Clinical trial NCT03230864
Conditions: Treatment-resistant Schizophrenia
Keywords: Treatment-resistant schizophrenia Lu AF35700
Sponsor: H. Lundbeck A/S
Start date: 2017-07-20; Completion date: 2019-02-05
Enrollment: 119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the efficacy of 10 mg/day Lu AF35700 on symptoms of schizophrenia in patients with early-in-disease (ED) or late-in-disease (LD) treatment-resistant schizophrenia (TRS)

Detailed description:
In the study, patients will receive risperidone (4-6 mg/day), or, if recently failed on risperidone, olanzapine (15-20mg/day). Later during the study, patients will be randomized to either receive Lu AF35700 (10 mg/day), or continue their treatment from the prospective confirmation (PC) period.

The study consists of a Screening Period (up to 3 weeks), a single-blind PC Period (6 weeks), a Double-blind Treatment (DBT) Period (8 weeks), and a Safety Follow-up Period (6 weeks).

Patients who did not fulfil the randomization criteria for the DBT Period, were withdrawn from the study after the PC period.

Patients who fulfilled the randomization criteria for the DBT Period, continued into the DBT period and were randomized into one of the 2 treatmetn arms (1:1) with either Lu AF35700 10 mg or to continue the treatment allocated in the PC period (olanzapine or risperidone) at the dose set at the last visit of the PC period. This means that approximately half of the confirmed treatment-resistant patients were randomised back to the failed treatment in the PC period.

Data was not collected seperately for the DBT olanzapine and DBT risperidone participants, and there was no intent to compare Lu AF35700 to each drug seperately.

Arms: arm 1: Single (patient)-blinded treatment period with risperidone or olanzapine for 6 weeks arm 2: Eligible patients from PC period (based on criteria to which investigator and patient are blinded ), will be randomly assigned (1:1) double-blind treatment in DBT period, 8 weeks arm 3: Eligible patients from PC period (based on criteria to which investigator and patient are blinded ), will be randomly assigned (1:1) double-blind treatment in DBT period, 8 weeks. Patients in this arm will continue with the same treatment and dose as at the last visit of the PC Period
Interventions: intervention 1: Lu AF35700 intervention 2: Risperidone intervention 3: Olanzapine
Intervention descriptions: intervention 1: 10 mg/day, encapsulated tablets, orally intervention 2: 4-6 mg/day, encapsulated tablets, orally intervention 3: 15-20 mg/day, encapsulated tablets, orally

Protocol documents:
Prot_000.pdf: 
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Study 17303A - Clinical Study Protocol
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Clinical Study Protocol
Interventional, randomized, double-blind, active-controlled study 
of the efficacy of Lu AF35700 in patients with early-in-disease or 
late-in-disease treatment-resistant schizophrenia
Lu AF35700
Study No.:
17303A (Anew)
EudraCT/IND:
2017-000788-34 (EU)/ 116,335 (US)
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
4.0 (including PA3)
(the version No. in the footer is the system version No.)
Date of edition:
7 September 2018
Edition history:
Edition 3.0, 25 April 2018 (including PA2)
Edition 2.2, 15 November 2017 (including CSPA1 for United 
Kingdom)
Edition 2.1, 11 August 2017 (including CSPA1 for Japan)
Edition 2.0 (original protocol), 29 June 2017
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.


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Synopsis – Study 17303A
Sponsor
H. Lundbeck A/S
Investigational Medicinal Product
Lu AF35700
EudraCT/IND No.
2017-000788-34 / 116335
Title of Study
Interventional, randomized, double-blind, active-controlled study of the efficacy of Lu AF35700 in patients with 
early-in-disease or late-in-disease treatment-resistant schizophrenia 
Study Sites and Number of Patients Planned
Approximately 100 sites in US, Europe, Japan, or South America are planned (in-/outpatient clinics).
Approximately 490 patients in US, Europe, Japan, or South America are planned for randomization with 245 
randomized patients per treatment group.
Objectives
Primary objective:
to assess the efficacy of Lu AF35700 on symptoms of schizophrenia in patients with early-in-disease (ED) 
or late-in-disease (LD) treatment-resistant schizophrenia (TRS)
Secondary objectives:
to assess the efficacy of Lu AF35700 on symptoms of schizophrenia in patients with ED TRS
to assess the efficacy of Lu AF35700 on negative symptoms of schizophrenia in patients with ED or LD 
TRS
Exploratory objectives:
to assess the efficacy of Lu AF35700 in patients with ED TRS versus patients with LD TRS 
to assess the efficacy of Lu AF35700 in patients with TRS first diagnosed with schizophrenia ≤5 years prior 
to the Screening Visit versus patients with LD TRS
to assess the efficacy of Lu AF35700 in patients with TRS first diagnosed with schizophrenia ≤5 years prior 
to the Screening Visit
to assess the effect of Lu AF35700 on cognitive performance and functioning in patients with ED TRS,
LD TRS, or patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit
to explore patient historical and demographic characteristics predictive of response to treatment with 
Lu AF35700
to explore genetic markers (genotype and expression) predictive of, or associated with, response to 
treatment with Lu AF35700
Safety objective:
to evaluate the safety and tolerability of Lu AF35700 in patients with ED or LD TRS


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Study Methodology
This is an interventional, multi-national, multi-site, randomized, double-blind, parallel-group, active-
controlled, fixed-dose study.
The study is planned to include patients from US, Europe, Japan, or South America.
In total, 490 patients will be randomized. 
In this study patients are blinded to any transition in care from Period A to Period B; specifically, the patients
are kept blinded to the time point of randomization at Baseline 2 and to the treatment that they may receive 
during this study. In addition, patients must remain blinded to any association with their response to the 
treatment and their continuation in the study.
The study will consist of 4 Periods:
1. Screening Period
Patients will enter a Screening Period of up to 21 days to assess eligibility.
2. Period A – Prospective Confirmation Period (6 weeks)
Patients, who meet the pre-specified selection criteria for either ED or LD TRS, will enter a single 
(patient)-blinded treatment period with risperidone or olanzapine to confirm their resistance to antipsychotic 
drug treatment. 
Patients will be initiated on risperidone 2 mg/day and up-titrated to 6 mg/day by the end of the first week, 
except if they have failed on risperidone (or 9-hydroxy-risperidone; Invega™) in the most recent treatment trial, 
or in a documented treatment failure in the past 2 years, or have a documented history of intolerance to 
risperidone (or 9-hydroxy-risperidone; Invega™) treatment in the past 2 years, in which case patients will be 
initiated on olanzapine at 5 mg/day and up-titrated to 15 mg/day by the end of the first week. For patients 
treated with risperidone or InvegaTM more than 2 years ago and for whom the treatment resulted in an 
inadequate response or intolerance to the treatment, the investigator may consult with Lundbeck and/or its 
designee whether such patients may receive olanzapine; this decision must be approved by Lundbeck and/or 
designee. Current antipsychotic drug treatment will be down-tapered within the first 7 days of Period A. 
Thereafter the dose of olanzapine may be adjusted up once from 15 to 20 mg/day during Weeks 3 and 4, 
according to the investigator’s clinical judgement. If necessary for tolerability, dose may be decreased once 
back to 4 mg/day risperidone, or 15 mg/day olanzapine, during Weeks 3 and 4. No dose adjustments are 
allowed during the last 2 weeks (5 and 6) of Period A. Patients currently treated with ‘depot’ antipsychotics can, 
after signing the ICF, be down-tapered by skipping one full treatment cycle plus 3 days before Baseline 1. 
Patients who do not fulfil the inclusion criteria for Period B (inclusion criteria blinded to site and patient) will 
be withdrawn from the study.
3. Period B – Double-blind Treatment Period (8 weeks)
Patients who fulfil the entry criteria Period B will enter the double-blind treatment period (Period B) at 
Baseline 2.  The specific inclusion criteria for Period B will be blinded to the site and patient.  Patients will be 
randomly assigned (1:1) to 8 weeks of double-blind treatment with either Lu AF35700 (10 mg/day) or to 
continue their treatment with risperidone or olanzapine at a dose set at the end of Week 4 (Visit 5) of Period A.  
The randomization will be stratified by duration of disease (ED and LD). Patients with ED or LD TRS will be 
enrolled such that an approximate 1:2 ratio is achieved.
Patients who complete the study treatment until Visit 11 (Primary Outcome) may be eligible to enter a 52-week, 
open-label extension study.


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Study Methodology (continued)
The dose of Lu AF35700, risperidone or olanzapine will be fixed throughout Period B (Lu AF35700: 
10 mg/day; risperidone:  4 mg/day or 6 mg/day, determined in Period A; olanzapine:  15 mg/day or 20 mg/day, 
as determined in Period A).  For patients randomized to Lu AF35700, discontinuation of risperidone or 
olanzapine will be done gradually in a blinded fashion during the initial 7 days of Period B.
4. Safety Follow-up Period (6 weeks)
All patients, including those who prematurely discontinue will be scheduled for a Safety Follow-up Visit for 
safety assessments 6 weeks after the last dose of IMP, with the exception of those patients entering the optional 
open-label extension study.
Efficacy Follow-up (14 weeks)
Patients withdrawn during Period B (except those withdrawing due to withdrawal of consent) will, in addition to 
the Withdrawal Visit, also be asked to attend an Efficacy Follow-up Visit (Visit 13), for assessment of efficacy, 
safety and concomitant medication. This visit coincides with the time point of the Primary Outcome Visit 
(Week 14) that should have taken place, had the patient not been withdrawn from the study.
The study design is presented in Panel 1 and the scheduled assessments are summarized in Panel 2.
Target Patient Population
The target population for randomization in the current study is patients with treatment-resistant schizophrenia. 
Patients to be enrolled in the current study should fulfil either the criteria for ED TRS or LD TRS. The study
population will be patients from US, Europe, Japan, or South America.
Key Inclusion Criteria – Period A
Criteria for Patients with ED TRS
The patient has schizophrenia, first diagnosed <10 years prior to the Screening Visit and according to 
DSM-5TM and confirmed by the Mini International Neuropsychiatric Interview (MINI)
Criteria for Patients with LD TRS
The patient has schizophrenia, first diagnosed ≥10 years prior to the Screening Visit and according to 
DSM-5TM and confirmed by the Mini International Neuropsychiatric Interview (MINI)
General Criteria (Both Patients with ED and LD TRS)
The patient is a man or woman, aged ≥18 years.
The patient is receiving treatment with a psychiatrist in either an inpatient or outpatient facility.
The patient has been treated with adequate dose(s) of antipsychotic drug treatment for at least 2 weeks prior to
the Screening Visit.
The patient has failed to show an adequate response in the level of psychotic symptoms during at least one 
documented treatment trial with an adequate dose of an antipsychotic drug prescribed for an adequate time (at 
least lasting for 6 weeks) within 2 years prior to the Screening Visit. The failure to respond to the current 
antipsychotic drug treatment trial may be considered a retrospective failed treatment, if the patient has been
treated for 6 weeks with adequate dose(s) of antipsychotic drug(s).
The patient has a PANSS total score of ≥80 (on 1-7 scale) and a score of ≥4 (≥ “Moderate” on 1-7 scale) on at 
least 2 of the following PANSS items at the Screening and at Baseline 1 [Week 0] Visits.
P2 – Conceptual disorganization
P3 – Hallucinatory behaviour
P6 – Suspiciousness/persecution
G9 – Unusual thought content; AND
The patient has a CGI-S score of ≥4 (≥“Moderately ill”) at the Screening and at Baseline 1 (Week 0) Visits.


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Target Patient Population (continued)
Entry Criteria – Period B
The patient has completed Period A of the study
Response criteria, blinded to site and patient and described in the Clinical Study Protocol Addendum –
Unmasked Information, are satisfied.
Patient is considered to have been adherent with assigned medication in Period A. Adherence is assumed 
based upon taking at least 80% of assigned IMP during Period A. 
The patient’s designation as ED TRS or LD TRS does not invalidate the a priori specified stratification plan 
for patients randomized into Period B
Investigational Medicinal Products, Doses and Mode of Administration
Lu AF35700 – 10 mg/day; encapsulated tablets, orally, once daily
Risperidone – 2, 4, and 6 mg/day, encapsulated tablets, orally, once daily
Olanzapine – 5, 10, 15, and 20 mg/day, encapsulated tablets, orally, once daily
Placebo – encapsulated tablets, orally, once daily
In order to reduce biases associated with changes in treatment between the study periods and for blinding 
purposes during the down titration of risperidone or olanzapine, patients will be given two identical capsules 
throughout both treatment periods.
Administration: The two capsules will be taken together in the morning or evening based on the patients’ 
preference. The first dose is to be taken the day after IMP has been dispensed to the patient.
Period A – Prospective Treatment Period
Patients will be initiated on the lowest dose and titrated up to 6 mg/day risperidone, or if recently failed on 
risperidone, up to 15 mg/day olanzapine during the first week according to the following scheme:
Risperidone: 2 mg/day for the first 2 days; then 4 mg/day for the next 2 days ; 6 mg/day for the last 3 days. 
If necessary for tolerability, the dose may be decreased once back to 4 mg/day during Weeks 3 and 4. The 
dose must not be adjusted during Weeks 5 and 6.
Olanzapine: 5 mg/day for the first 2 days; then, 10 mg/day for the next 2 days; then, 15 mg/day for the last 
3 days. The dose may be increased once to 20 mg/day at during Weeks 3 and 4. If necessary for tolerability, 
the dose may be decreased once back to 15 mg/day during Weeks 3 and 4. The dose must not be adjusted
during Weeks 5 and 6.
The last possible time point for dose adjustment is at Visit 5.
Period B – Double-blind Treatment Period
Patients randomized to Lu AF35700 will be initiated with 10 mg/day Lu AF35700 without titration during the 
first week. 
Patients randomized to continued treatment (risperidone or olanzapine) will be treated with the same dose 
during Period B as set at the end of Week 4 (Visit 5) of Period A.
For patients randomized to Lu AF35700, discontinuation of risperidone or olanzapine will be done gradually 
in a blinded fashion and completed in the 7 days following the baseline for Period B (Baseline 2) according to 
the following scheme:
Risperidone: 4 mg/day for the first 3 days; 2 mg/day for the 4 subsequent days
Olanzapine: 10 mg/day for the first 3 days; 5 mg/day for the 4 subsequent days


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Investigational Medicinal Products, Doses and Mode of Administration (continued)
Discontinuation of IMP
Discontinuation of IMP will be initiated at the Primary Outcome or Withdrawal Visit for all patients who 
discontinue the study for any reason after Week 1 of Period A or anytime during Period B. The investigator
has the option to discontinue IMP through down-titration (recommended) or to stop IMP abruptly for safety or 
tolerability issues. Down-titration proceed according to the following scheme:
Risperidone (4 mg/day): 2 mg/day for the first 4 days; placebo for the 3 subsequent days
Risperidone (6 mg/day): 4 mg/day for the first 3 days; 2 mg/day for the 4 subsequent days
Olanzapine: 10 mg/day for the first 3 days; 5 mg/day for the 4 subsequent days
Lu AF35700: Placebo for 7 days
Discontinuation of IMP during the first week of Period A will be abrupt
Efficacy Assessments
Positive and Negative Syndrome Scale (PANSS) – Total Score, and:
PANSS – Positive Factor Score (Marder Positive Score)
PANSS – Negative Factor Score (Marder Negative Score)
Clinical Global Impression – Severity of Illness (CGI-S)
16-item Negative Symptom Assessment (NSA-16)
Personal and Social Performance Scale (PSP)
Brief Assessment of Cognition in Schizophrenia (BACS)
Demographic and Historical Predictors of Response, including:
Number of years from first schizophrenia diagnosis
Premorbid Adjustment Scale (PAS)
Number of failed antipsychotic drug (APD) treatment episodes
Pharmacoeconomic Assessments
Subjective Well-being Under Neuroleptic – short version (SWN-S)
Drug Attitude inventory-10 (DAI-10)
Pharmacokinetic Assessments
Blood samples will be collected during the study for:
Pharmacokinetic analyses of Lu AF35700 and its major metabolite (Lu AF36152)
Analyses of plasma levels of olanzapine and risperidone plus 9-hydroxy-risperidone
CYP genotyping
Safety Assessments
Adverse events (AEs)
Clinical safety laboratory tests
Vital signs
Weight/BMI/waist circumference
Electrocardiograms (ECGs)
Physical examinations
Columbia Suicide Severity Rating Scale (C-SSRS)
Serum prolactin, HBA1c, and blood lipid profile


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Biobanking
Mandatory blood samples are collected for possible future for gene expression profiling and metabolomic/
proteomic exploratory biomarkers analysis at time points specified in Panel 2.
Optional blood samples are collected for in-study and possible future DNA extraction and pharmacogenetics 
analysis at time point specified in Panel 2.
Optional blood samples are collected for separation of peripheral blood mononuclear cell (PBMC) to facilitate 
possible future generation of induced Pluripotent Stem Cells lines. Patients consenting for PBMC separation 
must undergo mandatory infectious disease testing (IDT), that is blood samples must be collected and tested 
for HIV, HBV, and HCV.


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Endpoints
Primary endpoint:
symptoms of schizophrenia (primary endpoint for primary, secondary, and exploratory objectives)
change from Baseline 2 to Week 14 in PANSS total score
Key secondary endpoints
global clinical impression (supportive of primary and secondary objectives)
change from Baseline 2 to Week 14 in CGI-S score 
functioning (supportive of explorative objective)
change from Baseline 2 to Week 14 in PSP total score)
Secondary endpoints:
proportion of responders at Week 14 (supportive of primary and secondary objective).
Responders criteria will be blinded to investigator and described in the Clinical Study Protocol 
Addendum- Unmasked Information.
negative symptoms (supportive of secondary objective)
change from Baseline 2 to Week 14 in NSA-16 total score
change from Baseline 2 to Week 14 in PANSS Negative Factor Score (Marder Negative Score)
Exploratory endpoints:
cognitive performance (supportive of explorative objective)
change from Baseline 2 to Week 14 in BACS score
analysis of patient historical and demographic predictors of response (supportive of exploratory objective), 
in:
Patients with ED TRS
Patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit
Patients with ED TRS versus LD TRS
Patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit versus patients 
with LD TRS
event-related potentials (mismatch negativity; supportive of exploratory objective) - assess correlations 
between effects on mismatch negativity and treatment response in:
Patients with ED TRS
Patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit
Patients with ED TRS versus LD TRS
Patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit versus patients 
with LD TRS
Genetic analysis (for example CYP genotyping and polygenetic risk-score)
Safety endpoints:
adverse events
absolute values and changes from Baseline 2 in clinical safety laboratory tests, vital signs, weight, and ECG 
parameters
potentially clinically significant clinical safety laboratory test values, vital signs, weight, and ECG 
parameter values
C-SSRS categorisation


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Statistical Methodology
The following analysis sets will be used to analyse and present the data for each of the above groups of 
patients:
all-patients-treated set Period A (APTS_A) – all patients who took at least one dose of IMP during Period A 
(risperidone/olanzapine)
all-patients-treated set (APTS) – all randomized patients who took at least one dose of double-blind IMP
(Lu AF35700 or risperidone/olanzapine) after randomization (Period B)
full-analysis set (FAS) – all patients in the APTS who had a valid Baseline 2 assessment and at least one 
valid post-Baseline-2 assessment of PANSS total score
The efficacy analyses will be based on the FAS. A two-sided significance level of 0.05 is used unless 
otherwise indicated. For all endpoints, the effects of Lu AF35700 will be evaluated by testing the null 
hypothesis of no difference to the active control.
Testing strategy
If Lu AF35700 is superior to risperidone/olanzapine for the primary endpoint, the null hypothesis of no 
difference between Lu AF35700 compared to risperidone/olanzapine will be tested for the key secondary 
endpoints in the following order:
1. Change from Baseline 2 to Week 14 in CGI-S score
2. Change from Baseline 2 to Week 14 in PSP total score
Change in PSP will only be tested if Lu AF35700 is superior to risperidone/olanzapine for CGI-S.
Analysis of the primary endpoint:
Changes from Baseline 2 (Week 6) in total PANSS score at Weeks 7, 8, 10, 12, and 14 will be analysed 
using a restricted-maximum-likelihood-(REML)-based mixed model for repeated measures (MMRM) 
approach. All patients in the FAS will be included with their observed data in Period B. Data retrieved at 
Week 14 from withdrawals will not be included in the primary analysis.  The model will include the fixed, 
categorical effects of treatment (Lu AF35700 and risperidone/olanzapine), strata, country, visit, treatment-
by-visit interaction, stratum-by-visit interaction, fixed covariates of baseline scores (Baseline 1 and Baseline 
2) and baseline scores-by-visit interaction.  An unstructured (co)variance structure will be used to model the 
within-patient errors.  If this analysis fails to converge, the following within-patient (co)variance structures 
will be applied in the listed order; first-order ante-dependence, heterogeneous compound symmetry, 
compound symmetry. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. The primary comparisons will be the difference between Lu AF35700 and risperidone/olanzapine
at Week 14 based on the least squares means for the treatment-by-visit interaction effect. The estimated 
mean difference between Lu AF35700 and risperidone/olanzapine based on this model will be reported with 
two-sided symmetric 95% confidence intervals and corresponding p-values.
Supportive of secondary and exploratory objectives;
The changes in PANSS total score from Baseline 2 (Week 6) to Week 14 for In patients with TRS first 
diagnosed with schizophrenia ≤5 years prior to the Screening Visit, ED TRS, LD TRS, ED TRS versus LD 
TRS, and patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit versus
patients with LD TRS will be examined using the same methodology as that described for the primary 
endpoint. The model will include the fixed, categorical effects of treatment (Lu AF35700 and
risperidone/olanzapine), subgroup, country, visit, treatment-by-visit-by-subgroup interaction, and fixed 
covariates of baseline scores (Baseline 1 and Baseline 2) and baseline scores-by-visit interaction. The 
patients will be classified into subgroups according to whether they were first diagnosed with schizophrenia 
≤5 years prior to the Screening Visit, between 5 and 10 years prior to the Screening Visit, or ≥10 years prior 
to the Screening Visit. From this model, the difference between treatments within each subgroup at Week 14 
will be derived from the treatment-by-visit-by-subgroup interaction. Also, this interaction will be used to 
explore the efficacy in ED TRS versus LD TRS by estimating of (Lu AF35700 ED – risperidone/
olanzapine ED) versus (Lu AF35700 LD – risperidone/olanzapine LD). In the same way, 


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Statistical Methodology (continued)
the efficacy in patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit 
versus LD TRS will be explored.
Analysis of the secondary endpoints:
For CGI-S, NSA-16, and PANSS Negative Factor Score, the same model as that described for the primary 
endpoint will be used.
The proportion of patients responding at Week 14 will be compared for Lu AF35700 versus
risperidone/olanzapine using logistic regression with strata, country and treatment as factors and baseline 
PANSS total scores (Baseline 1 and Baseline 2) as covariates. The analysis will be done for observed cases 
without imputation using the FAS, as well as imputing non-response for all patients discontinued prior to 
Week 14. The definition of response will be defined in the Clinical Study Protocol Addendum – Unmasked 
Information.
Additional responder analyses using alternative cut-offs of the primary endpoint will be used to present the 
efficacy as measured by changes from Baseline 2 in PANSS total score.
Analysis of the exploratory endpoints:
For BACS and PSP, the same model as that described for the primary endpoint will be used.
The proportion of patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening 
Visit, patients with ED TRS or LD TRS, the difference between patients with ED TRS and those with LD 
TRS, and the difference between patients with TRS first diagnosed with schizophrenia ≤5 years prior to the 
Screening Visit and those with LD TRS responding at Week 14 will be compared for Lu AF35700 versus
risperidone/olanzapine using logistic regression with country as factor and treatment-by-subgroup
interaction and baseline PANSS total score as covariate. The analysis will be done for observed cases 
without imputation using the FAS, imputing non-response for all patients discontinued prior to Week 14.
The effect of potential demographic and historical predictors of response (number of years from first 
schizophrenia diagnosis, and number of failed AP treatment episodes) will be investigated for the primary 
and secondary endpoints. MMRM and logistic regression models similar to those described above will be 
applied with the different predictors included as factors or covariates, both interacting with treatment, as 
appropriate. These analyses will be detailed in the statistical analysis plan.
The effect of genetic analysis will be investigated for the primary and secondary endpoints. These analyses 
will be detailed in a separate protocol and statistical analysis plan, and will be reported separately.
Plasma concentrations of Lu AF35700 and metabolite Lu AF36152, risperidone and 9-hydroxy-risperidone, 
olanzapine will be summarized using descriptive statistics and may be used in population pharmacokinetic 
analyses (to be reported separately).
Sensitivity analyses for the primary endpoint:
MMRM model as the primary analysis, including the retrieved data for withdrawals.
Pattern-mixture models. Different delta (imputation of how much worse response those who discontinue 
would have compared to those who do complete the study and who have the same profile up to time to 
withdrawal) will be applied. These analyses will be detailed in the statistical analysis plan.
The primary analysis will be repeated for the subgroup of patients that were randomized after protocol 
amendment PA3 was approved in the relevant country.
Analysis of safety endpoints:
The safety analyses will be based on the APTS.
Adverse events, clinical safety laboratory tests, vital signs, weight/BMI, ECG parameters, and C-SSRS 
scores will be summarized using descriptive statistics.
Patient disposition and demographics will be summarized using descriptive statistics.


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Sample Size Considerations
The study will include 245 randomized patients per group in Period B.
Assuming a common standard deviation of 15, there is approximately 93% power for showing a mean 
improvement in change in PANSS total score of 5.25 (standardized effect size 0.35) of Lu AF35700 over 
risperidone/olanzapine with 196 patients per treatment arm.
Assuming an information loss of ~20% due to dropout in Period B, n=245 (=196/0.8) will be randomized to 
each treatment group, bringing the total number of randomized patients to 490. 
With an attrition rate of ~40% in Period A, approximately 817 (=490/0.6) patients are expected to be enrolled to 
meet the target of randomizing 490 patients in Period B.
A blinded re-assessment of sample size will be considered if the blinded standard deviation estimate or the 
dropout rate deviates from the assumptions. A maximum of 300 randomized patients per treatment arm will be 
allowed in the study. The pooled standard deviation will be estimated from the Covariance Parameter Estimates 
from an MMRM model identical to the one to be used for the primary analysis, except without the effect of 
treatment, i.e. the following:
The model will include the fixed, categorical effects of country, visit, stratum-by-visit interaction as well as the 
fixed covariates of baseline scores (Baseline 1 and Baseline 2) and baseline scores-by-visit interaction. An 
unstructured (co)variance structure will be used to model the within-patient errors.


