence which resolved after a few hours.  The blinded data from the ongoing PET 
study showed that anxiety, insomnia, and headache have been reported as adverse events in 
that study. 
Please refer to the Investigator Brochure4 for a summary of the TEAEs with the highest 
incidence in MAD study 14754A.
In the MAD study, an explorative analysis of the effect of treatment on QTcF indicated a 
treatment and dose-related trend for QTcF prolongation.  None of the patients in the study had 
any symptoms or QTcF values that met the potentially clinically significant (PCS) criterion 
(>500 ms or >60 ms increase from baseline) and no observations from ECG or cardiac 
telemetry were reported as adverse events. 
In the MAD study, in the cohorts with the daily dosing regimen, an increase n creatine 
phosphokinase (CPK) value was observed in the Follow-up Period on assessment days 
immediately after the termination of Lu AF35700 treatment or one week thereafter.  The 
increase occurred in all Lu AF35700 dosing groups and was greatest (descending order) in the 
cohorts where patients received 20, 5, and 16 mg/day.  The median CPK values were within 
the reference range (for men:  60 to 400 IU/L) and never >320 IU/L.  The cohort in which 
women were treated with Lu AF35700 showed no increase in CPK values during the 
treatment period.  The fractionated CPK analysis showed that the post-treatment increased 
CPK values were derived from muscle tissue.  In the cohorts with the once-weekly dosing 
regimen, there were no apparent treatment or dose-related trends in mean or individual CPK 
values.  There were no apparent treatment or dose-related trends in mean or individual data 
for any of the other clinical laboratory parameters. 
In the MAD study, the safety and tolerability was not influenced by the formulation (oral 
solution versus tablet) or the sex of the patient.
The total number of healthy subjects (74) who have received Lu AF35700 is lower than that 
for patients (84) and they have generally been exposed to lower doses of Lu AF35700 for 
shorter duration.  However, the most frequently reported adverse events in healthy subjects 
(somnolence, fatigue, headache, and dizziness) were similar to those in patients.
Based on safety and tolerability data from the single-dose PET and AME studies 
(studies 15867A and 15868A) and the FIH study in healthy subjects (study 14198A), and the 
MAD study in patients with schizophrenia (study 14754A), a single dose of up to 30 mg 
Lu AF35700 and multiple doses in the dose range 5 to 30 mg/day or 45 or 75 mg once weekly 
for 21 days, are safe and well tolerated.


H. Lundbeck A/S 
Confidential
Page 27 of 87
1.1.6
Target Occupancy
A Lu AF35700 PET study (study 15868A) was conducted in 6 young healthy men to 
characterise the relationship between the combined plasma concentration of Lu AF35700 and 
Lu AF36152 and the D2 receptor occupancy using [11C]-PHNO at different time points from 8 
to 126 hours after dosing.5  A pharmacokinetic/pharmacodynamic (PK/PD) model was 
established to predict the relationship between plasma exposure of Lu AF35700/Lu AF36152 
and striatal D2 dopamine receptor occupancy. Two Emax models were combined with 
simulated plasma concentrations of Lu AF35700 and Lu AF36152 when dosing 10 mg and 
20 mg Lu AF35700 QD for 12 weeks. After 5 weeks of daily doses of 10 mg and 20 mg, the 
contribution of both Lu AF37500 and Lu AF36152 are expected to result in a 48% and 65% 
D2 receptor occupancy, respectively.6
1.2
Rationale for the Study
The current phase III study, in conjunction with other studies, is part of the LuAF35700 
clinical development programme that is designed to evaluate the safety and efficacy of Lu 
AF35700 for the treatment of adults with schizophrenia. 
The design of the current study is in accordance with EMA draft Guideline on clinical 
investigation of medicinal products in the treatment of schizophrenia.7 This open-label 
extension study will provide long-term data of Lu AF35700 for the treatment of patients with 
schizophrenia.
Blood samples will be collected in an attempt to increase the understanding of the 
pharmacokinetic properties of Lu AF35700, and its metabolite (Lu AF36152).
2
Objectives
Primary Objective
• To evaluate the safety and tolerability of the long-term treatment with Lu AF35700
Exploratory Objective(s)
• to evaluate the long-term safety and tolerability of daily and weekly doses of Lu AF35700 
in patients with schizophrenia during the 52-week treatment period
• to evaluate the therapeutic effect of daily and weekly doses of Lu AF35700 in patients with 
schizophrenia over a period of 52 weeks on:
psychotic symptoms
negative symptoms 
global clinical impression
remission rate
quality of life and functioning


H. Lundbeck A/S 
Confidential
Page 28 of 87
treatment satisfaction
resource utilisation
3
Study Design
3.1
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki.8
This is an interventional, open-label, flexible-dose, long-term safety study.
This study will be conducted in compliance with the protocol, Good Clinical Practice9 and 
applicable regulatory requirements.
An overview of the study is presented in Panel 1.
Any patient with schizophrenia, who has participated and completed a study investigating Lu
AF35700, can be included in this study. In addition, patients who are not experiencing an 
acute exacerbation, who are currently under antipsychotic treatment and who, according to the 
investigator’s clinical judgement, can potentially benefit from treatment with Lu AF35700, 
can also be included in this study.
The total study duration per patient from screening to safety follow up will be up to 60 weeks. 
The study will consist of 3 periods:
• Screening period – up to 2 weeks (only for patients not previously participating in a study 
investigating Lu AF35700) 
• Treatment period – 52 weeks 
• Safety follow up period – 6 weeks
Only the patients not previously participating in a study investigating Lu AF35700 will enter
this study at the Screening Visit, for a screening period of up to 14 days to assess eligibility. 
Patients previously participating in a study investigating Lu AF35700 will enter this study
directly at the Baseline Visit.
120 sites are planned in approximately 15 countries (in-/out-patient clinics). The selected sites 
will be the sites which participated in studies investigating Lu AF35700 including and not 
limited to the studies 16159A and 16323A (cardiac study).
Approximately 400 patients with schizophrenia are planned to be enrolled with the following 
assumptions: approximately 270 patients who will have completed the study 16159A, 
approximately 30 patients who will have completed the dosing period of the study 16323A 
and approximately 100 additional patients who will need to change their antipsychotic 
treatment. The distribution of the number of patients may be adjusted upon the recruitment 
rate in each group.


H. Lundbeck A/S 
Confidential
Page 29 of 87
All eligible patients will be initiated on a daily dose of 10 mg Lu AF35700 at Day 1. Patients 
previously treated with another antipsychotic than Lu AF35700 will initiate down-titration of 
their current treatment at Day 1.
At the end of the 1st week (Week 1 Visit), all patients included in this long-term safety study 
16159B will be treated with one antipsychotic, Lu AF35700 at daily dose of 10 mg. At visits 
following the Week 1 Visit, according to the investigator’s clinical judgement, the 10 mg/day 
dose can be increased to 20 mg/day based on the patient’s response. Thereafter, the 20 
mg/day dose can be reduced to 10 mg/day based on the patient’s tolerability to treatment.
Patients previously participating in a study investigating Lu AF35700 will receive a down-
titration wallet from the previous study. The down-titration will be done in a blinded fashion 
and will be completed at Day 7. 
For patients who can potentially benefit from treatment with Lu AF35700 the discontinuation 
of the current oral antipsychotic medication will be gradually down-titrated according to the 
corresponding current SmPC or equivalent document/label and will be completed at Day 7.
Only for patients who completed the 16159A study; at the end of the 8th week (Week 8 
Visit), according to the investigator’s clinical judgment, the treatment with Lu AF35700 daily 
dosing regimen can be switched to a weekly 70 mg Lu AF35700 dosing regimen. The first 
weekly tablet will be taken 7 days after the last daily tablet. Thereafter, the switch from Lu 
AF35700 daily dosing regimen to Lu AF35700 weekly dosing regimen can be performed at 
any consecutive visit according to the investigator’s clinical judgment. The first weekly tablet 
will be taken 7 days after the last daily tablet. The treatment with Lu AF35700 weekly dosing 
regimen can be switched back to daily dose of 10 mg for tolerability reasons or to daily dose 
of 20 mg for worsening of the patient’s clinical status. This can occur at scheduled or 
unscheduled visits. The first daily tablet will be taken 7 days after the last weekly tablet.
The adjustment of Lu AF35700 dosing regimen (10 mg/day or 20 mg/day) will be left to the 
investigator’s clinical judgement. The number of patients under weekly dosing regimen will 
be limited to 50 patients by the IVRS/IWRS.
All patients, including patients who withdraw, will be scheduled for a Safety Follow-Up Visit 
42 days after last dose of IMP. 
An internal Safety Committee at H. Lundbeck A/S has been established for Lu AF35700 and 
the committee will perform regular evaluations of the safety data.
No interim analysis is planned.
After completion of the study, the patients will be treated according to normal practise.
3.2
Rationale for the Study Design
The open-label, flexible-dose, long-term safety study design aims to obtain information on the 
long-term safety and tolerability of Lu AF35700, a new potential treatment for Schizophrenia


H. Lundbeck A/S 
Confidential
Page 30 of 87
as it is intended to be used in clinical practice. The 52-week treatment period is considered to 
be of adequate length to determine the sustained safety, tolerability and antipsychotic 
effectiveness of Lu AF35700.
All patients with treatment resistant schizophrenia who completed study 16159A are eligible 
to participate in this study. This will enable treatment continuity for patients that received 
treatment with Lu AF35700, as well as, for patients treated with risperidone or olanzapine in 
study 16159A the opportunity to derive the possible benefits of treatment with Lu AF35700
for 52 weeks. In addition, all patients with schizophrenia who completed study 16323A, a 
cardiac safety study, are also eligible to participate in this study and will receive treatment 
with Lu AF35700. Finally, patients with schizophrenia in need of change in antipsychotic 
treatment will also be eligible to participate in this study, to have the opportunity to benefit 
from the possible benefits of Lu AF35700.
The doses of Lu AF35700 to be used in this study were selected based on the aggregate 
safety, efficacy, pharmacokinetic profile and receptor occupancy data. Daily doses of 10 and 
20 mg are estimated to include the therapeutic dose range of Lu AF35700 tested in study
16159A. In addition, taking advantage of the long half-life of Lu AF35700 a once-weekly 
dose of 70 mg will also be tested. The rationale for testing the safety, tolerability, and 
effectiveness of a weekly dosing is to explore the feasibility of such a dosing scheme for 
maintenance dosing; which could result in potential benefits to treatment adherence; which is 
an issue of considerable interest in patients with schizophrenia.
Safety and tolerability will be assessed by means of withdrawal, reported adverse events,
vitals signs, weight, clinical safety laboratory tests, ECGs, and physical examinations.
Metabolic adverse events including body weight gain, dyslipidemia, and hyperglycemia are
adverse events associated with antipsychotic treatment and represent an important long-term
safety risk.10 The primary variables for assessing those parameters include body weight/BMI,
waist circumference, fasting plasma glucose, glycosylated haemoglobin [HbA1c] and lipids
(triglycerides, total cholesterol, low-density lipoprotein [LDL], and high density lipoprotein
[HDL] cholesterol).
The long-term efficacy will be explored based on the PANSS11 a well established scale for 
assessing severity of the symptoms of schizophrenia. The CGI-S12 will be used as an 
additional exploratory efficacy measure of clinical response to treatment. The exploratory 
assessment of the severity of the negative symptoms of schizophrenia will be done using the 
NSA-4.13
Improvement in functional outcome and quality of life are important treatment goals in the
long-term management of patients with schizophrenia. In the current study, effects on 
functional outcomes will be explored using clinician-reported outcomes such as the PSP,14
QLS15 and WoRQ.16
Taking into account the substantial health economic burden of schizophrenia, the effect of the 
Lu AF35700 on subjective well-being, treatment satisfaction, disability and health care 
resource utilisation will be explored. These will be assessed in the study through patient 
reported outcomes such as MSQ,17 TooL18 and HEA.


H. Lundbeck A/S 
Confidential
Page 31 of 87
4
Ethics
4.1
Ethical Rationale
Schizophrenia is a severe, complex, chronic, debilitating, and disabling mental disorder with a 
poor prognosis. Despite the availability of numerous treatment options, individual response to 
antipsychotic medication is generally sub-optimal and variable. The majority of patients does
not adequately respond to treatment and studies have indicated that only around 10% of the 
patients with schizophrenia achieve functional remission.19 The tolerability of the current 
antipsychotic medications is also limited by numerous adverse events, which hampers the 
treatment adherence, and in turn, the overall outcome of the treatment. Thus, it is clear that 
the current treatment options for schizophrenia are far from ideal and development of better 
therapies for this indication should be an important priority.
The dose regimen of 10, 20 mg/day and 70 mg/week of Lu AF35700 were determined to be
safe and well tolerated in the ongoing phase I programme in patients with schizophrenia and
elicited the targeted range of D2 receptor occupancy in healthy volunteers (see Investigator’s 
Brochure).4
This open-label long-term study will provide long-term data of Lu AF35700 for the treatment 
of patients with schizophrenia who have completed a study investigating Lu AF35700 or for 
patients for whom a switch to an antipsychotic treatment with Lu AF35700 can be beneficial 
according to the investigator’s clinical judgement (either due to sub-optimal symptom control 
or lack of tolerability). 
The design of the current study is in accordance with the Declaration of Helsinki (ethical 
principles for medical research involving human subjects).
The following aspects of the current study design will serve as safeguards for the safety and 
well-being of the enrolled patients:
• At each visit, the investigator will evaluate safety, tolerability, and benefit of treatment, 
and decide whether the patient will continue in the study.
• Safety follow-up contact will be performed up to 6 weeks after the last dose of 
Lu AF35700 (whether it will be a Primary Outcome or Withdrawal Visit) to ensure a 
proper follow-up of the enrolled patients.
• The patient may withdraw from the study at any time, for any reason, specified or 
unspecified and without penalty or loss of benefits to which the patient is otherwise 
entitled. Unscheduled visits can be made and immediate withdrawal is possible if his/her 
condition worsens.
The patient will be fully informed about the study including the risks and benefits of his/her 
participation in the study. Patients entering this study after having completed a study 
investigating Lu AF35700 should be informed about this study as early as possible during 
their participation in the previous study investigating Lu AF35700. In accordance with Good 
Clinical Practice,9 qualified medical personnel at Lundbeck will be readily available to advise 
on study-related medical questions. Medical monitoring will be performed throughout the 


H. Lundbeck A/S 
Confidential
Page 32 of 87
study. Safety data will be reviewed regularly by the Lundbeck Lu AF35700 Safety Committee 
to ensure that prompt action is taken, if needed, to maximise patient safety.
In accordance with Good Clinical Practice,9 the investigator will be responsible for all study-
related medical decisions.
The consent procedures described above will only be implemented if allowed by local law 
and regulations and will only be initiated after appropriate approval by the relevant ethics 
committees.
4.2
Informed Consent
For patients not previously participating in a study investigating Lu AF35700, written 
informed consent must be obtained before the Screening Visit in this study. For patients 
previously participating in a study investigating Lu AF35700, written informed consent must 
be obtained before the Baseline Visit in this study.
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written informed consent from the patient and/or his or her legal
representative (if applicable).
Changing (for example, discontinuing or down-tapering) a patient’s concomitant medications 
prior to the Screening Visit to ensure that the patient meets the selection criteria is a study-
related activity and must not occur before the Informed Consent Form has been signed.
As fasting samples are to be taken at the Screening Visit, the Informed Consent Form must be 
signed a suitable number of days before the Screening Visit.
If the informed consent process may be delegated, the requirements for the delegates must be
documented prior to the start of the study. National laws must always be adhered to when 
allowing potential delegation. Any delegation must be documented in the site delegation log.
The Investigator must exclude any adult patient who lacks capacity to consent for 
himself/herself from participation in the study.The investigator must identify vulnerable 
patients, that is, patients whose willingness to participate in this study might be unduly
influenced by the expectation, regardless of whether it is justified, of benefits associated with 
participation, or of a retaliatory response from senior members of a hierarchy in case of 
refusal to participate. Patients thus identified must be excluded from participation in the 
study.
Prior to obtaining written informed consent, the investigator or a designee must explain to the
patients and their legal representatives (if applicable) the aims, methods, and potential hazards 
of the study and any discomfort it may entail. The patients and their legal representatives (if 
applicable) must be informed that their participation in the study is voluntary and that they are 
free to withdraw from the study at any time without justifying their decision. The patients and
their legal representatives (if applicable) must be informed of the possibility of withdrawing 
consent (section 8.4).


H. Lundbeck A/S 
Confidential
Page 33 of 87
The patients and their legal representatives (if applicable) must be given ample time and 
opportunity to enquire about details of the study prior to deciding whether to participate in the 
study.
The Informed Consent Form includes a statement whereby the patient agrees to communicate 
with their regular doctor of their participation in the study. If the patient does not want his/her 
regular doctor to be contacted and there is no other way to verify or establish that the patient 
qualifies for the study, the patient should not be enrolled.
It is the responsibility of the investigator to ensure that all questions about the study are 
answered to the satisfaction of the patients and their legal representatives (if applicable). Prior 
to including a patient in the study, an Informed Consent Form must be signed and dated by
the patient and his or her legal representative (if applicable) and signed and dated by the 
investigator or a designee. The patients and their legal representatives (if applicable) must
receive a copy of the written information (Patient Information Sheet) as well as a copy of the 
signed Informed Consent Form.
The consent procedures described above will only be implemented if allowed by local law 
and regulations and will only be initiated after approval by the relevant ethics committees
(IECs) or institutional review boards (IRBs).
The blood samples for exploratory biomarker analysis may be shared with academic or public 
institutions; however, Lundbeck will remain full control of the samples and their use on 
accordance with the information in the Patient Information Sheet and a material transfer 
agreement.
4.3
Personal Data Protection
In accordance with European Union Directive 95/46/EC,20 the data will be processed in 
accordance with the specifications outlined by the Danish Data Protection Agency to ensure 
that requirements regarding personal data protection are met. If an external organisation will 
process data on behalf of Lundbeck, a contractual procedure will be signed between 
Lundbeck and the external organisation to ensure compliance with the above-mentioned 
legislation.
If applicable, the participation of patients in this study will be reported to the appropriate local 
data protection agencies, in accordance with European Union Directive 95/46/EC and 
country-specific guidelines and laws.
4.4
Independent Ethics Committee(s) (IEC(s)) and Institutional Review Board(s)
(IRB(s))
This study will be conducted only after approval of the protocol has been granted by the 
appropriate IEC or IRB and a copy of the written approval has been received by Lundbeck.


H. Lundbeck A/S 
Confidential
Page 34 of 87
The investigator must not screen or include any patients before receiving written approval 
from the IEC or IRB.
The IEC or IRB must be informed when specific types of protocol amendments have been 
made and must be asked whether a re-evaluation of the ethical aspects of the study is 
necessary.
If applicable, interim reports on the study and reviews of its progress will be submitted to the 
IEC or IRB by the investigator at intervals stipulated in its guidelines.
4.5
Regulatory Approval/Notification Requirements
In accordance with local requirements, this study will be submitted to the regulatory 
authorities for approval or notification. The study will only be undertaken when Lundbeck has 
received written approval or confirmation of notification from the regulatory authorities.
5
Study Population
5.1
Numbers of Patients and Sites
Planned regions:
North America, Europe and South America 
Approximately planned number of patients:
to be enrolled:
400
to complete the study:
200
Approximately planned number of:
study sites:
120
5.2
Recruitment of patients who can potentially benefit from treatment with Lu 
AF35700
The recruitment of patients who can potentially benefit from treatment with Lu AF35700 can 
start in a given site only after the recruitment of the patients in the study 16159A or in the 
study 16323A is completed.
Competitive patient recruitment between countries and sites will be used during the entire 
recruitment period to ensure that the required number of patients is enrolled within the 
planned recruitment period.
The investigators will be notified immediately when the recruitment period comes to an end.


H. Lundbeck A/S 
Confidential
Page 35 of 87
5.3
Selection Criteria
Patient selection to study 16159B is based on the inclusion and exclusion criteria listed below.
Patients who meet each of the inclusion criteria at the Screening Visit (unless otherwise 
specified) and none of the exclusion criteria at the Screening Visit (unless otherwise 
specified) are eligible to participate in this study. 
Inclusion Criteria
For patients who completed study 16159A
Patients who meet each of the inclusion criteria and none of the exclusion criteria at the 
Baseline Visit (unless otherwise specified; some criteria assessed as part of the Primary 
Outcome Visit in study 16159A) are eligible to participate in this study.
1.
The patient has completed study 16159A.
2.
The patient is still capable of communicating with the site personnel.
3.
The patient and if applicable his or her legal representative is/are able to read and 
understand the Informed Consent Form.
4.
The patient and if applicable his or her legal representative has/have signed the 
Informed Consent Form for study 16159B.
5.
The patient is willing and able to attend study appointments within the specified time 
windows.
6.
The patient can potentially benefit from 52-week treatment with Lu AF35700 
according to the investigator’s clinical judgment.
7.
The patient has a caregiver or an identified responsible person considered reliable by 
the investigator (for example, family member, social worker, case worker, or nurse) 
considered reliable by the investigator in providing support to the patient to ensure 
compliance with study treatment, outpatient visits, and protocol procedures.
8.
The patient has a stable living environment, as demonstrated by the ability to provide 
contact information for themselves and/or family/friend(s)/caregiver(s).
9.
The patient, if a woman, must:
agree not to try to become pregnant during the study, AND
use adequate, highly effective contraception (defined as those that result in a low failure 
rate [that is, <1% per year] when used consistently and correctly, for example, implants, 
injectables, combined oral contraceptives in combination with a double barrier method, 
some intrauterine devices, sexual abstinence, vasectomised partner), OR
have had her last natural menstruation ≥28 months prior to the Primary Outcome Visit 
in study 16159A, OR
have been surgically sterilised prior to the Primary Outcome Visit in study 16159A, OR
have had a hysterectomy prior to the Primary Outcome Visit in study 16159A.
10. The patient, if a man, must:
use two methods of contraception in combination if his female partner is of childbearing 
potential; this combination of contraceptive methods must be used from the Baseline 
Visit to ≥3 months after the last dose of IMP, OR 


H. Lundbeck A/S 
Confidential
Page 36 of 87
have been surgically sterilised prior to the Primary Outcome Visit in study 16159A.
The following assessments from the Primary Outcome Visit in study 16159A will be linked to 
the Baseline Visit: PANSS, CGI-S, PSP, NSA-4, QLS, TooL, MSQ, WorQ, HEA, ongoing
adverse events, physical examination, waist circumference, weight, vital signs, 12-lead ECG, 
mSAS, AIMS, BARS, C-SSRS, ongoing concomitant medication, clinical safety laboratory 
data (including S-βhCG pregnancy test, HBA1c, blood lipid profile) (see Panel 2).
Additionally, diagnosis, demographics, relevant medical, psychiatric and social history and 
height will be linked from the Screening Visit in study 16159A to Baseline Visit in this study.
For patients who completed the dosing period of study 16323A
Patients who meet each of the inclusion criteria and none of the exclusion criteria at the 
Baseline Visit (unless otherwise specified; some criteria assessed as part of the last visit of the 
dosing period in study 16323A) are eligible to participate in this study.
1.
The patient has completed the dosing period of study 16323A.
2.
The patient is still capable of communicating with the site personnel.
3.
The patient and if applicable his or her legal representative is/are able to read and 
understand the Informed Consent Form.
4.
The patient and if applicable his or her legal representative has/have signed the Informed 
Consent Form for study 16159B.
5.
The patient is willing and able to attend study appointments within the specified time 
windows.
6.
The patient can potentially benefit from 52-week treatment with Lu AF35700 according 
to the investigator’s clinical judgment.
7.
The patient has a caregiver or an identified responsible person considered reliable by the 
investigator (for example, family member, social worker, case worker, or nurse) 
considered reliable by the investigator in providing support to the patient to ensure 
compliance with study treatment, outpatient visits, and protocol procedures.
8.
The patient has a stable living environment, as demonstrated by the ability to provide 
contact information for themselves and/or family/friend(s)/caregiver(s).
9.
The patient, if a woman, must:
agree not to try to become pregnant during the study, AND
use adequate, highly effective contraception (defined as those that result in a low failure 
rate [that is, <1% per year] when used consistently and correctly, for example, implants, 
injectables, combined oral contraceptives in combination with a double barrier method, 
some intrauterine devices, sexual abstinence, vasectomised partner), OR
have had her last natural menstruation ≥28 months prior to the Primary Outcome Visit 
in study 16323A, OR
have been surgically sterilised prior to the last visit of the dosing period in 
study 16323A, OR
have had a hysterectomy prior to the last visit of the dosing period in study 16323A.