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Ethical Rationale for Study and Study Design
This study will be conducted in compliance with the principles of Good Clinical Practice.
Identification of novel antipsychotic agents that can effectively treat patients with schizophrenia who have 
failed to respond to antipsychotic therapies represents a great unmet clinical need. Per definition, these 
patients are highly symptomatic with associated low level of functioning and require extensive periods of 
hospital care which contributes disproportionally to the overall cost of treating schizophrenia.
Targeted enrolment and stratification of patients with ED TRS and LD TRS, as defined in this protocol, may 
increase the understanding of how Lu AF35700 may be an effective treatment across the longitudinal course 
of disease.
Given the unique receptor binding profile of Lu AF35700 characterized by a high affinity to dopamine D1 and 
serotonin 5-HT6 receptors combined with a low level of dopamine D2 interaction, Lu AF35700 has the 
potential to offer an effective alternative treatment option for patients with treatment resistant schizophrenia.
Based on data from the ongoing clinical pharmacology programme in healthy subjects and patients with 
schizophrenia, the dose used in the current study is considered to be safe and well tolerated.
The aim of the study is to generate supporting evidence for efficacy and safety of Lu AF35700 in patients with 
TRS. The design of the current study is in accordance with the Declaration of Helsinki (Ethical principles for 
medical research involving human subjects) as well as the recommendations provided for conducting studies 
in patients with TRS as outlined in the EMA guideline on clinical investigation of medicinal products, 
including depot preparations in the treatment of schizophrenia.
In the current study, eligible patients who have had a recent treatment failure will enter a single (patient)-
blinded confirmation period and initiate a treatment trial with risperidone or olanzapine (well-known and 
widely used antipsychotic drugs, to assess treatment response. Only patients where a lack of adequate 
treatment response is confirmed will be randomized to double-blind treatment with either Lu AF35700 or to 
continued treatment (risperidone or olanzapine) for a period of 8 weeks. Patients who respond to the initial 
treatment with risperidone or olanzapine will be excluded from the study. Thus, approximately half of the 
non-responding patients will be randomized back to the failed treatment used in the initial period of the 
current study. This study design is considered ethically justifiable given the limited treatment options for this 
patient population and the need to utilize a rigorous scientific design to develop new safe and effective 
treatments for TRS. Blinding of the patients and of the investigators, as described in the study design, to actual 
treatment received reduces bias that would otherwise be introduced and that may influence the reliability of 
the study results.
The duration of the double-blind treatment period in the current study is 8 weeks in order to provide sufficient 
time to determine the extent of attainable symptom reduction and allow safety evaluation. In general, an 
adequate treatment trial in TRS should have a minimum duration of 6 weeks. The 8-week duration in this 
study further allows adequate time for patients to receive Lu AF35700 under steady state conditions while 
their response is being assessed. Enrolled patients will be asked to visit the site regularly where the 
investigator will evaluate the treatment outcome and decide whether it is in the patients’ best interest to 
continue in the study. Patients who complete the study treatment until Visit 11 (Primary Outcome) may be 
eligible to enter a 52-week, open-label extension study. Also, 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.  Patients enrolled in the current study will be scheduled for a Safety Follow-up Visit 6 
weeks after last dose of IMP for those who do not enter the open-label extension study.
Blood samples for exploratory biomarkers will be collected in an attempt to increase the understanding of the 
properties of Lu AF35700, aetiology of schizophrenia, and the molecular basis of drug response.










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of consent) will be asked to attend an Efficacy Follow-up Visit at the date of their last scheduled visit of 
Period B (Week 14) for the assessment of efficacy, safety and concomitant medication. If patient attends the 
Withdrawal Visit 5 days prior to week 14 (planned Primary Outcome Visit) the patient should not be asked to 
come for an Efficacy Follow-up Visit.
h
If the date of a patient visit does not conform to the study plan, subsequent visits must be planned to maintain 
the visit schedule relative to the Baseline 1 Visit.
i
Includes Premorbid Adjustment Scale.
j
The patient's demographics information (age, sex, race) is to be recorded in the eCRF at Informed Consent
Form signature date.
k
Informed Consent process for in-study pharmacogenetic testing is covered in section 4.2. For patients not 
qualifying for study period B this sample must be discarded. 
l
BACS is applicable for US and Europe only.
m The blood samples for Lu AF35700 and metabolite or olanzapine, risperidone and 9-hydroxy-risperidone 
analysis should be drawn in association to the blood sampling for clinical safety laboratory tests (as 
applicable). Lu AF35700 and the major metabolite Lu AF36152 will only be analysed in samples from Visits
8, 9, and 11. Olanzapine, risperidone and 9-hydroxy-risperidone will be analysed in all six samples.
n
Exploratory gene expression profiling (RNA) and metabolomics/proteomics are an integrated part of the 
study and are covered by the main Patient Information Sheet.
o
Sampling for pharmacogenetics is optional and a separate Patient Information Sheet and Informed Consent 
Form covers this analysis. See section 4.2. Sampling may be scheduled to another visit if needed.
p
Sampling for PBMC collection (US only) for possible future generation of induced pluripotent stem cells 
lines is optional and a separate Patient Information Sheet and Informed Consent Form covers this. Sampling 
may be scheduled to another visit if needed.
q
Sampling for Infectious Disease Testing refer only to patients enrolled for PBMC collection for which this is 
mandatory and will be addressed in the separate Patient Information Sheet/Informed Consent Form referring 
to the PBMC collection.
r
Signs and symptoms present at the Screening and/or Baseline 1 Visits (before IMP intake) must be recorded 
on an Adverse Event Form.
s
Only for adverse events ongoing at Primary Outcome/Withdrawal Visit and new SAEs.
t
Only to be taken if the laboratory test was clinically significantly abnormal at the Primary 
Outcome/Withdrawal Visit.
u
Results will remain blinded throughout the study.
v
One week supply will be provided for down-titration of blinded IMP
w The dose of IMP can be increased for efficacy or decreased for tolerability at scheduled or unscheduled visits 
during weeks 3 and 4. Last possible time point for dose adjustment is at Visit 5.
x
Urine drug screen tests can be repeated any time during the study at the discretion of the investigator.
y
S-βhCG pregnancy test should be performed at the Screening and the Primary Outcome/Withdrawal Visits
for women of childbearing potential. Urine pregnancy test should be performed at Baseline 2 Visit and can be 
performed any time during the study at the discretion of the investigator. Any positive urine pregnancy test 
must be confirmed by a S-βhCG pregnancy test.
[Country-specific Protocol Amendment 1 for UK:
y
S-βhCG pregnancy test should be performed at the Screening and the Primary Outcome/Withdrawal Visits 
for women of childbearing potential. Urine pregnancy test should be performed at Baseline 1 (Visit 2), Visit 
5, Baseline 2 (Visit 6) and Visit 9 and can be performed any time during the study at the discretion of the 
investigator. Any positive urine pregnancy test must be confirmed by a S-βhCG pregnancy test.]


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Table of Contents
Synopsis – Study 17303A.......................................................................................................................2
List of Panels.........................................................................................................................................23
List of Abbreviations and Definitions of Terms ................................................................................24
1
Introduction .................................................................................................................................27
1.1
Background........................................................................................................................27
1.1.1
Overview............................................................................................................27
1.1.2
Schizophrenia.....................................................................................................27
1.1.3
Nonclinical Data.................................................................................................28
Primary Pharmacology ......................................................................28
1.1.3.1
Toxicology.........................................................................................28
1.1.3.2
1.1.4
Clinical Data.......................................................................................................28
Overview - Clinical Studies...............................................................28
1.1.4.1
Pharmacokinetics...............................................................................29
1.1.4.2
Safety and Tolerability.......................................................................30
1.1.4.3
Target Occupancy..............................................................................31
1.1.4.4
1.2
Rationale for the Study......................................................................................................31
2
Objectives.....................................................................................................................................32
3
Study Design.................................................................................................................................33
3.1
Overview of the Study Design...........................................................................................33
3.2
Rationale for the Study Design..........................................................................................35
4
Ethics ............................................................................................................................................36
4.1
Ethical Rationale................................................................................................................36
4.2
Informed Consent ..............................................................................................................38
4.3
Personal Data Protection....................................................................................................40
4.4
Independent Ethics Committees (IECs) and Institutional Review Boards (IRBs) ............40
4.5
Regulatory Approval/Notification Requirements..............................................................41
5
Study Population .........................................................................................................................41
5.1
Numbers of Patients and Sites ...........................................................................................41
5.2
Patient Recruitment ...........................................................................................................41
5.3
Selection Criteria ...............................................................................................................42
5.4
Withdrawal Criteria ...........................................................................................................46
6
Investigational Medicinal Products (IMPs) ..............................................................................47
6.1
Treatment Regimen ...........................................................................................................47
6.2
IMPs, Formulations, and Strengths....................................................................................49
6.3
Manufacturing, Packaging, Labelling, and Storage of IMPs.............................................49
6.4
Method of Assigning Patients to Treatment ......................................................................50
6.5
IMP Accountability ...........................................................................................................50
6.6
Unblinding Procedures ......................................................................................................50
6.7
Post-study Access to IMPs ................................................................................................51
7
Concomitant and Rescue Medication ........................................................................................51
7.1
Concomitant Medication ...................................................................................................51
7.2
Rescue Medication.............................................................................................................52


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8
Study Visit Plan ...........................................................................................................................52
8.1
Overview............................................................................................................................52
8.2
Screening Visit (Visit 1)....................................................................................................52
8.2.1
Pre-screening......................................................................................................53
8.2.2
Patient Identification Card..................................................................................53
8.2.3
Re-screening and Re-consenting........................................................................54
8.3
Baseline 1 Visit (Visit 2) ...................................................................................................54
8.4
Withdrawal Visit................................................................................................................54
8.5
Safety Follow-up Visit (Visit 12) ......................................................................................55
8.6
Efficacy Follow-up Visit (Visit 13)...................................................................................55
8.7
End-of-study Definition.....................................................................................................55
9
Assessments..................................................................................................................................56
9.1
Screening and Baseline Procedures and Assessments.......................................................56
9.1.1
Informed Consent Date and Demographics .......................................................56
9.1.2
Other Baseline Characteristics ...........................................................................56
Premorbid Adjustment Scale (PAS) ..................................................56
9.1.2.1
Rater Qualification and Certification for PAS...................................57
9.1.2.2
9.1.3
Diagnostic Assessments.....................................................................................57
Mini International Neuropsychiatric Interview for Psychotic 
9.1.3.1
Disorders Studies (MINI) ..................................................................57
Rater Qualification and Certification for MINI.................................58
9.1.3.2
9.1.4
Drug Screen........................................................................................................58
9.1.5
Genotyping (Baseline 2).....................................................................................58
9.2
Efficacy Assessments ........................................................................................................59
9.2.1
Use of Assessment Tools ...................................................................................59
Positive and Negative Syndrome Scale (PANSS) .............................59
9.2.1.1
Clinical Global Impression Scale – Severity (CGI-S) .......................60
9.2.1.2
16-item Negative Symptom Assessment (NSA-16) ..........................60
9.2.1.3
Brief Assessment of Cognition in Schizophrenia (BACS) –
9.2.1.4
(US/Europe only)...............................................................................60
Personal and Social Performance Scale (PSP)...................................61
9.2.1.5
Rater Qualification and Certification.................................................61
9.2.1.6
9.3
Pharmacoeconomic Assessments ......................................................................................62
9.3.1
Use of Assessment Tools ...................................................................................62
Subjective Well-Being under Neuroleptic Treatment – Short 
9.3.1.1
Version (SWN-S)...............................................................................63
Drug Attitude Inventory-10 (DAI-10) ...............................................63
9.3.1.2
9.4
Pharmacokinetic Assessments...........................................................................................63
9.5
Safety Assessments............................................................................................................64
9.5.1
Adverse Events...................................................................................................64
9.5.2
Clinical Safety Laboratory Tests........................................................................64
9.5.3
Vital Signs..........................................................................................................66
9.5.4
Weight and Waist Circumference ......................................................................66
9.5.5
Electrocardiograms (ECGs) ...............................................................................66
9.5.6
Physical Examinations .......................................................................................67
9.5.7
Safety Assessment Tools....................................................................................67
Columbia-Suicide Severity Rating Scale (C-SSRS)..........................67
9.5.7.1
Rater Qualification and Certification.................................................68
9.5.7.2
Order of Assessments ........................................................................68
9.5.7.3
9.6
Other Assessments.............................................................................................................68


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9.6.1
Blood Sampling for Pharmacogenetics – Optional ............................................68
9.6.2
Days of Hospitalization......................................................................................69
9.7
Biobanking.........................................................................................................................69
9.7.1
General Considerations ......................................................................................69
9.7.2
Blood Sampling for Gene Expression Profiling.................................................70
9.7.3
Blood Sampling for Metabolomic/Proteomic Biomarkers.................................70
9.7.4
Blood Sampling for Pharmacogenetics..............................................................70
9.7.5
Blood Sampling for Isolation of Peripheral Blood Mononuclear Cell 
(PBMC) (US only) .............................................................................................70
9.8
Total Volume of Blood Drawn and Destruction of Biological Material ...........................71
9.9
IMP Compliance................................................................................................................71
10
Adverse Events.............................................................................................................................72
10.1
Definitions .........................................................................................................................72
10.1.1
Adverse Event Definitions .................................................................................72
10.1.2
Adverse Event Assessment Definitions .............................................................73
10.2
Pregnancy ..........................................................................................................................74
10.3
Recording Adverse Events ................................................................................................74
10.4
Reporting Serious Adverse Events (SAEs) .......................................................................75
10.5
Treatment and Follow-up of Adverse Events....................................................................76
11
Data Handling and Record Keeping..........................................................................................76
11.1
Data Collection..................................................................................................................76
11.1.1
Electronic Case Report Forms (eCRFs) .............................................................76
11.1.2
Patient Binders ...................................................................................................77
Use of Patient Binders .......................................................................77
11.1.2.1
Rating Scales and Patient-reported Outcomes (PROs)......................77
11.1.2.2
Serious Adverse Event Fallback Forms.............................................77
11.1.2.3
11.1.3
External Data......................................................................................................77
11.2
Retention of Study Documents at the Site.........................................................................78
11.2.1
eCRF Data..........................................................................................................78
11.2.2
Other Study Documents .....................................................................................78
12
Monitoring Procedures ...............................................................................................................78
13
Audits and Inspections................................................................................................................79
14
Protocol Compliance ...................................................................................................................80
15
Study Termination.......................................................................................................................80
16
Endpoints .....................................................................................................................................80
16.1
Primary Endpoint...............................................................................................................80
16.2
Key Secondary Endpoints..................................................................................................80
16.3
Secondary Endpoints .........................................................................................................81
16.4
Exploratory Endpoints.......................................................................................................81
16.5
Safety Endpoints................................................................................................................81
17
Statistical Methodology...............................................................................................................82
17.1
Responsibilities..................................................................................................................82
17.2
Analysis Sets......................................................................................................................82
17.3
Descriptive Statistics .........................................................................................................82
17.4
Patient Disposition.............................................................................................................82
17.5
Demographics and Baseline Characteristics......................................................................83


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17.6
Recent and Concomitant Medication.................................................................................83
17.7
Exposure and Compliance .................................................................................................83
17.8
Period A Evaluation...........................................................................................................84
17.9
Efficacy Analyses..............................................................................................................84
17.9.1
General Efficacy Analysis Methodology ...........................................................84
17.9.2
Analysis of the Primary Endpoint ......................................................................84
17.9.3
Sensitivity Analyses of the Primary Endpoint....................................................85
17.9.4
Testing Strategy for Primary and Key Secondary Endpoints.............................86
17.9.5
Analysis of the Key Secondary and Secondary Endpoints ................................86
17.9.6
Analysis of the Exploratory Endpoints ..............................................................86
17.9.7
Analysis of Subgroups .......................................................................................87
17.9.8
Pharmacokinetic Analysis..................................................................................87
17.10 Safety Analyses .................................................................................................................88
17.10.1
Analysis of Adverse Events ...............................................................................88
17.10.2
Analysis of Other Safety Endpoints...................................................................88
17.11 Interim Analyses................................................................................................................88
17.12 Sample Size and Power .....................................................................................................88
17.13 Statistical Analysis Plan ....................................................................................................89
18
Clinical Study Report and Publications ....................................................................................89
18.1
Clinical Study Report ........................................................................................................89
18.2
Data Ownership .................................................................................................................89
18.3
Publications........................................................................................................................89
18.4
Summary of Clinical Study Results...................................................................................90
19
Indemnity and Insurance............................................................................................................90
20
Finance .........................................................................................................................................90
20.1
Site Agreements.................................................................................................................90
20.2
Financial Disclosure ..........................................................................................................90
20.3
Equipment..........................................................................................................................90
References.............................................................................................................................................91


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Appendices
Appendix I
Clinical Study Protocol Authentication and Authorization.................................94
Appendix II
Recent and Concomitant Medication:  Disallowed or Allowed with 
Restrictions...............................................................................................................96


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List of Panels
Panel 1
Study Design.....................................................................................................................13
Panel 2
Study Procedures and Assessments................................................................................14
Panel 3
Clinical Safety Laboratory Tests....................................................................................65


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List of Abbreviations and Definitions of Terms
GT
-glutamyl transferase
AE
adverse events
ALT
alanine aminotransferase
AME
absorption, metabolism and excretion
APTS
all-patients-treated set
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
BACS
Brief Assessment of Cognition in Schizophrenia
BMI
body mass index
bpm
beats per minute
BUN
blood urea nitrogen
CGI-S
Clinical Global Impression – Severity of Illness
CHMP
Committee for Medicinal Products for Human Use (European Union)
CI
confidence interval
CIOMS-I
Suspect Adverse Reaction Report Form of the Council for International 
Organizations of Medical Sciences
Cmax
maximum observed concentration
CNV
copy number variation
CPK
S-creatine phosphokinase
CRA
clinical research associate
CRF
case report form
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale 
CYP
cytochrome P450 isoenzyme
DAI-10
Drug Attitude Inventory - 10
DNA
deoxyribonucleic acid
DSM-5TM
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
electrocardiogram
eCRF
electronic case report form
ED
early-in-disease
EEG
electroencephalogram
EMA
European Medicines Agency
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
full-analysis set
FDA
Food and Drug Administration
FIH
first in human
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin


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HCV
hepatitis C virus
HDL
high density lipoprotein
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IDT
infectious disease testing
IEC
independent ethics committee
IMP
investigational medicinal product
IND
Investigational New Drug Application
IRB
institutional review board
I-TMF
investigator trial master file
IVRS
interactive voice response system
LD
late-in-disease
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LLOQ
lower limit of quantification
Lu
Lundbeck
MAD
multiple ascending dose
MD
medical doctor
MINI
Mini International Neuropsychiatric Interview for Psychotic Disorders Studies
MMRM
mixed model for repeated measurements
mRNA
messenger ribonucleic acid
NA
not applicable
NSA-16
Negative Symptom Assessment - 16
NSAIDS
non-steroidal anti-inflammatory drugs
PANSS
Positive and Negative Syndrome Scale
PAS
Premorbid Adjustment Scale
PBMC
peripheral blood mononuclear cell
PBO
Placebo
PCR
polymerase chain reaction
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


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QP
qualified person
qPCR
quantitative polymerase chain reaction
QRS
specific ECG interval describing ventricular depolarization
QT
specific ECG interval describing ventricular depolarization/repolarization
QTc
heart-rate corrected QT interval
QTcF
heart-rate corrected QT interval using Fridericia’s correction formula
QTcI
heart-rate corrected QT interval, individually corrected
REML
restricted-maximum-likelihood
RR
specific ECG interval describing the ventricular depolarization/repolarization cycle
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SE
standard error 
SNP
single-nucleotide polymorphism
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SWN-S
Subjective Well-Being under Neuroleptic Treatment
TEAE
treatment-emergent adverse event
tmax
time to maximum observed concentration
TMF
trial master file
TRS
treatment resistant schizophrenia
US FDA
United States Food and Drug Administration


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1
Introduction
1.1
Background
1.1.1
Overview
Lu AF35700 is a novel compound with affinity for serotonergic, dopaminergic, and α-
adrenergic receptors, and acts as an antagonist of those receptor types.  Lu AF35700 has a 
novel pharmacological profile compared to existing therapies.  Lu AF35700 is a potential 
antipsychotic drug in development by H. Lundbeck A/S for the proposed indication of 
treatment-resistant schizophrenia (TRS) as a once daily tablet formulation. 
1.1.2
Schizophrenia
Schizophrenia is a severe, complex, chronic, and disabling psychiatric disorder with a 
substantial impact on day-to-day functioning and an estimated lifetime prevalence of 0.3 to 
0.7%.1
Schizophrenia is characterized 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 disorganized 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).  Schizophrenia is among the world’s 
most disabling conditions among people in developed countries and is frequently associated 
with a high degree of social burden as well as great suffering to afflicted individuals and those 
who care for them.2 The seriousness of this condition is also reflected by the average 
reduction in life expectancy of 25 years among people with schizophrenia compared to that in 
the general population; often as a result of personal neglect, poverty, or suicide.3
Schizophrenia is a treatable condition with several therapeutic alternatives available. 
However, despite advances in the pharmacotherapy of schizophrenia, managing the lack of 
adequate response to antipsychotic drug treatment remains a great unmet medical need.  It has 
been estimated that one-fifth to one-third of patients with schizophrenia experience persistent 
symptoms including significant levels of positive symptoms despite several treatment trials 
and may be classified as being resistant to treatment.4,5,6,7,8 The treatment of these patients has 
remained a persistent public health challenge, since they often have a decreased social 
functioning and a low quality of life, and their treatment is related to high overall costs and 
increased healthcare resources use.9
The following sections provide a brief overview of the nonclinical and clinical data currently 
available for Lu AF35700. Refer to the current version of the Investigator’s Brochure for 
more detailed information.10


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1.1.3
Nonclinical Data
Primary Pharmacology
1.1.3.1
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 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 potent binding of Lu AF35700 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, 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.  
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.
Toxicology
1.1.3.2
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity or genotoxicity. Toxicologically significant effects were 
observed only at exposures that were sufficiently in excess of the expected human exposures 
at a daily dose of 10 mg, indicating that these effects were limited or of no relevance to 
clinical use.
In dogs, the cardiovascular system was identified as the main target organ system. ECG 
waveform morphology changes (junctional escape beats and supraventricular ectopic beats) 
were observed in a cardiovascular safety pharmacology study and in a 4-week oral toxicity 
study. QTc-prolongation was observed in a 13-week oral toxicity study, but no ECG changes 
were observed in the 39-week oral toxicity study. Although the observed changes in QTc
interval cannot be clearly attributed to treatment, a drug related effect cannot be excluded.
The carcinogenic potential of Lu AF35700 is currently being investigated.
In conclusion Lu AF35700 was found to be safe and well tolerated at clinically relevant 
exposure levels.  Please see the current version of the Investigator’s Brochure for more 
detailed information.10
1.1.4
Clinical Data
Overview - Clinical Studies
1.1.4.1
Currently, four studies with Lu AF35700 have been completed in healthy subjects (studies 
14198A, 15867A, 15868A, and 16156A).  Two studies in patients with schizophrenia studies 


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14754A and 15859A) have been completed. The completed studies in healthy subjects (all 
men) comprise the first-in-human (FIH) study (14198A), an absorption, metabolism, and 
excretion (AME) study (15867A), a single-dose PET study (PET SD) (15868A), and a 
pharmacokinetic (PK) study (16156A) in Japanese and Caucasian subjects (PK JAPAN).
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 SD studies, 6 subjects received a single dose of 30 mg 
Lu AF35700.  The PK JAPAN study consisted of three parts: Part A, in which 12 Japanese 
and 12 Caucasian men received a single dose of 5 mg Lu AF35700; Part B, in which 
12 Japanese men received a single dose of 10 mg Lu AF35700; and Part C, in which 
12 Japanese and 12 Caucasian men received a dose of 10 mg/day Lu AF35700 for 5 days.  No 
serious adverse events have been reported in healthy subjects and the majority of adverse 
events related to the treatment have been mild.  Based on these studies, Lu AF35700 was safe 
and well tolerated by healthy subjects.  Please see the Investigator’s Brochure for more 
detailed information.10
Multiple daily doses of Lu AF35700 in the dose range of 5 to 30 mg/day for up to 21 days 
have been administered in a multiple ascending dose (MAD) study (14754A) with a total of 
70 male and female patients and a PET (PET MD) study (15859A) in 22 male patients with 
schizophrenia.  In the MAD study, there was no difference in tolerability and safety with 
respect to sex (men versus women).  In addition, in the MAD study, doses of 45 and 75 mg 
have been administered on Study Days 7 and 14 after 6 days of daily dose titration to the 
same patient population.  The daily and the weekly dosing regimens were safe and well 
tolerated by the patients with schizophrenia.
Currently three studies are ongoing; one pivotal study in patients with treatment resistant 
schizophrenia (TRS1, Study 16159A), an open label safety extension study to TRS1 (Study 
16159B), and a dedicated ECG study in patient with schizophrenia (Study 16323A).  As of 
November 2016, a total of 83 healthy subjects and 96 patients with schizophrenia have been 
exposed to Lu AF35700 and 36 patients with TRS have been exposed to Lu AF35700 or 
risperidone/olanzapine. 
Pharmacokinetics
1.1.4.2
1.1.4.2.1
Pharmacokinetics of Lu AF35700 and Lu AF36152
The exposure of Lu AF35700 and the metabolite Lu AF36152 appears to be dose proportional 
in the dose range investigated and there do not seem to be a difference in the PK parameters 
between healthy subjects and patients with schizophrenia.
Preliminary data points to about 35% lower exposure after oral tablet administration 
compared to that after oral solution administration. Comparing 4 fasting and 5 fed patients 
receiving the tablet formulation showed that the exposure of Lu AF35700, as assessed by 
AUC0-72 and Cmax was 22% and 11% higher, respectively, in the fed state compared to the 