H. Lundbeck A/S 
Confidential
Page 37 of 87
10. The patient, if a man, must:
use two methods of contraception in combination if his female partner is of childbearing 
potential; this combination of contraceptive methods must be used from the Baseline 
Visit to ≥3 months after the last dose of IMP, OR 
have been surgically sterilised prior to the last visit of the dosing period in 
study 16323A.
11. The patient has a confirmed diagnosis of schizophrenia according to DSM-5TM.
12. The patient is willing to discontinue all prohibited psychotropic medications to meet
protocol-required washout prior and during the study.
For patients who can potentially benefit from treatment with Lu AF35700
Patients who meet each of the inclusion criteria at the Screening and Baseline Visits (unless 
otherwise specified) and none of the exclusion criteria at the Screening and Baseline Visits 
(unless otherwise specified) are eligible to participate in this study.
1.
The patient is capable of communicating with the site personnel. 
2.
The patient and if applicable his or her legal representative is/are able to read and 
understand the Informed Consent Form.
3.
The patient and if applicable his or her legal representative has/have signed the Informed 
Consent Form for study 16159B.
4.
The patient is willing and able to attend study appointments within the specified time 
windows.
5.
The patient is either an inpatient at a psychiatric setting or outpatient consulting a 
psychiatrist.
6.
The patient has schizophrenia, diagnosed according to DSM-5™.
7.
The patient is a man or woman, aged ≥18 years. 
8.
The patient has been prescribed an oral antipsychotic treatment at recommended dose 
range as stated in the SmPC or equivalent document/label for 6 weeks prior the Screening 
Visit.
9.
The patient has a PANSS total score of ≥60 and 90 at Screening and Baseline Visits.
10. The patient has a Clinical Global Impression-Severity of Illness (CGI-S) score 4
11. The patient is in need of a change in the current antipsychotic treatment and according to 
the investigator’s clinical, the patient would potentially benefit from a switch to another 
treatment, including but not limited to any of the following reasons:
lack of adequate response to his or her current antipsychotic medication,
poor tolerability to his or her current antipsychotic medication,
unwillingness of the patient to adhere to his or her current antipsychotic medication.
13. The patient is willing to discontinue all prohibited psychotropic medications to meet 
protocol-required washout prior and during the study.
14. The patient has a caregiver or an identified responsible person (for example, family 
member, social worker, case worker, or nurse), considered reliable by the investigator 
in providing support to the patient to ensure compliance with study treatment, 
outpatient visits, and protocol procedures.


H. Lundbeck A/S 
Confidential
Page 38 of 87
15. The patient has a stable living environment, as demonstrated by the ability to provide 
contact information for themselves and/or family/friend(s)/caregiver(s).
16. The patient, if a woman, must:
agree not to try to become pregnant during the study, AND
use adequate, highly effective contraception (defined as those that result in a low failure 
rate [that is, <1% per year] when used consistently and correctly, for example, implants, 
injectables, combined oral contraceptives in combination with a double barrier method, 
some intrauterine devices, sexual abstinence, vasectomised partner), OR
have had her last natural menstruation ≥12 months prior to the Screening Visit, OR
have been surgically sterilised prior to the Screening Visit, OR
have had a hysterectomy prior to the Screening Visit
17. The patient, if a man, must:
use 2 methods of contraception in combination if his female partner is of childbearing 
potential; this combination of contraceptive methods must be used from the Baseline 
Visit to ≥1 month after the last dose of IMP, OR
have been surgically sterilised prior to the Screening Visit
Exclusion Criteria
For patients who completed study 16159A
General
1.
The patient has previously been screened in this study.
2.
The patient is a member of the study personnel or of their immediate families, or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel.
3.
The patient has developed a severe drug allergy or hypersensitivity to the IMP or its 
excipients during study 16159A.
4.
The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
Psychiatric
5.
The patient has been diagnosed with a primary psychiatric disorder other than 
schizophrenia during study 16159A.
6.
The patient has a clinically significant unstable illness diagnosed during study 16159A.
7.
The patient is experiencing an acute exacerbation of his/her psychotic symptoms 
according to the investigator’s clinical judgement.
8.
The patient has a current diagnosis of substance use disorder according to DSM 5™ 
criteria during study 16159A with the exception of tobacco, or mild cannabis or mild 
alcohol use disorder. Patients with a positive drug screen test at the Baseline Visit, with 
the exception of cannabis and verified by repeated testing, are excluded from the study. 
9.
The patient, in the opinion of the investigator, is at significant risk of suicide, or the 
patient:


H. Lundbeck A/S 
Confidential
Page 39 of 87
Answers “Yes” to any question on the Suicidal Behaviour section of the C-SSRS, OR
Answers “Yes” to questions 4 and 5 on the Suicidal Ideation section of the C-SSRS.
10. The patient has started formal cognitive or behavioural therapy or systematic 
psychotherapy during study 16159A. Any ongoing formal psychotherapy initiated more 
than 6 weeks prior to Screening Visit of study 16 159A should be continued with the 
same methodology and at the same frequency and intensity during the entire study.
11. The patient has experienced neuroleptic malignant syndrome during study 16159A.
Medical
12. The patient has any other medical disease for which the treatment takes priority over 
treatment of schizophrenia or is likely to interfere with study treatment or impair 
treatment compliance.
13. The patient has a moderate or severe ongoing adverse event related to IMP from study
16159A considered of potential safety risk by the investigator.
14. The patient takes or has taken disallowed recent or concomitant medication (specified in 
Appendix II) in study 16159A.
15. The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, tolerability or efficacy, or interfere with the 
conduct or interpretation of the study.
16. The patient has clinically significant abnormal vital signs considered of potential safety 
risk by the investigator.
17. The patient has one or more laboratory values outside the reference range, based on the 
last available blood or urine samples taken during study 16159A that are, in the 
investigator’s opinion, of potential risk to the patient’s safety, or the patient has any of the 
following values at study 16159A (the medical monitor should be contacted in case of 
uncertainty):
a serum creatinine value >1.5 times the upper limit of the reference range
a serum total bilirubin value >1.5 times the upper limit of the reference range
a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 times the upper limit of the reference range
18. The patient has not previously been diagnosed with diabetes, but meets ANY of the 
following criteria (newly diagnosed diabetes) based on the last available blood samples 
taken during study 16159A:
HbA1C >6.5%, OR 
fasting plasma glucose >126 mg/dL (7.0 mmol/L), OR 
non-fasting plasma glucose >200 mg/dL (11.1. mmol).
19. The patient has previously been diagnosed with diabetes, but the condition is unstable as 
determined by ANY of the following criteria based on the last available blood samples 
taken during study 16159A:
HbA1c ≥7.0%, OR 
glucose >6.94 mmol/L (fasting, >125 mg/dL) or 11.1 mmol/L (nonfasting, 200 mg/dL)


H. Lundbeck A/S 
Confidential
Page 40 of 87
any other abnormal laboratory tests that in the investigator’s clinical judgement are 
medically significant and would impact on the safety of the patient or the interpretation 
of the study results.
20. The patient has orthostatic hypotension (defined as a decrease in systolic blood pressure 
>20 mmHg between two measurements, first in the supine position and then sitting, and 
standing after the patient has rested in each position for at least 3 minutes.
21. The patient has, based on the last available ECG measurement taken during 
study 16159A:
an abnormal ECG that is, in the investigator’s opinion, clinically significant
a PR interval >250 ms
a QRS interval >130 ms
a QTcF interval >450 ms (for men) or >470 ms (for women) (based on the Fridericia 
correction where QTcF = QT/RR0.33)
A patient should also be excluded if he or she has any other abnormal ECG tests that in 
the investigator’s clinical judgment are medically significant and would impact the 
safety of the patient or the interpretation of the study results.
For patients who completed the dosing period of study 16323A
General
1.
The patient has previously been enrolled in this study.
2.
The patient is a member of the study personnel or of their immediate families, or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel.
3.
The patient has developed a severe drug allergy or hypersensitivity to the IMP or its 
excipients during study 16323A.
4.
The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
Psychiatric
5.
The patient has been diagnosed with a primary psychiatric disorder other than 
schizophrenia during study 16323A.
6.
The patient has a clinically significant unstable illness diagnosed during study 16323A.
7.
The patient is experiencing an acute exacerbation of his/her psychotic symptoms 
according to the investigator’s clinical judgement.
8.
The patient has a current diagnosis of substance use disorder according to DSM 5™ 
criteria during study 16323A with the exception of tobacco, or mild cannabis or mild 
alcohol use disorder. Patients with a positive drug screen test at the Baseline Visit, with 
the exception of cannabis and verified by repeated testing, are excluded from the study. 
9.
The patient, in the opinion of the investigator, is at significant risk of suicide, or the 
patient:

Answers “Yes” to any question on the Suicidal Behaviour section of the C-SSRS, OR

Answers “Yes” to questions 4 and 5 on the Suicidal Ideation section of the C-SSRS.


H. Lundbeck A/S 
Confidential
Page 41 of 87
10. The patient has started formal cognitive or behavioural therapy or systematic 
psychotherapy during study 16323A. Any ongoing formal psychotherapy initiated more 
than 6 weeks prior to Screening Visit of study 16323A should be continued with the same 
methodology and at the same frequency and intensity during the entire study.
11. The patient has experienced neuroleptic malignant syndrome during study 16323A.
Medical
12. The patient has any other medical disease for which the treatment takes priority over 
treatment of schizophrenia or is likely to interfere with study treatment or impair 
treatment compliance.
13. The patient has a moderate or severe ongoing adverse event related to IMP from 
study 16323A considered of potential safety risk by the investigator.
14. The patient takes or has taken disallowed recent or concomitant medication (specified in 
Appendix II) in study 16323A.
15. The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, tolerability or efficacy, or interfere with the 
conduct or interpretation of the study.
16. The patient has clinically significant abnormal vital signs considered of potential safety 
risk by the investigator.
17. The patient has one or more laboratory values outside the reference range, based on the 
last available blood or urine samples taken during study 16323A that are, in the 
investigator’s opinion, of potential risk to the patient’s safety, or the patient has any of the 
following values at study 16323A (the medical monitor should be contacted in case of 
uncertainty): 
a serum creatinine value >1.5 times the upper limit of the reference range
a serum total bilirubin value >1.5 times the upper limit of the reference range
a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 times the upper limit of the reference range
18. The patient has not previously been diagnosed with diabetes, but meets ANY of the 
following criteria (newly diagnosed diabetes) based on the last available blood samples 
taken during study 16323A:
HbA1c ≥7.0%, OR 
glucose >6.94 mmol/L (fasting, >125 mg/dL) or >11.1 mmol/L (nonfasting, >200 
mg/dL)
any other abnormal laboratory tests that in the investigator’s clinical judgement are 
medically significant and would impact on the safety of the patient or the interpretation 
of the study results.
19. The patient has orthostatic hypotension (defined as a decrease in systolic blood pressure 
>20 mmHg between two measurements, first in the supine position and then sitting, and 
standing after the patient has rested in each position for at least 3 minutes.
20. The patient has, based on the last available ECG measurement taken during 
study 16323A:
an abnormal ECG that is, in the investigator’s opinion, clinically significant


H. Lundbeck A/S 
Confidential
Page 42 of 87
a PR interval >250 ms
a QRS interval >130 ms
a QTcF interval >450 ms (for men) or >470 ms (for women) (based on the Fridericia 
correction where QTcF = QT/RR0.33)
A patient should also be excluded if he or she has any other abnormal ECG tests that in 
the investigator’s judgment are medically significant and would impact the safety of the 
patient or the interpretation of the study results.
For patients who can potentially benefit from treatment with Lu AF35700
General
1.
The patient has previously been enrolled in this study.
2.
The patient has participated in a clinical study <30 days prior to the Screening Visit.
3.
The patient is a member of the study personnel or of their immediate families, or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel.
4.
The patient is under forced treatment.
5.
The patient is pregnant or breast-feeding.
6.
The patient has a history of severe drug allergy or hypersensitivity, or known 
hypersensitivity to any of the IMP(s) or its/their excipients.
7.
The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, tolerability, or efficacy, or interfere with the 
conduct or interpretation of the study.
8.
The patient takes or has taken disallowed recent or concomitant medication (specified in
Appendix II) or it is anticipated that the patient will require treatment with at least one of 
the disallowed concomitant medications during the study.
9.
The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
Psychiatric
10. The patient has any current psychiatric disorder (DSM-5™ criteria) other than 
schizophrenia established as the primary diagnosis.
11. The patient suffers from intellectual disability, organic mental disorders, or mental 
disorders due to a general medical condition (DSM-5™ criteria).
12. The patient is experiencing acute exacerbation of his/her psychotic symptoms at the 
Screening Visit, between the Screening and Baseline Visits or at the Baseline Visit 
according to the investigator’s judgment. 
13. The patient is treated with clozapine at the time of the Screening Visit.
14. The patient has a current diagnosis or a history of substance use disorder according to 
DSM-5™ criteria within 6 months prior to the Screening Visit with the exception of 
tobacco, or mild cannabis or mild alcohol use disorder. Patients with a positive drug 
screen test with the exception of cannabis and verified by repeated testing are excluded 
from the study. 


H. Lundbeck A/S 
Confidential
Page 43 of 87
15. The patient is at significant risk of harming himself/herself or others according to the 
investigator’s clinical judgement, or who on the C-SSRS:
Answers ”Yes” to questions 4 or 5 on the Suicidal Ideation section within the last 
3 months at Screening, OR
Answers “Yes” to any question on the Suicidal Behaviour section within the last 
3 months at Screening, OR
Answers “Yes” to questions 4 or 5 on the on the Suicidal Ideation section at Baseline.
16. The patient has had neuroleptic malignant syndrome.
17. The patient has started formal cognitive or behavioural therapy or systematic 
psychotherapy within 6 weeks prior to Screening, or plans to start such therapy during the 
study. Any ongoing formal psychotherapy initiated more than 6 weeks prior to Screening 
should be continued with the same methodology and at the same frequency and intensity 
during the entire study.
Medical
18. The patient has any other medical disease for which the treatment takes priority over 
treatment of schizophrenia or is likely to interfere with study treatment or impair 
treatment compliance.
19. The patient has a history of moderate or severe head trauma or other neurological 
disorders or systemic medical diseases that are, in the investigator’s opinion, likely to 
affect central nervous system functioning.
20. The patient has epilepsy or a history of seizures, except for a single seizure episode (e.g., 
childhood febrile seizure, post traumatic, or alcohol withdrawal).
21. The patient has or has had one or more of the following conditions that is/are considered 
clinically relevant in the context of the study:
neurological disorder
cardiovascular disease
seizure disorder or encephalopathy
congestive heart failure
cardiac hypertrophy
arrhythmia
bradycardia (pulse <50 bpm)
respiratory disease
hepatic impairment or renal insufficiency
metabolic disorder
endocrine disorder
gastrointestinal disorder
haematological disorder
infectious disorder
any clinically significant immunological condition
dermatological disorder


H. Lundbeck A/S 
Confidential
Page 44 of 87
venereal disease
elevated intra-ocular pressure or is at risk of acute narrow-angle glaucoma
22. The patient has clinically significant abnormal vital signs.
23. The patient has one or more clinical laboratory test values outside the reference range, 
based on the blood and urine samples taken at the Screening Visit, that are of potential 
risk to the patient’s safety, or the patient has, at the Screening Visit:
a serum creatinine value >1.5 times the upper limit of the reference range
a serum total bilirubin value >1.5 times the upper limit of the reference range
a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 times the upper limit of the reference range
24. The patient has not previously been diagnosed with diabetes, but meets ANY of the 
following criteria (newly diagnosed diabetes):
HbA1C >6.5%, OR
Fasting plasma glucose >126 mg/dL (7.0 mmol/L), OR
Non-fasting plasma glucose >200 mg/dL (11.1 mmol).
25. The patient has previously been diagnosed with diabetes, but the condition is unstable as 
determined by ANY of the following criteria:
HbA1c ≥7.0%, OR
Screening glucose is >6.94 mmol/L (fasting, >125 mg/dL) or 11.1 mmol/L (nonfasting, 
200 mg/dL). If the non-fasting screening glucose is 11.1 mmol/L (200 mg/dL), patients 
must be retested in a fasted state and the retest value must be ≤6.94 mmol/L 
(125 mg/dL) to be eligible for the study, OR
The patient has not been maintained on a stable regimen of insulin and/or oral 
antidiabetic medication(s) for at least 28 days prior to Screening or the diabetes has not 
been well-controlled by diet for at least 28 days prior to Screening, OR

The patient has been hospitalized within 6 months prior to Screening due to diabetes or 
complications related to diabetes
26. The patient has orthostatic hypotension (defined as a decrease in systolic blood pressure 
>20 mmHg between two measurements, first in the supine position and then sitting, and 
standing after the patient has rested in each position for at least 3 minutes.
27. The patient has, at the Screening or at the Baseline Visit:
an abnormal ECG that is, in the investigator’s opinion, clinically significant
a PR interval >250 ms
a QRS interval >130 ms
a QTcF interval >450 ms (for men) or >470 ms (for women) (based on the Fridericia 
correction where QTcF = QT/RR0.33)
A patient should also be excluded if he or she has any other abnormal ECG tests that in 
the investigator’s judgment are medically significant and would impact the safety of the 
patient or the interpretation of the study results. 
28. The patient has a history of cancer, other than basal cell or Stage 1 squamous cell 
carcinoma of the skin, that has not been in remission for >5 years prior to the first dose of 
IMP.


H. Lundbeck A/S 
Confidential
Page 45 of 87
5.4
Withdrawal Criteria
A patient must be withdrawn from the study if:
• the patient and/or his or her legal representative (if applicable) withdraw(s) his or her
consent (defined as a patient and/or his or her legal representative [if applicable] who 
explicitly take(s) back his or her consent); section 8.4 states how the patient’s data will be 
handled
• the patient is lost to follow-up (defined as a patient who fails to comply with scheduled 
study visits or contact, who has not actively withdrawn from the study, and for whom no 
alternative contact information is available [this implies that at least two documented 
attempts have been made to contact the patient via both phone and mail]).
A patient must be withdrawn from treatment if:
• the investigator considers it, for safety, lack of efficacy, and/or study compliance reasons, 
in the best interests of the patient that he or she be withdrawn
• the patient becomes pregnant
• the patient has a serum ALT or AST value >3 times the upper limit of the reference range 
and a serum total bilirubin value >2 times the upper limit of the reference range
• the patient has a serum ALT or AST value >5 times the upper limit of the reference range 
that is confirmed by testing <2 weeks later
• the patient has a QTcF interval >500 ms or a change from Screening (or from Baseline for 
16159A-patients and 16323A-patients) in the QTcF interval >60 ms concurrently with a 
QTcF interval >470 ms 
• the patient has a positive urine drug screen verified by repeated testing at the following site 
visit
• the patient fails to comply with study procedures
• the patient is <80% IMP compliant between two consecutive, scheduled visits
• the patient in the opinion of the investigator has significant risk of suicide or who answers 
“Yes” to suicidal ideation questions 4 or 5 or answers “Yes” to suicidal behaviour on the 
C-SSRS® at any time during the study
Patients who withdraw will not be replaced.
6
Investigational Medicinal Products
6.1
Treatment Regimen
A schematic representation of the Treatment Regimen is presented in Panel 3 below. The total 
treatment period is 52 weeks.


H. Lundbeck A/S 
Confidential
Page 46 of 87
For patients who completed study 16159A (16159A-patients)
The Baseline Visit will take place at the same visit as the Visit 12 (Primary Outcome Visit, 
end of Week 16) of the study 16159A. 
After the baseline assessment, for eligible patients, the treatment with Lu AF35700 will be 
initiated at daily dose of 10 mg at Day 1 of study 16159B. In addition, for 16159A-patients, 
the treatment (Lu AF35700, risperidone or olanzapine) received during study 16159A will be 
tapered down in a blinded fashion with wallets from study 16159A and will be completed in 7 
days according to the following scheme:
• Patients randomised to Risperidone: 4 mg/day for the first 3 days; 2 mg/day for the 4 
subsequent days, encapsulated tablets, orally, once daily
• Patients randomised to Olanzapine: 10 mg/day for the first 3 days; 5 mg/day for the 4 
subsequent days, encapsulated tablets, orally, once daily
• Patients randomised to Lu AF35700: Placebo for 7 days, encapsulated tablets, orally, once 
daily.
At the end of the first week (Week 1 Visit), all patients will be treated with 10 mg/day 
Lu AF35700 only. 
From the Week 1 Visit, according to the investigator’s clinical judgment, the 10 mg/day dose 
can be increased to 20 mg/day based on the patient’s response. Thereafter, the 20 mg/day 
dose can be reduced to 10 mg/day based on the patient’s tolerability to treatment. This can 
occur at scheduled or unscheduled visits.
From the Week 8 Visit, the switch from Lu AF35700 daily dosing regimen to Lu AF35700 
weekly dosing regimen can be performed at any consecutive visit according to the investiga-
tor’s clinical judgment. The first weekly tablet will be taken 7 days after the last daily tablet. 
The Lu AF35700 weekly dosing regimen can be switched back to a daily dosing regimen of 
10 mg/day for tolerability reasons or to 20 mg/day for worsening of the patient’s clinical 
status. This can occur at scheduled or unscheduled visits. The first daily tablet will be taken 
7 days after the last weekly tablet.
The number of patients under weekly dosing regimen will be limited to 50 patients by 
IVRS/IWRS.
For patients who completed the dosing period of the study 16323A (16323A-patients)
The Baseline Visit of study 16159B will take place at the same visit as the last day of the 
dosing period of study 16323A.
After the baseline assessment, for eligible patients, the treatment with Lu AF35700 will be 
initiated at daily dose of 10 mg at Day 1 of study 16159B. In addition, for 16323A-patients, 
the treatment (Lu AF35700 or quetiapine) received during study 16323A will be tapered 
down in a blinded fashion and will be completed in 7 days according to the following scheme:


H. Lundbeck A/S 
Confidential
Page 47 of 87
• Patients randomised to quetiapine: 600 mg/day for the first 3 days; 300 mg/day for the 4 
subsequent days, encapsulated tablets, orally, once daily.
• Patients randomised to Lu AF35700: Placebo for 7 days, encapsulated tablets, orally, once 
daily.
At the end of the first week (Week 1 Visit), all patients will be treated with 10 mg/day 
Lu AF35700 only. 
At visits following the Week 1 Visit, according to the investigator’s clinical judgment, the 
10 mg/day dose can be increased to 20 mg/day based on the patient’s response. Thereafter, 
the 20 mg/day dose can be reduced to 10 mg/day based on the patient’s tolerability to 
treatment. This can occur at scheduled or unscheduled visits.
For other patients who can potentially benefit from treatment with Lu AF35700 (Other 
Patients)
After the baseline assessment, for eligible patients, the current antipsychotic treatment will be 
tapered down and completed in 7 days, while the treatment with Lu AF35700 will be initiated 
at a 10 mg/day dose at Day 1. The 10 mg/day dose will be maintained during the first week of 
study 16159B.
At the end of the first week (Week 1 Visit), all patients will be treated with 10 mg/day Lu 
AF35700 only. 
At visits following the Week 1 Visit, according to the investigator’s clinical judgment, the 
10 mg/day dose can be increased to 20 mg/day based on the patient’s response. Thereafter,
the 20 mg/day dose can be reduced to 10 mg/day based on the patient’s tolerability to 
treatment. This can occur at scheduled or unscheduled visits.
The recruitment of Other Patients can start in a given site only after the recruitment of the 
patients in the study 16159A or in the study 16323A is completed.


H. Lundbeck A/S 
Confidential
Page 48 of 87
Panel 3
Treatment regimen
Patients who completed study 16159A
Patients who completed study 16323A
Other Patients
Investigational 
Medicinal Product 
(IMP)
Lu AF35700
10 or 20 mg/day
Encapsulated 
tablets
OLZ
15-20 mg/day
Encapsulated 
tablets
RIS
4-6 mg/day
Encapsulated 
tablets
Lu AF35700 
10 & 30 mg/day
Encapsulated tablets
Quetiapine 
800 mg/day
Encapsulated
tablets
N/A
Treatment that will be taken in study 16159B
Day 1 – Day 3
Down-titration 
wallet from the 
previous study 
Wallet from study
16159B
Placebo
Encapsulated 
tablets
Lu AF35700
10 mg/day, 
tablets
OLZ 10 mg/day
Encapsulated 
tablets
Lu AF35700
10 mg/day, 
tablets
RIS 4 mg/day
Encapsulated 
tablets
Lu AF35700
10 mg/day, 
tablets
Placebo
Encapsulated tablets
Lu AF35700
10 mg/day, tablets
QUE 600 mg/day
Encapsulated tablets
Lu AF35700
10 mg/day, tablets
N/A
Lu AF35700
10 mg/day, tablets
+
Current antipsychotic 
treatment will be 
gradually down-
titrated and 
completed in 7 days 
(based on the SmPC
or equivalent 
document/label)
Day 4 – Day 7
Down titration 
wallet from the 
previous study 
Wallet from study
16159B
Placebo
Encapsulated 
tablets
Lu AF35700
10 mg/day, 
tablets
OLZ 5 mg/day
Encapsulated 
tablets
Lu AF35700
10 mg/day, 
tablets
RIS 2 mg/day
Encapsulated 
tablets
Lu AF35700
10 mg/day, 
tablets
Placebo
Encapsulated tablets
Lu AF35700
10 mg/day, tablets
QUE 300 mg/day
Encapsulated tablets
Lu AF35700
10 mg/day, tablets
Day 8 – Day 55
Lu AF35700
10 or 20 mg/day, 
tablets
Lu AF35700
10 or 20 mg/day, 
tablets
Lu AF35700
10 or 20 mg/day, 
tablets
Lu AF35700
10 or 20 mg/day, 
tablets
Lu AF35700
10 or 20 mg/day, 
tablets
Lu AF35700
10 or 20 mg/day, 
tablets
From Day 56
Lu AF35700 10 or 20 mg/day, tablet
Lu AF35700 70 mg/week, tablets
-
The switch from Lu AF35700 daily dosing regimen 
(10 or 20 mg/day) to Lu AF35700 weekly dosing 
regimen can be performed at the end of the eighth 
week (Week 8 Visit), according to the investigator’s 
clinical judgment). First weekly tablet will be taken 
7 days after the last daily tablet.
-
No more than 50 patients can be assigned to weekly 
dosing regimen during the course of the study.
-
Possibility to switch back to daily dosing regimen 
(for lack of tolerability or symptoms worsening). 
First daily tablet will be taken 7 days after the last 
weekly tablet.
Lu AF35700
10 or 20 mg/day, tablets
6.2
IMPs, Formulations, and Strengths
The IMPs supplied by Lundbeck in this study are:
• Lu AF35700 – film-coated tablets in strengths of 10 and 20 mg (once daily) and 70 mg 
(once weekly) 
6.3
Manufacturing, Packaging, Labelling, and Storage of IMPs
The IMPs will be manufactured, packaged, labelled, released (by a qualified person [QP]), 
and distributed in accordance with the principles of Good Manufacturing Practice, under the 
responsibility of Lundbeck.