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fasted state.  No difference in tmax was observed between dietary states, therefore 
administration of Lu AF35700 can be made irrespective of meals.
The variability across the PK parameters is moderate to high for all PK parameters.
Please refer to the Investigator’s Brochure for a summary of PK parameters.10
1.1.4.2.2
Population Pharmacokinetic Analysis
An initial pooled integrated popPK analysis for Lu AF35700 and Lu AF36152 was performed 
on data from 7 studies.11
The absorption was described as slow and extended giving average tmax of Lu AF35700 of 
9 hours and 14 hours for Lu AF36152. Large volumes of distribution (~5000L) of 
Lu AF35700 and Lu AF36152 were estimated implying extensive distribution to peripheral 
tissue. Inferred metabolic status of CYP2C19 was found to affect the oral clearance of 
Lu AF35700. 
There was no consistent trend for a correlation between CYP2D6 inferred metabolic status 
and oral clearance for Lu AF35700. A relation between oral clearance of Lu AF36152 and the 
CYP2D6 inferred metabolic status was found.  Oral clearance of Lu AF36152 was found to 
increase with increasing creatinine clearance.
The pharmacokinetics of Lu AF35700 and Lu AF36152 were similar in healthy subjects and 
schizophrenic patients.
From the population estimates, the elimination half-life for Lu AF35700 and Lu AF36152 
was estimated to 153 hours and 249 hours, respectively.
Safety and Tolerability
1.1.4.3
The main body of safety data in patients with schizophrenia comes from the MAD study 
(70 patients, Study 14754A).  The safety data from the FIH, AME, and single-dose PET 
studies in healthy subjects and the multiple dose PET study in patients show a benign safety 
profile similar to that in the MAD study, but the total number of subjects and exposure with 
Lu AF35700 in those studies is small compared to the MAD study.
The total number of healthy subjects (83) who have received Lu AF35700 is slightly lower 
than that for patients (132 in total; with 36 of the 132 patients with schizophrenia still blinded 
and randomized to either Lu AF35700 or risperidone/olanzapine) 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.
In the MAD study, the adverse events with the highest incidence (>10%) in the Lu AF35700 
groups in the daily dosing cohorts were reported to be: somnolence (33%), anxiety (23%), 
headache (21%, placebo level), orthostatic hypotension (19%), dizziness (16%), psychotic 


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disorder (14%), and akathisia (11%).  In the once-weekly dosing cohorts, the adverse events 
occurring in ≥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 of 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.
Based on safety and tolerability data from the FIH, single-dose PET, AME, and PK JAPAN
studies in healthy subjects (Studies 14198A, 15868A, 15867A, and 16156A, respectively), a 
single dose of up to 30 mg Lu AF35700 was safe and well tolerated. Furthermore, in the 
MAD and MD PET studies in patients with schizophrenia (Studies 14754A and 15859A, 
respectively), multiple doses in the dose range 5 to 30 mg/day or 45 or 75 mg once weekly for 
21 days, were safe and well tolerated.
Target Occupancy
1.1.4.4
The multiple dose Lu AF35700 PET study (15859A) was conducted in 22 male patients with 
schizophrenia to characterize the relationship between plasma concentration of Lu AF35700 
and Lu AF36152 and the D1, D2 and 5-HT6 receptor occupancy. For the D1 receptor in the 
caudate nucleus, putamen, and ventral striatum, three weeks of 10 mg/day resulted in
maximum receptor occupancy levels of 88, 83 and 82%, respectively. For the D2 receptor in 
the caudate nucleus, putamen, and ventral striatum, three weeks of 20 mg/day resulted in 
maximum receptor occupancy levels of 67, 65 and 64%, respectively. For the 5-HT6 receptor 
in the caudate nucleus, putamen and ventral striatum, three weeks of 10 mg/day resulted in 
maximum receptor occupancy levels of 94, 90 and 88%, respectively.12
For all three receptors, the relationships between plasma concentration of Lu AF35700 and 
LuAF36152 and receptor occupancy (mean occupancy from caudate nucleus, putamen, and 
ventral striatum) could be described be Emax models. Daily doses of 10 mg are predicted to 
result in mean D1, D2 and 5-HT6 occupancy levels of 74, 43 and 87%, respectively, at steady 
state of Lu AF35700 and Lu AF36152.13
1.2
Rationale for the Study
The current study is a Phase III study included in the Lu AF35700 clinical development 
programme of Lu AF35700 as a potential treatment of treatment-resistant schizophrenia 
(TRS). The design was adopted from TRS1 (Study 16159A) and the dose was partly based on 
the PET MD study results. Targeted enrolment and stratification of patients with ED TRS and 
LD TRS, as defined in this protocol, may increase the understanding of how Lu AF35700 
may be an effective treatment across the longitudinal course of disease.
Clinical studies present an excellent opportunity for collecting large numbers of biological 
samples from well-characterized patient populations for research on the aetiology of 
schizophrenia and the molecular basis of the drug response (intended or adverse). Thus, 


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samples will be collected for future potential exploratory biomarker analyses to investigate 
associations between biological parameters, for example, genetic variants, mRNA 
concentrations, protein or endogenous metabolite concentrations and clinical features such as 
disease symptoms, drug response, and potential adverse events.
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 assess the efficacy of Lu AF35700 on symptoms of schizophrenia in patients with early-
in-disease (ED) or late-in-disease (LD) treatment–resistant schizophrenia (TRS)
Secondary Objectives
• to assess the efficacy of Lu AF35700 on symptoms of schizophrenia in patients with ED 
TRS
• to assess the efficacy of Lu AF35700 on negative symptoms of schizophrenia in patients 
with ED or LD TRS
Exploratory Objectives
• to assess the efficacy of Lu AF35700 in patients with ED TRS versus patients with LD 
TRS
• to assess the efficacy of Lu AF35700 in patients with TRS first diagnosed with 
schizophrenia ≤5 years prior to the Screening Visit versus patients with LD TRS
• to assess the efficacy of Lu AF35700 in patients with TRS first diagnosed with 
schizophrenia ≤5 years prior to the Screening Visit
• to assess the effect of Lu AF35700 on cognitive performance and functioning in patients 
with ED TRS, LD TRS, or patients with TRS first diagnosed with schizophrenia ≤5 years 
prior to the Screening Visit
• to explore patient historical and demographic characteristics predictive of response to 
treatment with Lu AF35700
• to explore genetic markers (genotype and expression) predictive of, or associated with, 
response to treatment with Lu AF35700
Safety Objective
• to evaluate the safety and tolerability of Lu AF35700 in patients with ED or LD TRS


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3
Study Design
3.1
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki.14
This is an interventional, multi-national, multi-site, randomized, double-blind, parallel-group, 
active-controlled, fixed-dose study.
This study will be conducted in compliance with the protocol, Good Clinical Practice,15 and 
applicable regulatory requirements.
An overview of the study is presented in Panel 1.
The target population for randomization in the current study is patients with treatment-
resistant schizophrenia. 
Patients to be enrolled in the current study should fulfil either the criteria for ED TRS or LD 
TRS.
The study is planned to include patients from US, Europe, Japan, or South America. In total, 
490 patients in US, Europe, Japan, or South America are planned for randomization with 245
randomized patients per treatment group.
The total study duration per patient from Screening to the end of Follow-up will be 23 weeks
(including 3 weeks screening period) For patients enrolling in the separate open-label 
extension study, the corresponding total study duration is 17 weeks (excluding the safety 
follow-up period).
The study will consist of 4 Periods:
• Screening Period (up to 3 weeks)
• Period A – Prospective Confirmation Period (6 weeks)
• Period B – Double-blind Treatment Period (8 weeks)
• Safety Follow-Up Period (6 weeks) – as applicable
Patients will enter a Screening Period of up to 21 days to assess eligibility.
In this study patients are blinded to any transition in care from Period A to Period B; 
specifically, the patients are kept blinded to the time point of randomization at Baseline 2 and 
to the treatment that they may receive during this study. In addition, patients must remain 
blinded to any association with their response to the treatment and their continuation in the 
study.
Patients, who meet the pre-specified selection criteria for either ED or LD TRS, will enter a 
single (patient)-blinded treatment period with risperidone or olanzapine to confirm their 
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Current antipsychotic drug treatment will be down-tapered within the first 7 days of Period A 
as described in section 6.1. Patients currently treated with depot antipsychotics can, after 
signing the ICF, be down-tapered by skipping one full treatment cycle plus 3 days before 
Baseline 1.
Patients will be initiated on risperidone 2 mg/day and up-titrated to 6 mg/day by the end of 
the first week, except if they have failed on risperidone (or 9-OH-risperidone; Invega™) in 
the most recent treatment trial or in a documented treatment failure in the past 2 years, or have 
a documented history of intolerance to risperidone (or 9-hydroxy-risperidone; Invega™) 
treatment in the past 2 years, in which case patients will be initiated on olanzapine at 
5 mg/day and up-titrated to 15 mg/day by the end of the first week. For patients treated with 
risperidone or InvegaTM more than 2 years ago and for whom the treatment resulted in an 
inadequate response or intolerance to the treatment, the investigator may consult with 
Lundbeck and/or its designee whether such patients may receive olanzapine; this decision 
must be approved by Lundbeck and/or designee. Thereafter, the dose of olanzapine may be 
adjusted up once from 15 to 20 mg/day during Weeks 3 and 4, for efficacy according to the 
investigator’s clinical judgement. If necessary for tolerability, dose may be decreased once 
back to 4 mg/day risperidone, or 15 mg/day olanzapine, during Weeks 3 and 4. No dose 
adjustments are allowed during the last 2 weeks of Period A (Weeks 5 and 6).
Patients who do not fulfil the inclusion criteria for Period B (blinded to site and patient) will 
be withdrawn from the study.
Patients who fulfil the entry criteria for Period B will enter the double-blind treatment period 
at Baseline 2.  The specific inclusion criteria for Period B will be blinded to the site and 
patient.  Patients will be randomly assigned (1:1) to 8 weeks of double-blind treatment with 
either Lu AF35700 (10 mg/day) or to continue the treatment with risperidone or olanzapine at 
a dose set at the end of Week 4 (Visit 5) of Period A.  The randomization will be stratified by 
duration of disease (early-in-disease and late-in-disease). Patients with ED and LD TRS will 
be enrolled such that an approximate 1:2 ratio is achieved.
For patients randomized to Lu AF35700, discontinuation of risperidone or olanzapine will be 
done gradually in a blinded fashion during the initial 7 days of Period B. The dose of 
Lu AF35700, risperidone or olanzapine will be fixed throughout Period B (Lu AF35700: 
10 mg/day; risperidone:  4 mg/day or 6 mg/day, determined in Period A; olanzapine:  
15 mg/day or 20 mg/day, as determined in Period A).
All patients, study completers, and those who prematurely discontinue will be scheduled for a 
Safety Follow-up Visit for safety assessments 6 weeks after the last dose of IMP, with the 
exception of those patients entering the open-label extension study.
Patients withdrawn during Period B (except those withdrawing due to withdrawal of consent) 
will, in addition to the Withdrawal Visit, be asked to attend an Efficacy Follow-up Visit
(Visit 13), for the assessment of efficacy, safety and concomitant medication. This visit 
coinciding with the time point of the Primary Outcome Visit (Week 14) that should have 
taken place, had the patient not been withdrawn from the study.


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An internal Safety Committee at H. Lundbeck A/S has been established for Lu AF35700 and 
the committee will perform regular evaluations of blinded safety data.
No interim analysis is planned.
Patients who complete or withdraw from the study should be treated according to current 
clinical practise at the discretion of the investigator.
3.2
Rationale for the Study Design
The randomized, double-blind, active-controlled, fixed dose design of the study aims to 
evaluate the safety and efficacy of Lu AF35700 on symptoms of schizophrenia in patients 
with ED TRS or LD TRS. Targeted enrolment and stratification of patients with ED TRS and 
LD TRS, as defined in this protocol, may increase the understanding of how Lu AF35700 
may be an effective treatment across the longitudinal course of disease. The criteria used to 
define treatment-resistance in this study are failure to respond after two trials of antipsychotic 
drug treatment of adequate dose and duration of at least 6 weeks.16 The first failed 
antipsychotic trial will be retrospectively documented as persistent positive symptoms and the 
current presence of at least moderately severe illness at study inclusion as defined by 
inclusion criteria 8, 9 and 10, as well as persistent illness and drug-resistant condition as 
defined by exclusion criterion 13. The second failed antipsychotic trial will be prospectively 
documented in Period A of this study. The rationale for considering two failed trials as 
sufficient evidence of TRS is supported by the finding that patients not responding to two 
adequate antipsychotic trials have less than 7% chance of responding to another trial;17 a 
criterion which has been broadly adapted in recent TRS studies.18
Patients entering Period B will be randomized to continue treatment with risperidone or 
olanzapine or to treatment with one dose (10 mg daily) of Lu AF35700. The rationale for the 
choice of risperidone or olanzapine for the prospective antipsychotic trial is their well-
established efficacy and effectiveness in drug-responsive patients with schizophrenia; which 
will enable a clear differentiation between responders and non-responders, and thus are an 
appropriate comparator for Lu AF35700 during Period B. The blinding of the investigators to 
the randomization criteria at the end of Period A is designed to further reduce possible sources 
of bias in the assessment of efficacy in patients with TRS.
In this study, patients withdrawing during Period B (except those withdrawing due to 
withdrawal of consent) will be asked to attend an Efficacy Follow-up Visit, in order to 
achieve a complete as possible dataset from these patients and thereby minimizing bias. The 
primary analysis assumes data are missing at random. As sensitivity analysis, this assumption 
will be investigated by utilizing the retrieved dropout data from the Efficacy Follow-up Visit.
The doses of risperidone and olanzapine used in this study are known to be safe, effective and 
well-tolerated.19 The 10 mg doses of Lu AF35700 was determined to be safe and well 
tolerated in the Phase I programme in patients with schizophrenia and elicited the targeted 
range of D2 receptor occupancy in healthy subjects (see Investigator’s Brochure).10 The 
treatment duration of 8 weeks was chosen as an adequate time period necessary to achieve 


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steady-state of the plasma levels of Lu AF35700 and its active metabolite (Lu AF36152) 
given their long half-lives and to provide sufficient time to determine the extent of attainable 
symptom reduction and allow safety evaluation.10
Efficacy and predictors of response to treatment will be assessed using:
• PANSS,20 a well established scale for assessing severity of the symptoms of schizophrenia.
• CGI-S,21,22 a global measure of outcome, 
• NSA-16,23 a validated rating of the severity of the negative symptoms of schizophrenia
• PSP,24 a validated rating for functional outcome in schizophrenia
• BACS,25,26 a validated assessment of cognitive function in schizophrenia
• SWN-S27 and DAI-10,28 both validated patient reported outcomes of studies in 
schizophrenia
• historical and demographic characteristics of the patient’s illness that may provide 
predictors of response to treatment
In addition, genetic markers will be assessed that may aid in understanding the risk associated 
with the development of TRS.
Safety and tolerability will be assessed by means of withdrawal, reported adverse events, 
vitals signs, weight, clinical safety laboratory tests, ECGs, physical examinations and 
C-SSRS.
Metabolic adverse events including body weight gain, dyslipidemia, and hyperglycemia are 
adverse events associated with antipsychotic drug treatment and represent an important long-
term safety risk.29 The primary variables for assessing those parameters include body 
weight/BMI, waist circumference, fasting blood glucose, glycosylated haemoglobin [HbA1c] 
and lipids (triglycerides, total cholesterol, low-density lipoprotein [LDL], and high density 
lipoprotein [HDL] cholesterol.
Blood samples will be collected to further understand the pharmacokinetic properties of 
Lu AF35700 and its metabolite (Lu AF36152), as well as to risperidone (including 
9-hydroxy-risperidone and olanzapine) and to explore genetic markers that my aid in 
understanding the risk associated with the development of TRS. 
4
Ethics
4.1
Ethical Rationale
This study will be conducted in compliance with the principles of Good Clinical Practice.15
Identification of novel antipsychotic agents that can effectively treat patients with 
schizophrenia who have failed to respond to antipsychotic therapies represents a great unmet 
clinical need. Per definition, these patients are highly symptomatic with associated low level 


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of functioning and require extensive periods of hospital care which contributes 
disproportionally to the overall cost of treating schizophrenia.
Targeted enrolment and stratification of patients with ED TRS and LD TRS, as defined in this 
protocol, may increase the understanding of how Lu AF35700 may be an effective treatment 
across the longitudinal course of disease.
Given the unique receptor binding profile of Lu AF35700 characterized by a high affinity to 
dopamine D1 and serotonin 5-HT6 receptors combined with a low level of dopamine D2
interaction, Lu AF35700 has the potential to offer an effective alternative treatment option for 
patients with TRS.
Based on data from the ongoing clinical pharmacology programme in patients with 
schizophrenia, the dose used in the current study is considered to be safe and well tolerated.
The aim of this study is to generate supporting evidence for efficacy and safety of 
Lu AF35700 in patients with TRS. The design of the current study is in accordance with the 
Declaration of Helsinki (ethical principles for medical research involving human subjects) as 
well as the recommendations provided for conducting studies inpatients with TRS as outlined 
in the EMA guideline on clinical investigation of medicinal products, including depot 
preparations, in the treatment of schizophrenia.14,30
In the current study, eligible patients who have had a recent treatment failure will enter a
single (patient) blind confirmation period and initiate a treatment trial with risperidone or 
olanzapine (well-known and widely used antipsychotic drugs), to assess treatment response. 
Only patients where a lack of adequate treatment response is confirmed will be randomized to 
double-blind treatment with either Lu AF35700 or to continued treatment (risperidone or 
olanzapine) for a period of 8 weeks. Patients who respond to the initial treatment with 
risperidone or olanzapine will be excluded from the study. Thus, approximately half of the 
non-responding patients will be randomized back to the failed treatment used in the initial 
period of the current study. This study design is considered ethically justifiable given the 
limited treatment options for this patient population and the need to utilize a rigorous 
scientific design to develop new safe and effective treatments for TRS.31,32 Blinding of the 
patients and of the investigators, as described in the study design, to actual treatment received 
reduces bias that would otherwise be introduced and that may influence the reliability of the 
study results.
The duration of the double-blind treatment period in the current study is 8 weeks in order to 
provide sufficient time to determine the extent of attainable symptom reduction and allow 
safety evaluation. In general, an adequate treatment trial in TRS should have a minimum 
duration of 6 weeks33. The 8-week duration in this study further allows adequate time for 
patients to receive Lu AF35700 under steady state conditions while their response is being 
assessed. Enrolled patients will be asked to visit the site regularly where the investigator will 
evaluate the treatment outcome and decide whether it is in the patients’ best interest to 
continue in the study. Also, 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. Patients who complete the study will be offered to continue in an optional


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52-week, open-label extension study (Study 17303B) if eligible according to the selection 
criteria for that study. All patients enrolled in the current study (Study 17303A) who do not 
continue in Study 17303B will be scheduled for a Safety Follow-up Visit 6 weeks after last 
dose of IMP.
Blood samples will be collected for in study and possible use in future exploratory research 
study(ies) in an attempt to increase the understanding of the properties of Lu AF35700, 
aetiology of schizophrenia, and the molecular basis of drug response.
In accordance with Good Clinical Practice,15 qualified medical personnel at CRO or 
Lundbeck will be readily available to advise on study-related medical questions. Medical 
monitoring will be performed throughout the study. Safety data will be reviewed regularly by 
the Lundbeck Lu AF35700 Safety Committee to ensure that prompt action is taken, if needed.
In accordance with Good Clinical Practice,15 the investigator will be responsible for all study-
related medical decisions.
The total volume of blood drawn from each patient will not exceed 250 mL, and is not 
considered to pose any risk or significant discomfort to the patients.
Based on the above-mentioned considerations the potential risk of participating in the study is 
well managed by the study set-up and considered negligible.
4.2
Informed Consent
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written informed consent from the patient.
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.


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Prior to obtaining written informed consent, the investigator or a designee must explain to the 
patients the aims, methods, and potential hazards of the study and any discomfort it may 
entail.
The patients 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
• of the possibility of withdrawing consent (section 8.4)
• that they have the right to request a copy of their personal data from the study via the 
investigator
• after the study has been reported, that they have the right to be informed by the investigator 
about which treatment they received
• about their right to receive information about the study results from the investigator on the 
patients’ own initiative; the results will be available approximately 1 year after the end of 
the study
The patients must be informed that persons authorized by Lundbeck and authorized personnel 
from certain authorities (domestic, foreign, data protection agencies, or ethics committees 
(ECs) or institutional review boards (IRBs)) may view their medical records. The patients 
must also be informed that de-personalized copies of certain parts of the patients’ medical 
records may be requested by authorized personnel from certain authorities (domestic, foreign, 
data protection agencies, or ECs or IRBs) for verification of study procedures and/or
data. The confidentiality of the patients will in all cases be respected.
The patients 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. Prior to including a patient in the study, an 
Informed Consent Form must be signed and dated by the patient and signed and dated by the 
investigator or a designee. The patients 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.
The blood samples for exploratory biomarker analysis may be shared with academic or public 
institutions; however, Lundbeck will retain full control of the samples and their use in 
accordance with the information in the separate Patient Information Sheet and a Material 
Transfer Agreement.


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A patient may, at any time and without stating a reason, specifically request the destruction of 
the patient’s DNA or PBMC sample, irrespective of the patient’s 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 or designee when the sample has been destroyed.
Listing of all potential Informed Consent Forms (ICFs):
• The study ICF covers all study assessment, including but not limited to, CYP genotyping,
gene expression profiling (RNA), metabolomics/proteomics and the optional in-study 
pharmacogenetics
• Pharmacogenetics biobank sampling ICF (optional)
• If applicable: Partner Pregnancy ICF (see section 10.2).
4.3
Personal Data Protection
The data collected in this study will be processed in accordance with the specifications 
outlined in the Danish Data Protection Act and in the European Union legislation34 to ensure 
that requirements regarding personal data protection are met.  If an external organization will 
process data on behalf of Lundbeck, a contractual procedure will be signed between 
Lundbeck and the external organization to ensure compliance with the above-mentioned 
legislation.
4.4
Independent Ethics Committees (IECs) and Institutional Review Boards (IRBs)
The Contract Research Organisation (CRO) will be responsible for submission of the protocol 
(blinded protocol and Clinical Study Protocol Addendum - Unmasked Information) and other 
appropriate documents to the IECs/IRBs. The blinding of the investigator should be ensured 
and any correspondence to and from the IECs /IRBs should be sent via the CRO. Members of 
the IECs/IRBs will be requested not to communicate directly with the investigators on the 
unblinded design of the study.
This study will be conducted only after Lundbeck has received confirmation that written 
approval of the protocol has been granted by the appropriate IEC or IRB.
The investigator must not allow any patients to participate in the study 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 written approval must be obtained before implementation of the amendment, if 
required by local law.
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.


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4.5
Regulatory Approval/Notification Requirements
In accordance with local requirements, this study (blinded protocol and Clinical Study 
Protocol Addendum - Unmasked Information) will be submitted to the regulatory authorities
for approval or notification. 
This study will be conducted only after Lundbeck has received confirmation that written 
approval or confirmation of notification has been received from the regulatory authorities.
5
Study Population
5.1
Numbers of Patients and Sites
Planned regions: US, Europe, Japan, and South America
Approximately planned number of patients:
to be screened (with signed informed consent):
1262
to be included-in Period A:
  817
to be randomized:
  490
to complete the treatment period:
  392
Approximately planned number of:
study sites:
  100
The number of enrolled patients is based on an assumed attrition rate of 40% in Period A and 
may be adjusted to meet the target of 490 randomized patients.
5.2
Patient Recruitment
Competitive patient recruitment between countries and sites will be used during the entire 
recruitment period to ensure that the required number of patients are randomized within the 
planned recruitment period.
The sponsor reserves the right to utilize quality oversight methods, to determine 
appropriateness of continued patient screening at a given site. In order to achieve the planned 
stratification of patients with ED and LD TRS randomized in Period B, the sponsor may 
instruct a given site, from time to time, to specifically and exclusively enrol patients with 
either ED or LD TRS. The stratification will be monitored by the IVRS system.


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The investigators will be notified immediately when the recruitment period comes to an end.
5.3
Selection Criteria
Patient selection 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
1.
The patient is capable of communicating with the site personnel.
2.
The patient is able to read and understand the Informed Consent Form.
3.
The patient has signed the Informed Consent Form.
4.
The patient is willing and able to attend study appointments within the specified time
windows.
5.
The patient is receiving treatment with a psychiatrist in either an inpatient or outpatient 
facility.
6.
The patient has schizophrenia, first diagnosed <10 years OR ≥10 years prior to the 
Screening Visit and according to DSM-5™ and confirmed by the Mini International 
Neuropsychiatric Interview (MINI).
7.
The patient has been treated with adequate dose(s) of antipsychotic drug treatment for at 
least 2 weeks prior to the Screening Visit.
8.
The patient has failed to show an adequate response in the level of psychotic symptoms
despite at least one documented treatment trial with an adequate dose of an antipsychotic
drug prescribed for an adequate time (at least lasting for 6 weeks) within 2 years prior to 
the ScreeningVisit. The failure to respond to the current antipsychotic drug treatment trial 
may be considered a retrospective failed treatment, if the patient has been treated for 
6 weeks with adequate dose(s) of antipsychotic drug(s). 
9.
The patient has a PANSS total score of ≥80 (on 1-7 scale) and a score of ≥4 
(≥“Moderate” on 1-7 scale) on at least 2 of the  following PANSS items (at the 
Screening and at the Baseline 1 [Week 0] Visits):
P2 - Conceptual disorganization
P3 - Hallucinatory behavior
P6 - Suspiciousness/persecution
G9 - Unusual thought content
10. The patient has a CGI-S score of ≥4 (≥ “Moderately ill”) at the Screening and at the 
Baseline 1 [Week 0] Visits.
11. The patient is a man or woman, aged ≥18 years.
12. 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.


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13. The patient has a stable living environment, as demonstrated by the ability to provide
contact information for him/herself and/or family/friend(s)/caregiver(s).
14. 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, intrauterine devices, sexual abstinence1, vasectomised partner); the 
contraception must be used from the Screening Visit to ≥3 months after the last dose 
of IMP, OR
have had her last natural menstruation ≥12 months prior to the Screening Visit, OR
have been surgically sterilized prior to the Screening Visit, OR
have had a hysterectomy prior to the Screening Visit
15. The patient, if a man, must:
use two methods of contraception in combination if his female partner is of
childbearing potential defined as a combination of male condom and female using an 
adequate, highly effective contraception; this combination of contraceptive methods 
must be used from the Baseline 1 Visit to ≥3 months after the last dose of IMP, OR
have been surgically sterilized prior to the Screening Visit
Entry criteria Period B
16. The patient has completed Period A of the study.
17. Response criteria, blinded to site and patient and described in the Clinical Study Protocol 
Addendum- Unmasked Information, are satisfied. 
18. Patient is considered to have been adherent with assigned IMP in Period A. Adherence is 
assumed based upon taking at least 80% of assigned IMP during Period A.
19. The patient’s designation as ED TRS or LD TRS does not invalidate the a priori
specified stratification plan for patients randomized into Period B
Exclusion Criteria
General
1.
The patient has previously been screened in this study or has received Lu AF35700.
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.
                                                
1
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the subject.]


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4.
Not applicable (Criterion removed in Protocol Amendment 2)
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 primary psychiatric disorder other than schizophrenia, as 
assessed using the MINI.
11. The patient suffers from mental retardation, organic mental disorders, or mental disorders 
due to a general medical condition (DSM-5™ criteria).
12. The patient is experiencing an acute exacerbation of his/her psychotic symptoms 
according to the investigator’s judgement.
13. The patient has experienced symptom relief corresponding to a CGI-S score of 3 (mild) 
or less as a result of antipsychotic drug treatment during the majority of time in the 2-year 
period prior to 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. 
15. The patient is at significant risk of harming himself/herself or others according to the 
investigator’s judgement, or the patient on the C-SSRS:
Answers ”Yes” to questions 4 or 5 on the Suicidal Ideation section within the last 
3 months at the Screening Visit, OR
Answers “Yes” to any question on the Suicidal Behaviour section within the last 
3 months at the Screening Visit, OR
Answers “Yes” to questions 4 or 5 on the on the Suicidal Ideation section at the 
Baseline 1 Visit
16. The patient has started formal cognitive or behavioural therapy or systematic 
psychotherapy within 6 weeks prior to the Screening Visit, or plans to start such therapy 
during the study. Any on-going formal psychotherapy initiated more than 6 weeks prior 
to the Screening Visit should be continued with the same methodology and at the same 
frequency and intensity during the entire study.
17. The patient has had neuroleptic malignant syndrome.


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18. The patient has been treated with, AND is resistant to, clozapine according to the 
investigator’s judgement
19. The patient has received electroconvulsive therapy <6 months prior to the Screening 
Visit.
Medical
20. The patient has any other disorder for which the treatment takes priority over treatment of 
schizophrenia or is likely to interfere with study treatment or impair treatment 
compliance.
21. 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.
22. The patient has epilepsy or a history of seizures, except for a single seizure episode (for 
example, childhood febrile seizure, post traumatic, or alcohol withdrawal).
23. 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
endocrinological disorder
gastrointestinal disorder
haematological disorder
infectious disorder
any clinically significant immunological condition
dermatological disorder
venereal disease
elevated intra-ocular pressure or is at risk of acute narrow-angle glaucoma
24. The patient has clinically significant abnormal vital signs at the Screening Visit.
25. 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 one of the 
following:
a serum creatinine value >1.5 times the upper limit of the reference range


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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
26. The patient has, at the Screening Visit, one of the following:
inadequately controlled diabetes or receives diabetes treatment, which is not 
considered stable in the investigator’s opinion
an HbA1C value >8%
in <12 months prior to Screening Visit experienced severe hypoglycaemia (according 
to American Diabetic Association criteria) OR has been hospitalized for ketoacidosis
27. The patient has orthostatic hypotension (defined as a decrease in systolic blood pressure 
>20 mmHg measured first in the supine or sitting position and then 1 to 3 minutes 
thereafter in the standing position) that is considered clinically relevant by the 
investigator.
28. The patient has, at the Screening Visit one of the following:
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)
29. 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.
5.4
Withdrawal Criteria
A patient must be withdrawn from the study if:
• the patient withdraws his or her consent (defined as a patient who explicitly takes 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]).
A patient must be withdrawn from treatment if:
• the investigator considers it, for safety and/or study compliance reasons, in the best 
interests of the patient that he or she be withdrawn from treatment
• any site personnel break the randomization code for that patient
• the patient becomes pregnant
• the patient has a critical value of prolactin >250ng/mL (>5285mUI/mL)
• 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


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• 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 the Screening Visit 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 that identifies substance use that jeopardizes patient safety or the reliability and 
integrity of the study protocol procedures
• the patient did not take IMP for at least 6 consecutive days 
• the patient in the opinion of the investigator has significant risk of suicide or the patient
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
A patient may be withdrawn from the study if:
• the patient fails to comply with study procedures
Patients who withdraw will not be replaced.
6
Investigational Medicinal Products (IMPs)
6.1
Treatment Regimen
Patients, who meet the pre-specified selection criteria for either ED or LD TRS, will enter a 
single (patient)-blinded treatment period with risperidone35 or olanzapine36 to confirm 
resistance to antipsychotic drug treatment.
Period A - Prospective Treatment Period
Patients will be initiated on risperidone 2 mg/day and up-titrated to 6 mg/day by the end of 
the first week, except if they have failed on risperidone (or 9-hydroxi-risperidone; Invega™)
in the most recent treatment trial, or in a documented treatment failure in the past 2 years, or 
have a documented history of intolerance to risperidone (or 9-hydroxy-risperidone; Invega™) 
treatment in the past 2 years, in which case patients will be initiated on olanzapine at 5 
mg/day and up-titrated to 15 mg/day by the end of the first week. Patients will be up-titrated 
according to the following scheme:
• Risperidone: 2 mg/day for the first 2 days; 4 mg/day for the next 2 days; 6 mg/day for the 
last 3 days. If necessary for tolerability, the dose may be decreased once back to 4 mg/day 
during Weeks 3 and 4. The dose must not be adjusted during Weeks 5 and 6.
• Olanzapine: 5 mg/day for the first 2 days; then, 10 mg/day for the next 2 days; then 
15 mg/day for the last 3 days. The dose may be increased once to 20 mg/day during Weeks 
3 and 4. If necessary for tolerability, the dose may be decreased once back to 15 mg/day 
during Weeks 3 and 4. The dose must not be adjusted during Weeks 5 and 6. 
The last possible time point for dose adjustment is at Visit 5.


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For patients treated with risperidone or InvegaTM more than 2 years ago and for whom the 
treatment resulted in an inadequate response or intolerance to the treatment, the investigator 
may consult with Lundbeck and/or its designee whether such patients may receive olanzapine; 
this decision must be approved by Lundbeck and/or designee. Current antipsychotic drug 
treatment will be down-tapered within the first 7 days of Period A. Patients currently treated 
with ‘depot’ antipsychotics can, after signing the ICF, be down-tapered by skipping one full 
treatment cycle plus 3 days before Baseline 1. Patients who do not fulfil the inclusion criteria 
for Period B (blinded to site and patient) will be withdrawn from the study.
Period B - Double-blind Treatment Period
Patients who fulfil the entry criteria Period B will enter the double-blind treatment Period
(Period B) at Baseline 2. The specific inclusion criteria for Period B will be blinded to the site 
and patient. Patients will be randomly assigned (1:1) to 8 weeks of double-blind treatment 
with either Lu AF35700 (10 mg/day) or to continue the treatment with risperidone or 
olanzapine at a dose set at the end of Week 4 (Visit 5) of Period A. The randomization will be 
stratified by duration of disease (ED and LD). Patients with ED TRS or LD TRS will be 
enrolled such that an approximate 1:2 ratio is achieved.
The dose of Lu AF35700, risperidone or olanzapine will be fixed throughout Period B 
(Lu AF35700: 10 mg/day; risperidone: 4 mg/day or 6 mg/day, determined in Period A; 
olanzapine: 15 mg/day or 20 mg/day, as determined in Period A). For patients randomized to 
Lu AF35700, discontinuation of risperidone or olanzapine will be done gradually in a blinded 
fashion during the initial 7 days of Period B according to the following scheme:
• Risperidone: 4 mg/day for the first 3 days; 2 mg/day for the 4 subsequent days
• Olanzapine: 10 mg/day for the first 3 days; 5 mg/day for the 4 subsequent days
Discontinuation of IMP
Discontinuation of IMP will be initiated at the Primary Outcome or Withdrawal Visit for all 
patients who discontinue the study for any reason after Week 1 of Period A or anytime during 
Period B. The investigator has the option to discontinue IMP through down-titration
(recommended) or to stop IMP abruptly for safety or tolerability issues. Down-titration 
proceed according to the following scheme:
• Risperidone (4 mg/day): 2 mg/day for the first 4 days; placebo for the 3 subsequent days
• Risperidone (6 mg/day): 4 mg/day for the first 3 days; 2 mg/day for the 4 subsequent days
• Olanzapine: 10 mg/day for the first 3 days; 5 mg/day for the 4 subsequent days
• Lu AF35700: Placebo for 7 days
Discontinuation of IMP during the first week of Period A will be abrupt.


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IMP Intake
In order to reduce biases associated with changes in treatment between the study periods and 
for blinding purposes during the down titration of risperidone or olanzapine, patients will be 
given two identical capsules per day throughout all treatment periods.
The patients will be instructed to take 2 capsules, for oral use, together in the morning or 
evening based on patients’ preference. The capsules are to be swallowed whole. The first dose 
is to be taken the day after IMP has been dispensed to the patient at Baseline 1.
Administration of IMP can be made irrespective of meals.
If the investigator during the study for tolerability reasons decides to switch a patient´s dosing 
schedule from taking the capsules in the evening to taking the capsules in the morning, it is 
accepted that IMP intake is skipped for one day.
6.2
IMPs, Formulations, and Strengths
The IMPs supplied by Lundbeck in this study are:
• Lu AF35700 – 10 mg/day; encapsulated tablets
• Risperidone – 2, 4, and 6 mg/day, encapsulated tablets
• Olanzapine – 5, 10, 15, and 20 mg/day, encapsulated tablets
• Placebo – encapsulated tablets
The IMPs will be identical in appearance.
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.
The IMP will be provided in wallet cards containing 20 capsules.
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.


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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
Each patient will be assigned a screening number by the eCRF system, and that number will 
be used to identify that patient throughout the study.
An interactive voice response system (IVRS) will be used in this study.  When a patient is to 
be enrolled and randomized, the investigator will contact the IVRS.  The IVRS will allocate 
the patient to a treatment group during the call, and at the Baseline 2 Visit assign the patient a 
randomization number in accordance with the specifications from Biostatistics, 
H. Lundbeck A/S, and then follow up by fax, e-mail, or the web (depending on availability or 
preference at the site).
Separate randomization lists have been prepared, one for US/Europe/South America and one 
for Japan.
6.5
IMP Accountability
The IMP accountability must be documented at each site:
• site-specific log to track the complete inventory (that is, what is shipped between the site
and Lundbeck)
• 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 IMPs 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
Unblinding Procedures
Pharmacovigilance, H. Lundbeck A/S, and the investigator or the pharmacist (if applicable), 
will have access to the unblinded information for the double-blind treatment for each patient. 
Access to these details will be via IVRS.
The IVRS unblinding procedure is described in the IVRS User Guide.
The investigator may only break the code for a patient if knowledge of the IMP is necessary 
to provide optimal treatment to the patient in an emergency situation. If possible, the 
investigator should consult the CRA before breaking the code. The investigator must record 
the date and reason for breaking the code on the IMP Code Break Form in the eCRF. If the 
emergency situation was an adverse event, it must be recorded on an Adverse Event Form. 
The CRA must be notified immediately. The IVRS will capture the date and time of the code 
break call.  Information on the allocated treatment will be provided during the call and by fax 
or e-mail, depending on availability/preference.  When the code is broken for a patient, the 


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patient must be immediately withdrawn from the study.  If this occurs during a visit, the 
investigator must complete the visit as a Withdrawal Visit; otherwise, the patient will be 
asked to attend a Withdrawal Visit.
6.7
Post-study Access to IMPs
Patients who completed treatment until Visit 11 (Primary Outcome) may continue into an 
optional 52-week open-label extension study (Study 17303B), if informed consent is obtained 
and the patient is eligible per Study 17303B eligibility criteria. Patients who do not continue 
into the extension study, or withdraw from this study, should be treated according to current 
clinical practice at the discretion of the investigator.
7
Concomitant and Rescue Medication
7.1
Concomitant Medication
Concomitant medication is any medication other than the IMPs that is taken during the study, 
including the Screening Period.
The recent and concomitant medications that are disallowed or allowed with restrictions 
during the study are summarized in Appendix II.
Details of all concomitant medication (prescription and over-the-counter) taken <3 months 
prior to the Screening Visit 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 initiated after the last dose of IMP must only be recorded if 
associated with an SAE or an ongoing AE.
The use of potent CYP2D6 and CYP1A2 inhibitors and CYP3A4 inducers is not permitted 
during the study, as they may affect the pharmacokinetic properties of risperidone or 
olanzapine in a manner that would require dose adjustment.35,36 Examples of inhibitors and 
inducers are provided in Appendix II. [Country-specific Protocol Amendment 1 for JP: 
Clinicians should use caution when prescribing the concomitant use of CYP3A inhibitors (eg. 
itoraconazole etc.) with risperidone as there is a risk of increasing blood concentrations of 
the risperidone parent compound and its metabolites].


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7.2
Rescue Medication
Guidance on use of rescue medication is outlined in Appendix II and specified for 
anticholinergics, anxiolytics and hypnotics.
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 treatment the patient must be treated in accordance with usual clinical 
practice, unless the patient enters the open-label extension study.
8.2
Screening Visit (Visit 1)
Informed consent must be obtained before any study-related procedures are initiated, 
including washout of disallowed medications. After informed consent is obtained, down 
tapering of depot antipsychotics and washout of disallowed medications begins, if applicable, 
and must comply with the requirements listed in Appendix II. The Screening Period begins at 
the Screening Visit. Screening evaluations are described in Panel 2.
The Screening Visit assessments may be extended over several days if needed. The date of the 
first assessment should be entered in the eCRF as the Visit Date.
Patients will enter a Screening Period of up to 21 days to assess eligibility. The patient’s 
eligibility will be reviewed by an external or sponsor 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 72 hours from the Screening Visit 
for review by external or sponsor medical team prior to proceeding to Baseline 1 Visit.
Decisions regarding inclusion of patients and assessment of patient safety throughout the trial 
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.
Only patients with schizophrenia that are resistant to treatment (patients with TRS) can be 
enrolled in this study. The main criterion to define TRS is a failure to respond to two 
antipsychotic drug treatment trials of adequate dose and duration. For the purpose of this 
study, at least one adequate antipsychotic drug treatment failure must be documented anytime 
in the past 2 years prior to the Screening Visit as described in inclusion criterion 8 
(retrospective documentation). The patient’s medical records are the most comprehensive 
source to document antipsychotic treatment failure. Thus, it is required that the investigator 
attempts to obtain copies of present or previous medical records of psychiatric and general 
medical history for every patient in order to document treatment failure. In case the 


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investigator does not have medical records for a patient at his/her own clinic, the investigator 
should attempt to obtain copies/written summary of relevant medical records from the 
previous treating physician. If original medical records are unavailable, any properly 
documented communication with the treating physician, letters, written summaries, 
photocopies of medical records, pharmacy records and specific letter templates may be used 
to document at least one previous treatment failure, including the current antipsychotic drug
treatment trial.
To help in the assessment of eligibility and for documentation purposes, sites should prepare a 
Psychiatric History of the patient, including the information on failed antipsychotic drug 
treatment trials in the last two years gathered from all available sources, including psychiatric 
interview and examination, and discussion with previous treating physician or treatment team. 
If the previous treating physician is no longer practicing and/or medical documentation has 
been destroyed as per local laws on archiving or by natural disaster, information from family 
members, caregivers or other persons close to the patient may help substantiating previous
psychiatric history. Pharmacy records can be used to support the documentation of the dose 
and duration of treatment with a prescribed medication.
The investigator is advised to contact the medical monitor to discuss the cases with 
unavailable documentation.
If there is no acceptable reason for not obtaining documentation of previous medical history 
and/or attempts are not documented in the source documents, the patient will be considered 
not eligible for the study.
The Informed Consent Form includes a statement whereby the patient agrees to the 
investigator communicating 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.
8.2.1
Pre-screening
Each site must record in a pre-screening log which patients attended the Screening Visit.  
Sites should also record in a log which patients have been pre-screened.
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.


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8.2.3
Re-screening and Re-consenting
Re-screening is not allowed in this study.
Patients who have previously signed the Informed Consent Form but not completed any other 
screening assessments may be considered for re-consenting upon discussion with the Medical 
Expert at Lundbeck. A new screening number will be assigned in the eCRF.
8.3
Baseline 1 Visit (Visit 2)
In exceptional cases, the visit interval between the Screening and Baseline 1 Visits may be 
extended with consent from the Medical Expert at Lundbeck, provided the Medical Expert 
accepts the rationale provided for the extension.
The pharmacogenetic sampling should be taken at the Baseline 1 Visit, but may be collected 
at a later visit including a clinical safety laboratory sample should it be missed.
8.4
Withdrawal Visit
Patients who withdraw from treatment OR 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 from the study, except 
information collected in relation to the scheduled Withdrawal Visit or Efficacy Follow-up 
Visit (see section 8.6) needed for the follow-up of adverse events (section 10.5). The reason 
for withdrawal must be recorded in the eCRF.
For a patient who withdraws consent:
• if the patient withdraws consent during a visit and then agree(s) 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 that visit will be used
• if the patient withdraws 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 that 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 records
• if the patient explicitly requests that the patient’s data collected from the time of 
withdrawal of consent onwards not be used, this will be respected


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8.5
Safety Follow-up Visit (Visit 12)
The Safety Follow-up Visit 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 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.  The safety follow-up must be conducted 6 weeks after the last dose of IMP.
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 Ongoing Adverse Event checkbox on the 
Adverse Event Form must be ticked.  SAEs must be followed until resolution or the outcome 
is known.
For patients with a clinically significant out-of-range clinical safety laboratory test value at 
the Primary Outcome or Withdrawal Visit or who withdrew due to an elevated AST or ALT 
value (see section 5.4), on site safety follow-up visits should be scheduled; see section 10.5
for details.
The safety follow-up for patients who withdraw consent must be performed, if at all possible; 
any information collected will only be recorded in the patients’ medical records.
8.6
Efficacy Follow-up Visit (Visit 13)
Patients withdrawn during Period B (except those withdrawing due to withdrawal of consent) 
will, in addition to the Withdrawal Visit, also be asked to attend an Efficacy Follow-up Visit 
(Visit 13), for assessment of efficacy, safety and concomitant medication. This visit coincides
with the time point of the Primary Outcome Visit (end of week 14) that should have taken 
place, had the patient not been withdrawn from the study.  If patient attends the Withdrawal 
Visit 5 days prior to week 14 (planned Primary Outcome Visit) the patient should not be 
asked to come for a Efficacy Follow-up Visit.
8.7
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 end of the study is defined as the last protocol-specified contact with 
the last patient ongoing in the study.  The overall end of the study is defined as the last 
protocol-specified contact with the last patient ongoing in the study.


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9
Assessments
9.1
Screening and Baseline Procedures and Assessments
9.1.1
Informed Consent Date and Demographics
Informed consent signature date and patient's demographics information (age, sex, race) is to 
be recorded in the eCRF after obtaining the signed informed consent.
9.1.2
Other Baseline Characteristics
At the Screening visit, the following will be recorded or assessed: 
• Diagnosis (DSM-5 TM), including:
age at first diagnosis of schizophrenia
• Relevant social, medical and psychiatric history, including:
Premorbid Adjustment Scale (only at Baseline 2)
estimation of the duration of untreated psychosis
• Disease-specific history including retrospective documentation of treatment failure, 
including:
timeline of previous antipsychotic drug treatment trials with outcomes
timeline of symptomatic psychosis
• Alcohol and substance use, past and current
• Family psychiatric history
• Prior antipsychotic and disallowed medication washout (see chapter 7)
• Height without shoes
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria.
Premorbid Adjustment Scale (PAS)
9.1.2.1
The PAS37 is a rating scale designed to evaluate the degree of achievement of developmental 
goals at each of several periods of a subject's life before the onset of schizophrenia (6 months 
prior to psychiatric symptomatology). The level of functioning evaluated in four major areas, 
at each of several periods of the subject's life, include: social accessibility- isolation, peer 
relationships, ability to function outside the nuclear family, and capacity to form intimate 
socio-sexual ties. Items evaluating age-appropriate functioning in these areas are repeated for 
each period of the subject's life. The four life period sections are as follows: Childhood, up to 
11 years; Early Adolescence, 12-15 years, Late Adolescence, 16-18 years; and Adulthood, 
19 years and beyond. The final section, labelled General, is more global, containing items 
meant to estimate the highest level of functioning that the subject achieved before becoming 
ill, as well as the time span and characteristics of onset of illness, and general information 
such as amount of education.


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Each section of the scale contains a number of items with a scoring range of 0 (hypothetically 
healthiest) to 6 (hypothetically least healthy). When no information is available for a 
particular item, the item is not scored. The General section contains 9 items with a score 
range of 0 (best) to 6 (worst).  The ratings received for each item in a section are summed and 
expressed as total score divided by the possible score. The possible score indicates the highest 
score obtainable by adding the maximum score for all items completed. An overall score for 
the whole scale is calculated by averaging the subscale scores for all the subscales rated for 
the patient. The rater of the PAS should obtain all necessary information from the patient 
interview as well as from available family members and from the patient’s medical history. 
The PAS can be administered by a clinician with experience working with patients with 
schizophrenia after a short training. It takes approximately 45 minutes to complete the PAS.
The PAS will be administered in the local language. 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 PAS will be provided to the site. 
Rater Qualification and Certification for PAS
9.1.2.2
The PAS should be administered by a clinician with experience working with patients with 
schizophrenia.
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. Exceptional situations must be discussed and 
approved by Lundbeck and/or designee.
Only raters who have been certified on a PAS study-specific rater training and certification 
programme will be authorized to rate the PAS for the study. Documentation of rater training 
and certification will be delivered to raters for archiving in the I-TMF. No patient must be 
rated before the documentation has been delivered. 
New raters joining the study will be trained and certified using the same certification 
processes.
Rater training and certification will be conducted by a third party vendor.
9.1.3
Diagnostic Assessments
Mini International Neuropsychiatric Interview for Psychotic Disorders 
9.1.3.1
Studies (MINI)
The MINI38 is a structured diagnostic interview designed to provide a brief standardized 
evaluation of major Axis I psychiatric disorders in DSM-5TM. In the study, the most current 
version of MINI 7 for DSM-5 will be used. Each of the 17 independent diagnostic modules 


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consists of screening and a series of secondary questions to be answered with “yes” or “no” 
responses. If the patient answers “no” to a screening question, the clinician starts asking 
questions from the next module. A clinician can use the MINI after a short training session.
It takes approximately 20 minutes to administer the MINI.
The MINI will be administered in the local language. 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 MINI will be provided to the site.
Rater Qualification and Certification for MINI
9.1.3.2
The MINI should be administered by clinicians (see 9.1.2.2) having experience in the 
diagnosis and treatment of patients with schizophrenia. 
Only raters who have been certified on a MINI study specific rater training and certification 
programme will be authorized to rate the MINI for the study.
Documentation of rater training and certification will be delivered to raters for archiving in 
the I-TMF. No patient must be rated before the documentation has been delivered. New raters 
joining the study will be trained and certified using the same certification processes.
Rater training and certification will be conducted by a third party vendor.
9.1.4
Drug Screen
A urine drug screen for opiates, methadone, cocaine, amphetamines (including 
ecstasy/methamphetamine), barbiturates, benzodiazepines, phencyclidine, and cannabinoids 
will be performed at designated visits, 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.
9.1.5
Genotyping (Baseline 2)
Blood samples for CYP genotyping analysis will be collected in an EDTA tube (2x2 mL). 
The blood sampling and handling procedure are described in the study-specific Laboratory 
Specification Manual or equivalent.
Based on in vitro examination of elimination routes for Lu AF35700, the following genetic 
variations for cytochrome P450 drug metabolizing enzymes will be determined:
• CYP2C19:  *1 (WT), *2, *3, *4, *5, *6, *7, *8, *9, *10, and *17 
• CYP2D6:  *1 (WT), *2, *3, *4, *5, *6, *7, *8, *9, *10, *12, *14, *17, *29, *41 and *2×N 
(gene duplication)


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If relevant, the genotyping laboratory must report single nucleotide polymorphism (SNP) 
results, conclusive genotype, and inferred phenotype for each sample.
The blood samples will be analysed at a central laboratory using a validated method. The 
samples will be destroyed after they have been analysed.
The genotyping results will be used for exploratory interpretation of the efficacy and 
pharmacokinetic results. The genotyping results are not required at the time of enrolment in 
the study hence reported separately by the central/genotyping laboratory at study end.
The results will not be reported back to the investigator.
9.2
Efficacy Assessments
9.2.1
Use of Assessment Tools
The following assessment tools will be used:
• PANSS − clinician-rated, assessing symptoms of schizophrenia
• CGI-S − clinician-rated, assessing global impression 
• NSA-16 – clinician-rated, assessing negative symptoms of schizophrenia
• BACS  – clinician-administered, assessing cognitive function
• PSP – clinician-rated, assessing personal and social performance
The scales will be administered in local language or English. 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.
Positive and Negative Syndrome Scale (PANSS)
9.2.1.1
The PANSS20 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.