H. Lundbeck A/S 
Confidential
Page 49 of 87
The IMP will be provided in wallet cards.
The wording on the labels will be in accordance with Good Manufacturing Practice regarding 
labelling and national and/or local regulatory requirements. If additional information is to be 
added when the IMP is dispensed to patients, this will be clearly stated on the labels, and the 
investigator will be instructed to do so.
No manipulation, repackaging, or relabelling of IMP is permitted after QP release by 
Lundbeck, unless a repackaging/relabelling agreement exists, and the documentation is 
available to the Department of Clinical Supply, H. Lundbeck A/S, and, where necessary, new 
QP releases are made.
The IMPs will be identified using a unique IMP number.
The IMPs must be stored in a safe and secure location, and in accordance with the storage
conditions specified on the labels.
6.4
Method of Assigning Patients to Treatment
All patients will be assigned a screening number by eCRF system and that will be used to 
identify them throughout the study.
An interactive voice response system (IVRS) will be used in this study. The IVRS will 
dispense Lu AF35700 daily dosing (10 or 20 mg), and provide the option to the investigator 
to switch to weekly dosing regime at the end of the eighth week. The IVRS will restrict the 
number of patients that can be assigned to weekly dosing to 50 patients. The IVRS will allow 
the patient to be switched back from weekly to daily dosing.
6.5
IMP Accountability
The IMPs must be tracked at each site using two logs:
• a site-specific log to track the complete inventory (that is, what is shipped between the site 
and the depot)
• a patient-specific log to track what is dispensed to and returned by the patient
The investigator and the pharmacist (if applicable) must agree to only dispense IMP to 
patients enrolled in the study. The investigator or the pharmacist (if applicable) must maintain 
an adequate record of the receipt and distribution of the IMPs. This record must be available 
for inspection at any time.
6.6
Post -study Access to IMP
Post-study access to IMP will not be available. Patients in the study will have access to 
appropriate medical care after they complete or withdraw from the study.


H. Lundbeck A/S 
Confidential
Page 50 of 87
7
Concomitant Medication
Concomitant medication is any medication other than the IMPs that are taken during the 
study, including during the Screening Period.
The recent and concomitant medications that are disallowed or allowed with restrictions 
during the study are summarised in Appendix II.
Details of all concomitant medication (prescription and over-the-counter) taken at the last 
visit of studies 16159A, and 16623A and taken <3 months prior to the Screening Visit for 
patients in need of a change in antipsychotic treatment must be recorded in the eCRF at the 
first visit. Any changes (including reason for changes) in concomitant medication must be 
recorded at each subsequent visit. For any concomitant medication initiated or for which the 
dose has changed due to a new disorder or worsening of a concurrent disorder, the disorder
must be recorded as an adverse event. Concomitant medication, associated with adverse 
events and SAEs, initiated after the last dose of IMP, must be recorded. 
8
Study Visit Plan
8.1
Overview
An overview of the procedures and assessments to be conducted during the study and their 
timing is presented in Panel 2. Further details are in chapter 9.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice.
8.2
Screening Visit (Visit 1)
Only patients who did not previously participate in a study investigating Lu AF35700 will 
enter this study at the screening visit.
The screening period begins after the informed consent has been obtained. Washout of 
disallowed medications begins, if applicable, and must comply with the requirements listed in
Appendix II. Screening evaluations are described in Panel 2.
In exceptional cases, the visit interval between the Screening and Baseline Visit may be 
extended with consent from the Sponsor Medical Expert, provided the Medical Expert accepts 
the rationale provided for the extension.
The patient’s eligibility assessment will be reviewed by an external medical team based on 
key protocol inclusion and exclusion criteria to promote appropriate patient enrolment and 
data quality. Sites should submit specific screening information within 48 hours from the 
Screening Visit. Once all information is obtained, the external medical team confirm the site 
whether the patient can continue screening.


H. Lundbeck A/S 
Confidential
Page 51 of 87
Decisions regarding inclusion of patients and assessment of patient safety throughout the 
study primarily remain at the discretion of the investigator; however, the sponsor or external 
medical team may request exclusion or discontinuation of a patient based on entry criteria or 
patient safety.
8.2.1
Pre-screening
Only for Other Patients - Each site must record in a pre-screening log which patients attended 
the Screening Visit
8.2.2
Patient Identification Card
Each patient will be provided with a patient identification card that states, at a minimum, the 
name of the IMP, the study number, the patient identification number, the investigator’s 
name, and an emergency telephone number providing 24-hour service.
The patient identification card should be returned to the investigator upon completion of the 
patient’s participation in the study.
8.2.3
Re-screening
Re-screening is not allowed in this study.
8.3
Baseline Visit (Visit 2)
Patients previously participating in a study investigating Lu AF35700 will enter in this study 
directly at the baseline visit. The investigator’s evaluation of the patient’s eligibility in this 
study will be done based on the latest data available in the previous LuAF35700 study.
After the baseline visit, the current antipsychotic or study treatment will be tapered down and 
completed in 7 days. 
8.4
Withdrawal Visit
Patients who withdraw from the study prior to the Primary Outcome Visit will be asked to 
attend a Withdrawal Visit, if at all possible. The visit must be scheduled as soon as possible 
after withdrawal.
No new information will be collected from patients who withdraw, except information 
collected in relation to the scheduled Withdrawal Visit or needed for the follow-up of adverse 
events (section 10.5).
The reason for withdrawal must be recorded on the Reason for Withdrawal Form.


H. Lundbeck A/S 
Confidential
Page 52 of 87
For a patient and his or her legal representative (if applicable) who withdraw(s) consent:
• if the patient and his or her legal representative (if applicable) withdraw(s) consent during 
a visit and then agrees to it being the final visit, the investigator will complete the visit as a 
Withdrawal Visit and all the data collected up to and including this visit will be used.
• if the patient and his or her legal representative (if applicable) withdraw(s) consent during 
a telephone conversation, the investigator will ask the patient if he or she will attend a 
Withdrawal Visit. If the patient:
agrees to attend a Withdrawal Visit, all the data collected up to and including this visit 
will be used.
refuses to attend a Withdrawal Visit, the investigator should attempt to follow the 
patient’s safety and future treatment; any information collected will only be recorded in 
the patient’s medical record.
• if the patient and his or her legal representative (if applicable) explicitly request(s) that his 
or her data collected from the time of withdrawal of consent onwards not be used, this will 
be respected.
8.5
Safety Follow-up Visit/Contact (Visit 18)
The safety follow-up is conducted to capture serious adverse events (SAEs) that occur during 
the Safety Follow-up Period as well as to follow up on the outcome of adverse events ongoing 
at the end of the Treatment Period. The safety follow-up must be conducted 42 days (+3 days) 
after the last dose of IMP. The safety follow-up may either be conducted as a visit to the site 
or as a telephone contact.
If any new SAEs have occurred since the last assessment at which the patient received IMP, 
the safety follow-up must, when possible, be a visit to the site.
For adverse events that were ongoing at the end of the Treatment Period and that resolved
during the Safety Follow-up Period, the stop date must be recorded. For non-serious adverse 
events still ongoing at the safety follow-up, the stop date must be recorded as “ongoing”. 
SAEs must be followed until resolution or the outcome is known.
Patients with a clinical safety laboratory test value that was out-of-range at the Primary 
Outcome or Withdrawal Visit and judged clinically significant must be followed according to 
accepted medical standards for up to 42 days or until the value normalises or stabilises or a 
diagnosis or a reasonable explanation has been established. For these patients, safety follow-
up visits must be scheduled to allow for a medical examination and/or blood sampling. The 
investigator must decide whether further safety follow-up visits are required after 42 days. If 
further safety follow-up visits are made, these must be documented in the patient’s medical 
record and not in the eCRF.
Patients who withdrew due to elevated AST or ALT values (see section 5.4) should be 
followed until the values normalise or stabilise or a diagnosis or a reasonable explanation has 
been established (see section 10.5).


H. Lundbeck A/S 
Confidential
Page 53 of 87
The safety follow-up for patients who withdraw consent must be performed, if at all possible; 
any information collected will be recorded in the patients’ medical records.
8.6
End-of-study Definition
The end of the study for an individual patient is defined as the last protocol-specified contact 
with that patient. The overall end of the study is defined as the last protocol-specified contact 
with the last patient ongoing in the study.
9
Assessments
9.1
Screening and Baseline Procedures and Assessments
9.1.1
Demographics and Other Baseline Characteristics
For Other Patients - At the Screening Visit, the following will be recorded or assessed:
• Diagnosis (DSM-5TM)
• Relevant medical and psychiatric history 
• Previous medications taken within (minimum) 3 months of screening; previous standard of 
care oral antipsychotic drugs taken within 3 months of screening. Washout from any 
prohibited concomitant medications will begin, if applicable (see Appendix II)
• Demographics: age, sex, race
• Height, weight, waist circumference
• Social history (e.g. education level, marital status, current living status, current 
employment status)
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria.
9.1.2
Drug Screen
A urine drug screen for opiates, methadone, cocaine, amphetamines (including 
ecstasy/methamphetamine), barbiturates, benzodiazepines, phencyclidine, and cannabinoids 
will be performed at designated times, but can be performed at any time during the study at 
the discretion of the investigator.
The urine drug screening kit will be supplied by a central laboratory.


H. Lundbeck A/S 
Confidential
Page 54 of 87
9.2
Effectiveness Assessments
9.2.1
Clinician-rated scales
9.2.1.1
Use of clinician-rated scales
The following clinician-rated scales will be used as exploratory effectiveness assessments:
• PANSS − assessing symptoms of schizophrenia
• PSP − assessing personal and social performance
• CGI-S − assessing global impression
• NSA-4 – assessing the severity of negative symptoms of schizophrenia
• QLS – assessing quality of life
• WoRQ – assessing readiness to work in patients with schizophrenia
The PANSS, NSA-4 and QLS will be administered in the local language. The PSP, CGI-S 
and WorQ will be administered in English only. Only scales provided by Lundbeck 
designated provider that, have been validated in the language to which they have been 
translated, will be used in this study.
Detailed instructions on how to administer the scales and how to score using the scales will be 
provided to the site.
9.2.1.2
Positive and Negative Syndrome Scale (PANSS)
The PANSS11 is a clinician-rated scale designed to measure severity of psychopathology in 
adult patients with schizophrenia, schizoaffective disorders, and other psychotic disorders. It 
emphasises positive and negative symptoms. The PANSS comprises 3 sub-scales with a total 
of 30 items: 7 items constitute the Positive Symptoms subscale (for example: delusions, 
conceptual disorganization, and hallucinatory behaviour), 7 items constitute the Negative 
Symptoms subscale (for example: blunted affect, emotional withdrawal, and poor rapport), 
and 16 items constitute the General Psychopathology subscale (for example: somatic concern, 
anxiety, and guilt feelings). Each item is rated from 1 (symptom not present) to 7 (symptom 
extremely severe). Raters using the PANSS should have training in psychiatric interview 
techniques and have clinical experience working with patients with schizophrenia and related 
psychotic disorders. The Structured Clinical Interview for PANSS21 (SCI–PANSS) will be 
used to facilitate the administration of the PANSS assessment.
It takes 30 to 40 minutes to administer and score the PANSS.
9.2.1.3
Personal and Social Performance Scale (PSP)
The PSP14 is a clinician-rated scale designed and validated to measure a patient’s current level 
of social functioning.


H. Lundbeck A/S 
Confidential
Page 55 of 87
The PSP consists of 4 items: socially useful activities (including work and study), personal 
and social relationships, self-care, and disturbing and aggressive behaviours. The 4 items are 
assessed on a 6-point scale, from absent to very severe. Based on these assessments and their 
combination, the global score ranges from 1 to 100.
The PSP can be administered by an experienced clinician after a short training session.
It takes approximately 5 minutes to administer and score the PSP.
9.2.1.4
Clinical Global Impression Scale- Severity (CGI-S)
The CGI12 was developed to provide global measures of the severity of a patient’s clinical 
condition during clinical studies. The CGI severity of illness (CGI-S) provides the clinician’s 
impression of the patient’s current state of mental illness. The clinician uses his or her clinical 
experience of this patient population to rate the severity of the patient’s current mental illness 
on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill 
patients). An experienced clinician can use the CGI after a short training session.
It takes 1 to 2 minutes to score the CGI after a clinical interview.
9.2.1.5
4-Item Negative Symptom Assessment (NSA-4)
The NSA-413 is a clinician rated scale designed to assess the severity of negative symptoms of 
schizophrenia. It consists of 4 items to measure: restricted speech quantity, reduced emotion, 
reduced social drive, and reduced interests, as well as an overall global rating of negative 
symptoms. Each of the four items is rated on a 1 to 6-point scale where ‘1’ represents no 
reduction from normal behaviors associated with the item and ‘6’ represents severe reduction 
or absence of the behavior. The scale also includes a ”non ratable” designation denoted as ‘9’.
It takes approximately 10 minutes to complete the NSA-4.
9.2.1.6
Quality of Life Scale (QLS)
The QLS15 is a clinician-rated scale designed to assess deficit symptoms of schizophrenia and 
functioning during the preceding 4 weeks. The QLS consists of 21 items in 4 subscales: 
Interpersonal Relations (8 items), Instrumental Role (4 items), Intrapsychic Foundations 
(7 items), and Common Objects and Activities (2 items). Each item is rated on a 7-point scale, 
from 0 (severe impairment) to 6 (normal or unimpaired functioning). Definitions are provided 
for 4 anchor points of the 7 points. Each item has a brief description of the judgement to be 
made and a set of suggested probes for the clinician. The mean score is calculated for each 
subscale and the total score for all items ranges from 0 to 126, where the higher score 
indicates normal or unimpaired functioning. The QLS can be administered by a clinician after 
a short training. 
It takes approximately 45 minutes to administer and score the QLS.


H. Lundbeck A/S 
Confidential
Page 56 of 87
9.2.1.7
Readiness for work questionnaire (WoRQ)
The WoRQ16 is a clinician-rated scale designed to measure readiness to work in patients with 
schizophrenia. The WoRQ consists of 8 items: the clinician must rate 7 statements and answer 
one question. The statements are rated on a 4-point scale, from strongly agree, agree, 
disagree or strongly disagree based on all material available (for example, personal notes, 
medical records, input from other health professionals, family members or caregivers); and in 
the final item, the clinician must indicate if the patient is ready for work or not. The WoRQ 
can be rated by a clinician after a short training session. 
It takes approximately 5 minutes to administer the WoRQ.
9.2.1.8
Rater Qualification and Certification
The PANSS, PSP, NSA-4, QLS, and WoRQ should be administrated by clinicians. 
The CGI-S must be administered by the clinician responsible for the patient.
A clinician in the context of the study is defined as a Medical Doctor (MD), Doctor of 
Osteopathic Medicine (DO), or anyone holding a Doctoral or Master’s Degree (or equivalent) 
in a medical or psychology related field. 
As a pre-requisite, PANSS raters must be experienced in patients with schizophrenia and in 
administering the PANSS. 
Any exceptions must be discussed and approved by Lundbeck.
Only raters who have been already trained and certified in studies 16159A and 16323A are 
allowed to rate the patients in study 16159B. New raters joining study 16159B will be trained 
and certified using the same certification processes as in study 16159A. 
Documentation of training and certification will be delivered to the raters for archiving in the 
investigator study master file (TMF). No patient may be rated before the documentation has 
been delivered.
Rater training and certification will be conducted by a third party vendor selected by the 
sponsor.
Each site should have a minimum of 2 certified raters per scale in order to provide back-up 
for each other. Any exceptions must be discussed and approved by Lundbeck.
9.2.2
Patient Reported Outcomes (PROs)
9.2.2.1
Use of patient reported outcomes
The following PROs will be used:


H. Lundbeck A/S 
Confidential
Page 57 of 87
• MSQ – patient reported, assessing satisfaction with medication
• TooL – patient reported, assessing impacts of side effects on quality of life
Only scales provided by H. Lundbeck A/S and that have been validated in the language to 
which they have been translated will be used in this study. The MSQ and TooL will be 
completed by the patient in the local language and guidance will be given to the patients on 
how to complete it/them.
Detailed instructions on how to administer the scales will be provided to the site.
9.2.2.2
Medication Satisfaction Questionnaire (MSQ)
The MSQ17 is a patient-rated scale designed and validated to assess the patient’s satisfaction 
with his or her current antipsychotic medication. The MSQ consists of one item that is rated
on a 7-point scale ranging from 1 (extremely dissatisfied) to 7 (extremely satisfied). The 
patient can complete the MSQ without any training.
It takes less than 1 minute to complete the MSQ.
9.2.2.3
Tolerability and Quality of Life questionnaire (TooL)
The TooL18 is a patient-rated scale developed to measure the impact of side-effects on the 
quality of life in patients treated with antipsychotic medication. The TooL consists of eight 
domains: mood (worry-upset), function capabilities, fatigue-weakness, weight gain, stiffness-
tremor, physical restlessness, sexual dysfunction and dizziness-nausea. Each domain is rated 
on a 4-point scale from 1 (no impact) to 4 (maximum impact). Total scores range from 8 (no 
impact) to 32 (maximum impact).
It takes approximately 5 minutes to complete the TooL.
9.2.3
Health Care Resource Utilisation
The Health Economic Assessment (HEA) questionnaire will be used to collect resource 
utilisation. The HEA will be provided in English only. Country specific version will be used 
for US and Canada. Instructions on how to complete the scale will be provided to the site.
The HEA is a questionnaire aiming at monitoring patients’ health care resource utilisation 
such as physicians’ visits, outpatient and inpatient services and other relevant services. Site 
personnel involved in the conduct of the study must ask these questions to the patients at 
selected visits. This allows for relating cost data to clinical efficacy and safety, and these data 
may be used for cost-effectiveness analyses.
The HEA is available in a Baseline Evaluation version which is to be used at the Baseline 
Visit and a Follow-Up Evaluation version which is to be used at Primary Outcome/
Withdrawal Visit.


H. Lundbeck A/S 
Confidential
Page 58 of 87
It takes approximately 15 minutes to complete the HEA.
9.3
Pharmacokinetic Assessments
Blood samples for IMP quantification (2 mL per time point) will be drawn in 2 mL K3 EDTA 
tube in accordance with Panel 2. The blood sampling and handling procedures are described 
in the study-specific Laboratory Specification Manual.
Sampling time point and sampling date should be recorded. At the visits for PK assessments, 
the time point and date of the latest intake of study medication should be recorded and the 
patient should be asked about the usual time of study medication intake during the period 
since the last visit. 
The blood samples will be analysed for Lu AF35700 and Lu AF36152 using an analytical 
method validated in accordance with the EMA Guideline on Bioanalytical Method 
Validation22 and  the FDA Guidance for Industry.23  
If other metabolites are identified and considered significant, these may be included in an 
exploratory analysis. The bioanalysis will be performed by the Department of Bioanalysis, 
H. Lundbeck A/S. A bioanalytical protocol will be prepared by Lundbeck before the plasma 
samples are analysed.
The result of the analysis will not be reported back to the investigator.
9.4
Translational Medicines Assessments (For Other Patients only)
9.4.1
General Considerations
Although the possible future exploratory biomarker analyses will help to increase our 
understanding of the aetiology of schizophrenia and the molecular basis of the drug response, 
the efforts described in this protocol are strictly research based. Therefore, as the complex 
interactions between genes and disease are currently not characterised to a level that translates 
to a meaningful clinical advantage, individual results from the exploratory biomarker analyses 
will not be given to the patients. For the same reasons, individual results will not be added to 
the patients’ medical records.
The patients will have no direct benefit from the exploratory biomarker analyses. As blood 
sampling for the exploratory genomics, proteomics, and metabolomics is an integral part of 
the study, the main Patient Information Sheet covers these analyses. Conversely, blood 
sampling for the possible future genetic biomarker analysis is optional and a separate Patient 
Information Sheet covers this analysis.
The blood samples for biobanking and possible future exploratory biomarker analysis, or the 
data derived from these blood samples, may be shared with academic and public institutions 
and other companies. However, Lundbeck will retain full control of the samples and their use 
in accordance with the information in the Patient Information Sheet and a Material Transfer 


H. Lundbeck A/S 
Confidential
Page 59 of 87
Agreement. Furthermore, the results based on the analysis of the samples may be pooled 
across studies to increase the statistical power of the analyses.
A patient and/or his or her legal representative (if applicable) may, at any time and without 
stating a reason, specifically request the destruction of the patient’s exploratory biomarker 
sample, irrespective of his or her continued participation in the study. The investigator must 
send a written request on behalf of the patient to the international study manager. The 
investigator will receive written confirmation from Lundbeck when the sample has been 
destroyed.
The blood samples for genomics, proteomics, and metabolomics will be single-coded using 
the patient’s screening number. The blood samples for genetic biomarker analysis will be 
double-coded as described in EMA’s position paper on pharmacogenetic terminology24 to 
ensure patient privacy protection.
The results of the possible future pharmacogenetics, proteomics/metabolomics and gene 
expression profiling will not be reported to the investigator.
9.4.2
Blood Sampling for Gene Expression Profiling
Blood samples for gene expression profiling (RNA) will be collected in two PAXgene tubes 
(2,5 mL) at each time point. The maximum volume of blood to be collected during the study 
for this purpose will be 10 mL. Samples for gene expression profiling will be shipped to a 
Central Laboratory, United States, for sample storage and possible preparation and analysis. 
The result of the analysis will not be reported back to the investigator.
Only the patients not previously participating in a study investigating Lu AF35700 will have 
blood drawn for gene expression profiling.
9.4.3
Blood Sampling for Metabolomic/Proteomic Biomarkers
Blood samples for metabolomic/proteomic biomarkers will be collected in one 10 mL K2 
EDTA tube at each time point. The maximum volume of blood to be collected during the
study for this purpose will be 20 mL. The samples for metabolomic/proteomic biomarkers 
will be shipped to a Central Laboratory, United States, for sample storage.
Only the patients not previously participating in a study investigating Lu AF35700 will have 
blood drawn for metabolomics/proteomic biomarkers.
9.4.4
Blood Sampling for Pharmacogenetics
It is optional for the patient to donate a blood sample for exploratory pharmacogenetic 
analysis. A blood sample (9 mL) will be collected in K3 EDTA tubes for subsequent DNA 
extraction. Blood tubes will be shipped on dry ice to a Central Laboratory, United States, 
where DNA will be extracted and retained. DNA aliquots will be shipped to a Central 


H. Lundbeck A/S 
Confidential
Page 60 of 87
Laboratory, for storage. The genetic variants to be analysed may include single nucleotide 
polymorphisms (SNPs) and copy number variations (CNVs). The analytical methods may be 
polymerase chain reaction (PCR), qPCR (quantitative PCR), sequencing, or whole genome 
scans on microarrays.
The results of these analyses are not specifically related to this study. The sample will be 
stored at a Central Laboratory, United States.
Only patients not previously participating in a study investigating Lu AF35700 will have 
blood drawn for pharmacogenetic analysis.
9.5
Safety Assessments
9.5.1
Adverse Events
The patients will be asked a non-leading question (for example, “how do you feel?”, “how 
have you felt since your last visit?”) at each visit, starting at the Screening Visit. Adverse 
events (including worsening of concurrent disorders, new disorders, and pregnancies) either 
observed by the investigator or reported spontaneously by the patient will be recorded, and 
the investigator will assess the seriousness and the intensity of the adverse event and its 
relationship to the IMP. Results from relevant tests and examinations, such as clinical safety 
laboratory tests, vital signs, and ECGs, or their corresponding conditions will also be recorded 
as adverse events if considered by the investigator to be clinically significant.
See chapter 10 for further information on adverse events.
9.5.2
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 4.