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The Structured Clinical Interview for PANSS39 (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.
Clinical Global Impression Scale – Severity (CGI-S)
9.2.1.2
The CGI21,22 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.
16-item Negative Symptom Assessment (NSA-16)
9.2.1.3
The NSA-1623 is a clinician-rated scale designed to assess the presence, severity, and range of 
negative symptoms associated with schizophrenia. The NSA-16 consists of 16 items arranged 
in 5 subdomains: communication dysfunction (items 1 to 4), emotional/affective dysfunction 
(items 5 to 7), dysfunction in sociality (items 8 to 10), motivational/hedonic dysfunction 
(items 11 to 14), and reduced psychomotor activity (items 15 and 16), and a Global Negative 
Symptom Rating. NSA-16 items are rated on a 6-point scale from 1 (behaviour is normal) to 6 
(behaviour severely reduced), and a score of 9 if the item is not-rateable. The Global Negative 
Symptom Rating is rated from 1 (no evidence of symptoms) to 7 (extremely severe 
symptoms). The 16 items are summed to yield a total score ranging from 16 to 96 and the 
global rating ranges from 1 to 7. The NSA-16 can be administered by an experienced clinician 
after a short training session. 
It takes approximately 20 minutes to complete the NSA-16.
Brief Assessment of Cognition in Schizophrenia (BACS) – (US/Europe only)
9.2.1.4
The BACS25, 26 is an assessment battery that assesses the aspects of cognition found to be 
most impaired and most strongly correlated with outcome of patients with schizophrenia.
The BACS comprises six tasks for the evaluation of the following cognitive domains: Verbal 
Memory Test (verbal memory) score 0-75, Digit Sequencing Task (working memory) score 0-
28, Token Motor Task (motor function) score 0-100, Verbal Fluency (semantic fluency and 
letter fluency) score 0-60, Symbol Coding Task (attention and processing speed) score 0-110, 
and Tower of London (executive functions) score 0-22. The score for each task is assessed by 
counting the number of correct answers. The BACS composite score is calculated by 
summing the z-scores for each of the six measures (obtained by comparing each measure with 
a normative sample of 400 controls matched to the 2005 Census) and dividing by the healthy 
control SD.40 The BACS is designed for use by clinical psychologists, neuro-psychologists, or 


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clinicians with prior experience in administering cognitive tests in patients with 
schizophrenia. 
It takes approximately 30 minutes to administer the BACS.
Personal and Social Performance Scale (PSP)
9.2.1.5
The PSP24 is a clinician-rated scale designed and validated to measure a patient’s current level 
of social functioning.
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.
Rater Qualification and Certification
9.2.1.6
The PANSS and NSA-16 should be administrated by clinicians (see 9.1.2.2) having expe-
rience in patients with schizophrenia and related psychotic disorders, and in administering the 
PANSS and NSA-16.
The CGI-S should be administered by the clinician (see 9.1.2.2) responsible for the patient.
The PSP should be administered by clinicians (see 9.1.2.2) having experience in patients with
schizophrenia.
The BACS should be administered by a clinician (see 9.1.2.2) or clinical research assistant 
having experience in patients with schizophrenia and with cognitive testing.
Exceptional situations must be discussed and approved by Lundbeck and/or designee.
Only raters who have been certified on a PANSS, NSA-16, CGI-S, PSP and BACS study 
specific rater training and certification programme will be authorized to rate the scales for the 
study.
The PANSS and NSA-16 rater must be blinded to the protocol and to other patient data. Any 
exceptions must be discussed and approved by Lundbeck.
A CGI-S, PSP and BACS training session will be organized prior to the start of the study.
Each site should have a minimum of 4 raters in order to provide back-up for each other and 
allow switching between raters: two raters for the PANSS and NSA-16, blinded to the 
protocol and to the patient’s treatment during the study, and two raters for the other scales, 


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who do not necessarily need to be blinded to the protocol and to the patient’s treatment during 
the study. 
Any exceptions must be discussed and approved by Lundbeck and/or designee.
The same blinded rater should not perform the PANSS and NSA-16 assessments at all the 
visits of a patient throughout the study. Instead, the two blinded raters should alternate 
performing these assessments at consecutive visits of a patient, or at a minimum, should 
alternate performing these assessments at the Baseline and at the Primary Outcome or 
Withdrawal Visits.
Documentation of rater training and certification will be delivered to raters for archiving in 
the investigator trial master file (I-TMF). No patient must be rated before the documentation 
has been delivered.
New raters joining the study will be trained and certified using the same certification 
processes.
Rater training and certification will be conducted by a third party vendor. BACS raters will be 
trained by a third party vendor supervising the assessment of the BACS in this study.
Lundbeck reserves the right to use external quality oversight methods (audio/video and
worksheet review) to verify the accuracy of the PANSS scoring. The process for scale data 
oversight will be outlined in a separate document. Audio/video monitoring and review will be 
performed on behalf of Lundbeck by a third party vendor. The audios/videos will be uploaded 
to a server with limited and controlled access.
In specific regions, where appropriate, Lundbeck may choose to collect PANSS and NSA-16 
scales’ data by a centralized rating vendor who will assess patients in an independent 
interview conducted via real time videoconference.
The recording equipment will be provided by a third party vendor.
9.3
Pharmacoeconomic Assessments
9.3.1
Use of Assessment Tools
The following assessment tools will be used:
• SWN-S − patient reported outcome, assessing subjective effects of neuroleptics
• DAI-10 – patient reported outcome, assessing attitude towards the use of antipsychotic 
medication
The scales will be administered in the local language. 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.


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The SWN-S and DAI-10 are patient-reported outcomes. Designated and trained site staff will 
be responsible for introducing and giving guidance to the patients on PRO completion.
The training for the designed site staff will be provided by a third party vendor and should be 
completed before performing this task.
The patients’ responses may only be corrected by the patient.
Subjective Well-Being under Neuroleptic Treatment – Short Version (SWN-S)
9.3.1.1
The SWN-S27 is a patient-rated scale designed to measure subjective effects of neuroleptic 
drugs to psychopathology, quality of life, and compliance over the past 7 days. The 20 items 
(10 positive and 10 negative statements) are grouped in 5 subscales (mental functioning, self 
control, physical functioning, emotional regulation, and social integration), Each subscale 
contains 4 items, each item is rated on a 6-point Likert scale, from 1 (not at all) to 6 (very 
much). A score is calculated for each subscale, and the total score ranges from 20 to 120, 
where the higher score indicates better well-being. 
It takes 5 to 10 minutes to complete the SWN-S.
Drug Attitude Inventory-10 (DAI-10)
9.3.1.2
The DAI-1028 is a patient-rated scale designed to assess their attitude towards the use of 
antipsychotic medication and their experiences on these drugs. The DAI-10 consists of 
10 statements, and the patient answers each statement as either true or false. Each answer is 
scored +1 or –1, and these are summed to give a total score ranging from +10 to –10: a 
negative total score indicates the patient has a “risk of non-compliance”. 
It takes 2 to 5 minutes to complete the DAI-10.
9.4
Pharmacokinetic Assessments
Blood samples (2 mL per time point) for Lu AF35700, Lu AF36152, olanzapine, risperidone,
and 9-hydroxy-risperidone quantification in plasma will be drawn according to Panel 2.  The 
blood sampling and handling procedures are described in the study-specific Laboratory 
Specification Manual or equivalent.
The plasma samples from Period B will be analysed for Lu AF35700 and the major 
metabolite Lu AF36152 using a bioanalytical method validated in accordance with the EMA 
Guideline on Bioanalytical Method Validation41 and the FDA Guidance for Industry.42  
The plasma samples from Period A and Period B will be analysed for olanzapine, risperidone,
and 9-hydroxy-risperidone using a bioanalytical method validated in accordance with the 
EMA Guideline on Bioanalytical Method Validation41 and the FDA Guidance for Industry.42
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.


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If other metabolites are identified and considered significant, these may be included in an 
exploratory 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 each 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 3.


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Panel 3
Clinical Safety Laboratory Tests
Haematology
Livera
Kidneya
B-haemoglobin
S-total bilirubin (BILI)
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) d
B-MCHC
S-aspartate aminotransferase (AST)
U-protein (dipstick)
B-total leucocyte count
S-lactate dehydrogenase (LDH)g
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 screen d
B-lymphocytes (% of total leucocytes)
S-potassium
U-Amphetamines
B-monocytes (% of total leucocytes)
S-calcium (total)
U-Barbiturates
B-thrombocyte count
S-chloride
U-Benzodiazepines
P- INR (prothrombin ratio) g
S-bicarbonate
U-Cannabiniods
Lipidsa
Endocrine and Metabolica
U-Cocaine
S-cholesterol (total) (fasting)
S-albumin
U-Methadone
S-triglycerides (fasting)
S-glucose (fasting)
U-Opiates
S-low density lipoprotein (LDL)
S-prolactin b
U-Phencyclidine
S-high density lipoprotein (HDL)
B-HbA1c c
Pregnancy (women only)
S-total protein
S-hCG 
Urine Dipsticke
Additional Test 
S-creatine phosphokinase 
(CPK)f
B – blood; P – plasma; S – serum; U – urine 
a
Clinical chemistry.
b
Result will remain blinded until unblinding of the study. Test results >250ng/mL (>5285mUI/L) will be 
reported by the central laboratory to the Medical Expert for clinical follow-up with the investigator.
c
Performed at the Screening, Baseline 2 and Primary Outcome/Withdrawal Visits only.
d
Urine samples will be collected and analysed at the site using dipsticks. 
e
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.
f
S-troponin T, reflex for CPK >500U/L.
g
Re-sampling for laboratory tests deemed not evaluable by the central laboratory will only be required for 
appropriate clinical follow-up due to Medical History or previous clinically relevant abnormal findings.
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 or equivalent.
The blood samples will be analysed at a central laboratory.


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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 
repeated, or an appropriate clinical follow-up must be arranged by the investigator and 
documented on the laboratory report, until the value has stabilized or until the value has 
returned to a clinically acceptable value (regardless of relationship to the IMP). A patient 
with a value that is out-of-range at the Primary Outcome or Withdrawal Visit and considered 
clinically significant must be followed in accordance with usual clinical practice for up to 
6 weeks or until the value normalizes or stabilizes 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 records.
Any out-of-range clinical safety laboratory test value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form.
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 or sitting measurement after 
resting for 5 minutes followed by standing measurement after standing 1minute, and if 
required measured after 2 and/or 3 minutes to allow for evaluation of orthostatic hypotension.
Any out-of-range vital sign considered clinically significant by the investigator 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. Any weight change 
considered clinically significant by the investigator must be recorded as an adverse event on 
an Adverse Event Form.
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 


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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 
considered clinically significant by the investigator must be recorded as an adverse event on 
an Adverse Event Form.
9.5.6
Physical Examinations
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 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.  
Any abnormal finding or out-of-range value considered clinically significant by the 
investigator 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
The C-SSRS will be administered in the local language. 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 C-SSRS will be provided to the site.
Columbia-Suicide Severity Rating Scale (C-SSRS)
9.5.7.1
The C-SSRS43 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. 


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It takes approximately 5 minutes to administer and rate the C-SSRS.
Rater Qualification and Certification
9.5.7.2
The C-SSRS should be rated by a clinician (see 9.1.2.2).  Any exceptions must be discussed 
and approved by Lundbeck.
All raters must have, or obtain after training on the author’s website, a valid C-SSRS Certifi-
cate of Training signed by the C-SSRS author Dr. Posner for archiving in the investigator 
TMF. No patient must be rated before the C-SSRS Certificate of Training has been delivered.
New raters joining the study will be trained and certified using the same certification 
processes.
Order of Assessments
9.5.7.3
The scales should preferably be administered in the following order at the applicable visits:
Screening Visit:
• MINI
• PANSS
• PSP
• C-SSRS
• CGI-S
All visits other than the Screening Visit:
• PANSS
• NSA-16
• BACS
• SWN-S and DAI-10 
• PSP
• C-SSRS
• CGI-S
9.6
Other Assessments
9.6.1
Blood Sampling for Pharmacogenetics – Optional
A blood sample (9 mL) will be collected in K3 EDTA tubes for subsequent DNA extraction at 
Visit 6. Blood tubes will be shipped on dry ice to a central laboratory where DNA will be 
extracted and retained. DNA aliquots will be shipped to a central laboratory, for storage. The 
genetic variants to be analysed may include but is not limited to single nucleotide 
polymorphisms (SNPs) and copy number variations (CNVs). The analytical methods may be 
but is not limited to polymerase chain reaction (PCR), qPCR (quantitative PCR), sequencing, 


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or whole genome scans on microarrays. The details will be described in a separate protocol. 
The exploratory analysis results will not be a part of the Clinical Study Report but will be 
reported separately. The result of the exploratory analysis will not be reported back to the 
patient or the investigator.
9.6.2
Days of Hospitalization
If a patient is hospitalized due to schizophrenia during the study, this must be recorded in the 
e-CRF at each visit, including admission date and discharge date.
9.7
Biobanking
9.7.1
General Considerations
This study includes collection of blood samples for long term storage and use in a possible 
future explorative biomarker research study and collection of blood samples for separation of 
peripheral blood mononuclear cell (PBMC) to facilitate possible future generation of induced 
Pluripotent Stem Cells lines for studying disease aetiologies at the molecular and cellular 
level. PBMC isolation is restricted to sites within USA and may involve up to approximately 
100 patients.
Although the possible future exploratory research studies will help to increase our 
understanding of the aetiology of schizophrenia and TRS and the molecular and cellular basis 
of the drug response, the efforts are strictly research based. Therefore, as the complex 
interactions between genes, biomarkers and disease biology are currently not characterized to 
a level that translates to a meaningful clinical advantage, individual results from the 
exploratory research studies will not be provided to neither the patient nor the investigator. 
For the same reasons, individual results will not be added to the patients’ medical records.
The patients will have no direct benefit from the potential exploratory research studies.
As blood sampling for the exploratory genomics gene expression profiling, 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 
and/or the establishment of cell lines from collected PBMCs is optional and a separate Patient 
Information Sheet covers these. Due to potential laboratory hazards associated with later 
handling of the PBMC based cell lines, all patients enrolled for PBMC collection must be 
tested for HIV, HBsAg, and anti-HCV.
The blood samples collected for the possible future exploratory biomarker analysis and the 
establishment of cell lines, or the data and cell lines 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 Agreement. Furthermore, the results based 
on the analysis of the samples may be pooled across studies to increase the statistical power of 
the analyses.


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The blood samples for genomics gene expression profiling, proteomics, and metabolomics 
analysis, and the cell line development 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 paper44 on pharmacogenetic terminology to ensure patient privacy 
protection.
Blood samples for biobanking will be collected as outlined in Panel 2.
9.7.2
Blood Sampling for Gene Expression Profiling
Blood samples for gene expression profiling (RNA) will be collected in two PAXgene tubes 
(2,5mL) at each time point. The maximum volume of blood to be collected during the study 
for this purpose will be 25 mL. Samples for gene expression profiling will be shipped to a 
central laboratory, United States for sample storage. 
9.7.3
Blood Sampling for Metabolomic/Proteomic Biomarkers
Blood samples for metabolomic/proteomic biomarkers will be collected in one 10mL K2 
EDTA tube at each time point. The maximum volume of blood to be collected during the 
study for this purpose will be 50 mL. The samples for metabolomic/proteomic biomarkers 
will be shipped to a central laboratory, United States, for sample storage.
9.7.4
Blood Sampling for Pharmacogenetics
The optional 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 where DNA will be 
extracted and retained. DNA aliquots will be shipped to a central laboratory, United States,
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.
9.7.5
Blood Sampling for Isolation of Peripheral Blood Mononuclear Cell (PBMC)
(US only)
The optional blood samples for PBMC isolation will be collected in 4 x CPT Tubes (8 mL). 
The maximum volume of blood to be collected during the study for this purpose will be 
32 mL. Blood tubes will be shipped on to a central laboratory where PBMCs will be isolated
and retained. The PBMC aliquots will be shipped to a central laboratory, United States, for
storage.
Later reprogramming of PBMC into pluripotent Stem Celle lines may enable generation of 
disease-affected cell types to be used for identifying novel therapies or for the identification 
of disease-specific phenotypes at the molecular, cellular and/or physiological level.


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9.8
Total Volume of Blood Drawn and Destruction of Biological Material
The total volume of blood drawn from each patient will be approximately 250 mL (including 
the optional blood samples) during the study.
Additional blood samples may be required if the original blood samples are not viable or if re-
testing is required.
The 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 8.78.7) by a central laboratory.
The 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 8.7) by a central laboratory.
The isolated PBMC will be destroyed ≤20 years after the end of the study (see definition in 
section 8.7) by a central laboratory. The created stem cell lines may be kept indefinitely for 
research use.
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.
9.9
IMP Compliance
The responsible study personnel will dispense the IMP. Patients must be counselled on the 
importance of taking the IMP as directed at all study visits. The patient should bring the IMP 
(including emptied wallets) to site at each visit to verify compliance. Accountability and 
compliance verification should be documented in the patient’s source documents and checked 
by the CRA during monitoring. 
The Sponsor Medical Monitor should be contacted if the investigator is uncertain whether a 
patient’s lack of compliance warrants withdrawal from the study.
In addition Lundbeck reserves the right to use an external vendor for IMP adherence 
assessment. Details of such an IMP adherence application, if applicable, are described in the
study specific guideline or equivalent.


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10 Adverse Events
10.1
Definitions
10.1.1
Adverse Event Definitions45
Adverse event – is any untoward medical occurrence in a patient or 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.
It is Lundbeck policy to collect and record all adverse events, including pre-treatment adverse 
events, that is, those that start after the patient has signed the Informed Consent Form and 
prior to the first dose of IMP.
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 hospitalization or prolongation of existing hospitalization
• 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 hospitalization, but may jeopardize 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 hospitalization; or development of drug 
dependency or drug abuse.
Planned hospitalizations 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 adverse 
events. 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).
In addition, planned support hospitalisation (in the opinion of the investigator) of outpatients, 
or prolongation of hospitalisation of inpatients after having signed Informed Consent Form
are not to be reported as SAEs. Adverse events occurring during a planned support 
hospitalisation of outpatients or during a prolongation of hospitalisation of inpatients are not 
to be reported as SAEs unless the AE fulfils other seriousness criteria than the hospitalisation. 


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Symptoms which are expected as part of underlying disease should not be reported as AEs 
unless the symptoms increase in intensity or frequency.
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.
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 Brochure10 or the UK Summary of Product Characteristics for 
risperidone35 and olanzapine,36 and related to an investigational product 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 the 
patient’s 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 
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An adverse event is considered causally related to the use of the IMP when the causality 
assessment is probable or possible.
For pre-treatment adverse events, a causality assessment is not relevant.
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.
• 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
10.2
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 reported as an SAE; hospitalization for a normal 
birth should not be reported as an SAE. If, however, the pregnancy is associated with an 
SAE, the appropriate serious criterion 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 (Partner Pregnancy ICF) 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 


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if the adverse event lasts less than 24 hours); intensity; causal relationship to the IMP; action 
taken; and outcome. If the adverse event is not related to the IMP, an alternative aetiology
must be recorded. 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).
If individual adverse events are later linked to a specific diagnosis, the diagnosis should be 
reported and linked to the previously reported adverse events.
10.4
Reporting Serious Adverse Events (SAEs)
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 Serious Adverse Event Form 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®(eCRF), then he or she must complete and 
sign the Serious Adverse Event Fallback Form and send it to:
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 requirements.
It is the responsibility of the CRO to be aware of any local requirements, to inform the 
investigator of these, and to follow up on this.
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 requirements.  In those Member States of the European Union that have 
implemented the European Union Clinical Trials Directive46 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 
in the 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 


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CIOMS-I reports are required (for example, by the local IEC or IRB), 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.
It is the responsibility of the investigator to follow up on all SAEs until the patient has 
recovered, stabilized, 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 Visit must be handled in the same manner as SAEs that occur during the study.  These 
SAEs will be recorded in the Lundbeck Safety database.
Patients with a clinically significant out-of-range clinical safety laboratory test value 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). If the clinically significant out-of-range clinical 
safety laboratory test value has not normalized or stabilized or a diagnosis or a reasonable 
explanation has not been established by the Safety Follow-up Visit, the investigator must 
decide whether further follow-up visits are required (this may include an additional medical 
examination and/or additional blood sampling).  If further follow-up visits are made, these 
must be documented in the patient’s medical records and not in the eCRF.
Patients who withdraw due to an elevated AST or ALT value (see section 5.4) must be 
followed until the values normalize or stabilize or a diagnosis or a reasonable explanation has 
been established.  Additional medical examinations (for example, ultrasound scanning and/or 
sampling for serology, conjugated bilirubin, prothrombin time) 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.


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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.
11.1.2
Patient Binders
Use of Patient Binders
11.1.2.1
Lundbeck or designee will provide a Patient Binder for each patient.  The Patient Binder
contains different types of source documents, organized by visit and type.  A ballpoint pen 
with waterproof ink must be used to enter information in the Patient Binder.
Rating Scales and Patient-reported Outcomes (PROs)
11.1.2.2
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.
Serious Adverse Event Fallback Forms
11.1.2.3
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 following electronic data will be transferred by the vendors and kept in a secure 
designated storage area outside the eCRF:
• The clinical safety laboratory test results including infectious status testing will be
transferred to Lundbeck Department of Biometrics by central laboratory.
• The in study pharmacogenetics (Baseline 2) data will be transferred to Lundbeck 
Department of Biometrics by central laboratory.


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• Lu AF35700, Lu AF36152, risperidone (including 9-hydroxy-risperidone) and olanzapine 
PK supportive data will be transferred to Lundbeck Department of Biometric and 
Lundbeck Department of Bioanalysis by central laboratory.
• Biobank supportive data for gene expression profiling (RNA), Metabolomics/proteomics 
(plasma) and pharmacogenetic and PBMC will be transferred to Lundbeck Department of 
Biometrics by central laboratory.
• For electronic assessment tools (for example PANSS, CGI-S, PSP, and NSA-16), the data
will be transferred to Lundbeck Department of Biometrics by the designated vendor.
• The ECG results will be transferred to Lundbeck Department of Biometrics by central 
ECG service provider.
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 until the study has been completed.  After the study has been 
completed, all user access to the eCRF will be revoked. Renewed access to the eCRF will be 
given if corrections or updates to the database are required.
At the end of the study, the site will be provided with all data related to the site (including 
eCRF data, queries, and the audit trail) using a secure electronic medium; the secure storage 
of these data at the site is the responsibility of the investigator. When confirmation of receipt 
of the data has been received from all sites, all user access to the eCRF will be revoked. If, for 
some reason, the data are not readable for the full retention period (25 years or in accordance 
with national requirements, whichever is longer), the investigator may request that the data 
related to the site be re-sent.
11.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 25 years after the Clinical Study Report has been approved or in accordance with 
national requirements, whichever is longer.
Lundbeck or designee will remind the investigator in writing of this obligation when the 
Clinical Study Report Synopsis is distributed to the site.
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 
device for eCOA.


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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.15  In addition, the CRA will be available for discussions by telephone.
In addition, the CRA will visit the site and review the screening log (or equivalent) 
maintained by the site which indicates the number of patients with ED and LD TRS who have 
entered the study. The CRA will advise the site regarding adjustments to further enrolment 
that may need to be made at their site to satisfy the appropriate ratio of patients with ED TRS
to patients with LD TRS that may enter the study based upon updates of global enrolment
patterns. 
Source data verification requires that the CRA be given direct access to all the source 
documents. Direct access includes permission to examine, and verify any records that are 
important for the evaluation of the study.
Any assessment tool ratings (rating scales) recorded directly on the electronic device will be 
considered source data.
It must be possible to verify all other data in the eCRFs against source documents in the 
patients’ medical record, or in the location stated in the source data agreement.
13 Audits and Inspections
Authorized personnel from Clinical Quality Assurance, H Lundbeck A/S, 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 Practice15 and all other 
relevant regulations.
The patients must be informed that authorized 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 request relevant parts of 
medical records.  No personal identification apart from the screening or randomization 
number will appear on these copies.


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Patient data will not be disclosed to unauthorized third parties, and patient confidentiality will 
be respected 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.
If the risk/benefit evaluation changes after the study is terminated, 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
Symptoms of schizophrenia (primary endpoint for primary, secondary and exploratory 
objectives)
• Change from Baseline 2 to Week 14 in PANSS total score
16.2
Key Secondary Endpoints
Clinical impression (supportive of primary and secondary objectives)
• Change from Baseline 2 to Week 14 in CGI-S score 


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Functioning (supportive of explorative objective)
• Change from Baseline 2 to Week 14 in PSP total score
16.3
Secondary Endpoints
Global clinical impression (supportive of primary and secondary objectives)
• Change from Baseline 2 to Week 14 in CGI-S score
Proportion of responders at Week 14 (supportive of primary and secondary objectives) 
• Responders criteria will be blinded to investigator and described in the Clinical Study 
Protocol Addendum - Unmasked Information. 
Negative symptoms (supportive of secondary objective)
• Change from Baseline 2 to Week 14 in NSA-16 total score
• Change from Baseline 2 to Week 14 in PANSS Negative Factor Score (Marder Negative 
Score)
16.4
Exploratory Endpoints
Cognitive performance (supportive of explorative objective)
• Change from Baseline 2 to Week 14 in BACS score
Functioning (supportive of exploratory objective)
• Change from Baseline 2 to Week 14 in PSP total score
Analysis of patient historical and demographic predictors of response (supportive of 
exploratory objective) in:
• Patients with ED TRS
• Patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit
• Patients with ED TRS versus LD TRS
• Patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit 
versus patients with LD TRS
• Genetic analysis (for example CYP genotyping and polygenetic risk-score)
16.5
Safety Endpoints
• Adverse events
• Absolute values and changes from Baseline 2 in Phase B in clinical safety laboratory tests, 
vital signs, weight, and ECG parameters
• Potentially clinically significant clinical safety laboratory test values, vital signs, weight, 
and ECG parameter values
• C-SSRS categorisation


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17 Statistical Methodology
17.1
Responsibilities
Biostatistics, H. Lundbeck A/S will perform the statistical analyses described below.
The population (pop) PK analysis will be performed and reported separately by the 
Department of Quantitative Pharmacology, H. Lundbeck A/S, or a designee CRO.
17.2
Analysis Sets
The following analysis sets will be used to analyse and present the data for each of the above 
groups of patients:
• all-patients-treated set Period A (APTS_A) – all patients who took at least one dose of IMP
during Period A (risperidone or olanzapine)
• all-patients-treated set (APTS) – all randomized patients who took at least one dose of 
double-blind IMP (Lu AF35700, risperidone, or olanzapine) after randomization 
(Period B)
• full-analysis set (FAS) – all patients in the APTS who had a valid Baseline 2 assessment
and at least one valid post-baseline 2 assessment of PANSS total score
The patients and data will be classified according to these definitions at a Classification 
Meeting held after all the data have been entered in the study database and verified and before 
the blind has been broken.
17.3
Descriptive Statistics
In general, summary statistics (n, arithmetic mean, standard deviation, 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.
17.4
Patient Disposition
Patient disposition will be summarized by treatment group and include the number of patients 
who completed and the number of patients who withdrew from treatment, as well as the 
number of patients in each analysis set (APTS_A, APTS, and FAS). 
Disposition will be summarized for the APTS_A by risperidone/olanzapine treatment group 
and for the APTS by randomized treatment group.
The number of patients who withdrew from treatment will be summarized by treatment group 
and primary reason for withdrawal as well as by treatment group and all reasons for 
withdrawal.


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Withdrawals during Period A will be summarized for the APTS_A by risperidone/olanzapine 
treatment group. Withdrawals during Period B will be summarized for the APTS by 
randomized treatment group.
Separate summaries of reasons for withdrawal from treatment will be presented by 
randomized treatment group for withdrawn patients who returned to the Efficacy Follow-up 
Visit.
17.5
Demographics and Baseline Characteristics
Demographics (sex, age, race), other baseline characteristics (for example height, weight, 
BMI, and mean waist circumference, number of years from first schizophrenia diagnosis, and 
number of failed antipsychotic treatment episodes), and baseline efficacy variables will be 
summarized by treatment group.
Demographics will be summarized for the APTS_A by risperidone/olanzapine therapy group 
and for the APTS by randomized treatment group.
17.6
Recent and Concomitant Medication
Recent and concomitant medication will be summarized by anatomical therapeutic chemical 
(ATC) code and generic drug name by treatment group.
Recent and concomitant medications will be summarized for the APTS_A by 
risperidone/olanzapine therapy group and for the APTS by randomized treatment group.
17.7
Exposure and Compliance
Exposure will be calculated per patient and summarized for the APTS_A by 
risperidone/olanzapine treatment group and for the APTS by randomized treatment group.
Compliance is defined as the percentage of planned medication taken by patients while 
enrolled in the study.
Compliance will be summarized for the APTS_A by risperidone/olanzapine therapy group 
and for the APTS by randomized treatment group.
Compliance during Period A will be summarized by risperidone/olanzapine therapy group for 
the responders, non-responders, and total patients in the APTS_A. 
Descriptive statistics will be summarized for the final dose level of risperidone/olanzapine 
that patients were titrated to in Period A by risperidone/olanzapine treatment group for the 
ATPS.


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17.8
Period A Evaluation
The percentage of patients responding to treatment at Weeks 1, 2, 4, and 6 as well as at any of 
those weeks will be summarized by treatment (risperidone/olanzapine) for APTS_A. 
Response criteria are blinded to investigators and described in Clinical Study Protocol 
Addendum - Unmasked Information.
The efficacy variables collected during Period A will be summarized by week number for the 
total patients in APTS_A and by treatment (risperidone/olanzapine) for APTS_A.
17.9
Efficacy Analyses
17.9.1
General Efficacy Analysis Methodology
The efficacy analyses will be based on the FAS. A two-sided significance level of 0.05 is 
used unless otherwise indicated. For all endpoints, the effects of Lu AF35700 will be 
evaluated by testing the null hypothesis of no difference to the risperidone/olanzapine group. 
17.9.2
Analysis of the Primary Endpoint
Changes from Baseline 2 in total PANSS score at Weeks 7, 8, 10, 12, and 14 will be analysed 
using a restricted maximum likelihood (REML)-based mixed model for repeated measures 
(MMRM) approach. All patients in the FAS will be included with their observed data in 
Period B. Data retrieved at Week 14 from withdrawals will not be included in the primary 
analysis.
The model will include the fixed, categorical effects of treatment (Lu AF35700 and 
risperidone/olanzapine groups), strata (ED and LD), country, visit, treatment-by-visit 
interaction, strata-by-visit interaction, fixed covariates of baseline scores (Baseline 1 and 
Baseline 2) and baseline scores-by-visit interaction.  An unstructured (co)variance structure 
will be used to model the within-patient errors.  If this analysis fails to converge, the 
following within patient (co)variance structures will be applied, in the listed order; first-order 
ante-dependence, heterogeneous compound symmetry, compound symmetry. The Kenward-
Roger approximation will be used to estimate denominator degrees of freedom. 
The primary comparisons will be the difference between Lu AF35700 and 
risperidone/olanzapine at Week 14 based on the least squares means for the treatment-by-visit 
interaction effect. The estimated mean difference between Lu AF35700 and 
risperidone/olanzapine based on this model will be reported with two-sided symmetric 95% 
confidence intervals and corresponding p-values.
In addition to the analysis specified above, the following analysis will be performed for the 
primary endpoint, supportive of secondary and exploratory objectives:


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The changes from Baseline 2 to Week 14 in PANSS total score for patients with TRS first 
diagnosed with schizophrenia ≤5 years prior to the Screening Visit, ED TRS, LD TRS, ED 
TRS versus LD TRS, and patients with TRS first diagnosed with schizophrenia ≤5 years prior 
to the Screening Visit versus LD TRS will be examined using the same methodology as 
described for the primary endpoint. The model will include the fixed, categorical effects of 
treatment (Lu AF35700 and risperidone/olanzapine), subgroup, country, visit, treatment-by-
visit-by-subgroup interaction, and fixed covariates of baseline scores (Baseline 1 and Baseline 
2) and baseline scores-by-visit interaction. The patients will be classified into subgroups 
according to whether they were first diagnosed with schizophrenia ≤5 years prior to the 
Screening Visit, between 5 and 10 years prior to the Screening Visit, or ≥10 years prior to the 
Screening Visit. From this model, the difference between treatments within each subgroup at 
Week 14 will be derived from the treatment-by-visit-by-subgroup interaction. Also, this 
interaction will be used to explore the efficacy in patients with ED TRS versus LD TRS by 
estimating (AF35700 ED – risperidone/olanzapine ED) versus (AF35700 LD –
risperidone/olanzapine LD). In the same way, the efficacy in patients with TRS first 
diagnosed with schizophrenia ≤5 years prior to the Screening Visit versus patients with LD 
TRS will be explored.
17.9.3
Sensitivity Analyses of the Primary Endpoint
Some level of missing data is expected, and the primary analysis, MMRM, is valid under the 
assumption that the data is Missing at Random. Simulation studies do suggest that MMRM is
sufficiently robust to accommodate some level of data Missing Not at Random (MNAR). 
Since it is unclear to which degree missing data will be of the MNAR type, choosing a pre-
specified primary analysis valid under MNAR accurately will be very difficult.
As such, sensitivity analyses valid under relevant cases of data MNAR will be performed. In 
particular, pattern-mixture models will be used. Different delta (imputation of how much 
worse response patients who withdraw would have compared to those who complete the 
treatment period and who have the same profile up to time to withdrawal) will be applied.47
MMRM model as the primary analysis, including the retrieved data for withdrawals, will be 
performed.
The sensitivity analyses described above will be further specified in more detail in the 
statistical analysis plan (SAP).
The primary analysis will be repeated for the subgroup of patients that were randomized after 
protocol amendment PA3 was approved in the relevant country.


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17.9.4
Testing Strategy for Primary and Key Secondary Endpoints
If Lu AF35700 is superior to risperidone/olanzapine for the primary endpoint, the null 
hypothesis of no difference between Lu AF35700 compared to risperidone/olanzapine will be 
tested for the key secondary endpoints in the following order:
1.
Change from Baseline 2 to Week 14 in CGI-S score
2.
Change from Baseline 2 to Week 14 in PSP total score
Change in PSP will only be tested if Lu AF35700 is superior to risperidone/olanzapine for 
CGI-S.
No multiplicity corrections will be applied for secondary and exploratory endpoints.
17.9.5
Analysis of the Key Secondary and Secondary Endpoints
For the analysis of the CGI-S, PSP total score, NSA-16, and PANSS Negative Factor scores, 
the same model as that described for the primary endpoint will be used.
The proportion of patients responding at Week 14 will be compared for Lu AF35700 versus
risperidone/olanzapine using logistic regression with strata, country and treatment as factors 
and baseline PANSS total scores (Baseline 1 and Baseline 2) as covariates. The analysis will 
be done for observed cases without imputation, as well as for the whole FAS, imputing non-
response for all patients discontinued prior to Week 14. The definition of response will be 
defined in the statistical analysis plan.
Additional responder analyses using alternative cut-offs of the primary endpoint will be used 
to present the efficacy as measured by changes from Baseline 2 in PANSS total score.
17.9.6
Analysis of the Exploratory Endpoints
For the analysis of BACS and PSP, the same model as that described for the primary endpoint 
will be used.
The proportion of patients with TRS first diagnosed with schizophrenia ≤5 years prior to the 
Screening Visit, patients with ED TRS, LD TRS, the difference between the proportions of 
patients with ED TRS and LD TRS, and the difference between the proportions of patients 
with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit and LD 
TRS responding at Week 14 will be compared for Lu AF35700 versus risperidone/olanzapine 
using logistic regression with country as a factor and treatment-by-subgroup interaction and 
baseline (Baseline 1 and Baseline 2) PANSS total score as covariate. The analysis will be 
done for observed cases without imputation, as well as for the whole FAS, imputing non-
response for all patients discontinued prior to Week 14. Similar to the secondary endpoint, 
different response criteria will be investigated.
The analyses described above assess the distinct categorical effect of early-in-disease and 
late-in-disease. Furthermore, the effect of number of years from first schizophrenia diagnosis, 


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and number of failed antipsychotic treatment episodes will be investigated by performing 
MMRM and logistic regression models with the different predictors included as factors or 
covariates, both interacting with treatment, as appropriate. These analyses will be detailed in
the statistical analysis plan.
The effect of genetic analysis will be investigated for the primary and secondary endpoints.  
These analyses will be detailed in a separate protocol (and statistical analysis plan), and 
reported separately.
The effect of MMN at Baseline 2 will be investigated for the primary and secondary 
endpoints by including the amplitude of deviant response to auditory stimulus as covariate in 
MMRM and logistic regression models similar to those described above. In addition the 
change in MMN from Baseline 2 to Week 14 will be summarised. These analyses will be 
detailed in the statistical analysis plan.
17.9.7
Analysis of Subgroups
Per design of the study, there are two distinct subgroups: patients with ED TRS and those 
with LD TRS. In addition, there is a subgroup of the ED TRS population defined as patients
with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit. The 
analyses for these are described above.
The analysis of the primary endpoint will be repeated by excluding patients with extremely 
low drug plasma concentrations (Lu AF35700/olanzapine/risperidone/ 9-hydroxy-risperidone) 
in Period B (Weeks 8, 10, and 14). Two analyses will be performed:
1.
Include patients with values > LLOQ at Weeks 8, 10, and 14
2.
Selection of patients based on population pharmacokinetic analysis. This analysis will be 
reported separately
17.9.8
Pharmacokinetic Analysis
The population pharmacokinetics of Lu AF35700, olanzapine and risperidone/ 9-hydroxy-
risperidone will be assessed by means of nonlinear mixed effect modelling, including 
covariate analysis. If deemed relevant, exploratory pharmacokinetic/pharmacodynamic 
(PK/PD) analysis will be performed, which will be specified in the population PK/PD analysis 
plan, prepared by the Department of Quantitative Pharmacology, Lundbeck, before the study 
is unblinded. The results from the analyses will be reported by the Department of Quantitative
Pharmacology, or designee CRO, in a separate population PK/PD report.
Individual oral clearance estimates will be estimated for each drug 
(Lu AF35700/olanzapine/risperidone) and be compared with historical data in order to find 
extreme values. The extreme clearance values will together with plasma concentrations below 
LLOQ form the basis for identifying patients with extremely low plasma concentrations to be 
used for the analysis of subgroups (see section 17.9.7). Further details will be given in the 
population PK/PD analysis plan.


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Plasma concentrations of Lu AF35700 and metabolite (Lu AF36152), risperidone, 9-hydroxy-
risperidone, and olanzapine, as well as CYP genotype will be listed.
17.10 Safety Analyses
17.10.1 Analysis of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:
• pre-treatment adverse event – an adverse event that starts on or after the date the patient 
signed the Informed Consent Form and prior to the date of first dose of IMP
• treatment-emergent adverse event (TEAE) – an adverse event that starts or increases in 
intensity on or after the date of first dose of IMP
Adverse events, sorted by system organ class (SOC) and preferred term, will be summarized 
by randomized treatment group for the APTS and by treatment for APTS_A.
Information from the optional exit interview related to AEs (serious and non-serious) shall 
flow back to the investigator via a special AE report prepared for exit interviews. The non-
serious AEs reported during these interviews will be reported in separate listings in the CSR.
The serious AEs shall be reported as specified in this protocol for SAEs occurring in the 
safety follow up period.
Allocation of TEAEs to Study Periods
TEAEs will as a minimum be allocated into study Periods A and B. Further division may be 
performed. This will be defined in the Statistical Analysis Plan.
17.10.2 Analysis of Other Safety Endpoints
Clinical safety laboratory tests, vital signs, weight/BMI, ECG parameters, and C-SSRS scores 
will be summarized by randomized treatment group using descriptive statistics. Potentially 
clinically significant (PCS) values will be flagged and summarized.
All safety analyses for period B will be based on the APTS, and all safety analyses for period 
A will be based on APTS_A. 
17.11 Interim Analyses
No interim analyses are planned.
17.12 Sample Size and Power
The study will include 245 randomized patients per group in Period B.


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Assuming a common standard deviation of 15, there is approximately 93% power for showing 
a mean improvement in change in PANSS total score of 5.25 (standardized effect size 0.35) of 
Lu AF35700 over risperidone/olanzapine with 196 patients per treatment arm.
Assuming an information loss of ~20% due to dropout in Period B, n=245 (=196/0.8) will be 
randomized to each treatment group, bringing the total number of randomized patients to 490. 
With an attrition rate of ~40% in Period A, approximately 817 (=490/0.6) patients are 
expected to be enrolled to meet the target of randomizing 490 patients in Period B.
A blinded re-assessment of sample size will be considered if the blinded standard deviation
estimate or the dropout rate deviates from the assumptions. A maximum of 300 randomized 
patients per treatment arm will be allowed in the study. The pooled standard deviation will be 
estimated from the Covariance Parameter Estimates from an MMRM model identical to the 
one to be used for the primary analysis, except without the effect of treatment, that is:
The model will include the fixed, categorical effects of country, visit, stratum-by-visit 
interaction as well as the fixed covariates of baseline scores (Baseline 1 and Baseline 2) and 
baseline scores-by-visit interaction. An unstructured (co)variance structure will be used to
model the within-patient errors.
17.13 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 Biostatistics, H. Lundbeck A/S before the study is 
unblinded.
18 Clinical Study Report and Publications
18.1
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared by 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. 
Lundbeck will submit results information
• to ClinicalTrials.gov
• to EudraCT


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The primary publication based on this study must be published before any secondary 
publications.Authors of the primary publication must fulfil the criteria defined by the 
International Committee of Medical Journal Editors (ICMJE).48
18.4
Summary of Clinical Study Results
Upon completion of the study and when the study results are available, the patient has the 
right to be informed by the investigator about the overall study results.
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.15
20 Finance
20.1
Site Agreements
The financial agreements for each site are addressed in one or more documents.  Both parties 
must sign the agreements before each 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.
20.3
Equipment
Equipment owned or rented by Lundbeck that has been provided to the sites for use during the 
study must be returned at the end of the study.


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Appendix I
Clinical Study Protocol Authentication and Authorization


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Clinical Study Protocol
Authentication and Authorization
Study title:
Interventional, randomized, double-blind, active-controlled study of the efficacy of 
Lu AF35700 in patients with early-in-disease or late-in-disease treatment resistant 
schizophrenia
Study No.:
17303A (Anew)
Edition No.:
4.0
Date of edition:
7 September 2018
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 of Biostatistics:
Head of Medical Safety
Authorization
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
Head of Clinical Research 
Development Psychiatry:


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Appendix II
Recent and Concomitant Medication:
Disallowed or Allowed with Restrictions


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Recent and Concomitant Medication:
Disallowed or Allowed with Restrictions 
Drug Class
Details
Any investigational drug

Prohibited <30 days before the Screening Visit
Antidepressants

Patients must not initiate any antidepressants in this study. Patients who have been 
treated with the same antidepressant for at least 3 months prior to Visit 1 may continue 
on this antidepressant in the study as long as its continuation on stable dose is anticipated 
throughout the study.
Anticonvulsants 

Prohibited <7 days before Baseline 1
Antipsychotics

Except for risperidone or olanzapine supplied as IMP

Patients currently receiving depot or long-acting antipsychotics can be enrolled after an 
adequate discontinuation period, defined as skipping one full treatment cycle plus 3 days 
(See  “Study Methodology, Period A”) 
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: benztropine (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 should be 
avoided. However, if delaying administration of efficacy and safety scales is not feasible, the 
scales should still be administered and the use of the anticholinergic medication documented, 
including a notation of the drug name, dose, and time of administration on the eCRF.
Anxiolytics and hypnotics

If the patient receives anxiolytic or hypnotic therapy prior the Screening Visit, 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 8 mg/day, orally or 
intramuscularly), oxazepam (up to 80 mg/day, orally), and alprazolam (up to 4 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 should be 
avoided. However, if delaying administration of efficacy and safety scales is not feasible, the 
scales should still be administered and the use of the anxiolytics or hypnotics documented, 
including a notation of the drug name, dose, and time of administration on the eCRF.
Non-benzodiazepine sleep 
aids

Non-benzodiazepine sleep aids are allowed, provided doses are stable ≥6 weeks prior to 
Baseline 1.
Mood stabilizers

Prohibited <7 days before Baseline 1 except valproic acid which should be tapered down 
carefully and be completed ≥2 days prior to Baseline 1.
Varenicline

Prohibited <7 days before Baseline 1
Barbiturates

Prohibited


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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
Psychotropic agents not 
otherwise specified

Prohibited

Cough preparations containing ephedrine, pseudoephedrine and codeine are allowed for 
treatment duration for a maximum of 1 week
Dopamine depleting agents

Prohibited <7 days before Baseline 1
Antihistamines

Antihistamines except loratadine, desloratidine, cetirizine, levocetirizine, mizolastine 
and fexofenadine are prohibited
Steroids

Systemic use is prohibited, inhaled and topical use is allowed
Hormones

Prohibited except for thyroid hormone replacement, contraceptives (oral, patch), 
estrogen and progesterone replacement therapy as well as benign prostatic hyperplasia 
treatment.
Vitamins, nutritional
supplements, and
non-prescritpion herbal 
preparations

Prohibited during the study, unless approved in advance by the Medical Monitor
Potent CYP2D6 inhibitors

See Panel for Prohibited CYP sub-enzyme influencing medications below
Potent CYP1A2 inhibitors

See Panel for Prohibited CYP sub-enzyme influencing medications below
Potent CYP3A4 inducers

See Panel for Prohibited CYP sub-enzyme influencing medications below
Hydroxyzine and 
diphenhydramine (not 
allowed for the treatment of 
agitation, anxiety, insomnia 
or EPS) 

Except for short term treatment (<14 days) of allergy 
Propranolol (for akathisia or 
tremor)

Prophylaxis treatment should be avoided

In case of need of rescue medication a maximum dose of 60mg/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 should be avoided.
However, if delaying administration of efficacy and safety scales is not feasible, the scales 
should still be administered and the use of propranolol documented, including a notation of 
the drug name, dose, and time of administration on the eCRF.
[Country-specific Protocol 
Amendment 1 for UK:
Concomitant drugs
associated with risk of QT
prolongation
-
As all the IMPs have a risk of QT prolongation, clinicians should use caution when
prescribing the concomitant use of drugs associated with a risk of QT prolongation in this 
study, especially in the elderly.]


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Prohibited CYP Sub-enzyme Influencing Medications
Selected CYP2D6 Inhibitors
Celecoxib
Chloroquine
Chlorpheniramine
Clemastine
Diphenhydraminea
Fluoxetine
Halofantrine
Hydroxyzinea
Methadone
Paroxetine
Pyrilamine
Quinidine
Terbinafine
Tripelennamine
Selected CYP1A2 Inhibitors
Ciprofloxacin
Enoxacin
Fluvoxamine
Selected CYP3A4 Inducers
Armodafinil
Bosentan 
Carbamazepine
Efavirenz
Etravirine
Modafinil
Nafcilin
Phenytoin 
Rifampicin
a
Short term use for allergy is permitted

SAP_001.pdf: 
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Study 17303A – Statistical Analysis Plan
Page 1 of 55
Statistical Analysis Plan
Interventional, randomized, double-blind, active-
controlled study of the efficacy of Lu AF35700 in patients 
with early-in-disease or late-in-disease treatment-resistant 
schizophrenia
Lu AF35700
Study No.:
17303A
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Biostatistician:
, Biostatistics
SAP date:
13 March 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.


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Table of Contents
List of Panels and Tables.......................................................................................................................5
List of Abbreviations and Definitions of Terms ..................................................................................6
Consequences of Early Study Termination..........................................................................................7
1
Objectives.......................................................................................................................................8
1.1
Primary Objective................................................................................................................8
1.2
Secondary Objective............................................................................................................8
1.3
Exploratory Objective(s) .....................................................................................................8
1.4
Safety Objective(s) ..............................................................................................................8
2
Study Design...................................................................................................................................8
3
Definitions ......................................................................................................................................9
3.1
Definition of Early-in and Late-in-Disease .........................................................................9
3.2
Definition of Baseline..........................................................................................................9
3.3
Definition of Periods..........................................................................................................10
4
Endpoints .....................................................................................................................................10
4.1
Primary Endpoint...............................................................................................................10
4.2
Secondary Endpoints .........................................................................................................10
4.3
Exploratory Endpoints.......................................................................................................11
4.4
Safety Endpoints................................................................................................................11
5
Analysis Sets.................................................................................................................................11
6
Descriptive Statistics ...................................................................................................................11
7
Patient Disposition.......................................................................................................................12
7.1
Summary of Patient Disposition........................................................................................12
7.2
Withdrawal ........................................................................................................................12
8
Demographics and Other Baseline Characteristics..................................................................13
9
Recent and Concomitant Medications.......................................................................................14
10
Exposure and Compliance..........................................................................................................14
11
Period A Evaluation ....................................................................................................................15
12
Efficacy.........................................................................................................................................15
12.1
General Efficacy Analysis Methodology...........................................................................15
12.2
Testing Strategy.................................................................................................................16
12.3
Analysis Methodology for the Primary Endpoint..............................................................16
12.3.1
Primary Analysis of the Primary Endpoint ........................................................16
12.3.2
Rationale for Selected Analysis Method for the Primary Endpoint...................16
12.3.3
Evaluation of Model Assumptions for the Primary Analysis of the Primary 
Endpoint .............................................................................................................17
12.4
Analysis of the Secondary Endpoints................................................................................17
12.5
Analysis of the Exploratory Endpoints..............................................................................18
13
Safety ............................................................................................................................................18
13.1
Adverse Events..................................................................................................................18


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13.1.1
General Methodology for Adverse Events.........................................................18
13.1.2
Coding of Adverse Events..................................................................................19
13.1.3
Classification of Adverse Events .......................................................................19
13.1.4
Allocation of TEAEs to Treatment Periods........................................................19
13.1.5
Presentation of Adverse Events..........................................................................19
13.1.6
Presentation of Treatment-emergent Adverse Events........................................20
13.1.7
Presentation of Deaths........................................................................................20
13.1.8
Presentation of Serious Adverse Events.............................................................20
13.1.9
Presentation of Adverse Events Leading to Withdrawal....................................20
13.2
General Methodology for Other Safety Data.....................................................................20
13.3
Clinical Safety Laboratory Test Data ................................................................................21
13.3.1
Data Presentation................................................................................................21
13.3.2
Potential Drug-induced Liver Injury (DILI).......................................................22
13.3.3
Changes in Fasting Lipid and Fasting Glucose Concentrations.........................22
13.4
Vital Signs and Weight......................................................................................................23
13.5
Electrocardiograms (ECGs)...............................................................................................23
13.6
Other Safety Endpoints(s)..................................................................................................23
13.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) ..........................................23
14
Pharmacokinetic/Pharmacodynamic Analyses.........................................................................25
15
Interim Analyses..........................................................................................................................25
16
Sample Size Considerations........................................................................................................25
17
Statistical Software......................................................................................................................26
18
Changes to Analyses Specified in the Protocol..........................................................................26
19
Details on Data Handling............................................................................................................28
19.1
Derived Variables..............................................................................................................28
19.1.1
Missing Items .....................................................................................................28
19.1.2
PANSS ...............................................................................................................28
19.1.3
CGI.....................................................................................................................30
19.1.4
PSP .....................................................................................................................30
19.1.5
16-item Negative Symptom Assessment (NSA-16)...........................................30
19.1.6
Subjective Well-being under Neuroleptics - Short Version (SWN-S)...............31
19.1.7
Brief Assessment of Cognition in Schizophrenia (BACS) – (US/Europe 
only) ...................................................................................................................31
19.1.8
Premorbid Adjustment Scale (PAS)...................................................................31
19.2
Assigning Data to Visits, and Rules for Selecting Value at Visits ....................................32
19.2.1
Laboratory Tests and ECG.................................................................................32
19.2.2
Other assessments ..............................................................................................34
19.3
Handling of Missing or Incomplete Dates/Times..............................................................35
19.3.1
IMP Start and Stop Dates...................................................................................35
19.3.2
Lifetime Schizophrenia History .........................................................................36
19.3.3
Medical Disorder Start and Stop Dates..............................................................36
19.3.4
Medication Start and Stop Dates........................................................................36
19.3.5
Adverse Event Start and Stop Dates...................................................................38
19.4
Data with Multiple Records...............................................................................................40
19.4.1
Medication Dose Changes..................................................................................40
19.4.2
Adverse Events Changing in Intensity or Seriousness.......................................40
References.............................................................................................................................................42


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Appendices
Appendix I
Statistical Analysis Plan  Authentication and Authorization.......................43
Appendix II
Study Flow Chart .............................................................................................45
Appendix III
SAS® Code.........................................................................................................50
Appendix IV
PCS Criteria......................................................................................................52


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List of Panels and Tables
Panel 1
Study Design.......................................................................................................................9
Panel 2
Classification of Fasting Lipids and Fasting Glucose...................................................23
Panel 3
C-SSRS Scores .................................................................................................................25
Panel 4
Maximum Number of Missing Items on Rating Scales................................................28
Panel 5
PANSS Items and Subscales ...........................................................................................29
Panel 6
Derivation of PANSS total Score and Subscales...........................................................29
Panel 7
Visit Windows not Randomized Patients or at or before first IMP in Period B 
for Randomized Patients:  Laboratory Tests and ECG...............................................32
Panel 8
Visit Windows After first IMP in Period B Randomized Patients: Laboratory 
Tests and ECG .................................................................................................................33
Panel 9
Visit Windows Patients Withdrawn from Treatment in Period A:  PANSS, 
CGI-S, C-SSRS, and Vital signs .....................................................................................34
Panel 10
Visit Windows Patients Withdrawn from Treatment in Period B:  PANSS, 
CGI-S, C-SSRS, and Vital signs .....................................................................................35
Panel 11
Visit Windows Patients Withdrawn from Treatment in Period B:  PSP, NSA-
16, SWN-S.........................................................................................................................35
Table 1
PCS Criteria for Clinical Safety Laboratory Tests ......................................................53
Table 2
PCS Criteria for Vital Signs, Weight/BMI and Waist Circumference.......................55
Table 3
PCS Criteria for ECG Parameters.................................................................................55


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List of Abbreviations and Definitions of Terms
ADaM
Analysis Data Model
AE
Adverse event
ALT
alanine aminotransferase
APES
all-patients-enrolled set
APRS
all-patients-randomized set
APTS
all-patients-treated set
APTS_PC
all-patients-treated set prospective confirmation period 
BACS
Brief Assessment of Cognition in Schizophrenia
CGI-S
Clinical Global Impression – Severity
CI
confidence interval
CSR
Clinical Study Report
DILI
potential drug-induced liver injury
eCRF
electronic case report form
ED
Early-in-disease
FAS
full-analysis set
IMP
investigational medicinal product
LD
Late-in-disease
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed model for repeated measurements
PANSS
Positive and Negative Syndrome Scale
PAS
Premorbid Adjustment Scale
PCS
potentially clinically significant
PSP
Personal And Social Performance
PYE
patient years of exposure
QQ
quantile-quantile
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS®
statistical software package from the SAS® Institute
SDTM
Study Data Tabulation Model
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
TFL
Tables, Figures and Listings
TRS
Treatment resistant schizophrenia
WHO-DDE
World Health Organization Drug Dictionary 


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Consequences of Early Study Termination
After the results from the first pivotal study with Lu AF35700 in treatment-resistant 
schizophrenia patients, Study 16159A, were revealed, it was decided to prematurely terminate 
Study 17303A. At the time of study termination, a total of 68 patients were randomized, 
compared to the 150 patients originally planned (plus approximately 20 patients from Japan). 
As a consequence some of the planned analyses will no longer be performed, due to the low 
number of patients randomized. In particular, no subgroup analyses will be performed, 
including the analyses for early-in-disease and late-in-disease patient populations and 
analyses of age sex, race, regional or baseline characteristics. The detailed changes can be 
seen in Section 18. For traceability, the original objectives are kept, but the endpoints and 
statistical analyses presented in the SAP will reflect the set of analyses that will be done.