H. Lundbeck A/S 
Confidential
Page 61 of 87
Panel 4
Clinical Safety Laboratory Tests
Haematology
Livera
Kidneya
B-haemoglobin
S-total bilirubin
S-creatinine
B-erythrocyte count
S-conjugated bilirubin
S-urea nitrogen (BUN)
B-haematocrit
S-alkaline phosphatase (AP)
S-uric acid
B-MCV
S-alanine aminotransferase (ALT)
Urine (dipstick)
B-MCHC
S-aspartate aminotransferase (AST)
U-protein (dipstick)
B-total leucocyte count
S-lactate dehydrogenase (LDH)
U-glucose (dipstick)
B-neutrophils (% of total leucocytes)
S-γ-glutamyl transferase (γGT)
U-blood (dipstick)
B-eosinophils (% of total leucocytes)
Electrolytesa
U-ketones (dipstick)
B-basophils (% of total leucocytes)
S-sodium
Urine drug screenc
B-lymphocytes (% of total leucocytes)
S-potassium
U-Amphetamine
B-monocytes (% of total leucocytes)
S-chloride
U-Barbiturates
B-thrombocyte count
S-bicarbonate
U-Benzodiazepines
P-INR (prothrombin ratio)
S-calcium (total)
U-Cannabinoids
Lipidsa
Endocrine and Metabolica
U-Cocaine
S-cholesterol (total) (fasting)
S-albumin
U-Methadone
S-triglycerides (fasting)
P-glucose (fasting)
U-Opiates 
S-low density lipoprotein (LDL)
S-prolactinb
U-Phencyclidine
S-high density lipoprotein (HDL)
B-HbA1c (fasting)
Pregnancy (women only)
S-total protein
S-hCG
Urine dipstickd
Additional Test
S-Creatine phosphokinase 
(CPK)e
B – blood; P – plasma; S – serum; U – urine
a. Clinical chemistry
b. Result will remain blinded
c. Urine samples will be collected and analysed at the site using dipsticks
d. Can be repeated at any time during the study at the discretion of the investigator. All positive urine 
pregnancy test results must be confirmed by a serum test.
e. S-troponin T, reflex for CPK >500U/l.
Blood samples for the clinical safety laboratory tests will be collected as outlined in Panel 2.
The blood sampling and handling procedures are described in the study-specific Laboratory 
Specification Manual.
The blood samples will be analysed at the central laboratory.
The investigator must review (initial and date) the results of the clinical safety laboratory tests 
as soon as possible after receipt of those results. Out-of-range values must be interpreted by 
the investigator as “not clinically significant” or “clinically significant” with a comment 
concerning the planned follow-up. Tests for clinically significant out-of-range values must be 


H. Lundbeck A/S 
Confidential
Page 62 of 87
repeated, or an appropriate clinical follow-up must be arranged by the investigator and 
documented on the laboratory report, until the value has stabilised or until the value has 
returned to a clinically acceptable value (regardless of relationship to IMP). Any value that is 
out-of-range at the Primary Outcome or Withdrawal Visit and judged clinically significant 
must be followed according to accepted medical standards for up to 42 days or until the value 
normalises or stabilises or a diagnosis or reasonable explanation has been established. Any 
out-of-range values followed after the last protocol-specified contact with the patient will be 
documented in the patient’s medical record.
Clinically significant out-of-range values must be recorded as an adverse event on an Adverse 
Event Form.
The central laboratory will be notified by the sponsor when the biological samples may be 
destroyed.
9.5.3
Vital Signs
Pulse rate and blood pressure will be measured using a standard digital meter.
Pulse rate and blood pressure will be measured in the following order: supine, sitting, and 
standing after the patient has rested in each position for at least 3 minutes.
Vital signs must be assessed prior to blood sampling.
Abnormalities of clinical significance must be recorded as an adverse event on an Adverse 
Event Form.
9.5.4
Weight and Waist Circumference
The patients will be weighed wearing light clothing and no shoes.  A similar amount of 
clothing must be worn on each occasion.
Waist circumference should be recorded before the patient’s meal and at approximately the 
same time at each visit. The measurement will be made by locating the upper hip bone and the 
top of the right iliac crest and placing a weighted measuring tape in a horizontal plane around 
the abdomen at the level of the crest. Before reading the tape measure, the assessor should 
ensure that the tape is snug, but does not compress the skin, and is parallel to the floor.  The 
measurement is to be made at the end of a normal exhalation.
Two waist measurements will be performed. If the two measurements are differing by 1 cm or 
more, a third measurement will be performed. Waist circumference is the average of all the 
measurements performed.
Abnormalities of clinical significance must be recorded as an adverse event on an Adverse 
Event Form.


H. Lundbeck A/S 
Confidential
Page 63 of 87
9.5.5
Electrocardiograms (ECGs)
A standard 12-lead ECG will be recorded using digital ECG recording equipment provided to 
the investigator or, upon agreement, to an external cardiology centre.  The ECGs will be 
transferred digitally to a central ECG laboratory for evaluation.  The investigator will be 
provided with the results and a cardiological interpretation of the ECG from the central ECG 
laboratory.
The results from the central ECG laboratory will include the RR, PR, QRS, QT, and QTc
intervals.
The investigator has the final decision on the interpretation of the ECG results. Abnormalities 
of clinical significance must be recorded as an adverse event on an Adverse Event Form.
ECGs will be recorded according to the time schedule provided in Panel 2.
For 16159A-patients, additional ECGs will be performed at the time of switching from daily 
dosing to weekly dosing; 1 ECG should be recorded before the daily dose is switched to 
weekly dosing (preferably on the day the decision of switching from daily dosing to weekly 
dosing is taken), and 1 ECG should be recorded the day after the first weekly dose in taken.
9.5.6
Physical Examination
The investigator may appoint a designee to be primarily responsible for performing the 
physical examinations provided this is permitted according to local regulations. The
investigator must take responsibility for reviewing the findings. Whenever possible, the same 
individual should perform all the physical examinations.
The physical examination (including height at the Screening and Baseline Visit) must, at a 
minimum, include an examination of appearance, extremities, skin, head, neck, eyes, ears, 
nose, throat, lungs, chest, heart, abdomen and musculoskeletal system and must be performed 
by a physician or physician assistant.
Genito-urinary system examinations are often not part of routine psychiatric practice.  For 
most patients, an external inspection of the genitals should be sufficient. A full 
gynaecological examination should only be performed if warranted by symptoms or medical 
history.  The renal regions will be examined as part of the abdominal examination.
Abnormalities of clinical significance must be recorded as an adverse event on an Adverse 
Event Form.
9.5.7
Safety Assessment Tools
The following safety assessments will be administered:
• C-SSRS – clinician-rated assessing suicidality
• AIMS – clinician-rated assessing abnormal involuntary movements


H. Lundbeck A/S 
Confidential
Page 64 of 87
• BARS – clinician-rated, assessing akathisia
• mSAS – clinician-rated, assessing extrapyramidal symptoms
The C-SSRS will be administered in the local language. The AIMS, BARS and mSAS will be 
administered in English only. Only scales provided by H. Lundbeck A/S and that have been 
validated in the language to which they have been translated will be used in this study.
Detailed instructions on how to administer the scales and how to score using the scales will be 
provided to the site.
9.5.7.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a semi-structured interview developed to systematically assess suicidal 
ideation and behaviour of patients participating in a clinical study. The C-SSRS has 4 
questions addressing suicidal behaviour, 5 questions addressing suicidal ideation, and sub-
questions assessing the severity.
The C-SSRS is available in a Baseline/Screening version which is to be used at the Screening 
Visit and a Since last visit version which is to be used at all subsequent visits.
An experienced clinician can use the C-SSRS after a short training session. It takes 
approximately 5 minutes to administer and rate the C-SSRS.
9.5.7.2
Abnormal Involuntary Movement Scale (AIMS)
The AIMS25 is a clinician-rated scale designed to assess abnormal involuntary movements 
(for example, dyskinesia) associated with anti-psychotic drugs. The AIMS consists of 12 
items: items 1 to 7 assess the severity of movements in 3 anatomical areas (facial/oral, 
extremities and trunk); items 8 and 9 assess the global severity and the incapacitation due to 
the movements; item 10 assesses the patient’s awareness of the movements and the distress 
due to them; items 11 and 12 clarify the patient’s dental status. The 12 items are assessed 
using a neurological examination: items 1 to 9 are rated on a 5-point scale, from 0 (none) to 4 
(severe); item 10 is rated on a 5-point scale, from 0 (no awareness) to 4 (aware, severe 
distress); and items 11 and 12 are rated on a 2-point scale, 0 (no) and 1 (yes). The total score 
ranges from 0 to 42. The AIMS can be administered by a physician after a short training. 
It takes approximately 5 to 10 minutes to administer and score the AIMS.
9.5.7.3
Barnes Akathisia Scale (BARS)
The BARS26 is a clinician-rated scale designed to assess the presence and severity of drug 
induced akathisia. The BARS consists of 4 items: one objective item (observed restlessness), 
two subjective items (patient’s awareness of restlessness and related distress), and a global 
clinical assessment of akathisia. The objective and subjective symptoms are rated on a 4-point 
scale, from 0 (no symptom) to 3 (severe symptoms). The global clinical assessment is rated 
on a 6-point scale from 0 (absent) to 5 (severe akathisia). Comprehensive definitions are 


H. Lundbeck A/S 
Confidential
Page 65 of 87
provided for each anchor point on the scales. The BARS can be administered by a physician 
after a short training session. 
It takes 10 to 15 minutes to administer and score the BARS.
9.5.7.4
Modified Simpson Angus Scale (mSAS)
The mSAS,27 is a clinician-rated scale designed to assess the presence and severity of drug-
induced parkinsonism. The mSAS consists of 10 items to evaluate gait, rigidity (arms and 
head), eye-blinking, tremor, salivation and akathisia. The 10 items are assessed using a 
neurological examination and rated on a 5-point scale, from 0 (absence of the condition) to 4 
(most extreme form of the condition). Comprehensive definitions are provided for each 
anchor point on the scale. The mSAS can be administered by a physician after a short training 
session. 
It takes 10 to 15 minutes to administer and score the mSAS.
9.5.7.5
Rater Qualification and Certification
The C-SSRS should be rated by a clinician (see 9.2.1.8). The AIMS, BARS, and mSAS must 
only be administrated by physicians having adequate experience in patients with
schizophrenia. Any exceptions must be discussed and approved by Lundbeck.
Only raters who have been already trained and certified in studies 16159A and 16323A are 
allowed to rate the patients in study 16159B. New raters joining study 16159B will be trained 
and certified using the same certification processes as in study 16159A. 
Documentation of training and certification will be delivered to the raters for archiving in the 
investigator study master file (TMF). No patient may be rated before the documentation has 
been delivered.
Rater training and certification will be conducted by a third party vendor selected by the 
sponsor.
Each site should have a minimum of 2 certified raters per scale in order to provide back-up 
for each other. Any exceptions must be discussed and approved by Lundbeck.
9.6
Order of Assessments
The scales should preferably be administered in the following order at the applicable visits:
Screening Visit:
• PANSS, PSP, and C-SSRS
• CGI-S


H. Lundbeck A/S 
Confidential
Page 66 of 87
All visits other than Screening Visit:
• TooL and MSQ 
• PANSS, NSA-4, QLS, PSP, C-SSRS and WoRQ
• CGI-S
• AIMS, BARS, and mSAS 
• HEA
9.7
Treatment Compliance
The responsible study personnel will dispense the IMPs. Accountability and compliance 
verification should be documented in the patient’s source documents. Patients must be 
counselled on the importance of taking the study medications as directed at all study visits.
The medical monitor should be contacted if the investigator is uncertain whether a patient’s 
lack of compliance warrants withdrawal from the study.
Patients must be counselled on the importance of taking the IMP as directed at all study visits. 
9.8
Total Volume of Blood Drawn and Destruction of Biological Material
The total volume of blood drawn from each patient will be approximately 110 mL during the 
study.
Additional blood samples may be required if the original blood samples are not viable or if re-
testing is required.
The biobank blood samples and any derived material for possible future exploratory 
pharmacogenetic analyses will be destroyed ≤15 years after the end of the study (see 
definition in section 8.6) by a Central Laboratory.
The biobank blood samples and any derived material for possible future exploratory gene 
expression profiling and metabolic or proteomic biomarker assessments will be destroyed 
≤10 years after the end of the study (see definition in section 8.6) by a Central Laboratory.
All samples for pharmacokinetic assessment will be retained at the bioanalytical facility until 
the results have been reported. The samples will subsequently be destroyed by the responsible 
analytical laboratory. The bioanalytical lab will retain the samples until the bioanalytical 
report is final. The ISM will be notified that the samples are to be destroyed, and the 
documentation for sample destruction will be kept in the bioanalytical study file.


H. Lundbeck A/S 
Confidential
Page 67 of 87
10 Adverse Events
10.1
Definitions
10.1.1
Adverse Event Definitions28
Adverse event – is any untoward medical occurrence in a clinical study patient administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment.
An adverse event can therefore be any unfavourable and unintended sign (including clinically 
significant out-of-range values from relevant tests, such as clinical safety laboratory tests, 
vital signs, ECGs), symptom, or disease temporally associated with the use of a medicinal
product, regardless of whether it is considered related to the medicinal product.
Serious adverse event (SAE) – is any adverse event that:
• results in death
• is life-threatening (this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
had it been more severe)
• requires inpatient hospitalisation or prolongation of existing hospitalisation
• results in persistent or significant disability/incapacity
• is a congenital anomaly/birth defect
• is medically important (this refers to an event that may not be immediately life-threatening 
or result in death or hospitalisation, but may jeopardise the patient or may require 
intervention to prevent any of the SAEs defined above)
Examples of medically important events are intensive treatment for allergic bronchospasm;
blood dyscrasia or convulsions that do not result in hospitalisation; or development of drug 
dependency or drug abuse.
Planned hospitalisations or surgical interventions for a condition that existed before the 
patient signed the Informed Consent Form and that did not change in intensity are not SAEs. 
Emergency room visits that do not result in admission to the hospital are not necessarily 
SAEs; however, they must be evaluated to determine whether they meet any of the SAE 
definitions (for example, life-threatening or other serious [medically important] event).
The C-SSRS has 5 questions addressing suicidal ideation. If level 4 or 5 has been answered 
“yes”, it must be considered by the investigator whether an SAE should be reported.
Non-serious adverse event – is any adverse event that does not meet the definition of an SAE.
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE.


H. Lundbeck A/S 
Confidential
Page 68 of 87
Suspected unexpected serious adverse reaction (SUSAR) – is any adverse event that is 
assessed as serious, unexpected (its nature or intensity is not consistent with the current 
version of the Investigator’s Brochure for Lu AF35700) and related to Lu AF35700 by either 
the investigator or the sponsor.
Overdose – is a dose taken by a patient that exceeds the dose prescribed to that patient. Any 
overdose (and associated symptoms) must, at a minimum, be recorded as a non-serious 
adverse event.
10.1.2
Adverse Event Assessment Definitions
Assessment of Intensity
The investigator must assess the intensity of the adverse event using the following definitions, 
and record it on the Adverse Event Form:
• Mild – the adverse event causes minimal discomfort and does not interfere in a significant 
manner with the patient’s normal activities.
• Moderate – the adverse event is sufficiently uncomfortable to produce some impairment of 
the patient’s normal activities.
• Severe – the adverse event is incapacitating, preventing the patient from participating in his 
or her normal activities.
Assessment of Causality
The investigator must assess the causal relationship between the adverse event and the IMP
using the following definitions, and record it on the Adverse Event Form and the Serious 
Adverse Event Form (if applicable):
• Probable – the adverse event has a strong temporal relationship to the IMP or recurs on 
rechallenge, and another aetiology is unlikely or significantly less likely.
• Possible – the adverse event has a suggestive temporal relationship to the IMP, and an 
alternative aetiology is equally or less likely.
• Not related – the adverse event has no temporal relationship to the IMP or is due to 
underlying/concurrent illness or effect of another drug (that is, there is no causal 
relationship between the IMP and the adverse event).
An adverse event is considered causally related to the use of the IMP when the causality 
assessment is probable or possible.
Assessment of Outcome
The investigator must assess the outcome of the adverse event using the following definitions, 
and record it on the Adverse Event Form and the Serious Adverse Event Form (if applicable):
• Recovered – the patient has recovered completely, and no symptoms remain.
• Recovering – the patient’s condition is improving, but symptoms still remain.


H. Lundbeck A/S 
Confidential
Page 69 of 87
• Recovered with sequelae – the patient has recovered, but some symptoms remain (for 
example, the patient had a stroke and is functioning normally, but has some motor 
impairment).
• Not recovered – the patient’s condition has not improved and the symptoms are unchanged 
(for example, an atrial fibrillation has become chronic).
• Death
10.1.3
Study-specific Adverse Event Definitions
10.2
Pregnancy
Although not necessarily considered an adverse event, a pregnancy in a patient in the study 
must be recorded on an Adverse Event Form, as well as on a Pregnancy Form (paper), even if 
no adverse event associated with the pregnancy has occurred. Pregnancies must be reported to
Lundbeck using the same expedited reporting timelines as those for SAEs.
An uncomplicated pregnancy should not be considered an SAE. If, however, the pregnancy is 
associated with an SAE, the appropriate serious criterion (for example, hospitalisation) must 
be indicated on the Serious Adverse Event Form. Examples of pregnancies to be reported as 
SAEs (medically important) are spontaneous abortions, stillbirths, and malformations.
The investigator must follow up on the outcome of the pregnancy and report it on a 
Pregnancy Form (paper).  The follow-up must include information on the neonate at least up 
until the age of 1 month.
If the partner of a man participating in the study becomes pregnant, the outcome of the 
pregnancy should be followed if the partner agrees.  The partner must sign an Informed 
Consent Form to allow the investigator to collect information to report to Lundbeck.
10.3
Recording Adverse Events
Adverse events (including pre-treatment adverse events) must be recorded on an Adverse 
Event Form. The investigator must provide information on the adverse event, preferably with 
a diagnosis, or at least with signs and symptoms; start and stop dates (and start and stop time 
if the adverse event lasts less than 24 hours); intensity; causal relationship to IMP; action 
taken; and outcome. If the adverse event is an overdose, the nature of the overdose must be 
stated (for example, medication error, accidental overdose, or intentional overdose). If the 
intensity changes during the course of the adverse event, this must be recorded on the AE 
Intensity Log.
If the adverse event is serious, this must be indicated on the Adverse Event Form. 
Furthermore, the investigator must fill out a Serious Adverse Event Form and report the SAE 
to Lundbeck immediately (within 24 hours) after becoming aware of it (section 10.4).
Adverse events, including clinically significant out-of-range clinical safety laboratory test 
values and findings from for example, ECGs, must be recorded individually, except when 


H. Lundbeck A/S 
Confidential
Page 70 of 87
considered manifestations of the same medical condition or disease state; in such cases, they 
must be recorded under a single diagnosis.
10.4
Reporting Serious Adverse Events
The investigator must report SAEs to Lundbeck immediately (within 24 hours) after 
becoming aware of them by completing a Serious Adverse Event Form.
The initial report must contain as much information as possible and, if more information 
about the patient’s condition becomes available, the Serious Adverse Event Form must be 
updated with the additional information.
If the investigator cannot report the SAE in Rave®, then he or she must complete and sign the 
Serious Adverse Event Fallback Form and send it to:
Pharmacovigilance (PV)
Fax: +45 36 30 99 67
e-mail: safety@lundbeck.com
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance with 
local regulations.
It is the investigator’s responsibility to be familiar with local requirements regarding reporting 
SAEs to the IEC or IRB and to act accordingly.
Lundbeck will assume responsibility for reporting SUSARs to the authorities in accordance 
with local regulations. In those Member States of the European Union that have implemented 
the European Union Clinical Trials Directive29 and in Norway, Liechtenstein, and Iceland, 
that is, in the countries where unblinded expedited safety reporting is required, Lundbeck will 
also assume responsibility for reporting SUSARs to the ethics committees.
Lundbeck will assess the expectedness of SAEs and inform the investigator(s) about 
SUSARs, at 6 monthly blinded SUSAR listings. CIOMS-I reports for SUSARS are not 
normally distributed to investigators in those countries where SUSAR listings are sufficient. 
However, if the CIOMS-I reports are required (for example, by the local EC/IRB/REB), they 
will be sent to the investigator.
10.5
Treatment and Follow-up of Adverse Events
Patients with adverse events must be treated in accordance with usual clinical practice at the 
discretion of the investigator.
Non-serious adverse events must be followed up until resolution or the safety follow-up 
assessment, whichever comes first. At the safety follow-up, information on new SAEs, if any, 
and stop dates for previously reported adverse events must be recorded.


H. Lundbeck A/S 
Confidential
Page 71 of 87
It is the responsibility of the investigator to follow up on all SAEs until the patient has 
recovered, stabilised, or recovered with sequelae, and to report to Lundbeck all relevant new 
information using the same procedures and timelines as those for the initial report. Relevant 
information includes discharge summaries, autopsy reports, and medical consultations.
SAEs that are spontaneously reported by a patient to the investigator after the safety follow-
up assessment must be handled in the same manner as SAEs that occur during the study. 
These SAEs will be captured in the PV database.
Patients with clinically significant out-of-range clinical safety laboratory test values at the 
Primary Outcome or Withdrawal Visit must be followed in accordance with usual clinical 
practice and be scheduled for a Safety Follow-up Visit to allow for a medical examination 
and/or blood sampling (see section 8.5).
Patients who withdraw due to elevated AST or ALT values (see section 5.4) must be followed 
until the values normalise or stabilise or a diagnosis or a reasonable explanation has been 
established. Additional medical examinations (for example, ultrasound scanning and/or 
sampling for serology, conjugated bilirubin, INR) should be considered. A gastroenterology 
or hepatology consultation should also be considered.
11 Data Handling and Record Keeping
11.1
Data Collection
11.1.1
Electronic Case Report Forms (eCRFs)
eCRFs will be used to collect all the data related to the study, except the external data 
described in section 11.1.3.
The eCRFs use third party software (Rave®) to capture data via an on-line system on a 
computer. Data related to the study will be recorded electronically in a central database over 
encrypted lines, and all entries and modifications to the data will be logged in an audit trail. 
Access to the system will only be granted after appropriate and documented training. Written 
instructions for using the system will be provided along with the training.
Electronic signatures will be used where signatures are required on pages and/or visits. 
Automated data entry checks will be implemented where appropriate; other data will be 
reviewed and evaluated for accuracy by the CRA. All entries, corrections, and changes must 
be made by the investigator or a delegate.


H. Lundbeck A/S 
Confidential
Page 72 of 87
11.1.2
Patient Binders
11.1.2.1
Use of Patient Binders
Lundbeck may provide a Patient Binder for each patient.  The Patient Binder contains
different types of source documents, organised by visit and type. A ballpoint pen with 
waterproof ink must be used to enter information in the Patient Binder.
11.1.2.2
Rating Scales and Patient-reported Outcomes (PROs)
The Patient Binder contains paper versions of the rating scales and PROs. They will be 
completed by the rater(s) and patient, respectively. The data will be transcribed to the Scoring 
Sheets in the eCRF by the investigator or a delegate.
The rater(s) must verify that all the entries in the Scale Section are accurate and correct by 
signing and dating the relevant pages.
The patients will be asked to complete the PROs in their local language. The patients’ 
responses may only be corrected by the patient.
11.1.2.3
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed.
11.1.3
External Data
All electronic data will be transferred using a secure method accepted by Lundbeck.
The electronic data received from the following vendors will be kept in a secure designated 
storage area outside the eCRF:
• The clinical safety laboratory test results will be transferred by central laboratory.
• The ECG results will be transferred by the central ECG service provider.
• If any electronic assessment tools (i.e PANSS, CGI-S, PSP, SAS, AIMS, BARS, NSA-4, 
QLS, WorQ, C-SSRS) and/or patient reported outcomes (i.e TooL, MSQ and HEA) will be 
used, the results will be transferred by the designated vendor.
11.2
Retention of Study Documents at the Site
11.2.1
eCRF Data
If a site closes before the study has been completed, the investigator will continue to have 
read-only access to the eCRF. If a site closes after the study has been completed, the 
investigator will no longer have read access to the eCRF. Instead, each site will be provided 
with a CD-ROM containing the data related to the site (including eCRF data, queries, and the 
audit trail). As a CD-ROM is not considered a durable medium and may therefore not be 


H. Lundbeck A/S 
Confidential
Page 73 of 87
readable for the full retention period (for example, 15 years [if required by the applicable 
regulatory requirements]), it is possible for the investigator to request a new CD-ROM with 
the data related to the site.
11.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 15 years after the Clinical Study Report has been approved or in accordance with 
national requirements, whichever is longer.
Since off-site storage is used, a study-specific binder will remain at the site after the other 
study-specific documents have been shipped for off-site storage. This binder is considered 
part of the investigator TMF and must be kept in a secure place by the site for the required 
period of time. The binder must contain, at a minimum, the following documents: a copy of 
the Investigator TMF Index, a certified copy of the Patient Identification Code List, and a 
Retrieval Form.
Lundbeck will notify the investigator in writing when the required storage period has expired 
and when the documents may be destroyed according to regulations.
12 Monitoring Procedures
Prior to including patients in the study, the investigator must sign a source data agreement that 
identifies the source documents (original documents, data, and records) at the site. The 
document will also list which data may be recorded directly on the eCRFs or any electronic 
clinical outcome assessment electronic clinical outcome assessment (eCOA).
If the investigator does not have a patient’s medical records, the investigator must attempt to 
obtain copies or a written summary of relevant medical records from the doctor who had 
treated the patient earlier and include the pertinent documentation in the patient’s medical 
records at the site. The investigator must obtain medical records documenting the patient’s 
lifetime (schizophrenia) episodes and general medical history for the 3 months prior to the 
study.
During the study, the CRA will visit the site to ensure that the protocol is being adhered to
and that all issues are being recorded, to perform source data verification, and to monitor IMP
accountability. The visit intervals will depend on the outcome of the remote monitoring of the 
eCRFs, the site’s recruitment rate, and the compliance of the site to the protocol and Good 
Clinical Practice.  In addition, the CRA will be available for discussions by telephone.
Source data verification requires that the CRA be given direct access to all the source 
documents. Direct access includes permission to examine, analyse, and verify any records and 
reports that are important for the evaluation of the study.