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1
Objectives
1.1
Primary Objective
• to assess the efficacy of Lu AF35700 on symptoms of schizophrenia in patients with early-
in-disease (ED) or late-in-disease (LD) treatment–resistant schizophrenia (TRS)
For definitions of ED and LD, see section 3.1.
1.2
Secondary Objective
• to assess the efficacy of Lu AF35700 on symptoms of schizophrenia in patients with ED 
TRS
• to assess the efficacy of Lu AF35700 on negative symptoms of schizophrenia in patients 
with ED or LD TRS
1.3
Exploratory Objective(s)
• to assess the efficacy of Lu AF35700 in patients with ED TRS versus patients with LD 
TRS
• to assess the efficacy of Lu AF35700 in patients with TRS first diagnosed with 
schizophrenia ≤5 years prior to the Screening Visit versus patients with LD TRS
• to assess the efficacy of Lu AF35700 in patients with TRS first diagnosed with 
schizophrenia ≤5 years prior to the Screening Visit
• to assess the effect of Lu AF35700 on cognitive performance and functioning in patients 
with ED TRS, LD TRS, or patients with TRS first diagnosed with schizophrenia ≤5 years 
prior to the Screening Visit
• to explore patient historical and demographic characteristics predictive of response to 
treatment with Lu AF35700
• to explore genetic markers (genotype and expression) predictive of, or associated with, 
response to treatment with Lu AF35700
1.4
Safety Objective(s)
• to evaluate the safety and tolerability of Lu AF35700 in patients with ED or LD TRS
2
Study Design
This is an interventional, multi-national, multi-site, randomized, double-blind, parallel-group, 
active-controlled, fixed-dose study. The time point of randomization was blinded to patients 
and blinded rater.
An overview of the study is presented in Panel 1. The criteria for response/non-response 
evaluated at Baseline 2 were kept blinded to patients and investigators. 


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Patients were randomized in Period B (randomization ration 1:1 to Lu AF35700 10 mg, or 
continued risperidone/olanzapine). Within the ED and LD subgroups, patients were stratified, 
ensuring an equal proportion of patients randomized to each treatment.
Panel 1
Study Design
The study includes an efficacy follow-up of withdrawn patients at the projected time of the 
primary endpoint. Patients withdrawn during Period B (except those withdrawing due to 
withdrawal of consent) will be asked to attend an Efficacy Follow-up visit at the date of their
last scheduled visit of Period B (Week 14) for the assessment of efficacy, safety and 
concomitant medication.
3
Definitions
3.1
Definition of Early-in and Late-in-Disease
Early-in-disease (ED): The patient has schizophrenia, first diagnosed<10 years prior to the 
Screening Visit and according to DSM-5TM and confirmed by the Mini International 
Neuropsychiatric Interview (MINI).
Late-in-disease (LD): The patient has schizophrenia, first diagnosed ≥10 years prior to the 
Screening Visit and according to DSM-5TM and confirmed by the Mini International 
Neuropsychiatric Interview (MINI)
3.2
Definition of Baseline
There are two baselines defined in this study (for details about data handling, see section 
19.2):
      NOTE: Randomized patients will be stratified in both Period B 
treatment arms across early-in-disease and late-in-disease 
patients (approx 2:1)


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Baseline 1 - the latest value captured at or before nominal Visit 2 (Week 0 of Period A).   
Baseline 2 (randomized patients) – for efficacy variables the latest value captured at or before 
nominal Visit 6  (Week 0 of Period B), and for pharmaco-economic and safety variables the 
latest value captured at nominal Visit 6 
For C-SSRS, the Baseline 1 will be the assessment at Visit 2, and no Baseline 2 will be
defined (see section 13.6.1).
In the TFLs and CSR, Baseline 1 will be named Baseline and Baseline 2 will be named 
Randomization.
3.3
Definition of Periods
Classification of adverse events into periods is defined in section 13.1.4. 
For other data, assessments from the withdrawal visit and unscheduled visits will be assigned 
to a nominal visit (see section 19.2.1 and 19.2.2), and then all nominal visits will be assigned 
to a period:
• Screening Period (3 weeks) - Starts at the Screening Visit and continues up to, and 
including, Visit 2
• Period A (6 weeks) - Starts after Visit 2 and continues up to, and including, Visit 6
• Period B (8 weeks) - Starts after Visit 6 and continues up to, and including, Visit 11
• Follow-Up Period - Starts after last Visit in Period A (non-randomized patients) or B
(randomized patients)
In the TFLs and CSR, Period A will be named Prospective Confirmation Period, and Period B 
will be named Double-blind Treatment Period.
4
Endpoints
Data handling rules are described in the sections 19.1 and 19.2.2.
In the TFLs and CSR, Baseline 2 in the endpoints will be named Randomization, and week 
will be specified relative to Period B, e.g. the primary endpoint will be Change from 
Randomization to Week 8 in PANSS total score.
4.1
Primary Endpoint
• Change from Baseline 2 to Week 14 in PANSS total score
4.2
Secondary Endpoints
• Change from Baseline 2 to Week 14 in CGI-S score
• Proportion of responders at Week 14 (supportive of primary and secondary objectives) 
(Response defined as ≥20% reduction in PANSS total score from Baseline 2)


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• Change from Baseline 2 to Week 14 in NSA-16 total score
• Change from Baseline 2 to Week 14 in PANSS Negative Factor Score (Marder Negative 
Score)
4.3
Exploratory Endpoints
• Change from Baseline 2 to Week 14 in BACS score
• Change from Baseline 2 to Week 14 in PSP total score
4.4
Safety Endpoints
• Adverse events
• Absolute values and changes from Baseline 2 in Period B in clinical safety laboratory tests, 
vital signs, weight, and ECG parameters
• Potentially clinically significant clinical safety laboratory test values, vital signs, weight, 
and ECG parameter values
• C-SSRS
5
Analysis Sets
The sets of patients to be analysed are defined as follows:
• all-patients-enrolled set (APES)
• all-patients-treated set prospective confirmation period (APTS_PC) – all patients who 
took at least one dose of study medication during Period A (risperidone or olanzapine)
• all-patients-randomized set (APRS) – all patients randomized
• all-patients-treated set (APTS) – all randomized patients who took at least one dose of 
double-blind study medication (Lu AF35700, risperidone, or olanzapine) 
• full-analysis set (FAS) – all patients in the APTS who had a valid Baseline 2 assessment 
and at least one valid post Baseline 2 assessment of PANSS total score. Assessments 
made at the Efficacy Follow-up Visit will not be considered as valid post-baseline 
assessments for classification into FAS
The patients and data will be classified into the analysis sets during a Classification Meeting
according to the definitions above after the study database has been released, but before the 
blind has been broken.
Note, in the protocol, APTS_PC was named all-patients-treated set Period A (APTS_A).
6
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.


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Unless otherwise specified, data listings will include site, period, treatment group (for 
randomized patients both treatment group in Period A and randomized treatment group will 
be included), patient screening number, sex, age, race, and weight at Baseline (for randomized 
patients weight at both Baseline 1 and Baseline 2 will be included).
Summaries for Period A will be based on APES or APTS_PC, and will be done by Period A 
treatment group (risperidone and olanzapine) for safety, and for the total group for efficacy. 
Summaries for Period B will be based on APRS or APTS, and will be done by randomized
treatment group (LuAF35700 and risperidone/olanzapine).
7
Patient Disposition
7.1
Summary of Patient Disposition
Patient disposition for Period A will be summarized for the APES, and for Period B for the 
APRS. 
Patient disposition will include the number of patients who completed treatment, and the 
number of patients who withdrew from treatment, as well as the number of patients in each 
analysis set defined for the period (see section 5). The summaries for Period A will also 
include number of screened patients and number of screening failures.
7.2
Withdrawal
Withdrawal summaries and plots will be presented separately for Period A and B and based 
on APTS_PC and APTS, respectively. 
Withdrawals from treatment in Period A and Period B will be summarized by primary reason 
for withdrawal as well as by all reasons for withdrawal based on the APTS_PC and APTS, 
respectively.
Summary of patients who were withdrawn from treatment in Period A due to efficacy 
response or not being adherent (taking less than 80% of assigned IMP during Period A) are
described in section 11.
Patients who withdrew from treatment or study will be listed. The listing will include both 
periods, indicating the period when the patient was withdrawn, the reason type (primary and 
secondary reason for withdrawal from treatment), the reason, specification of other reason, the
number of days from Visit 2 until withdrawal from treatment, the number of days on IMP
(IMP in Period A for non-randomized patients and IMP in Period A – IMP in Period B for 
randomized patients), and a flag indicating if drug code was broken.
Kaplan-Meier plots of time to withdrawal from treatment in Period B will be presented based 
on the APTS. The time will be calculated from the date of first dose of IMP in Period B to the 


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date of completion or withdrawal from treatment. Patients who completed treatment will be 
regarded as censored.
8
Demographics and Other Baseline Characteristics
The summaries will be done for APTS_PC and APTS. 
Demographics (sex, age, and race), height, weight, BMI, and waist circumference at Baseline 
1, years since diagnosis of schizophrenia (both as continuous and in categories ≤ 5 years, 6-9 
years and ≥ 10 years), Premorbid Adjustment Scale (PAS), social histories, and efficacy 
variables at Baseline 1 will be summarized. For patients in the APTS, weight, BMI, waist 
circumference, and efficacy variables at Baseline 2 will also be summarized.
From the lifetime schizophrenia history collected, the following parameters will be 
summarised:
• Duration of untreated psychosis: Time from first psychotic symptoms to date of first 
antipsychotic drug treatment or first psychiatric hospitalization for psychosis
• Number of antipsychotic treatment periods and response
o
Treatment periods: Antipsychotic treatment answered yes
o
Adequate treatment periods: Antipsychotic treatment, adequate duration, 
adequate dose and considered predominantly adherent all answered yes 
o
Adequate periods with adequate response: Adequate treatment period and 
demonstrate adequate response answered yes
o
Adequate periods without adequate response: Adequate treatment period and 
demonstrate adequate response answered no
• Cumulative time in symptomatic psychosis: Cumulative time of all periods where 
persistent psychotic symptoms answered yes (regardless whether any treatment was 
administered or treatment period was adequate or not) 
• Demonstration of tolerance: Treatment periods where tolerance to antipsychotic drug 
treatment is answered yes
• Tardive dyskinesia: Treatment periods where persistent tardive dyskinesia is answered yes
• Hospitalizations: Periods with a new hospitalization
• Clozapine treatment trials: Number of adequate treatment periods where patient received 
treatment with Clozapine
Details for handling (partially) missing dates is described in Section 19.3.2.
Concurrent as well as relevant past medical, and neurological, and psychiatric disorders 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. A past medical, neurological or psychiatric disorder is a disorder that ended 
prior to the Screening Visit.


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9
Recent and Concomitant Medications
Recent and concomitant medication will be coded using the WHO Drug Dictionary 
(WHO-DDE).
Medications will be classified into categories according to the start and end date. Handling of
missing or incomplete dates are specified in section 19.3.4. 
The following categories will be defined:
• Medications started before first dose of IMP in Period B and discontinued prior to first 
dose of IMP in Period B (randomized patients in APTS) or started before Follow-up 
Period (non-randomized patients and randomized patients not in APTS)
• Medication started before first dose of IMP in Period B and continued after first dose of 
IMP in Period B
• Medication started at or after first dose of IMP in Period B and at or before Visit 11
(Primary Outcome or Withdrawal Visit) 
• Medication started after Withdrawal Visit for Patients Withdrawn from Treatment in
Period B and before the efficacy follow-up Visit 
Medications will be summarized by anatomical therapeutic chemical (ATC) code levels 2 and 
3, and generic drug name. The three first categories will be summarized separately.
All disallowed medications will be listed based on the APES. The listing will include the 
generic drug name, the duration, the start and end dates, and dosing information.
10 Exposure and Compliance
Exposure (days) to IMP will be defined for Periods A and B as:
Last date of IMP in the Period - Start date of IMP in the Period + 1.
Compliance for Periods A and B is defined as the percentage of planned medication taken by 
patients while enrolled in the study.
Compliance (%) with IMP for a period will be defined as:
End date period − Start date period + 1 −Number of non-compliant days 
End date period −Date of first IMP in period + 1
× 100
End date period for Period A is Visit 6/Withdrawal visit (patient withdrawn from treatment in
Period A) and for Period B Visit 11/Withdrawal Visit. Number non-compliant days is defined
as the sum of all non-compliant days reported in the period. A Non-compliant day is defined
as a day 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.


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Compliance will also be calculated separately for missed/less than full dose (using Number of 
days with missed or less than full dose in the compliance formula), and overdoses (using
Number of days with overdoses in the compliance formula).
Exposure, including patient years of exposure (PYE) and compliance, and mean plasma
concentration at Week 2 and 4 in Period A will be summarized for patients in APTS_PC (see
Section 11). PYE will be calculated as the sum of the number of days of exposure to IMP for
each patient in a period, divided by 365.25 days.
The final dose level of risperidone/olanzapine that patients were titrated to in Period A will be
summarized by risperidone/olanzapine therapy group for the ATPS_A and ATPS.
Exposure and compliance in Period B will be summarized for the APTS.
Compliance with IMP will be categorized as ≤80% or >80% within each period. The number
and percentage of patients in each category for Period A will be summarized based on the
APTS_PC, and for Period B based on the APTS. The summary based on APTS_PC will also
be done by Period A non-response or response.
11 Period A Evaluation
The PANSS total score; PANSS Negative Symptoms, PANSS Positive Symptoms, and 
PANSS General Psychopathology subscale scores, and CGI-S score at Baseline 1 and in 
Period A will be summarized by week based on the FAS.
The time in the TFLs and CSR will be the nominal week in Period A, i.e. 0, 1, 2, 4, and 6. 
12 Efficacy
12.1
General Efficacy Analysis Methodology
For details about data handling, see section 19.1 and 19.2.2. 
If not otherwise stated, the efficacy analyses will be based on the FAS. For all endpoints, the 
effects of Lu AF35700 will be evaluated by testing the null hypothesis of no difference to the 
active control (risperidone or olanzapine).
The efficacy data collected after withdrawal from treatment were collected for a specific type 
of sensitivity analyses, which will no longer be performed. So the efficacy follow-up data 
collected will not be included in any efficacy analyses.
All tables and graphs will be presented by randomized treatment group.
All the p-values will be based on two-sided tests; the confidence intervals (CIs) will be two-
sided, and all analysed endpoints will be presented with p-values and 95% CIs.


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If not otherwise specified, the time in the TFLs and CSR will be the nominal week in Period 
B, i.e. 0, 1, 2, 4, 6, and 8. In the following description of the endpoints and analyses related to 
Period B, the time from Baseline 2 will be used.
Descriptive statistics for the absolute-and change from Baseline 2 efficacy scores will be
presented by week in Period B. The summaries for the absolute scores will also include the
Baseline 2 value.
12.2
Testing Strategy
No multiplicity corrections will be applied.
12.3
Analysis Methodology for the Primary Endpoint
12.3.1
Primary Analysis of the Primary Endpoint
Changes from Baseline 2 in PANSS total score at Weeks 1, 2, 4, 6, and 8 will be analysed 
using a restricted maximum likelihood (REML)-based mixed model for repeated measures 
(MMRM) approach. All patients in the FAS will be included.
The model will include the fixed, categorical effects of treatment (Lu AF35700 and 
risperidone/olanzapine groups), strata (ED and LD), visit, treatment-by-visit interaction, fixed 
covariates of baseline scores (Baseline 1 and Baseline 2) and baseline scores-by-visit 
interaction.  An unstructured (co)variance structure will be used to model the within-patient 
errors.  If this analysis fails to converge, the following within patient (co)variance structures 
will be applied, in the listed order; first-order ante-dependence, heterogeneous compound 
symmetry, compound symmetry.  The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. The SAS code for the primary analysis is shown in 
Appendix III.
The primary comparisons will be the difference between Lu AF35700 and 
risperidone/olanzapine at Week 8 based on the least squares means for the treatment-by-visit 
interaction effect. The estimated mean difference between Lu AF35700 and 
risperidone/olanzapine based on this model will be reported with two-sided symmetric 95% 
confidence intervals and corresponding p-values.
12.3.2
Rationale for Selected Analysis Method for the Primary Endpoint
The collected assessments from the PANSS total score are generally considered as continuous 
endpoints, and they are analysed using methods based on observations following a normal 
distribution. Given the repeated observation of approximately normally distributed data, an 
MMRM analysis using all available data is chosen for the primary analysis. Covariates are 
included in the model based on an approach including key factors representing study design 
features (visit, treatment and stratification factor (ED, LED)), and baseline and randomization 
levels of PANSS total score to account for differences in baseline and randomization level of 


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the PANSS total score and its predictive ability. When the MMRM analysis includes the 
individual factors mentioned as well as interaction of visit and treatment, and visit and 
baseline/randomization scores, and applies an unstructured covariance, as described in section 
12.3.1, it allows for flexibility in modelling the development over time and similarly provides 
robust estimation, even under some deviation from the assumption of normality.
This MMRM analysis estimates the treatment difference that would have been seen, had the 
drug been taken as directed. The pharmacological effect estimated by this MMRM analysis is 
considered a relevant measure to evaluate the efficacy of treatment in schizophrenia. In 
schizophrenia symptoms are treated, and therefore it is considered clinically relevant to 
investigate the effect that can be obtained on symptom level, if the prescribed medication 
treatment is taken in the prescribed period.
The MMRM analysis provides an unbiased estimate of the treatment effect under the 
assumption that missing data are missing-at-random (MAR). Published data support the 
robustness of the MMRM analysis regarding protection against type I error and against bias, 
also in situations with a non-negligible proportion of missing data. Using extensive 
simulations, it has been demonstrated that the type I error is only affected to a limited extent 
and that the bias is small under the assumption that 1/3 of the missing data are missing-not-at-
random (MNAR), even when there is a severe imbalance between the treatment groups in the 
proportion of withdrawals.1
12.3.3
Evaluation of Model Assumptions for the Primary Analysis of the Primary 
Endpoint
The assumption of normality will be investigated on an exploratory basis by inspection of a 
QQ-plot of the residuals.
The assumption of homoscedastic residuals will be investigated on an exploratory basis by 
inspection of a scatter-plot of the residuals versus the fitted values and by week.
12.4
Analysis of the Secondary Endpoints
Change from Baseline 2 in CGI-S, NSA-16 and PANSS Negative Factor Score (Marder 
Negative Score) will be analyzed using the same methodology as that described for the 
primary endpoint (see section 12.3.1).
Response is defined as ≥ 20% reduction in PANSS total score from Baseline 2. Please note, 
that for calculation of percentage change in PANSS total score, 1 will be subtracted from each 
item before calculating the percentage change, see section 19.1.
The proportion of patients responding at Week 8 will be compared for Lu AF35700 versus
active control using logistic regression with treatment as factor. The analysis will be done 
both for observed cases (OC) without imputation as well as for the whole FAS, imputing non-
response (NRI) for missing observations at Week 8. The logistic regression model will be 
fitted using the maximum likelihood (ML) method and the logit link function. The odds ratios 


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for AF 35700 compared to risperidone/olanzapine will be estimated from the model and 
presented with p-values based on the likelihood ratio test and 95% CIs based on the profile 
likelihood. 
12.5
Analysis of the Exploratory Endpoints
Change from Baseline 2 to Week 8 in BACS will be analyzed by analysis of covariance 
(ANCOVA). The model will include the fixed, categorical effects of treatment (Lu AF35700 
and risperidone/olanzapine groups), strata (ED and LD) and fixed covariates of baseline 
scores (Baseline 1 and Baseline 2).
Change from Baseline 2 in PSP will be analyzed using the same methodology as that 
described for the primary endpoint (see section 12.3.1).
13 Safety
13.1
Adverse Events
13.1.1
General Methodology for Adverse Events
Summaries for Period A will be based on APTS_PC, and summaries for Period B will be 
based in APTS, respectively. Only stop-dates for ongoing events at Primary Outcome or 
Withdrawal Visit, and new SAEs are collected in the safety follow-up period. Therefore, 
adverse events in the safety Follow-up Period for non-randomized patients, and adverse 
events in the follow-up period for randomized patients will be included in summaries for 
Period A and Period B, respectively (periods are defined in section 13.1.4).
Tables by preferred term and tables by system organ class (SOC) and preferred term will be 
sorted in descending order by the percentage of patients in the total treatment group for Period 
A, and the Lu AF35700 treatment group in Period B.
Unless otherwise specified, the summaries of adverse events will include the number and 
percentage of patients with an adverse event.
If not otherwise stated, listings will be based on the APTS_PC and presented for all periods. 
Listings of adverse events will be sorted by site, treatment group (information about both 
treatment group in Period A and randomized treatment group will be included for randomized
patients), patient screening number, and adverse event start date, and include preferred term, 
investigator term, period where AE has onset, adverse event start date, days since first IMP
intake (days since first IMP in Period A and Period B will be included for randomized
patients), 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 included. Imputed adverse event start-or stop 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).


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13.1.2
Coding of Adverse Events
Adverse events will be coded using MedDRA, version 20.0 or later.
13.1.3
Classification of Adverse Events
An adverse event will be classified as a Treatment Emergent Adverse Events (TEAE)
according to the time of onset of the adverse event (for handling of incomplete start dates, see
section 19.3.5):
Treatment-emergent adverse event (TEAE) - an adverse event that starts, or change from non-
serious to serious, or increases in intensity compared to the preceding intensity at or after date 
of first IMP in Period A.
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.
13.1.4
Allocation of TEAEs to Treatment Periods
Adverse events will be allocated to periods according to the date of onset of the adverse event
(for handling of incomplete start dates, see section 19.3.5):
• Screening Period – an adverse event that starts before date of first IMP in Period A
• Period A – an adverse event that starts at or after the date of first IMP in Period A and at or 
before Visit 6 or Withdrawal Visit (non-randomized patients), or before date of first IMP 
in Period B (randomized patients).
• Period B – an adverse event that starts at or after the date of first IMP in Period B and at or 
before Visit 11 or Withdrawal Visit
• Follow-up Period – an adverse event that starts after last Visit in Period A (nonrandomized
patients) or B (randomized patients)
13.1.5
Presentation of Adverse Events
All adverse events will be listed for the APES, including a flag for TEAE and indication of 
the period in which the AE started.
For each period an overview of the PYE, numbers, and percentages of patients with TEAEs, 
serious adverse events (SAEs), adverse events leading to withdrawal, and patients who died 
will be provided based on the APTS_PC and APTS respectively. For TEAEs, SAEs, and 
adverse events leading to withdrawal, the total number of events will be included.


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13.1.6
Presentation of Treatment-emergent Adverse Events
The following summaries will be provided for Period A and Period B:
• TEAEs by SOC and preferred term
• TEAEs by preferred term
The following summaries will be provided for Period B:
• 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 with onset within the first 2 weeks in Period A based on APTS_A, and TEAEs within 
the first 2 weeks in Period B based on APTS will be presented by preferred term.
13.1.7
Presentation of Deaths
All adverse events for patients who died will be listed.
13.1.8
Presentation of Serious Adverse Events
All SAEs will be listed.
Treatment-emergent SAEs in Period A and Period B will be presented by:
• SOC and preferred term
• preferred term
13.1.9
Presentation of Adverse Events Leading to Withdrawal
All adverse events leading to withdrawal will be listed.
TEAEs leading to withdrawal in Period A and Period B will be summarized for
• SOC and preferred term
• preferred term
13.2
General Methodology for Other Safety Data
For details about data handling, see section 19.1, 19.2.1, and 19.2.2.
Summaries based on Period A will be based on the APTS_PC, and Period B based on the
APTS.
The denominators for the summaries of a given variable will be based on the number of
patients with non-missing values at a given week or during the assessment period. All


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available post-Baseline 1/Baseline 2 assessments in the period will be included in the
identification of the last assessment in a Period.
For patients with post-Baseline 1/Baseline 2 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 adverse events for patients with PCS values will be listed by treatment group and patient
screening number and include the PCS value, the assessment date and the change from
baseline (for the period) of the PCS value, the preferred term for the adverse event, start date,
start period, 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.
If relevant, shift tables displaying shifts of out-of-the-reference range from Baseline 2 to any
week in Period B will be provided for a test and include the numbers and percentages of
patients.
For selected variables, the following graphical presentations may be provided:
• box plots by week and the last assessment
• patient line plots with all available assessments. Reference lines for reference ranges 
and/or PCS limits may also be included. If more than one value is available at a given 
assessment time point, the minimum/maximum value will be used in the plots.
13.3
Clinical Safety Laboratory Test Data
13.3.1
Data Presentation
The clinical safety laboratory test values will be presented either in conventional or Système 
International (SI) units. The PCS criteria for the clinical safety laboratory tests are shown in
Appendix IV.
Descriptive statistics for the laboratory tests in Period A and Period B, both absolute values
and changes from Baseline 1/Baseline 2, will be presented by test and week and the last
assessment in the Period. The summaries for the absolute values will also include summaries
for Baseline 1 and Baseline 2, respectively.
The number and percentage of patients with at least one PCS low value or PCS high value at
any post-Baseline 1 assessment in Period A and at any post-Baseline 2 assessment in Period B
will be summarized by test. 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 sex.