H. Lundbeck A/S 
Confidential
Page 74 of 87
13 Audits and Inspections
Authorised personnel from Global Clinical Quality Assurance at Lundbeck and quality 
assurance personnel from business partners may audit the study at any time to assess 
compliance with the protocol and the principles of Good Clinical Practice and all other 
relevant regulations.
The patients must be informed that authorised personnel from Lundbeck may wish to review
their medical records. The investigator must be aware and the patients must be informed that 
representatives from regulatory authorities may also wish to inspect source data, such as 
medical records.
The investigator must notify Lundbeck, without delay, of an announced inspection by a 
regulatory authority.
During audits and inspections, the investigator must permit direct access to all the source 
documents, including medical records and other documents pertinent to the study.
During audits and inspections, the auditors and inspectors may copy relevant parts of medical 
records. No personal identification apart from the screening number will appear on these 
copies.
Patient data will not be disclosed to unauthorised third parties, and patient confidentiality will 
be maintained at all times.
14 Protocol Compliance
Lundbeck has a “no-waiver” policy, which means that permission will not be given to deviate 
from the protocol.
If deviations occur, the investigator must inform the CRA and they must review, discuss, and 
document the implications of the deviation.
15 Study Termination
Lundbeck or a pertinent regulatory authority may terminate the study or part of the study at 
any time. The reasons for such action may include, but are not limited to:
• safety concerns
• proven lack of efficacy of the IMP in other studies
If the study is terminated or suspended, the investigator must promptly inform the patients 
and ensure appropriate therapy and follow-up. Furthermore, the investigator and/or sponsor 
must promptly inform the IEC or IRB and provide a detailed written explanation. The 
pertinent regulatory authorities must be informed in accordance with national regulations.


H. Lundbeck A/S 
Confidential
Page 75 of 87
If the risk/benefit analysis changes after the termination of the study, the new evaluation must 
be provided to the IEC or IRB if it will have an impact on the planned follow-up of the 
patients who participated in the study. If so, the actions needed to protect the patients must be 
described.
16 Endpoints
16.1
Primary Endpoint(s)
• Primary safety and tolerability endpoints:
Adverse events
Absolute values, changes values from baseline and potentially clinically significant 
values in: 

Clinical safety laboratory tests

Body weight, BMI, and waist circumference

Vital signs (systolic blood pressure, diastolic blood pressure, and pulse)

ECG parameters (ventricular rate, RR, PR, QRS, QT, and QTcF)
16.2
Exploratory Endpoint(s)
• Exploratory safety and tolerability endpoints:
Mean change from baseline in AIMS, BARS and mSAS total scores 
C-SSRS categorisation 
• Exploratory effectiveness endpoints:
Psychotic symptoms 

Mean change from baseline in PANSS total score

Mean change from baseline in PANSS subscale scores (PANSS Negative Symptoms 
subscale, PANSS Positive Symptoms subscale, PANSS General Psychopathology 
subscale)
Negative symptoms

Mean change from baseline in NSA-4 total score
Global clinical impression

Mean change from baseline in CGI-S score
Andreason symptoms remission rate

Binary variable (Y/N) of remission rate (simultaneous ratings of mild or less on 
PANSS specific items: P1, G9, P3, P2, G5, N1, N4, and N6) at Week 52 Visit
Quality of life and functioning

Mean change from baseline in QLS score

Mean change from baseline in TooL score

Mean change from baseline in WorQ score

Mean change from baseline in PSP total score


H. Lundbeck A/S 
Confidential
Page 76 of 87
Treatment satisfaction

Mean change from baseline in MSQ score
Health care resource used during the 52-week study period
17 Statistical Methodology
17.1
Responsibilities
The Department of Biostatistics, H. Lundbeck A/S will perform the statistical analyses 
described below.
17.2
Analysis Sets
The following analysis sets are defined.
• all-patients-treated set (APTS) – all patients who took at least one dose of Lu AF35700 in 
study 16159B.
• full analysis set (FAS) –all patients in the APTS who had at least one valid post baseline 
effectiveness assessment in study 16159B. 
The APTS will mainly be used for presentations of safety data whereas the FAS will be used 
for effectiveness data.
17.3
Descriptive Statistics
In general, summary statistics (n, arithmetic mean, standard deviation, median, minimum and 
maximum values) will be presented for continuous variables and counts and, if relevant, 
percentages will be presented for categorical variables.
For patients coming from 16159A, summaries will be prepared with respect to two baselines: 
• Baseline I: Baseline just prior to randomisation in study 16159A (Baseline 2 in 16159A)
• Baseline II: Baseline in study 16159B. 
Unless otherwise specified, baseline will be Baseline II.
Summaries will be prepared overall and by the previous treatment (treatment group in the 
studies feeding into this extension study or previous treatment for patients not included in any 
Lu AF35700 study before). In order not to have too many “previous treatments”, these will be 
grouped into the following categories:
• Lu AF35700
• Risperidone/Olanzapine (16159A patients)
• Quetiapine 
• Previous treatment for patients not included in any Lu AF35700 study before


H. Lundbeck A/S 
Confidential
Page 77 of 87
To explore the safety and effectiveness of daily dosing with Lu AF35700, separate displays 
will be prepared for patients only receiving daily dosing in this study.
17.4
Patient Disposition
Patient disposition will be summarised by reason for withdrawal and other relevant 
parameters and include the number of patients who completed and the number of patients who 
withdrew from the study.
17.5
Demographics and Other Baseline Characteristics
Demographics (sex, age, race), and other baseline characteristics will be summarised.
17.6
Recent and Concomitant Medication
Recent and concomitant medication will be summarised by anatomical therapeutic chemical 
(ATC) code and generic drug name.
17.7
Exposure and Compliance
Exposure and compliance will be calculated per patient and summarised.
In particular, the amount of weekly dosing, frequency, duration, and reasons for initiation and 
termination, will be summarised.
17.8
Effectiveness Analyses
Effectiveness assessment will be summarised descriptively using Observed Cases (OC).
Summaries will be performed with respect to both Baseline I and Baseline II. On an 
exploratory basis, the maintenance of effectiveness will be analysed using Mixed Models for 
Repeated Measurements (MMRM). 
Quality of life, treatment satisfaction and health care resource utilization will be summarised.
Based on the FAS and observed cases (OC), the effectiveness endpoints will be analysed 
using a mixed model for repeated measurements (MMRM) with an unstructured covariance 
structure. The model will include terms for country, baseline 1/2 score visit, and previous 
treatment.


H. Lundbeck A/S 
Confidential
Page 78 of 87
17.9
Safety Analyses
17.9.1
Analysis of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:
• pre-study adverse event – an adverse event that starts before the date of first dose of IMP 
in study 16159B.
• Treatment-emergent adverse event (TEAE) – an adverse event that starts or increases in 
intensity on or after the date of first dose of Lu AF35700 in study 16159B. 
Adverse events, sorted by system organ class (SOC) and preferred term, will be summarised.
Specific tables of adverse events after weekly dosing will be prepared. Displays of all events 
while on weekly dosing, as well as events seen shortly after initiation of weekly dosing will 
be prepared.
Allocation of TEAEs to Treatment Periods
TEAEs may be allocated into study periods (these will be defined in the Statistical Analysis 
Plan).
Where relevant, Kaplan-Meier plots of time to TEAEs, will be prepared.
17.9.2
Analysis of Other Safety Endpoints
The clinical safety laboratory test values, body weight, BMI and waist circumference, vital 
signs, and ECG parameters will be summarized. Potentially clinically significant (PCS) 
values will be flagged and summarized.
Mean change from baseline in AIMS, BARS and mSAS total scores will be summarized.
The C-SSRS will be summarized descriptively.
17.10 Interim Analyses
No interim analyses are planned.
17.11 Sample Size and Power
No formal sample size calculation has been performed for the present study. 
Approximately 400 patients with schizophrenia are planned to be enrolled in total in order to 
provide relevant long-term safety data. It is assumed that about 270 patients will come from 
study 16159A, 30 patients from study 16323A, and an additional 100 patients who need to 
change their antipsychotic treatment will be included. The distribution of the number of 
patients may be adjusted based upon the recruitment rate in each group. With approximately 


H. Lundbeck A/S 
Confidential
Page 79 of 87
400 patients included, it will be possible to obtain solid information on long-term safety of 
treatment with Lu AF35700. 
To ensure sufficient exposure to the daily dosing regimen, the number of patients who 
completed study 16159A and who can be treated with the weekly dosing regimen will be 
limited to 50 patients.
17.12 Statistical Analysis Plan
A Statistical Analysis Plan describing the handling of data issues and the planned statistical 
analyses in more detail will be prepared by the Department of Biostatistics, H. Lundbeck A/S.
18 Clinical Study Report and Publications
18.1
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared by the Department of 
Medical Writing, H. Lundbeck A/S.
18.2
Data Ownership
The data collected in this study are the property of Lundbeck.
18.3
Publications
The results of this study will be submitted for publication.
The primary publication based on this study must be published before any secondary 
publications are submitted for publication.
Authors of the primary publication must fulfil the criteria defined by the International 
Committee of Medical Journal Editors (ICMJE).30
19 Indemnity and Insurance
In the event of study-related injuries or deaths, insurance for the patients and indemnity of the 
investigators and those of their employees, servants, or agents whose participation in this 
study has been documented are provided. Insurance and liability will be in accordance with 
applicable laws and Good Clinical Practice.


H. Lundbeck A/S 
Confidential
Page 80 of 87
20 Finance
20.1
Site Agreement
The financial agreements for the site are addressed in one or more documents.  Both parties 
must sign the agreements before the site is initiated.
20.2
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form in order to comply with the United States Food and 
Drug Administration (FDA) Financial Disclosure requirements.
20.3
Equipment
Equipment owned or rented by Lundbeck that has been provided to the site for use during the 
study must be returned at the end of the study.


H. Lundbeck A/S 
Confidential
Page 81 of 87
References
1.
Carpenter WT Jr, Buchanan RW. Schizophrenia. N Engl J Med. 1994; 330: 681-690.
2.
Adler LA, Angrist B, Reiter S, Rotrosen J. Neuroleptic-induced akathisia: a review. 
Psychopharmacology (Berl). 1989; 97: 1-11.
3.
Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and 
reconceptualization. Am J Psychiatry. 1991; 148: 1474-1486.
4.
H. Lundbeck A/S. Investigator’s Brochure: Lu AF35700, current version.
5.
H. Lundbeck A/S. Interventional, open-label, positron emission tomography (PET) study 
investigating D2 dopamine receptor occupancy after multiple oral dosing of Lu AF35700 in 
healthy men using [11C]-PHNO as tracer compound, reporting.
6.
H. Lundbeck A/S. Analysis of D2 receptor occupancy versus plasma concentration of 
Lu AF35700 and Lu AF36152 and simulation of D2 receptor occupancy time profiles. 23 Oct 
2014.
7.
EMA. Committee for Medicinal Products for Human (CMPH). Guideline on clinical 
investigation of medicinal products in the treatment of schizophrenia. EMA/CHMP/40072/2010. 
2011.
8.
World Medical Association (WMA). Declaration of Helsinki: Ethical principles for medical 
research involving human subjects. [Internet]
wma.net/en/30publications/10policies/b3/index.html
9.
ICH. ICH Harmonised Tripartite Guideline E6 (R1): Guideline for Good Clinical Practice. 1996.
10. Newcomer JW. Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry. 
2007; 68 (Suppl 4): 8-13.
11. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987; 13(2): 261-276.
12. Haro JM, Kamath SA, Ochoa S, Novick D, Rele K, Fargas A, et al. The Clinical Global 
Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms 
present in schizophrenia. Acta Psychiatr Scand. 2003; Suppl 416: 16-23.
13. Alphs L, Morlock R, Coon C, van Willigenburg A, Panagides J. The 4-item negative symptom 
assessment (NSA-4) instrument: A simple tool for evaluating negative symptoms in 
schizophrenia following brief training. Psychiatry. 2010; 7: 26-32.
14. Nasrallah H, Morosini, PL, Gagnon DD. Reliability, validity and ability to detect change of the 
Personal and Social Performance scale in patients with stable schizophrenia. Psychiatry Res. 
2008; 161(2): 213-224.
15. Heinrichs DW, Hanlon TE, Carpenter WT. The Quality of Life Scale: an instrument for rating the 
schizophrenic deficit syndrome. Schizophr Bull. 1984; 10: 388-398.
16. Potkin SG, Bugarski-Kirola D, Edgar CJ, Soliman S, Le Scouiller S, Kunovac J et al. 
Psychometric evaluation of the Work Readiness Questionnaire in schizophrenia. CNS Spectr. 
2014; Oct 1: 1–8.


H. Lundbeck A/S 
Confidential
Page 82 of 87
17. Vernon MK, Revicki DA, Awad AG, Dirani R, Panish J, Canuso CM 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.
18. Lindström E, Jönsson L, Berntsson A. A patient perspective on side effects of antipsychotic 
therapy: the TooL instrument. Value Health. 2009; 12: A361.
19. Novick D, Haro JM, Suarez D, Vieta E, Naber D. Recovery in the outpatient setting: 36-month 
results from the Schizophrenia Outpatients Health Outcomes (SOHO) study. Schizophr Res.
2009; 108(1-3): 223-230.
20. European Parliament and Council of the European Union. Directive 95/46/EC: Protection of 
individuals with regard to the processing of personal data and on the free movement of such data.  
24 October 1995.  Official Journal of the European Communities L 281, 23 November 1995.
21. Kay SR, Opler RA, Fiszbein A. The Structured Clinical Interview for Positive and Negative
Syndromes of Schizophrenia Multi-Health Systems, New York 1992.  
22. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Guideline on bioanalytical method validation. EMEA/CHMP/EWP/192217/2009 Rev. 
1 Corr. 2. 2015.
23. United States Food and Drug Administration (FDA). Guidance for Industry: Bioanalytical 
method validation. 2001.
24. European Agency for the Evaluation of Medicinal Products (EMEA). Committee for Proprietary 
Medicinal Products (CPMP). Position paper on terminology in pharmacogenetics. 
EMEA/CPMP/3070/01. 21 November 2002.
25. Guy W. ECDEU Assessment Manual for Psychopharmacology, revised ed. Washington, DC, US 
Department of Health, Education, and Welfare, 1976.
26. Barnes TRE. A rating scale for drug-induced akathisia. Br. J. Psychiatry. 1989; 154: 672–676.
27. Simpson GM, Angus JWS.  A rating scale for extrapyramidal side effects.  Acta Psychiatr Scand 
1970; 212: 11-19.
28. ICH. ICH Harmonised Tripartite Guideline E2A: Clinical safety data management: definitions 
and standards for expedited reporting. 1994.
29. European Parliament and Council of the European Union. Directive 2001/20/EC: Approximation 
of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal products for 
human use.  4 April 2001.  Official Journal of the European Communities L 121, 1 May 2001.
30. International Committee of Medical Journal Editors (ICMJE). [Internet] 
icmje.org/urm_main.html. Recommendations for the conduct, reporting, editing, and publication 
of scholarly work in medical journals. August 2013. 


H. Lundbeck A/S 
Confidential
Page 83 of 87
Appendix I
Clinical Study Protocol Authentication and Authorisation


H. Lundbeck A/S 
Confidential
Page 84 of 87
Clinical Study Protocol
Authentication and Authorisation
Study title:
Interventional, open-label, flexible-dose, long-term safety study of 
Lu AF35700 in adult patients with schizophrenia 
Study No.:
16159B
Edition No.:
1.0
Date of edition:
24 May 2016
This document has been signed electronically.  The signatories are listed below.
Authentication
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
International study manager:
 
Clinical research scientist:
Head, Biostatistics:
Head of Risk Management (PV):
Authorisation
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
Vice President, Clinical Research & 
Development, Psychiatry:


H. Lundbeck A/S 
Confidential
Page 85 of 87
Appendix II
Recent and Concomitant Medication:
Disallowed or Allowed with Restrictions


H. Lundbeck A/S 
Confidential
Page 86 of 87
Recent and Concomitant Medication: 
Disallowed or Allowed with Restrictions 
In the table below disallowed recent and concomitant medications are listed, including any 
restrictions with respect to their use prior to and during the study.
Disallowed and restricted medications during the study
Drug Class
Details
Analgesics
Opioid analgesics are not allowed, except for brief episodic use during 
emergency procedures or appropriate indication (e.g. tooth extraction) and not 
within 24 hour before a study visit.
NSAIDs are prohibited as chronic use; NSAIDs may be used episodically.
Anticholinergics
The use of anticholinergic medication as prophylaxis of extrapyramidal 
symptoms should be avoided.
In case of need of rescue medication, the use of multiple anticholinergic 
medications concurrently is prohibited.
The allowed rescue medications are the following: benzotropine (up to 
4 mg/day p.o. or i.m.), biperiden (up to 8 mg/day p.o. or i.m.) and 
thrihexyphenidyl (up to 10 mg/day p.o. or i.m.).
Administration of anticholinergics less than 8 hours prior a scheduled visit is 
not allowed.
Anticonvulsants
Prohibited during the study
Antidepressants
Prohibited during the study
Antihistamines
Antihistamines except loratadine, desloratidine, cetirizine, levocetirizine,
mizolastine and fexofenadine are prohibited.
Antipsychotics
Depot or long-acting injectable antipsychotics are not allowed as current 
treatment.
Current oral antipsychotics to be down tapered and discontinued as indicated in 
Panel 3.
Oral antipsychotics other than LuAF35700 is disallowed during the study.
Anxiolytics and hypnotics
If the patient receives anxiolytic or hypnotic therapy during study 16159A, this 
medication may continue. A careful down tapering of anxiolytic or hypnotic 
treatment should be performed if a discontinuation has been decided.
In case of need of rescue medication for anxiety, dose adjustment of currently 
prescribed anxiolytic medication is recommended if applicable. If new 
medication is initiated, short-acting benzodiazepines such as lorazepam (up to 3 
mg/day, orally or intramuscularly), oxazepam (up to 45 mg/day, orally), and 
alprazolam (up to 1.5 mg/day) are recommended. 
In case of need of rescue medication for sleep disorders, short acting hypnotics 
such as zolpidem (up to 5 mg/day for immediate release formulations and 6.25 
mg/day for extended release formulations, orally) and zopiclone (up to 7.5 
mg/day) are recommended.
Administration of anxiolytics or hypnotics less than 8 hours prior a scheduled 
visit is not allowed.
Barbiturates
Prohibited during the study


H. Lundbeck A/S 
Confidential
Page 87 of 87
Drug Class
Details
Dopamine depleting agents
Prohibited during the study
Hormones
Prohibited except for thyroid hormone replacement, contraceptives (oral, 
patch), estrogen and progesterone replacement therapy as well as benign 
prostatic hyperplasia treatment.
Hydroxyzine and 
diphenhydramine (not 
allowed for the treatment 
of agitation, anxiety, 
insomnia or EPS) 
Except for short term treatment (<14 days) of allergy.
Mood stabilizers
Prohibited during the study
Non-benzodiazepine sleep 
aids
Prohibited during the study
Propranolol (for akathisia 
or tremor)
Prophylaxis treatment should be avoided.
In case of need of rescue medication a maximum dose of 60 mg/day is allowed.
If propranolol is prescribed for cardiovascular reasons at doses greater than 60 
mg/day, the eligibility of the patients should be discussed with the Medical 
Monitor. 
Administration of propranolol less than 8 hours of a scheduled visit is not 
allowed.
Psychotropic agents not 
otherwise specified
Prohibited during the study
Cough preparations containing ephedrine, pseudoephedrine and codeine are 
allowed for treatment duration for a maximum of 1 week.
Steroids
Systemic use is prohibited, inhaled and topical use is allowed.
Varenicline
Prohibited during the study
Vitamins, nutritional
supplements, and non-
prescritpion herbal 
preparations
Prohibited during the study, unless approved in advance by the Medical 
Monitor.

SAP_001.pdf: 
H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 1 of 50
Statistical Analysis Plan
Interventional, open-label, flexible-dose, long-term safety study of 
Lu AF35700 in adult patients with schizophrenia
Lu AF35700
Study No.:
16159B
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Biostatistician:
, Biostatistics
SAP date:
5 November 2019
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S is the holder of any and all 
related intellectual property rights, including, but not limited to, copyrights.  This document is 
confidential.  It is not to be copied or distributed to other parties without prior written authorization 
from H. Lundbeck A/S.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 2 of 50
Table of Contents
List of Panels and Tables.......................................................................................................... 5
List of Abbreviations and Definitions of Terms....................................................................... 6
Objectives ......................................................................................................................... 7
Primary Objective................................................................................................... 7
Exploratory Objective(s) ......................................................................................... 7
Study Design..................................................................................................................... 7
Definitions......................................................................................................................... 8
Definition of Baseline ............................................................................................. 8
Definition of Periods............................................................................................... 9
Definition of Withdrawal from Treatment and Study............................................... 9
Endpoints.......................................................................................................................... 9
Primary Endpoints................................................................................................... 9
Exploratory Endpoints........................................................................................... 10
Analysis Sets ................................................................................................................... 10
Descriptive Statistics....................................................................................................... 11
Patient Disposition.......................................................................................................... 11
Summary of Patient Disposition............................................................................ 11
Withdrawals.......................................................................................................... 12
Demographics and Baseline Characteristics.................................................................. 12
Recent and Concomitant Medication............................................................................. 13
Exposure and Compliance.............................................................................................. 13
Efficacy ........................................................................................................................... 14
General Efficacy Analysis Methodology ............................................................... 14
Exploratory Analysis of Efficacy........................................................................... 14
Safety .............................................................................................................................. 15
Adverse Events ..................................................................................................... 15
General Methodology for Adverse Events .............................................. 15
Classification of Adverse Events ............................................................ 16
Coding of Adverse Events...................................................................... 16
Allocation of AEs to Treatment Periods.................................................. 16
Presentation of Adverse Events .............................................................. 16
Presentation of Treatment-emergent Adverse Events .............................. 17
Presentation of Deaths............................................................................ 17
Presentation of Serious Adverse Events.................................................. 17
Presentation of Adverse Events Leading to Withdrawal.......................... 17
Adverse Events Leading to Dose Reduction............................................ 17
General Methodology for Other Safety Data.......................................................... 18
Clinical Safety Laboratory Test Data..................................................................... 18
Data Presentation ................................................................................... 18
Potential Drug-induced Liver Injury (DILI)............................................ 19
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 3 of 50
Vital Signs and Weight.......................................................................................... 20
ECGs .................................................................................................................... 20
Other Safety Endpoints(s) ..................................................................................... 21
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores ..................... 21
EPS Rating Scale Scores ........................................................................ 22
Pharmacokinetic/Pharmacodynamic Analyses.............................................................. 23
Blinded Data Reviews..................................................................................................... 23
Interim Analyses............................................................................................................. 23
Sample Size Considerations ........................................................................................... 23
Statistical Software......................................................................................................... 23
Changes to Analyses Specified in the Protocol .............................................................. 23
Details on Data Handling ............................................................................................... 24
Derived Variables ................................................................................................. 24
Missing Items......................................................................................... 24
PANSS................................................................................................... 25
Clinical Global Impression Scale - Severity (CGI-S) .............................. 27
Personal and Social Performance Scale (PSP)......................................... 27
4-Item Negative Symptom Assessment (NSA-4) .................................... 27
Quality of Life Scale (QLS).................................................................... 27
Readiness for work questionnaire (WoRQ)............................................. 28
Medication Satisfaction Questionnaire (MSQ)........................................ 28
Tolerability and Quality of Life questionnaire (TooL)............................. 28
Abnormal Involuntary Movement Scale (AIMS) .................................... 28
Barnes Akathisia Scale (BARS).............................................................. 29
Modified Simpson Angus Scale (mSAS) ................................................ 29
Health Care Resource Utilisation (HEA)................................................. 29
Assigning Data to Visits........................................................................................ 29
Rating Scales.......................................................................................... 29
Safety Variables ..................................................................................... 31
Handling Missing or Incomplete Dates/Times ....................................................... 33
IMP Start and Stop Dates ....................................................................... 33
Withdrawal Date .................................................................................... 33
Medical Disorder Start and Stop Dates ................................................... 33
Medication Start and Stop Dates............................................................. 33
Adverse Event Start and Stop Dates........................................................ 34
Data with Multiple Records................................................................................... 36
Dose Changes in Medication.................................................................. 36
Changes in Intensity or Seriousness of Adverse Events........................... 36
References ............................................................................................................................... 38
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 4 of 50
Appendices
Appendix I
Statistical Analysis Plan Authentication and Authorization ............................ 39
Appendix II
SAS® Code.................................................................................................... 41
Appendix III
PCS Criteria .................................................................................................. 43
Appendix IV
Study Flow Chart........................................................................................... 47
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 5 of 50
List of Panels and Tables
Panel 1
Study Design...........................................................................................................8
Panel 2
C-SSRS Scores .....................................................................................................22
Panel 3
Maximum Number of Missing Items on Rating Scales ..........................................25
Panel 4
PANSS Items and Subscales .................................................................................26
Panel 5
Derivation of PANSS Total Score and Subscales...................................................26
Panel 6
Visit Windows: PANSS, CGI-S, C-SSRS..............................................................30
Panel 7
Visit Windows: PSP, NSA-4, QLS, WoRQ, TooL, MSQ, AIMS, BARS, mSAS ...30
Panel 8
Visit Windows: Vital Signs ...................................................................................31
Panel 9
Visit Windows: Laboratory Tests, Body weight, and Waist circumference.............32
Panel 10
Visit Windows: ECG.............................................................................................32
Table 1
PCS Criteria for Clinical Safety Laboratory Tests..................................................44
Table 2
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference....................46
Table 3
PCS Criteria for ECG Parameters..........................................................................46
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 6 of 50
List of Abbreviations and Definitions of Terms
APES
all-patients-enrolled set
APTS
all-patients-treated set
CI
confidence interval
DILI
drug-induced liver injury
eCRF
electronic case report form
EPS
extrapyramidal symptom(s)
FAS
full-analysis set
IMP
investigational medicinal product
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed model for repeated measurements
PCS
potentially clinically significant
PYE
patient years of exposure
SAE
serious adverse event
SAS®
statistical software package from the SAS® Institute
SOC
system organ class
TEAE
treatment-emergent adverse event
WHO-DD
World Health Organization Drug Dictionary 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 7 of 50
Objectives
Primary Objective
• To evaluate the safety and tolerability of the long-term treatment with Lu AF35700
Exploratory Objective(s)
• to evaluate the long-term safety and tolerability of daily and weekly doses of Lu AF35700 
in patients with schizophrenia during the 52-week treatment period
• to evaluate the therapeutic effect of daily and weekly doses of Lu AF35700 in patients with 
schizophrenia over a period of 52 weeks on:
psychotic symptoms
negative symptoms 
global clinical impression
remission rate
quality of life and functioning
treatment satisfaction
resource utilisation
Study Design
• This study was a multi-national, multi-site, open-label, flexible-dose, long-term (52-week) 
safety study in patients with schizophrenia who had participated and completed a study 
investigating Lu AF35700 including studies 16159A and 16323A. 
• Originally, it was planned to also include patients, who had not previously participated in a 
study investigating Lu AF35700. However, this was never implemented due to a very high 
roll-over rate from study 16159A. 
• The adjustment of Lu AF35700 dosing regimen (10 mg/day or 20 mg/day) during the 
course of the study was left to the investigator’s clinical judgement. 
• For patients who had completed the study 16159A, the daily dosing regimen (10 mg/day or 
20 mg/day) could be switched to weekly dosing regimen (70 mg/week) according to the 
investigator’s clinical judgement. The number of patients under weekly dosing regimen 
was limited to 50 patients by IVRS/IWRS.
An overview of the study is presented in Panel 1.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 8 of 50
Panel 1
Study Design
All patients, including patients who withdraw, are scheduled for a Safety Follow-Up Visit 42 
days after last dose of IMP. The follow-up includes collection of data to address the primary 
endpoint in a limited sense, i.e. AEs are collected if they are on-going at the Primary 
Outcome/Withdrawal Visit or if new SAEs have occurred. Laboratory tests are taken if these 
were clinically significantly abnormal at the Primary Outcome/Withdrawal Visit.  
Definitions
Definition of Baseline
The baseline value is the value captured at the Baseline Visit of study 16159B. For 
efficacy/safety assessments and blood/urine samples this will be the value captured at the 
Primary Outcome Visit of study 16159A or at the last day of the dosing period (Day 42) in 
study 16323A.
For baseline characteristics captured at screening of the lead-in study, the baseline value in 
this study is the one captured either at the screening or baseline visit of the lead-in-study, 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 9 of 50
whichever is later. An exception to this is blood sampling for CYP2D6 and CYP2C19 
genotyping, which is performed at randomization for 16159A patients. 
Definition of Periods
The total study duration per patient from baseline to safety follow-up will be up to 58 weeks.
The study will consist of 2 periods: 
• Treatment period – 52 weeks 
• Safety follow up period – 6 weeks
Definition of Withdrawal from Treatment and Study
The group of patients who withdrew from treatment and the scheduled visits in the Treatment 
Period will be described as withdrawn from treatment. The complementary group will be 
described as completed treatment.
Patients who withdraw from treatment due to withdrawal of consent or lost to follow-up will 
also be described as withdrawn from study. In this case, the reason for withdrawal from study 
will be set to the same reason as that for withdrawal from treatment.
Patients who attend the Safety Follow-up visit (scheduled six weeks after last dose of IMP), 
regardless of whether they complete the Treatment period will be described as completed
study. Patients who do not attend the Safety Follow-up visit will be described as withdrawn 
from study. This definition reflects the “Summary of Study” form in the eCRF.
Endpoints
Rules for calculation of derived scores and for assigning data to visits as well as descriptions 
of the scales used in the study are described in Section 19.
Primary Endpoints
• Primary safety and tolerability endpoints:
Adverse events
Absolute values, changes values from baseline and potentially clinically significant 
values in: 

Clinical safety laboratory tests

Body weight, BMI, and waist circumference

Vital signs (systolic blood pressure, diastolic blood pressure, and pulse)

ECG parameters (ventricular rate, RR, PR, QRS, QT, and QTcF)
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 10 of 50
Exploratory Endpoints
• Exploratory safety and tolerability endpoints:
Change from baseline in AIMS, BARS Global Clinical Assessment of Akathisia score
(item 4) score and mSAS total score
C-SSRS 
• Exploratory efficacy endpoints:
Psychotic symptoms 
Change from baseline in PANSS total score
Change from baseline in PANSS subscale scores (PANSS Negative Symptoms 
subscale, PANSS Positive Symptoms subscale, PANSS General Psychopathology 
subscale)
Negative symptoms
Change from baseline in NSA-4 total score
Change from baseline in PANSS Marder factor score (negative symptoms)
Global clinical impression
Mean change from baseline in CGI-S score
Andreasen symptoms remission
Remission (simultaneous ratings of mild or less on PANSS specific items: P1, G9, P3, 
P2, G5, N1, N4, and N6) at Week 52 Visit
Quality of life and functioning 
Change from baseline in QLS score
Change from baseline in TooL score
Change from baseline in WorQ score
Change from baseline in PSP total score
Treatment satisfaction
Change from baseline in MSQ score
Health care resource used during the 52-week study period
Analysis Sets
The patients will be assigned to analysis sets based on IMP intake and post-baseline 
assessments of the efficacy variable(s) in the Treatment Period.
Due to a higher-than-anticipated roll-over rate and a lower-than-anticipated attrition rate from 
study 16159A, only patients from study 16159A and 16323A are enrolled in the study, i.e. no 
patients who have not previously participated in a study investigating Lu AF35700 are 
enrolled.
Only 4 patients from study 16323A are enrolled. Therefore, data from these will only be 
presented in listings, i.e. they will not contribute to any summary tables.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 11 of 50
The sets of patients to be analysed are defined as follows:
• all-patients-enrolled set (APES) – all patients enrolled, including patients from study 
16323A
• all-patients-treated set (APTS) – all patients from study 16159A who took at least one 
dose of Lu AF35700 in study 16159B
• full-analysis set (FAS) – all patients in the APTS (i.e. only patients from study 16159A are 
included) who had a valid baseline assessment and at least one valid post baseline
assessment of PANSS total score in study 16159B.
Since this is an open-label study each patient will be classified according to these definitions 
based on information in data and no Classification Meeting will be held. 
The classification will be done by the biostatistician.
The APTS will be used for presentations of safety data whereas the FAS will be used for
presentation of efficacy data. Data listings will be based on the APES unless otherwise 
specified.
Descriptive Statistics
Unless otherwise specified, summary statistics (n, arithmetic mean, standard deviation [SD], 
median, lower and upper quartiles, minimum and maximum values) will be presented for 
continuous variables, and counts and, if relevant, percentages will be presented for categorical 
variables.
Summaries will be prepared overall and by the previous treatment (treatment group in study
16159A). To reflect the grouping of treatments in study 16159A, these will be grouped into 
the following categories (for 16159A patients only):
• Lu AF35700 10 mg
• Lu AF35700 20mg
• RIS/OLZ
Unless otherwise specified, data listings will include site, previous treatment group, patient 
screening number (from extension study), and lead-in study-Baseline information on sex, age, 
race, and weight. For the data listings, the previous treatment will be displayed as the specific
treatment received in the lead-in study, i.e. it will belong to one of the categories Lu AF35700 
10mg, Lu AF35700 20mg, Lu AF35700 30mg, Risperidone, Olanzapine, or Quetiapine.
Patient Disposition
Summary of Patient Disposition
Patient disposition in the treatment period will be summarised by previous treatment group
and in total, as well as by country, and will include the number of patients in each analysis set 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 12 of 50
defined in chapter 5, and the number of patients in the APTS who completed or withdrew 
from treatment. The number of enrolment failures will also be displayed. 
Withdrawals
The number of patients who withdrew from treatment will be summarized overall and by 
previous treatment both by primary reason for withdrawal, and all reasons for withdrawal.
Patients who withdrew from treatment will be listed and the listing will include
the reason type (primary or secondary reason for withdrawal from treatment), the reason, 
specification of other reason, previous treatment group, date of Visit 2, date of withdrawal 
from treatment, and number of days on IMP in this study. Note that patients can have more 
than one secondary reason for withdrawal from treatment so the listing will include both the 
primary reason for withdrawal from treatment and all reasons for withdrawal from treatment. 
Kaplan-Meier failure plots of time to withdrawal from treatment will be presented for the total
group. The time will be calculated from the date of first dose of IMP in this extension study
(for handling of missing IMP start date, see section 19.3.1) to the date of completion or 
withdrawal from treatment. Patients who completed treatment will be regarded as censored.
All tables and graphs will be based on the APTS. Listings will be based on the APES.
Demographics and Baseline Characteristics
Demographics (sex, age, age group, race, and ethnicity); baseline characteristics (height, 
weight, BMI, and waist circumference); baseline disease characteristics (age – and years since 
diagnosis of schizophrenia, years since first – and number of antipsychotic treatments, 
number of psychiatric hospitalizations), social histories; and baseline efficacy variables 
(PANSS total and subscale scores, CGI-S score, and PSP total score) will be summarized
overall and by previous treatment group. CGI-S will be summarized both as a continuous and 
a categorical variable.
Concurrent as well as relevant past medical, neurological, and psychiatric disorders at the 
lead-in study Screening Visit will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized.
A concurrent medical, neurological, or psychiatric disorder is a disorder that is ongoing at the 
Screening Visit of the lead-in study. A past medical, neurological, or psychiatric disorder is a 
disorder that ended prior to the Screening Visit of the lead-in study.
Demographics and baseline characteristics will be summarized based on the APTS, and 
baseline efficacy variables will be summarized based on the FAS.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 13 of 50
Recent and Concomitant Medication
Recent and concomitant medication will be coded using the WHO Drug Dictionary
(WHO-DDE).
Medications will be classified according to the start and stop time and summarized by 
anatomical therapeutic chemical (ATC) code levels 2 and 3, generic drug name, previous 
treatment group, and for each of the categories:
• Medication started before first dose of IMP (i.e. on-going concomitant medication from the 
lead-in study) and continued after first dose of IMP
• Concomitant medication started at or after first dose of IMP
The tables will be based on the APTS.
Exposure and Compliance
Exposure (days) to IMP in study 16159B will be calculated as:
Last date of IMP – Start date of IMP + 1
For details about handling of missing IMP start or stop date, see section 19.3.1 (IMP Start and 
Stop Dates).
The exposure for patients on the weekly dosing regimen will be summarized together with the
exposure for patients on the daily dosing regimens.
Exposure to IMP will be summarized overall and by previous treatment group using 
descriptive statistics, and summaries will include the patient years of exposure (PYE).  PYE 
will be calculated as the sum of the number of days of exposure to IMP for each patient, 
divided by 365.25 days.
In addition, exposure to IMP will be categorized in intervals 1 – 84 days [0 – 3 months], 
85 – 168 days [3 – 6 months], 169 – 252 days [6 – 9 months], 253 – 336 days [9 – 12
months], > 336 days [>12 months], and summarized overall and by previous treatment group.
The final dose level for patients in APTS will summarized overall and by previous treatment 
group.
The number of patients switching to the weekly dosing regimen will be summarized based on 
the APTS. The summary will include the number of patients going back to daily dosing after 
initiating weekly dosing. 
Non-compliant days are days on which no IMP has been taken, less than the full dose of IMP 
has been taken, or more than the full dose of IMP has been taken.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 14 of 50
Compliance (%) with IMP for the Treatment Period will be calculated as:
Last date of IMP  – Start date of IMP + 1 – Number of non-compliant days
Last date of IMP  – Start date of IMP + 1
×100
where the number of non-compliant days is defined as the sum of all non-compliant days 
from the start of the interval to the end of the interval.
The compliance for patients on the weekly dosing regimen will be summarized together with 
the compliance for patients on the daily dosing regimens.
Compliance with IMP will be categorized as “≤80% compliant” or “>80% compliant”. The 
number and percentage of patients in each category will be summarised by previous treatment 
group and in total based on the APTS.
Exposure and compliance will be summarized based on the APTS.
Efficacy
General Efficacy Analysis Methodology
Unless otherwise specified, all the efficacy analyses will be based on the FAS.
All the tables and graphs will be presented overall and by previous treatment group unless 
otherwise specified.
All the confidence intervals (CIs) will be two-sided, 95% CIs.
Descriptive statistics for the absolute scores and the change from baseline scores for the 
efficacy variables will be presented by study week using all available observations (observed 
cases [OC] data). The tables will be repeated for LOCF values. 
Exploratory Analysis of Efficacy
Changes from baseline in PANSS total score, PANSS subscale scores (PANSS Negative 
Symptoms subscale, PANSS Positive Symptoms subscale, PANSS General Psychopathology 
subscale, and PANSS Marder factors), NSA-4 total score, CGI-S score, QLS score, TooL 
score, WorQ score, PSP total score, and MSQ score will be analysed using a restricted 
maximum likelihood (REML)-based Mixed Models for Repeated Measurements (MMRM)
approach. The analysis will be based on the FAS.
The model will include the following fixed effects: country and week as factors, baseline 
score as a continuous covariate, and baseline score-by-week interaction. An unstructured
covariance structure will be used to model the within-patient errors. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 15 of 50
The estimated mean changes from baseline will be reported with two-sided 95% confidence 
intervals.
The estimated mean change from baseline in PANSS total score by visit week will be plotted 
for the total group. 
The SAS code for fitting the MMRM models is shown in Appendix II.
For PANSS total score, PANSS Negative Symptoms subscale score, PANSS Positive 
Symptoms subscale score, PANSS Negative Symptoms Marder factor score, a further
exploratory analysis will be presented where previous treatment and previous-treatment-by-
week interaction are added as fixed effects to the model described above. For these analyses, 
the estimates from the MMRM analysis will be presented by previous treatment. 
Tables displaying the counts and proportion of patients in remission according to the 
Andreasen symptoms remission criteria described in section 19.1.2 (simultaneous ratings of 
mild or less on items P1, G9, P3, P2, G5, N1, N4, and N6, see Panel 4 and Panel 5) will be 
presented both by previous treatment and for the total group, for LOCF values only. 
HEA items will be summarized overall and by previous treatment group for the Baseline Visit
and the Primary Outcome/Withdrawal Visit based on the APTS.
Safety
Adverse Events
General Methodology for Adverse Events
Unless otherwise specified, tables, and graphs will be based on the APTS. Listings will be 
based on the APES. 
All the tables will be presented for the total group. Three tables will be split by previous 
treatment as well, see section 12.1.6 and 12.1.9.
Unless otherwise specified, the summaries of adverse events will include the number and 
percentage of patients with an adverse event.
Only stop-dates for ongoing events at the Primary Outcome/Withdrawal Visit, and new SAEs 
are collected in the Follow-up Period. Therefore, adverse events in the Follow-up Period will 
be included in the summaries for the Treatment Period (periods are defined in section 12.1.3).
Listings of adverse events will be sorted by site, previous treatment group, patient screening 
number (from the extension study), and adverse event start date, and include preferred term, 
investigator term, adverse event start date, days since first dose of IMP, duration of the 
adverse event, date of death, action taken, causality, intensity, seriousness, and outcome. For 
adverse events that change in intensity/seriousness, each intensity/seriousness will be 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 16 of 50
included. Imputed adverse event start dates (see section 19.3.5) will be included in the 
listings, where information about the imputation will be included as a flag in the end of the 
date (M = month and day imputed or D = day imputed). 
Classification of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event (for 
handling of incomplete start dates, see section 19.3.5):
• pre-study adverse event – an adverse event that starts before the date of first dose of IMP
in study 16159B.
• treatment-emergent adverse event (TEAE) – an adverse event that starts, increases in 
intensity compared to the preceding intensity, or changes from non-serious to serious on or 
after the date of first dose of IMP in study 16159B.
Handling of adverse events that increase in intensity or seriousness is further specified in 
section 19.4.2.
An adverse event is considered causally related to the use of the IMP when the causality 
assessment by the investigator is probable or possible.
Coding of Adverse Events
Adverse events will be coded using MedDRA, Version 22.0 or later.
Allocation of AEs to Treatment Periods
AEs will be allocated to treatment periods according to the time of onset of the adverse event
(for handling of incomplete start dates, see section 19.3.5):
• AE in Lead-in Study Period – an AE that starts before first dose of IMP in study 16159B
• AE in the Treatment Period – an AE that starts at or after the date of first dose of IMP in 
study 16159B and at or before the date of the Primary Outcome/Withdrawal Visit
• AE in the Safety Follow-up Period– an AE that starts after the last visit in the Treatment 
Period
Presentation of Adverse Events
All adverse events will be listed for the APES, including a flag for TEAEs. 
A listing of all AEs occurring while on weekly dosing will also be presented.
An overview of the PYE, number and percentages of patients with TEAEs, serious adverse 
events (SAEs), TEAEs leading to withdrawal, and of patients who died will be provided 
based on the APTS. For TEAEs, SAEs, and adverse events leading to withdrawal, the total 
number of events will be included.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 17 of 50
Presentation of Treatment-emergent Adverse Events
The following summaries will be provided for the APTS:
• TEAEs by SOC and preferred term
• TEAEs by preferred term – both by previous treatment and overall
• TEAEs occurring while on weekly dosing by preferred term
• TEAEs by sex and preferred term 
• causally related TEAEs by SOC and preferred term
• TEAEs by intensity (mild/moderate/severe) and preferred term
• causally related TEAEs by intensity and preferred term
• TEAEs within the first 2 weeks of study 16159B by preferred term – both by previous 
treatment and overall
Presentation of Deaths
All adverse events for patients who died will be listed. 
Presentation of Serious Adverse Events
All SAEs will be listed. 
Treatment-emergent SAEs for the APTS will be summarized by:
• SOC and preferred term
• preferred term
Treatment-emergent SAEs for the APTS occurring while on weekly dosing will also be 
summarized by preferred term.
Presentation of Adverse Events Leading to Withdrawal
All adverse events leading to withdrawal will be listed.
TEAEs leading to withdrawal for the APTS will be summarized by:
• SOC and preferred term
• preferred term and previous treatment
Treatment-emergent AEs leading to the withdrawal occurring while on weekly dosing will 
also be summarized by preferred term for the APTS.
Adverse Events Leading to Dose Reduction 
Adverse events leading to reduction of dose of Lu AF35700 in the Treatment Period will be 
listed. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 18 of 50
Adverse events leading to reduction of dose of Lu AF35700 in the Treatment Period will be 
summarized by preferred term.
General Methodology for Other Safety Data
For details about data handling, see sections 19.1 and 19.2.
Unless otherwise specified, tables and graphs will be based on the APTS, and listings will be 
based on the APES.
All the tables and graphs will be presented for the total group.
The denominators for the summaries of a given variable will be based on the number of 
patients with non-missing values at a given visit or during the assessment period.
Descriptive statistics for the safety variables, both absolute values and changes from baseline, 
will be presented by visit and for the last assessment. All available post-baseline assessments 
will be included in the identification of the last assessment except for assessments made at the 
safety-follow-up visit.
The number and percentage of patients with at least one PCS value at any post-baseline
assessment time point will be summarized by variable. All available assessments will be 
included in the evaluation of PCS values except for assessments made at the safety-follow-up 
visit. 
For patients with post-baseline PCS values, listings will be provided including all available 
values for the variable, with flagging of PCS values and out-of-reference-range values.
All the adverse events in patients with post-baseline PCS values will be listed by previous 
treatment group and patient screening number (from the extension study); the listings will 
include all available values for the variable with flagging of PCS values and out-of-reference-
range values, the assessment date, the change from baseline in PCS value, the preferred term 
for the adverse event, and start date, and stop date of the adverse event. The PCS values and 
adverse events will be listed in chronological order according to assessment date and the start 
date of the adverse event.
Clinical Safety Laboratory Test Data
Data Presentation
The PCS criteria used for the clinical safety laboratory tests are the Lundbeck standard PCS 
criteria described in SOP_09978: PV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included in
Table 1.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 19 of 50
The clinical safety laboratory test values will be presented either in conventional or Système 
International (SI) units.
Descriptive statistics for the laboratory parameters in the Treatment Period, both absolute 
values and changes from baseline, will be presented by test and week and the last assessment 
in the Treatment Period. The summaries for the absolute values will also include summaries 
for baseline.
The number and percentage of patients with at least one PCS low value or PCS high value at 
any post-baseline assessment in the Treatment Period will be summarized by laboratory 
parameter. All available assessments in the period will be included in the evaluation of PCS.
Non-fasting tests of S-Cholesterol, S-Glucose, S-HDL Cholesterol, S-LDL Cholesterol, and 
S-Triglycerides will be evaluated separately and only for PCS values.
Prolactin will also be presented by detailed previous treatment group, i.e. where the RIS/OLZ 
group is split into whether the patient received Risperidone or Olanzapine in the lead-in study 
as well as by sex. 
Potential Drug-induced Liver Injury (DILI)
Signals of DILI will be assessed according to the FDA guideline1 using the following criteria:
• alanine or aspartate aminotransferase (ALT or AST) >2×, >3×, >5×, >10×, or >20×ULN
• total bilirubin (BILI) >2×ULN
• alkaline phosphatase (ALP) >1.5×ULN
• ALT or AST >3×ULN AND BILI >1.5× or >2×ULN
Patients fulfilling any of the criteria (ALT/AST, ALP, or BILI) will be listed, and the listing 
will include all available ALT, AST, BILI, and ALP, BILI, EOSLE (Eosinophils (% of total 
leukocytes)), and GGT (gamma glutamyl transferase) values (absolute and normalised) sorted 
by assessment date in ascending order. 
In addition, assessment time points for patients for whom Hy’s Law is potentially fulfilled 
will also be flagged in the listing (pHYL):
• ALT or AST >3×ULN AND
• alkaline phosphatase <2×ULN AND
• total bilirubin >2×ULN
In the summaries, each patient should be counted only once using the maximum assessment, 
or the most severe for the combined criteria. The summaries will also include number of 
potential Hy’s Law cases. 
Evaluation of potential Drug-Induced Serious Hepatotoxicity (eDISH) will also be done by 
plots. Scatter plots of maximum ALT/AST versus maximum BILI will be presented for the 
Treatment Period. The criteria for the individual tests will be considered separately (this 
means that the maximum of ALT/AST and the maximum BILI may not occur at the same 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 20 of 50
assessment timepoint). The values will be normalised by the ULN (unit xULN) and the X-and 
Y-axes will be on the log scale. The plot will include a reference line for ALT/AST values 
>3xULN, and a reference line for BILI values>2xULN. Four quadrants are defined by the 
reference lines, where the right upper quadrant being the most specific indicator for a drug’s 
potential for causing serious liver injury (Hy’s law quadrant). The plot will include number of 
patients in each quadrant for each treatment group.
Subject line plots with values-by-time for ALT, AST, ALP, BILI, GGT and EOSLE (overlaid 
in the same plot) will be generated for patients with ALT/AST > 3xULN in the Treatment 
Period. The test values will be normalised by the ULN (unit xULN) and the Y-axis will be on 
the log scale. All assessments at baseline or later will be included, and the time will be days 
since first IMP in the extension study. Reference lines for the day of first and last date of IMP
(in the extension study) will be included. If there is more than one assessment at the same 
time point for a test, the maximum value will be used.
Vital Signs and Weight
The PCS criteria used for vital signs and weight are the Lundbeck standard PCS criteria 
described in SOP_09978: PV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included in 
Table 2.
Descriptive statistics for the body measurements (weight, BMI, and waist circumference) in 
the Treatment Period, both absolute values and changes from baseline, will be presented by 
variable and week and the last assessment in the Treatment Period. The summaries for the 
absolute values will also include summaries for Baseline.
Descriptive statistics for the vital signs parameters, both absolute values and changes from 
baseline, will be presented by test and week and the last assessment in the Treatment Period. 
The summaries for the absolute values will also include summaries for baseline.
The number and percentage of patients with at least one PCS low value or PCS high value at 
any post-baseline assessment in the Treatment Period will be summarized by vital signs and 
body measurement parameter. All available assessments in the period will be included in the 
evaluation of PCS.
ECGs
The PCS criteria used for the ECG parameters are the Lundbeck standard PCS criteria 
described in SOP_09978: PV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included in 
Table 3.
Descriptive statistics for the ECG parameters in the Treatment Period, both absolute values 
and changes from baseline, will be presented by test and week and the last assessment in the 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 21 of 50
Treatment Period. The summaries for the absolute values will also include summaries for 
baseline.
The number and percentage of patients with at least one PCS low value or PCS high value at 
any post-baseline assessment in the Treatment Period will be summarized by ECG parameter. 
All available assessments in the period will be included in the evaluation of PCS.
Other Safety Endpoints(s)
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores
Since no patients who had not previously participated in a study investigating Lu AF35700 
were enrolled in study 16159B, only the Since Last Visit Version of the C-SSRS will be 
considered. 
The C-SSRS was administered:
• at baseline (using the Since Last Visit Version) – the C-SSRS assessment at baseline that 
collects information since the previous visit. For 16159A patients this is the assessment 
performed at the Primary Outcome Visit of study 16159A and for 16323A patients this is
the assessment performed at the last day of the dosing period in study 16323A. 
• post-baseline (using the Since Last Visit Version) – the C-SSRS assessments after baseline
The C-SSRS scores post-baseline will be summarized based on the APTS. For the post-
baseline assessments the score will be derived as the most severe item that the patient 
answered “Yes” to during the entire Treatment Period. 
The definition of “most severe” is given by the ordering in Panel 2.
The number and percentage of patients with no suicidal ideation or behaviour will be 
included in the summaries. Patients in this category are those who:
• answered ‘no’ to all ideation and behaviour questions; that is, answered ‘no’ to items 1 to 5 
in Panel 2 (related to suicidal ideation) and answered ‘no’ to items 6 to 10 in Panel 2
(related to suicidal behaviour)
For the summary of the post-baseline scores, these patients will be the ones that at all 
assessments during the Treatment Period fulfilled this criterion. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 22 of 50
Panel 2
C-SSRS Scores
C-SSRS Score
Related to:
1
Wish to be dead
Suicidal ideation
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
6
Preparatory acts or behaviour
Suicidal behaviour
7
Aborted attempt
8
Interrupted attempt
9
Non-fatal suicide attempt
10
Completed suicide (only applicable for the post-baseline assessments)
Missing C-SSRS scores will not be imputed.
Non-suicidal self-injurious behaviour is considered separately. For the post-baseline 
assessments it will be identified whether the patient had non-suicidal self-injurious behaviour
(patient answered ‘Yes’ to the item at any of the visit(s) in the Treatment Period). The number 
and percentage of patients with non-suicidal self-injurious behaviour will be included in the 
summaries. 
For patients with any post-baseline suicidal behaviour (C-SSRS scores of 6 to 10), listings 
will be provided including all C-SSRS scores for those patients; C-SSRS scores related to 
suicidal behaviour will be flagged.
EPS Rating Scale Scores
For details about data handling, see section 19.1, 19.2.
Absolute and change from baseline in AIMS total score, mSAS total score, and BARS Global 
Clinical Assessment of Akathisia score (item 4) will be summarised at by week in the 
Treatment Period based on the APTS (baseline will also be included in the summaries of the 
absolute scores). The maximum change from baseline in the Treatment Period will also be 
summarised.
In addition, the BARS Global Clinical Assessment of Akathisia will be presented with 
descriptive tables showing number and percentage of patients in each category for baseline 
and by week in the Treatment Period based on the APTS.
The single-item scores for AIMS items 8 to 12 and BARS items 1 to 4 will be summarized by 
visit.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 23 of 50
Pharmacokinetic/Pharmacodynamic Analyses
No pharmacokinetic/pharmacodynamics analyses are planned. 
Blinded Data Reviews
Not applicable. 
Interim Analyses
Not applicable. 
Sample Size Considerations
No formal sample size calculation has been performed for the present study.
As stated in the clinical study protocol, it was expected that approximately 400 patients would 
be enrolled in the study distributed as follows: 270 from study 16159A, 30 from study 
16323A and 100 patients who had not previously participated in a study investigating Lu 
AF35700. However, the distribution of the number of patients could be adjusted based upon 
the recruitment rate in each group. As mentioned in section 2, the actual patients recruited 
were for the most part from study 16159A except for 4 patients from study 16323A. 
Since more than 500 patients are included in the study, it will be possible to obtain solid 
information on long-term safety of Lu AF35700. 
To ensure sufficient exposure to the daily dosing regimen, the number of patients who 
completed study 16159A and who could be treated with the weekly dosing regimen was 
limited to 50 patients.
Statistical Software
The statistical software used will be SAS®, Version 9.4 or later.
Changes to Analyses Specified in the Protocol
Due to the results from the lead-in study 16159A from which the majority of patients come 
from, the following changes have been made:
As mentioned in section 2, due to a higher-than-anticipated roll-over rate and a lower-than-
anticipated attrition rate from study 16159A, only patients from study 16159A and 16323A
are enrolled in the study and the majority of the patients enrolled are from study 16159A. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 24 of 50
The 4 patients enrolled from study 16323A come from different treatment regimens than 
those from study 16159A. Therefore, data from these 4 patients will only be presented in 
listings, i.e. they will not contribute to any summary tables. 
This also means that the definition of the previous treatment groups included in this document
have been changed from what was defined in the study protocol to accurately reflect the
treatment received in the lead-in study.
Another implication of this change is that the analysis sets defined in section 5 have been
updated to facilitate the analyses as well as to make it possible to include the patients from 
16323A in listings. 
The clinical study protocol defines the baseline just prior to randomization in study 16159A
as an additional baseline and specifies that summary tables will be prepared both with respect 
to that baseline and the baseline defined in this document. However, these additional 
summaries will not be created, as it is considered sufficient to evaluate the data captured in 
this long-term study alone.
The above change also means that the baseline term referring to baseline just prior to 
randomization in study 16159A is removed from all statistical models. 
In the protocol, it is stated that separate displays of descriptive statistics will be prepared for 
patients only receiving daily dosing in study 16159B. This will not be done, as it is considered 
sufficient to provide the tables including all patients regardless of dosing regimen.
Details on Data Handling
Derived Variables
Missing Items
If >20% of the items for a rating scale or subscale are missing, the total score or subscore will 
be set to missing. For the NSA-4 rating scale, however, the total score will be set to missing, 
if any of the individual items are missing, see also section 19.1.5. The implications of these
rules are summarized in Panel 3. If ≤20% of the items is missing and imputation should be 
done, the missing items will be imputed with the mean of the recorded items. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 25 of 50
Panel 3
Maximum Number of Missing Items on Rating Scales
PARAMCD
Description
Maximum Number of 
Missing Items
PANSSTOT
PANSS total score
6
POSITOT
PANSS Positive Symptom subscale score
1
NEGATOT
PANSS Negative Symptom subscale score
1
GENTOT
PANSS General Psychopathology subscale score
3
FACNEG
PANSS Negative symptoms Marder factor
score
1
FACPOS
PANSS Positive Symptoms Marder factor
score
1
FACDISOR
PANSS Disorganized Thought Marder factor
score
1
FACUNC
PANSS Uncontrolled Hostility/Excitement
Marder factor score
0
FACANDEP
PANSS Anxiety/Depression Marder factor
score
0
ANREMIS
PANSS Andreasen Symptoms remission score
0
NSATOT
NSA-4 total score
0
QLSTOT
QLS total score
4
WORQTOT
WoRQ total score
1
TOOLTOT
TooL total score
1
MSASTOT
Modified Simpson-Angus Scale (mSAS) total score
2
AIMSTOT
Abnormal Involuntary Movement Scale (AIMS) total score
1
PANSS
The PANSS2 is a clinician-rated scale designed to measure severity of psychopathology in 
adult patients with schizophrenia, schizoaffective disorders, and other psychotic disorders. It 
emphasises positive and negative symptoms.
The PANSS consists of 30 individual items. Each item is rated from 1 (symptom not present) 
to 7 (symptom extremely severe).
The PANSS is grouped into three subscales: Positive Symptoms subscale, Negative
Symptoms subscale, and General Psychopathology subscale. Furthermore, the division of 
PANSS into the 5 PANSS Marder factors3 is used. The five factors are: Negative symptoms, 
Positive Symptoms, Disorganized Thought, Uncontrolled Hostility/Excitement, and 
Anxiety/Depression. The binary Andreasen score of remission will also be derived from the 
PANSS scores. If any of the items used in the derivation of the remission score are missing, 
the derived score is also set to missing. 
The PANSS items and the derivation of the total score, the subscale scores, the factor scores, 
and the remission scores are described in Panel 4 and Panel 5.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 26 of 50
Panel 4
PANSS Items and Subscales
PANSS Individual Item
PARAMCD
PANSS Individual Item
PARAMCD
Positive Scale
General Psychopathology Scale
Delusions
PANSS01
Somatic concern
PANSS15
Conceptual disorganization
PANSS02
Anxiety
PANSS16
Hallucinatory behaviour
PANSS03
Guilt feelings
PANSS17
Excitement
PANSS04
Tension
PANSS18
Grandiosity
PANSS05
Mannerisms & posturing
PANSS19
Suspiciousness
PANSS06
Depression
PANSS20
Hostility
PANSS07
Motor retardation
PANSS21
Negative Scale
Uncooperativeness
PANSS22
Blunted affect
PANSS08
Unusual thought content
PANSS23
Emotional withdrawal
PANSS09
Disorientation
PANSS24
Poor rapport
PANSS10
Poor attention
PANSS25
Passive-apathetic social withdrawal
PANSS11
Lack of judgement & insight
PANSS26
Difficulty in abstract thinking
PANSS12
Disturbance of volition
PANSS27
Lack of spontaneity & flow of 
conversation
PANSS13
Poor impulse control
PANSS28
Stereotyped thinking
PANSS14
Preoccupation
PANSS29
Active social avoidance
PANSS30
Panel 5
Derivation of PANSS Total Score and Subscales
PANSS Total Score and Subscales
Derivation
PANSS Total Score
Sum of all items PANSS01 to PANSS30 
PANSS Positive Symptoms subscale score
Sum of items PANSS01 to PANSS07
PANSS Negative Symptoms subscale score
Sum of  items PANSS08 to  PANSS14
PANSS General Psychopathology subscale score
Sum of items PANSS15 to PANSS30
PANSS Negative Symptoms factor score
Sum of items PANSS08 to PANSS11, 
PANSS13, PANSS21, and PANSS30
PANSS Positive Symptoms factor score
Sum of items PANSS01, PANSS03, PANSS05, 
PANSS06, PANSS14, PANSS15, PANSS23, 
and PANSS26
PANSS Disorganized Thought factor score
Sum of items PANSS02, PANSS12, PANSS19, 
PANSS24, PANSS25, PANSS27, and PANSS29
PANSS Uncontrolled Hostility/Excitement factor score
Sum of items PANSS04, PANSS07, PANSS22, 
and PANSS28
PANSS Anxiety/Depression factor score
Sum of items PANSS16 to PANSS18, and 
PANSS20
PANSS Andreasen Symptoms remission score
If PANSS01, PANSS02, PANSS03, PANSS08, 
PANSS11, PANSS13, PANSS19, PANSS23 ≤ 3 
then it equals ‘Yes’ otherwise it equals ‘No’
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 27 of 50
Clinical Global Impression Scale - Severity (CGI-S)
The CGI4 severity of illness (CGI-S) is a clinician-rated scale.
CGI-S rates the severity of the patient’s current mental illness on a 7-point scale ranging from 
1 (normal – not at all ill) to 7 (among the most extremely ill patients).
If the CGI-S takes the value 0 (= not assessed) the score will be set to missing.
Personal and Social Performance Scale (PSP)
The PSP5 is a clinician-rated scale designed and validated to measure a patient’s current level 
of social functioning.
The PSP scale consists of a 100-point single-item rating scale, subdivided into 10 equal 
intervals. Scores of 1 to 10 indicate lack of autonomy in basic functioning, whereas scores of 
91 to 100 reflect excellent functioning. The 4 primary domains are: socially useful activities 
(including work and study), personal and social relationships, self-care, and disturbing and 
aggressive behaviours. The 4 domains are assessed on a 6-point scale, from absent to very 
severe.
The total score is rated by the investigator and is based on an algorithm which takes both the 
ratings of the 4 primary domains of PSP, and the combination of these ratings into account.
4-Item Negative Symptom Assessment (NSA-4)
The NSA-46 is a clinician rated scale designed to assess the severity of negative symptoms of 
schizophrenia. It consists of 4 items to measure: restricted speech quantity, reduced emotion, 
reduced social drive, and reduced interests, as well as an overall global rating of negative 
symptoms. Each of the four items is rated on a 1 to 6-point scale where ‘1’ represents no 
reduction from normal behaviours associated with the item and ‘6’ represents severe 
reduction or absence of the behaviour. The scale also includes a ”non ratable” designation 
denoted as ‘9’ for the 4 items. The overall global rating of negative symptoms is rated on a 1 
to 7-point scale where ‘1’ represents no evidence of the symptoms and ‘7’ represents 
extremely severe symptoms. 
The NSA-4 Total Score is the sum of all 4 items and the global rating and thus ranges from 5 
to 31. Since the global rating has a different range than the 4 items, the total score is only 
calculated if no items are missing. When calculating the total score, items rated as ‘9’ (non-
ratable) are treated as missing. This implies that if a patient has a score of ‘9’ in any of the 4 
items, the total score is also set to “missing”, following the specification given in Panel 3.
Quality of Life Scale (QLS)
The QLS7 is a clinician-rated scale designed to assess deficit symptoms of schizophrenia and 
functioning during the preceding 4 weeks. The QLS consists of 21 items in 4 subscales: 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 28 of 50
Interpersonal Relations (8 items), Instrumental Role (4 items), Intrapsychic Foundations (7 
items), and Common Objects and Activities (2 items). Each item is rated on a 7-point scale, 
from 0 (severe impairment) to 6 (normal or unimpaired functioning). Definitions are provided 
for 4 anchor points of the 7 points.
The total score is the sum of all 21 items and ranges from 0 to 126. 
Note, if item 1 is rated 9, the calculation of Interpersonal Relations subscale score and the 
total score are based on items 2-8. If item 9 is rated less than 3, item 12 should be rated as 
9=”Not applicable” and the calculation of the Instrumental Role subscale score and total score 
are based on items 9 to 11. Note, item 1 or 12 recorded as 9 are not counted as missing items 
in the calculation of the total score (see Panel 3).
Readiness for work questionnaire (WoRQ)
The WoRQ8 is a clinician-rated scale designed to measure readiness to work in patients with 
schizophrenia. The WoRQ consists of 8 items: the clinician must rate 7 statements and answer 
one question. The statements are rated on a 4-point scale, from strongly agree, agree, disagree 
or strongly disagree based on all material available (for example, personal notes, medical 
records, input from other health professionals, family members or caregivers); and in the final 
item, the clinician must indicate if the patient is ready for work or not.
The total score will be derived as the sum of items 1-7. 
Medication Satisfaction Questionnaire (MSQ)
The MSQ9 is a patient-rated scale designed and validated to assess the patient’s satisfaction 
with his or her current antipsychotic medication. The MSQ consists of one item that is rated 
on a 7-point scale ranging from 1 (extremely dissatisfied) to 7 (extremely satisfied).
Tolerability and Quality of Life questionnaire (TooL)
The TooL10 a patient-rated scale developed to measure the impact of side-effects on the 
quality of life in patients treated with antipsychotic medication. The TooL consists of eight 
domains: mood (worry-upset), function capabilities, fatigue-weakness, weight gain, stiffness-
tremor, physical restlessness, sexual dysfunction and dizziness-nausea. Each domain is rated 
on a 4-point scale from 1 (no impact) to 4 (maximum impact). 
Total scores are derived as the sum of the single items and range from 8 (no impact) to 32 
(maximum impact).
Abnormal Involuntary Movement Scale (AIMS)
The AIMS11 is a clinician-rated scale designed to assess abnormal involuntary movements 
(for example, dyskinesia) associated with anti-psychotic drugs. The AIMS consists of 12 
items: items 1 to 7 assess the severity of movements in 3 anatomical areas (facial/oral, 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 29 of 50
extremities and trunk); items 8 and 9 assess the global severity and the incapacitation due to 
the movements; item 10 assesses the patient’s awareness of the movements and the distress 
due to them; items 11 and 12 clarify the patient’s dental status. The 12 items are assessed 
using a neurological examination: items 1 to 9 are rated on a 5-point scale, from 0 (none) to 4 
(severe); item 10 is rated on a 5-point scale, from 0 (no awareness) to 4 (aware, severe 
distress); and items 11 and 12 are rated yes/no. 
The AIMS Total Score is the sum of item 1 to 7 and ranges from 0 to 28.
Barnes Akathisia Scale (BARS)
The BARS12 is a clinician-rated scale designed to assess the presence and severity of drug
induced akathisia. The BARS consists of 4 items: one objective item (observed restlessness), 
two subjective items (patient’s awareness of restlessness and related distress), and a global 
clinical assessment of akathisia. The objective and subjective symptoms are rated on a 4-point 
scale, from 0 (no symptom) to 3 (severe symptoms). The global clinical assessment is rated 
on a 6-point scale from 0 (absent) to 5 (severe akathisia).
In the analyses, the global clinical assessment (item 4) will be used.
Modified Simpson Angus Scale (mSAS)
The SAS13 is a clinician-rated scale designed to assess the presence and severity of drug-
induced parkinsonism. The mSAS consists of 10 items to evaluate gait, rigidity (arms and 
head), eye-blinking, tremor, salivation and akathisia. The 10 items are assessed using a 
neurological examination and rated on a 5-point scale, from 0 (absence of the condition) to 4 
(most extreme form of the condition). Comprehensive definitions are provided for each 
anchor point on the scale.
The mSAS Total Score is the sum of all 10 items and ranges from 0 to 40.
Health Care Resource Utilisation (HEA)
The HEA is a questionnaire aiming at monitoring patients’ health care resource utilisation 
such as physicians’ visits, outpatient and inpatient services and other relevant services. 
Assigning Data to Visits
Rating Scales
The assessment at the Withdrawal Visit for patients withdrawn from treatment will be 
assigned to a nominal visit in the Treatment Period, according to the visit windowing 
specified in Panel 6 and Panel 7.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 30 of 50
In analyses of efficacy, if the Withdrawal Visit is assigned to the same visit as a scheduled 
visit, the assessment from the Withdrawal Visit, which by definition always will be the latest,
will be used. 
In analyses of safety scales using visit, if the Withdrawal Visit is assigned to the same visit as 
a scheduled visit, the assessment at the Scheduled Visit will be used.
Otherwise, the assessments at the scheduled visits will be used.
If there is more than one assessment for the EPS rating scales with the maximum post-
Baseline value, the first value will be flagged as the maximum value.
Panel 6
Visit Windows: PANSS, CGI-S, C-SSRS
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V2 (Baseline Visit)
0
0
NA
V3
1
7
Day after V2 – 11
V4
2
14
12-21
V5
4
28
22-42
V6
8
56
43-70
V7
12
84
71-98
V8
16
112
99-126
V9
20
140
127-154
V10
24
168
155-182
V11
28
196
183-210
V12
32
224
211-238
V13
36
252
239-266
V14
40
280
267-294
V15
44
308
295-322
V16
48
336
323-350
V17 (Primary Outcome/Withdrawal 
Visit)
52
364
>350
Panel 7
Visit Windows: PSP, NSA-4, QLS, WoRQ, TooL, MSQ, AIMS, BARS, mSAS
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V2 (Baseline Visit)
0
0
NA
V5
4
28
14-42
V10
24
168
154-182
V17 (Primary Outcome/Withdrawal 
Visit)
52
364
>350
For efficacy assessments, the last usable assessment in the Treatment Period will be used to 
impute missing values for the LOCF. For patients that have a missing visit, the value from the 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 31 of 50
visit before will be used for imputing the missing value for the LOCF. If the missing visit is 
the one directly following the baseline visit, however, the value will not be imputed for the 
LOCF, as baseline observations will not be carried forward.
The Health Economics Assessment (HEA) scale is only scheduled to be assessed at Visit 17. 
For these assessments, the Withdrawal Visit for patients withdrawn from treatment in the 
Treatment Period will be assigned to Visit 17.  
Safety Variables
The assessments at the Withdrawal Visit and Unscheduled Visits (assessments not recorded at 
a scheduled visit) will be assigned to a nominal visit according to the visit windowing 
specified in Panel 8, Panel 9 and Panel 10. Note, assessments after Visit 2 for enrolled 
patients that did not have any IMP intake will be assigned to nominal Visit 2.
In analyses of vital signs parameters using visit, if the Withdrawal Visit is assigned to the 
same visit as a scheduled visit, the assessment at the Scheduled Visit will be used.
For 16159A-patients, additional ECG assessments will be performed if the daily dosing is 
switched to weekly dosing. These assessments will not be windowed. 
Panel 8
Visit Windows: Vital Signs
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V2 (Baseline Visit)
0
0
NA
V3
1
7
Day after first IMP – 11
V4
2
14
12-21
V5
4
28
22-35
V6
8
56
49-63
V7
12
84
77-91
V8
16
112
105-119
V9
20
140
133-147
V10
24
168
161-175
V11
28
196
189-203
V12
32
224
217-231
V13
36
252
245-259
V14
40
280
273-287
V15
44
308
301-315
V16
48
336
329-343
V17 (Primary Outcome/Withdrawal 
Visit)
52
364
>357
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 32 of 50
Panel 9
Visit Windows: Laboratory Tests, Body weight, and Waist circumference
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V2 (Baseline Visit)
0
0
NA
V5
4
28
22-35
V10
24
168
161-175
V17 (Primary Outcome/Withdrawal 
Visit)
52
364
>357
Panel 10
Visit Windows: ECG
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V2 (Baseline Visit)
0
0
NA
V5
4
28
22-35
V8
16
112
105-119
V11
28
196
189-203
V14
40
280
273-287
V17 (Primary Outcome/Withdrawal 
Visit)
52
364
>357
Note that if the first IMP in the Treatment Period is the same day as the assessment, the 
assessment is assumed to be before the IMP intake.
Laboratory tests for which fasting is relevant (blood and serum tests for CDISC terms CHOL, 
GLUC, HDL, LDL, and TRIG) will have separate PARAM values in ADaM data, one for 
fasting and one for non-fasting/unknown, and fasting and non-fasting/unknown assessments 
will be considered separately.
The Baseline value will be the last assessment at or before Visit 2. If there is more than one 
assessment at the day of the last assessment, they will be ordered after date and time where 
assessment without recorded time will be considered to come after assessments recorded with 
time. The assessment last in the ordering will be used. If there is more than one assessment on 
the same date (and time), e.g. two assessments on the same date without recorded time, the 
maximum value will be used.
For last post-baseline assessments in the Treatment Period, the same ordering rule will be 
used as for Baseline.
In analyses using visit, if there is more than one assessment at a nominal visit, the value will 
be selected using the following prioritization rule:
1.
Scheduled Visit
If there is more than one assessment recorded at a scheduled visit, the one closest to the 
nominal day for the visit will be used in analyses using visit. If there are more than one 
assessment that are equally close to the nominal day, they will be ordered after date and 
time where assessments without recorded time will be considered to come after 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 33 of 50
assessments recorded with time. The assessment first in the ordering will be used. If there 
is more than one assessment on the same date (and time), the maximum value will be 
used.
2.
Withdrawal Visit or Unscheduled Visit
If there is more than one assessment, the value for analyses using visit will be selected 
using the same ranking as for multiple assessments at scheduled visits. 
Handling Missing or Incomplete Dates/Times
IMP Start and Stop Dates
A missing IMP start date will be imputed with the date of Visit 2.
A missing IMP stop date will not be imputed.
Exposure and compliance will not be calculated for patients with missing IMP start-or-stop 
dates. Thus, a patient with a missing IMP start-or-stop date will contribute as having no 
exposure in the calculation of PYE. This also holds for patients not receiving any IMP.
Withdrawal Date
Missing withdrawal dates will not be imputed and time to withdrawal from treatment will not 
be calculated for missing withdrawal dates. 
Medical Disorder Start and Stop Dates
Incomplete dates will not be imputed. Classification of events into concurrent medical 
disorders or past disorders will be based on the reported on-going status.
Medication Start and Stop Dates
Imputation of incomplete or partially missing dates will be done in order to assigning the 
medication to the categories specified in chapter 9. No duration will be calculated for 
medications with imputed start-or stop date, or for on-going medications.
Incomplete or missing medication dates will be imputed according to the algorithm below. If 
an imputed start date after this procedure is after the end date, the start date will be set to the 
end date.
In general, if the medication start date is partially or completely missing and if the medication 
is on-going from the lead-in study, the start date will be imputed with the imputation value 
used in the lead-in study.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 34 of 50
Otherwise, the following rules will be applied:
• Incomplete start date where day is missing:
The start date will be imputed with the latest of either the date of first IMP in the 
extension study or the medication start date assuming that the day is the 1st of the 
month.
• Incomplete start date where month and day are missing:
If the year is equal to the year of first IMP in the extension study the date will be 
imputed with the date of first IMP in the extension study. 
If the year is after the year of first IMP in the extension study the date will be imputed 
with the medication start date assuming the month and day are January 1st.
• Missing start date:
The medication start date will be imputed with the date of first IMP in the extension 
study
• Incomplete end date where day is missing:
The date will be imputed with the minimum value of either the last day of the reported 
month and year or the end of study date. 
• Incomplete end date where month and day are missing:
The date will be imputed with the minimum value of either December 31st of the 
reported year or the end of study date.
• Missing end date:
If the medication end date is missing and the medication is not reported as on-going, the 
end date will be imputed with the end of study date.  
Adverse Event Start and Stop Dates
Imputation of partially missing dates will be done in order to classify the treatment emergent 
status and assigning the adverse event to a period. No duration will be calculated for adverse 
events with incomplete start-or stop dates, or for on-going adverse events.
Incomplete adverse start-and stop dates will be imputed before handling of incomplete dates 
for change in intensity or seriousness (see section 19.4.2)
Incomplete adverse event start dates will be imputed according to the algorithm below. If an 
imputed start date after this procedure is after the adverse event end date, the start date will be 
set to the end date.
In general, if the AE is on-going at Baseline and the start date is partially or completely 
missing, the start date will be imputed with the imputation value used in the lead-in study.
• Patients not in APTS:

Incomplete start date where day is missing
The start date will be imputed with the latest of adverse event start date 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 35 of 50
assuming the day is the 1st of the month (e.g. if year=2017, and month=MAY, 
the start date would assumed to be 01MAY2017), and date of Visit 2

Incomplete start date where month and day are missing
The start date will be imputed with the latest of adverse event start date 
assuming the month and day are JAN the 1st, and date of Visit 2
• Patients in APTS:

Incomplete start date where day is missing

If the start year and month are before the year and month of first IMP 
in the Treatment Period, the date will be imputed with the latest of 
adverse event start date assuming the day is the 1st of the month, and 
Visit 2

If the start year and month are at or after the year and month of first 
IMP in the Treatment Period and at or before the last visit in the 
Treatment Period, the date will be imputed with the latest of adverse 
event start date assuming the day is the 1st of the month, and the date of 
first IMP in study 16159B

If the start year and month are after the year and month of the last visit 
in the Treatment Period, the date will be imputed with the latest of 
adverse event start date assuming the day is the 1st of the month, and 
the day after last visit in the Treatment Period

Incomplete start date where month and day are missing

If the year is before the year of first IMP, the date will be imputed with 
the latest of adverse event start date assuming the month and day are 
JAN 1st, and date of Visit 2

If the year is equal to the year of first IMP in the Treatment Period, the 
date will be imputed with the date of first IMP in study 16159B
For adverse events with incomplete end dates where the day is missing, the date will be 
imputed with the minimum of the last day in the reported month and year and the end of study 
date. If both month and day are missing for an end date, the date will be imputed with the 
minimum of the adverse event end date assuming month and day are Dec 31, and the end of 
study date.
If the day in the date of intensity-or seriousness change is incomplete the date will imputed 
using the same algorithm as for incomplete start dates of adverse events but where the start 
date of the original event (that may have been imputed) or the preceding intensity if more than 
one intensity change is also taken into account. Three examples to illustrate this for a patient 
in APTS:
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 36 of 50
• If the adverse event start date of the original event was 15MAY2017, the date of first IMP 
in the Treatment Period was 17MAY2017, and the incomplete date for change in intensity 
was MAY2017, the change in intensity date would be imputed with the latest of 
01MAY2017, 15MAY2017, and 17MAY2017, i.e. 17MAY2017.
• If the adverse event start date of the original event was 15MAY2017, the date of first IMP 
in the Treatment Period was 02MAY2017, and the incomplete date for change in intensity 
was MAY2017, the change in intensity date would be imputed with the latest of 
01MAY2017, 15MAY2017, and 02MAY2017, i.e. 15MAY2017.
• If the adverse event start date of the original event was 15APR2017, the date of first IMP 
in the Treatment Period was 13APR2017, and the incomplete date for change in intensity
was MAY2017, the change in intensity date would be imputed with the latest of 
01MAY2017, 15APR2017, and 13APR2017, i.e. 01MAY2017.
If an imputed start date for an intensity change is after the end date for the original event, or 
after a later intensity change, the date of the intensity change will be set to the end date of the 
original event or the date of the intensity change that comes after.
The imputed start dates will be used in the classification of adverse events as TEAEs (see 
section 12.1.2). TEAEs will be flagged in the data. 
Data with Multiple Records
Dose Changes in Medication
Dose changes or change in treatment regimen in concomitant medications are recorded on 
multiple rows in the eCRF, with different start and stop dates. When classifying medications 
into categories (see chapter 9), each record is considered as a separate medication, and the 
same drug name can be assigned to several categories for the same patient. Within a category, 
multiple entries will contribute as a single count in the summaries.
Changes in Intensity or Seriousness of Adverse Events
Changes in adverse event intensity are included as additional rows in the ADaM data, where 
each change in intensity will be represented as an additional row, e.g. an adverse event that 
changes from mild to moderate will have one additional row, one with intensity mild and one 
with intensity moderate (variable ASEV). The stop date for the intensity will be the stop date 
for the originally recorded event for the last intensity, and for the preceding rows the stop date 
will be set to the date of change in intensity minus 1 or the date of change if a change 
occurring on the same day as the originally reported event, or if there is more than one change 
on a day (for handling of incomplete dates, see section 19.3.5).
If the recorded start date of a serious adverse event is after the start date of the reported 
adverse event, the event is considered as having changed from non-serious to serious.
Recorded seriousness for an adverse event will be the most serious (mapped to SDTM 
variable AESER, i.e. AESER=Y for an adverse event that change from non-serious to 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 37 of 50
serious). In ADaM data, one additional row will be added for an adverse event that change 
from non-serious to serious, one with seriousness non-serious and one with seriousness 
serious (ADaM variable ASER). The stop date for the first row (ASER=N) will be the start 
date of the serious adverse event minus 1, and the stop date for the second row (ASER=Y) 
will be the stop date for the adverse event. After having changed to serious, the adverse event 
is considered as serious onwards.
If an intensity and seriousness is reported on the same date, rows will be added reflecting both 
the change in intensity and seriousness, one for each change type. This is to keep the 
transparency and to keep the value of the SDTM variable FASTRESC, which is mapped to 
the ADaM dataset. To be able to summarize the number of adverse events without counting 
these events twice, a flag will be added to the data indicating which adverse events that will
go into the summaries.
As an example, an adverse event originally reported as being mild and non-serious, which 
additionally is reported as having changed to severe and serious on the same date, will have a 
total of 3 rows in data. One row with intensity mild, seriousness non-serious, and ANL01FL = 
‘Y’, one row with intensity severe, seriousness non-serious, and ANL01FL = ‘’ (empty), and 
one row with intensity severe, seriousness serious, and ANL01FL = ‘Y’. 
Duration (days) will be calculated for each intensity/seriousness based on the 
intensity/seriousness start-and stop dates.
When classifying adverse events into periods, an event may be assigned to more than one 
period. An adverse event that changes in intensity or seriousness in a period will contribute to 
the count of events as a single event in the summaries.
In summaries of adverse events presented by intensity, the maximum intensity of the adverse 
event will be used. The maximum intensity is searched for in events with changes, as well as 
over repeated events based on the preferred term. Adverse events for which information on 
intensity is missing will be classified as severe.
Adverse events for which information on seriousness is missing will be classified as serious.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 38 of 50
References
1.
United States Food and Drug Administration (US FDA). Guidance for Industry: Drug-induced 
liver injury: premarketing clinical evaluation. July 2009.
2 .
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987; 13(2): 261-276.
3.
Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of 
schizophrenia derived by factor analysis: combined results of the North American trials. J Clin 
Psychiatry. 1997; 58(12):538-546. 
4.
Guy W, editor. Clinical Global Impressions. In: Guy W, editor. ECDEU Assessment Manual for 
Psychopharmacology. Revised ed. Rockville, MD: National Institute of Mental Health; 1976; 
217-222. 
5. 
Morosini P-L, Magliano L, Brambilla L et al.  Development, reliability and acceptability of a new 
version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to 
assess routine social functioning. Acta Psychiatrica Scandinavica 2000; 101: 323-9
6. 
Alphs L, Morlock R, Coon C, van Willigenburg A, Panagides J. The 4-item negative symptom 
assessment (NSA-4) instrument: A simple tool for evaluating negative symptoms in 
schizophrenia following brief training. Psychiatry. 2010; 7: 26-32.
7 .
Heinrichs DW, Hanlon TE, Carpenter WT. The Quality of Life Scale: an instrument for rating the 
schizophrenic deficit syndrome. Schizophr Bull. 1984; 10: 388-398.
8 .
Potkin SG, Bugarski-Kirola D, Edgar CJ, Soliman S, Le Scouiller S, Kunovac J et al. 
Psychometric evaluation of the Work Readiness Questionnaire in schizophrenia. CNS Spectr. 
2014; Oct 1: 1–8.
9 .
Vernon MK, Revicki DA, Awad AG, Dirani R, Panish J, Canuso CM 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.
10 . Lindström E, Jönsson L, Berntsson A. A patient perspective on side effects of antipsychotic 
therapy: the TooL instrument. Value Health. 2009; 12: A361.
11. Guy W editor. ECDEU Assessment Manual for Psychopharmacology. Revised ed. Rockville, 
MD: National Institute of Mental Health; 1976:534-6
12. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry.1989;154:672-6
13. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects.  Acta Psychiatr Scand 
1970;212:11-9
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 39 of 50
Appendix I
Statistical Analysis Plan
Authentication and Authorization
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 40 of 50
Statistical Analysis Plan
Authentication and Authorization
Study title:
Interventional, open-label, flexible-dose, long-term safety study of Lu AF35700 in 
adult patients with schizophrenia
Study No.:
16159B
SAP date:
5 November 2019
This document has been signed electronically. The signatories are listed below.
Authentication
Biostatistician:
Clinical research scientist:
Authorization
Head of Biostatistics:
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 41 of 50
Appendix II
SAS® Code
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 42 of 50
SAS® Code
The code for fitting the overall models mentioned in section 11.2 is given below. 
The variable CHG refers to the change from baseline value, NOMWEEK refers to the week variable, 
COUNTRY to the country variable, USUBJID to the subject identifier variable, and BASE refers to 
the baseline value.  
proc mixed data = xxx order = internal method = reml;
        class COUNTRY NOMWEEK USUBJID;
model CHG = COUNTRY NOMWEEK BASE BASE * NOMWEEK / ddfm = kr;
        repeated NOMWEEK / subject = USUBJID type = un;
        lsmeans NOMWEEK / cl alpha = 0.05;
quit;
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 43 of 50
Appendix III
PCS Criteria
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 44 of 50
PCS Criteria
Table 1
PCS Criteria for Clinical Safety Laboratory Tests
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Haematology / Coagulation
B-haemoglobin
HGB
g/dL
≤ 9.5 (women)
≥ 16.5 (women)
≤ 11.5 (men)
≥ 18.5 (men)
B-erythrocytes (red cell count)
RBC
x 10E12/L
≤ 3.5 (women)
≥ 6.0 (women)
≤ 3.8 (men)
≥ 7.0 (men)
B-haematocrit (packed cell 
volume)
HCT
V/V
≤ 0.32 (women)
≥ 0.50 (women)
≤ 0.37 (men)
≥ 0.55 (men)
B-MCV (mean cell volume)
MCV
fL
≤ 0.8 x LLN
≥ 1.2 x ULN
B-total leucocyte (white cell 
count)
WBC
x 10E9/L
≤ 2.8
≥ 16
B-neutrophils/leucocytes
NEUTLE
%
≤ 20
≥ 85
B-eosinophils/leucocytes
EOSLE
%
≥ 10
B-basophils/leucocytes
BASOLE
%
≥ 10
B-lymphocytes/leucocytes
LYMLE
%
≤ 10
≥ 75
B-monocytes/leucocytes
MONOLE
%
≥ 15
B-thrombocytes (platelet count)
PLAT
x 10E9/L
≤ 75
≥ 600
P-INR (prothrombin ratio)
INR
Ratio
≥ 2.0
B-prothrombin time
PT
Sec
≥ 18
Liver
S-aspartate aminotransferase
AST
IU/L
≥ 3 × ULN
S-alanine aminotransferase
ALT
IU/L
≥ 3 × ULN
S-bilirubin
BILI
μmol/L
≥ 34
S-bilirubin, direct
BILDIR
μmol/L
≥ 12
S-bilirubin, indirect
BILIND
μmol/L
≥ 22
S-alkaline phosphatase
ALP
IU/L
≥ 3 × ULN
S-gamma glutamyl transferase
GGT
IU/L
≥ 200
S-alpha-glutathione S-transferase
(alpha-GST)
GSTAL
μg/L
≥ 20
Kidney
S-creatinine
CREAT
μmol/L
≥ 1.5 x ULN
B-urea nitrogen (BUN)
BUN
mmol/L
≥ 11
S-uric acid (urate)
URATE
μmol/L
≥ 510 (women)
≥ 630 (men)
Electrolytes
S-sodium (natrium)
SODIUM
mmol/L
≤ 125
≥ 155
S-potassium (kalium)
K
mmol/L
≤ 3.0
≥ 6.0
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 45 of 50
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
S-calcium
CA
mmol/L
≤ 1.8
≥ 3.0
S-chloride
CL
mmol/L
≤ 90
≥ 117
S-magnesium
MG
mmol/L
≤ 0.6
≥ 1.3
S-phosphate (phosphorus, 
(inorganic)
PHOS
mmol/L
≤ 0.65
≥ 1.95
S-bicarbonate
BICARB
mmol/L
≤ 12
≥ 38
Endocrine / Metabolic
B-glucose, non-fasting/unknown
GLUC
mmol/L
≤ 3.4
≥ 9.4
B-glucose, fasting
GLUC
mmol/L
≤ 3.0
≥ 6.0
S-glucose, non-fasting/unknown
GLUC
mmol/L
≤ 3.9
≥ 11.1
S-glucose, fasting
GLUC
mmol/L
≤ 3.5
≥ 7.0
B-glycosylated haemoglobin, 
fasting
HBA1C
%
≥ 6.5
S-prolactin
PROLCTN
mIU/L
≥ 1350
S-thyrotropin/TSH
TSH
mIU/L
≤ 0.3
≥ 5.5
S-protein (total)
PROT
g/L
≤ 45
≥ 95
S-albumin
ALB
g/L
≤ 27
Lipids
S-cholesterol total, non-
fasting/unknown
CHOL
mmol/L
≥ 7.8
S-cholesterol total, fasting
CHOL
mmol/L
≥ 6.2
S-triglycerides, non-
fasting/unknown
TRIG
mmol/L
≥ 5.65
S-triglycerides, fasting
TRIG
mmol/L
≥ 4.2
S-LDL cholesterol, non-
fasting/unknown
LDL
mmol/L
≥ 5.3
S-LDL cholesterol, fasting
LDL
mmol/L
≥ 4.9
S-HDL cholesterol, non-
fasting/unknown
HDL
mmol/L
≤ 0.8
S-HDL cholesterol, fasting
HDL
mmol/L
≤ 0.9
Cardiac/Skeletal/Muscle
S-creatine kinase (total)
CK
IU/L
≥ 400 (women)
≥ 750 (men)
S-creatine kinase MB isoenzyme
CKMB
μg/L
≥ 8.5 or
CKMBCK
%
≥ 3.5% of total 
CK
S-lactate dehydrogenase (total)
LDH
IU/L
≥ 750
S-troponin I
TROPONI
μg/L
≥ 1.5
S-troponin T
TROPONT
μg/L
≥ 0.4
Infection
S-C-reactive protein
CRP
mg/L
≥ 25
S-globulin (total)
GLOBUL
g/L
≤ 15
≥ 55
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 46 of 50
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Urine
Urinary pH
PH
≤ 4
≥ 9
S=serum; B=whole blood; U=urine
Table 2
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference
Variable
CDISC Term
Unit
PCS Low
PCS High
Waist circumference
WSTCIR
Cm
decrease ≥ 7%
increase ≥ 7%
Weight
WEIGHT
Kg
decrease ≥ 7%
increase ≥ 7%
Body Mass Index
BMI
kg/m2
decrease ≥ 7%
increase ≥ 7%
Pulse rate, 
supine/sitting/unknown
PULSE
beats/min
< 50 and
decrease ≥ 15
≥ 120 and
increase ≥ 15
Diastolic blood pressure,
supine/sitting/unknown
DIABP
mmHg
≤ 50 and
decrease ≥ 15
≥ 105 and
increase ≥ 15
Systolic blood pressure,
supine/sitting/unknown
SYSBP
mmHg
≤ 90 and
decrease ≥ 20
≥ 180 and
increase ≥ 20
Orthostatic systolic blood 
pressure
OBP
mmHg
≤ -30
Orthostatic pulse rate
OPR
beats/min
≥ 20
Temperature
TEMP
ºC
decrease ≥ 2
≥ 38.3 and
increase ≥ 2
Increase/decrease is relative to the baseline value.
Table 3
PCS Criteria for ECG Parameters
ECG Parameter
CDISC Term
Unit
PCS Low
PCS High
Absolute Time Interval
PR interval
PRMEAN
Msec
≥ 260
QRS interval
QRSDUR
Msec
≥ 150
QT interval
QTMEAN
Msec
≥ 500
Derived Time Interval
Heart rate
HRMEAN
beats/min
< 50 and
decrease ≥ 15
≥ 120 and
increase ≥ 15
QTcB interval
QTCB
Msec
< 300
> 500 or
increase > 60
QTcF interval
QTCF
Msec
< 300
> 500 or
increase > 60
Increase/decrease is relative to the baseline value.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 47 of 50
Appendix IV
Study Flow Chart
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 48 of 50
Study Flow Chart
Study Procedures and Assessments
Visit
Screeninga
Baselineb
Treatment Period
Primary 
Outcome or 
Withdrawalc
Safety 
Follow-Upd
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
End of Week
-
0
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52
Day
-14/-7
0
7
14
28
56
84
112 140 168 196 224
252 280 308 336
364
Visit Window (days)e
3
3
3
6
7
7
7
7
7
7
7
7
7
7
7
+3
Baseline Procedures and Assessments
Signed informed consent
a

Diagnosis (DSM-5TM)
a
f
Demographics (age, sex, 
race)
a
f
Relevant social, medical 
and psychiatric history
a
f
Height
a
f
Inclusion/exclusion criteria


Effectiveness Assessments
PANSS 

g















CGI-S

g















PSP

g



NSA-4
g



QLS
g



WoRQ
g



TooL
g



MSQ
g



HEA
h

Pharmacokinetic Assessments
Blood sampling for 
Lu AF35700 and 
metabolite assay
g



Translational Medicines Assessmentsi
Blood sampling for gene 
expression profiling 
(RNA)j
i
i
Blood sampling for 
metabolomics/proteomics 
(plasma) j
i
i
Blood sampling for 
pharmacogenetics 
(optional) k
i
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 49 of 50
Visit
Screeninga
Baselineb
Treatment Period
Primary 
Outcome or 
Withdrawalc
Safety 
Follow-Upd
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
End of Week
-
0
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52
Day
-14/-7
0
7
14
28
56
84
112 140 168 196 224
252 280 308 336
364
Visit Window (days)e
3
3
3
6
7
7
7
7
7
7
7
7
7
7
7
+3
Safety Assessments
Adverse events

l















m
Blood and urine sampling for 
clinical safety laboratory 
tests
a
g



n
Serum prolactino
a
g



HBA1c (fasting)
a
g



Fasting blood glucose (P-
glucose) and lipid profile 
(S-cholesterol,  
S-triglycerides, S-low 
density lipoprotein (LDL), S-
high density lipoprotein 
(HDL))
a
g



Vital signs

g















ECGs p

g





Body weight

g



Waist circumference

g



Physical Examination
a
g

Abnormal movements 
rating scales
(AIMS, BARS, mSAS)
g



C-SSRS

g















Other Study Procedures
IMP dispensedq















Possible change in IMP 
doseq














IMP returned and 
accountability















Recent and concomitant 
medication

s
















Urine drug screen
a
t

Pregnancy testu
a
g



a.
Screening Visit will be performed only for newly recruited patients and screening assessments marketed 
with an “a” will not be repeated at Baseline Visit. 16159A-patients and 16323A-patients will proceed 
from their lead-in study directly to the Baseline Visit. The ICF must be signed before any study related 
activities take place.
b.
For 16159A-patients, the Baseline Visit will be performed the same day as the Primary Outcome Visit 
of study 16159A. For 16323A-patients, the Baseline Visit will be performed the same day as the last 
day of the dosing period of study 16323A. The inclusion/exclusion criteria are confirmed based on the 
evaluation of the latest data available in the study 16323A or 16159A as applicable.
c.
This visit should take place as soon as possible after the patient withdraws from the study treatment. 
d.
The Safety Follow-up Visit will be done 6 weeks (+3 days) after the last dose of IMP. This visit can be 
a telephone contact, unless an SAE has occurred since last visit or unless there was a clinically
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170


H. Lundbeck A/S
Confidential
Study 16159B – Statistical Analysis Plan
Page 50 of 50
significant abnormal safety laboratory test value at the last visit. In such cases, safety follow-up(s) must 
be scheduled to allow for a medical examination and/or blood sampling. Further Safety Follow-up 
Visits beyond 6 weeks may be needed as judged by the investigator (if further Safety Follow-up Visits 
are performed, these must be recorded in the patient’s medical record, and not in the CRF).
e.
If the date of a patient visit does not conform to the study plan, subsequent visits should be planned to 
maintain the visit schedule relative to the Baseline Visit. The number of days between 2 visits should 
not exceed the number of days for which the patient has been dispensed IMP.
f.
For 16159A-patients and 16323A-patients, the data will be linked respectively from the Screening Visit 
in the study 16159A eCRF or from the Screening Visit in the study 16323A eCRF, when applicable.
g.
For 16159A-patients and 16323A-patients, results from effectiveness/safety assessments and 
blood/urine samples performed respectively at the Primary Outcome Visit (Visit 12) in study 16159A or 
at the last day of the dosing period (Day 42) in study 16323A (when available) will be linked to the 
Baseline Visit (Visit 1) in study 16159B, when applicable.
h.
For 16159A-patients, HEA data will be linked from the Baseline A Visit in the study 16159A eCRF.
i.
To be performed only for newly recruited patients not previously participating in a study investigating 
Lu F35700.
j.
Exploratory gene expression profiling (RNA) and metabolomics/proteomics are covered by the main 
Patient Information Sheet. 
k.
Sampling for pharmacogenetics is optional and a separate Patient Information Sheet covers this 
analysis. This sampling should preferably be at the Baseline Visit, but may be collected at any visit that 
includes a clinical safety laboratory sample. 
l.
For 16159A-patients and 16323A-patients, on-going adverse events from study 16159A and 16323A, 
respectively, are to be transferred by the investigator to the eCRF, when applicable.
m. Only for adverse events on-going at the Primary Outcome/Withdrawal Visit and new SAEs.
n.
Only to be taken if the laboratory test was clinically significantly abnormal at the Primary 
Outcome/Withdrawal Visit.
o.
Prolactin results will remain blinded throughout the study.
p.
For 16159A-patients, additional ECGs will be done; 1 ECG recording before the daily dose is switched 
to weekly dosing (preferably on the day the decision of switching from daily to weekly dosing is taken)
and 1 ECG recording the day after the first weekly dose is taken.
q.
The first dose of IMP should be taken after the Baseline Visit is completed. All treatment assignment 
and subsequent IMP assignment is done via the IVRS/IWRS. The IVRS/IWRS will be assessed at the 
unscheduled visit only if the dose adjustment requires dispensing of IMP.
r.
The dose of IMP can be increased for efficacy or decreased for tolerability at scheduled or unscheduled 
visits from Week 1 Visit.
s.
For 16159A-patients and 16323A-patients, on-going concomitant medication in study 16159A and 
16323A, respectively, must be transferred by the investigators to the 16159B eCRF. All prescription, 
non-prescription medications, and herbal medications taken during study 16159B will be recorded as 
concomitant medications. 
t.
Urine drug screen tests can be repeated any time during the study at the discretion of the investigator.
u.
S-βhCG pregnancy test should be performed at the Screening Visit (Only for Other-patients), Visit 5, 
Visit 10 and the Primary Outcome/Withdrawal Visit for women of childbearing potential. Urine 
pregnancy tests can be performed at any time during the study at the discretion of the investigator.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.1
16159B
Draft
CLI_01081170