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13.3.2
Potential Drug-induced Liver Injury (DILI)
Signals of DILI will be assessed according to the FDA guideline2 using the following criteria:
• alanine 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
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
• BILI >2xULN AND
• ALP<2
In the summaries, each patient should be counted only once using the maximum assessment, 
or the most severe for the combined criteria.
Patients fulfilling any of the individual criteria in Period B (ALT/AST, ALP, or BILI) will be 
listed, and the listing will include all available ALT, AST, BILI, and ALP, BILI, EOSLE, and 
GGT values (absolute and normalised), sorted by assessment date in ascending order. 
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 
Period B. The criteria for the individual tests will be considered separately (that this means 
that the maximum of ALT/AST and the maximum BILI may not occur at the same 
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 Period B. The test 
values will be normalised by the ULN (unit xULN) and the Y-axis will be on the log scale. 
All assessments at Visit 6 or in Period B will be included, and the time will be days since first 
IMP in Period B. Reference lines for the day of first-and last IMP in Period B will be 
included. If there is more than one assessment at the same time point for a test, the maximum 
value will be used.
13.3.3
Changes in Fasting Lipid and Fasting Glucose Concentrations
Shift tables displaying the change in classification for fasting lipids and fasting glucose (Panel 
2) from Baseline 2 to any visit in Period B will be provided for each test and include the 
numbers and percentages of patients. Note that only fasting tests will be considered.


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Panel 2
Classification of Fasting Lipids and Fasting Glucose
Laboratory Test
Unit
Classification 
Fasting S-triglycerides
mmol/L
Normal: 0.5-2.8; Borderline: >2.8 and < 4.2; PCS High: ≥ 4.2
Fasting total S-cholesterol
mmol/L
Normal: 3.2-5.2; Borderline: >5.2 and < 6.2; PCS High: ≥ 6.2
Fasting S-LDL cholesterol
mmol/L
Normal: 0.5-2.6; Borderline: >2.6 and < 4.9; PCS High: ≥4.9
Fasting S-HDL cholesterol
mmol/L
Normal: 0.9-1.6; PCS Low < 0.9
Fasting S- glucose
mmol/L
Normal:  4.5-5.6; Borderline: >5.6 and <7; PCS High: ≥7
13.4
Vital Signs and Weight
The PCS criteria for vital signs and weight are in Table 2.
Descriptive statistics for the body measurements (weight, BMI, and waist circumference) in
Period A and Period B, both absolute values and changes from Baseline 1/Baseline 2, will be
presented by variable and week and the last assessment in the Period. The summaries for the
absolute values will also include summaries for Baseline 1 and Baseline 2, respectively.
Descriptive statistics for the vital signs parameters in Period B, both absolute values and
changes from Baseline 2, will be presented by test and week and the last assessment in the
Period. The summaries for the absolute values will also include summaries for Baseline 2.
The number and percentage of patients with at least one PCS low value or PCS high value at
any post-Baseline 1 assessment in Period A and at any post-Baseline 2 assessment in Period B
will be summarized by vital signs and body measurement parameter. All available
assessments in the period will be included in the evaluation of PCS.
13.5
Electrocardiograms (ECGs)
The PCS criteria for the ECG parameters are in Table 3.
Descriptive statistics for the ECG parameters in Period B, both absolute values and changes
from Baseline 2, will be presented by test and week and the last assessment in the Period. The
summaries for the absolute values will also include summaries for Baseline 2.
The number and percentage of patients with at least one PCS low value or PCS high value at
any post-Baseline 1 assessment in Period A and at any post-Baseline 2 assessment in Period B
will be summarized by ECG parameter. All available assessments in the period will be
included in the evaluation of PCS.
13.6
Other Safety Endpoints(s)
13.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
The Withdrawal Visit is windowed to a nominal visit according to the specification in section 
19.2.2.


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The C-SSRS was assessed at the following periods:
• for lifetime (using the Baseline/Screening Version) – the C-SSRS assessment obtained at
screening that collects a lifetime recall
• in the past 3 months at screening (using the Baseline/Screening Version) – the C-SSRS 
assessment obtained at screening that focuses on the last 3 months
• at Baseline 1 (using the Since Last Visit Version) – the C-SSRS assessment obtained at 
Visit 2 that collects information from the Screening Visit to Visit 2
• Period A (using the Since Last Visit Version) – based on the C-SSRS assessments obtained 
after Visit 2 and at or before Visit 6
• Period B (using the Since Last Visit Version) – based on the C-SSRS assessments obtained 
after Visit 6 and at or before Visit 11
• Safety Follow-up (using the Since Last Visit Version) – based on the C-SSRS assessment
obtained after last visit in Period A (non-randomized patients) or Period B (randomized
patients)
For each period, it will be assessed whether the patient had no suicidal ideation or behaviour
(patients that answered ‘No’ to all items in Panel 3 at visit(s) included in the period), and for 
each item in Panel 3 whether the most severe score (given by the ascending order in Panel 3) 
in the period was the item. Non-suicidal self-injurious behaviour is considered separately, and 
for each period it will be identified whether the patient had non-suicidal self-injurious 
behaviour (patients that answered ‘Yes’ to the item at any of the visit(s) included in the 
period). Missing C-SSRS scores will not be imputed.
For patients with any post-baseline suicidal behaviour (C-SSRS items 6 to 10), listings will be 
prepared including all C-SSRS scores based on the APES.
The derived C-SSRS items in each period will be summarized based on the APTS (data from
the Safety Follow-up will only be included in the listing of patients with any post-baseline 
suicidal behaviour). The summaries will show the numbers and percentages of patients with 
no suicidal ideation or behaviour, the number and percentages of patients for each item for 
which the most severe score is the item, and number and percentages of patients with non-
suicidal self-injurious behaviour.


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Panel 3
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)
14 Pharmacokinetic/Pharmacodynamic Analyses
A separate analysis plan for pharmacokinetic/pharmacodynamic analyses will be prepared by 
the Department of Quantitative Pharmacology, H. Lundbeck A/S.
15 Interim Analyses
No interim analysis is planned.
16 Sample Size Considerations
The sample size calculations as described in the protocol were as described below. As 
described in the preface, the study was prematurely stopped, and a total of 68 patients were 
randomized. Hence, the study is no longer powered to detect any of the mentioned difference. 
For reference, the protocol text is included below:
The sample size calculations are based on the US/Europe part of the study alone.
The study will include 75 randomized patients per group.  
With 75 randomized patients per group in Period B, and assuming a common standard 
deviation of 18, there is approximately 80% power for showing a mean improvement in 
change in PANSS total score of 8 (standardized effect size 0.44) of Lu AF35700 over 
risperidone/olanzapine; with standard deviations of 16 and 20, there is approximately 86% 
and 70% power, respectively, to detect a difference of 8. 
For the exploratory endpoint assessing efficacy in patients with ED TRS, with 50 randomized 
patients per group in Period B, and assuming a common standard deviation of 18, there is 
approximately 80% power for showing a mean improvement in change in PANSS total score 


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of 10 (standardized effect size 0.56) of Lu AF35700 over the active control; with standard 
deviations 16 and 20, there is approximately 87% and 70% power, respectively, to detect a 
difference of 10.  The a priori assumption is that patients with ED TRS are a more 
homogeneous subgroup of patients with TRS than the overall TRS population and therefore 
will demonstrate a greater effect size for improvement in PANSS score. 
Assuming an attrition rate of 40% in Period A, approximately 250 (=150/0.6) patients are 
expected to be enrolled to meet the target of randomizing 150 patients in Period B.  The 
number of enrolled patients may be adjusted to meet the target of 150 randomized patients in 
the US/Europe part of the study. 
In addition, it is planned to randomize approximately 20 patients from Japan.  No formal 
sample size calculations have been performed for the Japanese cohort. 
A blinded re-assessment of sample size will be considered if the blinded standard deviation 
estimate or the dropout rate deviates from the assumptions.  A maximum of 300 randomized 
patients per treatment arm will be allowed in the study.  The pooled standard deviation will 
be estimated from the Covariance Parameter Estimates from an MMRM model identical to 
the one to be used for the primary analysis, except without the effect of treatment, that is:
The model will include the fixed, categorical effects of region, Period A treatment, visit, 
stratum-by-visit interaction as well as the fixed covariates of baseline scores (Baseline 1 and 
Baseline 2) and baseline scores-by-visit interaction.  An unstructured (co)variance structure 
will be used to model the within-patient errors.
No sample size re-assessment was performed.
17 Statistical Software
The statistical software used will be SAS®, Version 9.4 or later.
18 Changes to Analyses Specified in the Protocol
The statistical methodology section in the protocol describes that the following three 
populations will be evaluated upon:
1.
US and Europe. This will be the study population
2.
Japan
3.
Pooled (US, Europe and Japan)
Only analyses based on the pooled population will be reported.
Period A treatment factor will not be included as a factor in the primary MMRM model. The 
rationale for the change is that the Period A treatment factor (olanzapine or risperidone) mixes 
up a pre-randomisation characteristic with the post-randomisation treatment received for those 
randomized to continued treatment. Thus it models a common difference between those that 


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receives different treatment (olanzapine or risperidone) in Period B with the difference in 
those receiving Lu AF35700 in Period B who were on olanzapine or risperidone in Period A. 
It seems unrealistic that the difference between the olanzapine and risperidone groups should 
be the same for those who continued to receive the olanzapine or risperidone treatment in
Period B as it is for those who only received olanzapine or risperidone in Period A. For this
reason the term “Period A treatment” should be removed from the model, both for the primary
analysis and from all similar analyses based on MMRM as well as the logistic regression
analyses.
It was planned to include region in the MMRM analysis. In total, 55 patients from Europe 
(Bulgaria and Russia), 6 from Japan and 7 from the USA were randomized. With this low 
numbers of patients, region is removed from all statistical models.
Due to the early termination of the study, and the reduced sample size, the analyses focusing 
on evaluating efficacy within/between early-in-disease and late-in-disease patient populations
will not be performed. Hence the following endpoints will not be evaluated:
Analysis of patient historical and demographic predictors of response (supportive of 
exploratory objective) in:
• Patients with ED TRS
• Patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit
• Patients with ED TRS versus LD TRS
• Patients with TRS first diagnosed with schizophrenia ≤5 years prior to the Screening Visit 
versus patients with LD TRS
• Genetic analysis (for example CYP genotyping and polygenetic risk-score)
The planned sensitivity analyses of the primary endpoint using Multiple Imputation Methods 
will not be performed.
For the responder analysis, the protocol stipulates a logistic regression model with Period A 
treatment, strata, region and treatment as factors and baseline PANSS total scores (Baseline 1 
and Baseline 2) as covariates. Due to the reduced sample size, only treatment will be included 
as factor.
The protocol describes “Additional responder analyses using alternative cut-offs of the 
primary endpoint …”. No such analysis will be performed.
The efficacy data collected after withdrawal from treatment were collected for a specific type 
of sensitivity analyses, which will no longer be performed. So the efficacy follow-up data 
collected will not be included in any efficacy analyses.
The relative time from Baseline 2 will be used in all displays related to Period B, i.e. Weeks 
0, 1, 2, 4, 6 and 8 instead of Week 6, 7, 8, 10, 12, 14. This affects only terminology and does 
not change any of the specified analyses.


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19 Details on Data Handling
19.1
Derived Variables
19.1.1
Missing Items
If ≤20% of the items are missing in the derivation of a variable based on a scale (see sections
19.1.2 to 19.1.6), the  missing items will be imputed with the mean of the recorded items. The 
maximum number of missing items corresponding to ≤20% are specified in Panel 4. If more 
than 20% of the items are missing, the score will be missing.
Panel 4
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 Psyhopathology subscale score
3
FACNEG
PANSS Negative symptoms factor score
1
FACPOS
PANSS Positive Symptoms factor score
1
FACDISOR
PANSS Disorganized Thought factor score
1
FACUNC
PANSS Uncontrolled Hostility/Excitement factor 
score
0
FACANDEP
PANSS Anxiety/Depression factor score
0
NSA-16
16-item Negative Symptom Assessment
3
SWNSTOT
Subjective Well-being under Neuroleptics
                      4
BACS
Brief Assessment of Cognition in Schizophrenia
(BACS)
1
19.1.2
PANSS
The PANSS3 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 Subscale Scores, Negative Subscale 
Score, and General Psychopathology Subscale Score. PANSS will also be grouped in five
factor scores: Negative symptoms, Positive Symptoms, Disorganized Thought, Uncontrolled 
Hostility/Excitement, and Anxiety/Depression. The PANSS items and the derivation of the 
total score, the subscale scores, and the factor scores are described in Panel 5 and Panel 6.


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Panel 5
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
Stereotype thinking
PANSS14
Preoccupation
PANSS29
Active social avoidance
PANSS30
Panel 6
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 Symptom subscale score
Sum of items PANSS01 to PANSS07
PANSS Negative Symptom 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
In the calculation of percentage change in PANSS total score, 1 will be subtracted from each 
item (i.e. 30 subtracted from the total scores) in the calculation.3 This transformation makes it 
possible to measure a change from the worst possible score to a complete absence of 
symptoms as a 100% change as the individual items ranges from 1 to 7 (e.g. if not doing the 


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subtraction, a change from the worst possible score of 210 to no lowest score corresponding 
to completely asymptomatic, the percentage change would be -86).
19.1.3
CGI
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 CGI-S takes the value 0 (= not assessed) the score will be set to missing.
19.1.4
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 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. 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. 
PSP Functional Remission is defined as a PSP total score ≥71. PSP Functional Response is 
defined as an improvement of at least 10 points of the PSP total score from Baseline.
The PSP domain D “Disturbing and aggressive behaviours” is categorized as “aggressive” 
(corresponding to ‘Mild’, ‘Manifest’, ‘Marked’, ‘Severe’, or ‘Very Severe’) and “non-
aggressive” (corresponding to ‘Absent’).
19.1.5
16-item Negative Symptom Assessment (NSA-16)
The NSA-166 is a clinician-rated scale designed to assess the presence, severity, and range of 
negative symptoms associated with schizophrenia. The NSA-16 consists of 16 items arranged 
in 5 subdomains: communication dysfunction (items 1 to 4), emotional/affective dysfunction 
(items 5 to 7), dysfunction in sociality (items 8 to 10), motivational/hedonic dysfunction 
(items 11 to 14), and reduced psychomotor activity (items 15 and 16), and a Global Negative 
Symptom Rating. NSA-16 items are rated on a 6-point scale from 1 (behaviour is normal) to 6 
(behaviour severely reduced), and a score of 9 if the item is not-rateable. The Global Negative 
Symptom Rating is rated from 1 (no evidence of symptoms) to 7 (extremely severe 
symptoms). The 16 items are summed to yield a total score ranging from 16 to 96 and the 
global rating ranges from 1 to 7. The NSA-16 can be administered by an experienced clinician 
after a short training session.


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19.1.6
Subjective Well-being under Neuroleptics - Short Version (SWN-S)
The SWN-S7 is a patient-rated scale designed to measure subjective effects of neuroleptic 
drugs to psychopathology, quality of life, and compliance over the past 7 days. The 20 items 
(10 positive and 10 negative statements) are grouped in 5 subscales (mental functioning, 
self-control, physical functioning, emotional regulation and social integration), Each subscale 
contains 4 items, each item is rated on a 6-point Likert scale, from 1 (not at all) to 6 (very 
much). A score is calculated for each subscale, and the total score ranges from 20 to 120, 
where the higher score indicates better well-being. 
19.1.7
Brief Assessment of Cognition in Schizophrenia (BACS) – (US/Europe only)
The BACS8,9 is an assessment battery that assesses the aspects of cognition found to be most 
impaired and most strongly correlated with outcome of patients with schizophrenia.
The BACS comprise six tasks for the evaluation of the following cognitive domains: Verbal 
Memory Test (verbal memory) score 0-75, Digit Sequencing Task (working memory) score 0-
28, Token Motor Task (motor function) score 0-100, Verbal Fluency (semantic fluency and 
letter fluency) score 0-60, Symbol Coding Task (attention and processing speed) score 0-110, 
and Tower of London (executive functions) score 0-22. The score for each task is assessed by 
counting the number of correct answers. The BACS composite score is calculated by 
summing the z-scores for each of the six measures (obtained by comparing each measure with 
a normative sample of 400 controls matched to the 2005 Census) and dividing by the healthy 
control SD.10 The BACS is designed for use by clinical psychologists, neuro-psychologists, or 
clinicians with prior experience in administering cognitive tests in patients with 
schizophrenia. 
19.1.8
Premorbid Adjustment Scale (PAS)
The PAS11 is a rating scale designed to evaluate the degree of achievement of developmental 
goals at each of several periods of a subject's life before the onset of schizophrenia (6 months 
prior to psychiatric symptomatology). The level of functioning evaluated in four major areas, 
at each of several periods of the subject's life, include: social accessibility- isolation, peer 
relationships, ability to function outside the nuclear family, and capacity to form intimate 
socio-sexual ties. Items evaluating age-appropriate functioning in these areas are repeated for 
each period of the subject's life. The four life period sections are as follows: Childhood, up to 
11 years; Early Adolescence, 12-15 years, Late Adolescence, 16-18 years; and Adulthood, 
19 years and beyond. The final section, labelled General, is more global, containing items 
meant to estimate the highest level of functioning that the subject achieved before becoming 
ill, as well as the time span and characteristics of onset of illness, and general information 
such as amount of education.
Each section of the scale contains a number of items with a scoring range of 0 (hypothetically 
healthiest) to 6 (hypothetically least healthy). When no information is available for a 
particular item, the item is not scored. The General section contains 9 items with a score 
range of 0 (best) to 6 (worst).  The ratings received for each item in a section are summed and 


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expressed as total score divided by the possible score. The possible score indicates the highest 
score obtainable by adding the maximum score for all items completed. An overall score for 
the whole scale is calculated by averaging the subscale scores for all the subscales rated for 
the patient.
19.2
Assigning Data to Visits, and Rules for Selecting Value at Visits
19.2.1
Laboratory Tests and ECG
Assessments at the Withdrawal Visit for patient withdrawn from treatment in Period A due to 
Did not fulfil inclusion criteria for Period B will be assigned to nominal Visit 6. Otherwise 
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 7 and Panel 8. Note, assessments after Visit 2 for enrolled patients that did
not have any IMP intake in Period A (i.e. enrolled patients not in APTS_PC) will be assigned 
to nominal Visit 1, and assessments after Visit 6 for randomized patients that did not have any 
IMP intake in Period B (i.e. randomized patients not in APTS) will be assigned to nominal 
Visit 6.
Panel 7
Visit Windows not Randomized Patients or at or before first IMP in Period B
for Randomized Patients:  Laboratory Tests and ECG
Time Window (days)
Nominal Visit Number
Nominal Visit 
Week
Nominal Visit 
Day
Laboratory Tests
ECG
V1 
-3
-21
≤day of first IMP
  ≤day of first IMP
V4
2
14
day after first IMP -
28
  NA
Not randomized patients
V6
      6
42
>28
     >day of first IMP
Randomized patients
V6
      6          
42              
29 -
day of first IMP in 
Period B
     day after first IMP -
     day of first IMP in
     Period B


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Panel 8
Visit Windows After first IMP in Period B Randomized Patients: Laboratory 
Tests and ECG
Nominal Visit 
Number
Nominal Visit 
Week
Nominal Visit 
Day
Time Window (days)
V8
  2
14
day after first IMP in Period B - 21
V9
  4
28
22 – 42
V11
  8
56
>42
Note that if the first IMP in Period A or Period B 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.
Baseline 1 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.
Baseline 2 will be the last assessment at or before Visit 6. If there is more than one 
assessment at the day of the last assessment, the Baseline 2 value will be selected using the 
same rule as for Baseline 1. For assessments recorded at Visit 6 that are after first IMP intake 
in Period B, the value will be considered as a valid Baseline 2 assessment if less than 7 days 
after the date of first IMP intake in Period B. 
For last post-baseline assessment in Period A/Period B, 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 assessment without recorded time will be considered to come after 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.


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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
Note, the visit value and baseline value may not be the same, e.g. if a patient has a scheduled 
assessment at Visit 1 and an unscheduled assessment at Visit 2 assigned to nominal Visit 1, 
the scheduled assessment at Visit 1 will be used as Visit 1 value, and the unscheduled 
assessment at Visit 2 will be used as Baseline 1 value.
Serum prolactin, HBA1c, and blood lipid profile are only scheduled to Visit 6 in Period A and 
Visit 11 in Period B, and the Withdrawal Visit will be assigned to Visit 6 for patients 
withdrawn from treatment in Period A and to Visit 11 for patients withdrawn from treatment 
in Period B.
19.2.2
Other assessments
For assessments only scheduled at Visit 6 in Period A, the Withdrawal Visit for patients 
withdrawn from treatment in Period A will be assigned to Visit 6. For assessments only 
scheduled at Visit 11 in Period B, the Withdrawal Visit for patients withdrawn from treatment 
in Period B will be assigned to Visit 11. 
Assessments at the Withdrawal Visit for patient withdrawn from treatment in Period A due to 
Did not fulfil inclusion criteria for Period B will be assigned to nominal Visit 6. Otherwise,
the assessment at the Withdrawal Visit for patients withdrawn from treatment in Period A and 
B will be assigned to a visit according to the windowing specified in Panel 9, Panel 10, and
Panel 11.
Panel 9
Visit Windows Patients Withdrawn from Treatment in Period A:  PANSS, 
CGI-S, C-SSRS, and Vital signs
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window (days)
V1 
-3
-21
NA
V2
0
0
NA
V3
1
7
Day after V2 - 11
V4
2
14
12-21
V5
4
28
22-35
V6 
6
42
>35


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Panel 10
Visit Windows Patients Withdrawn from Treatment in Period B:  PANSS, 
CGI-S, C-SSRS, and Vital signs
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window (days)
V6 
0
0
NA
V7
1
  7
Day after V6-11
V8
2
14
12-21
V9
4
28
22-35
V10
6
42
36-49
V11
8
56
>49
Panel 11
Visit Windows Patients Withdrawn from Treatment in Period B:  PSP, NSA-
16, SWN-S
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window (days)
V6 
0
0
NA
V9
4
28
day after V6-42
V11
8
56
>42
In analyses of efficacy (variables based on efficacy, exploratory, and Pharmaco-economic 
rating scales), if the Withdrawal Visit is assigned to the same visit as a scheduled visit, the 
assessments at the Withdrawal Visit will be used
For rating scales assessed at the Efficacy Follow-up Visit, the data from this visit will by 
definition be assigned to Visit 11 (Primary Outcome Visit). The follow-up efficacy data will 
only be used in a sensitivity analysis. In the sensitivity analysis, if there are more than one 
assessments assigned to the same visit, the value will be selected using the following 
prioritization order:
1.
Efficacy Follow-up Visit
2.
Withdrawal Visit
3.
Scheduled Visit
In analyses of safety scales using visit, if the Withdrawal Visit is assigned to the same visit as 
a scheduled visit, the assessments at the Scheduled Visit will be used. 
19.3
Handling of Missing or Incomplete Dates/Times
19.3.1
IMP Start and Stop Dates
A missing IMP start date for Period A will be imputed with the date of Visit 2, and a missing 
IMP start date for Period B will be imputed with the date of Visit 6.
A missing IMP stop date will not be imputed. 


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For enrolled patients, not in APTS_PC exposure will be set to 0, and for randomized patients 
not in APTS exposure in Period B will be set to 0.  Exposure for patients in APTS_PC/APTS 
with missing IMP start-or stop date in Period A/Period B will not be calculated.
19.3.2
Lifetime Schizophrenia History
For the lifetime schizophrenia  history, incomplete dates will be handled as follows. This 
applies both for calculating the duration of untreated psychosis and duration of treatment 
episodes:
• If only day is missing, this will be imputed to the 15th of the month
• If either start (first symptoms or start of treatment period) or end (first drug or end of 
treatment period) day is missing and start and end month and year are the same, the 
duration will be imputed to 15 days 
• If day and month are missing for both start and end time, and end-year is not the same as 
start-year, duration will be imputed as difference in years
• If day and month are missing for both start and end time, and end-year is the same as start-
year, duration will be imputed to 4 month. This is based on the average of all duration 
possibilities. E.g. if a patient start in January, he/she could end in January, February, …,
or December, with possible durations of ½, 1½, 2½, …, 11½ months. A patient with start 
in February could end in February,  March, … or December, with possible durations of 
½, 1½, 2½, …, 10½ months. And so on, ending with a patient with start in December 
who can only have a duration of ½ month. Averaging these possibilities yields 4.17 
months, which will be set as 4.
• A similar approach as above will be applied if only start-year is entered and end-year and 
month is entered (or vice versa). E.g. if end-month is February, then the duration can be 
1½ month (if start month is January) or ½ month (if start month is February). The 
duration will be set to the average of these two possibilities = 1 month.
19.3.3
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 ongoing status.
19.3.4
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 section 9. No duration will be calculated for 
medications with imputed start-or stop date, or for ongoing 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.
• Patients in APTS_PC that are not randomized or randomized patients not in APTS: 
•
Incomplete start date where day is missing


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•
If the start year and month are before the year and month of first IMP in Period A or 
after the year and month of the last visit in Period A (Visit 6 or Withdrawal Visit): 
date will be imputed with the medication start date assuming the day is the 1:st of the 
month
•
If the start year and month are at or after the year and month of first IMP in Period A 
and at or before Visit 6 (including the withdrawal Visit): date will be imputed with 
the latest of medication start date assuming the day is the 1:st of the month, and the 
date of first IMP 
•
Incomplete start date where month and day are missing
•
If the year is equal to the year of first IMP in Period A:  date will be imputed with the 
date of first IMP
•
If the year is before the year of first IMP, or after the year of Visit 6 (including the 
withdrawal Visit): date will be imputed with medication start date assuming the 
month and day are JAN the 1:st
•
Missing start date
The start date will be imputed with the date of first IMP in Period A
• 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 Period A or 
after the year and month of Visit 11 or Withdrawal Visit:  date will be imputed with 
the medication start date assuming the day is the 1st of the month
•
If the start year and month are at or after the year and month of first IMP in Period A 
and before year and month of the first IMP in Period B:  date will be imputed with 
the latest of medication start date assuming the day is the 1st of the month, and the 
date of first IMP in Period A. 
•
If the start year and month are at or after the year and month of first IMP in Period B 
and at or before Visit 11 or Withdrawal Visit:  date will be imputed with latest of 
medication start date assuming the day is the 1st of the month, and the date of first 
IMP in Period B. 
•
Incomplete start date where month and day are missing
•
If the year is equal to the year of first IMP in Period A and before the year of the first 
IMP in Period B: date will be imputed with the date of first IMP in Period A. 
•
If the year is equal to the year of first IMP in Period B:  date will be imputed with the 
date of first IMP in Period B. 


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•
If the year is before the year of first IMP in Period A, or after the year of Visit 11 or 
Withdrawal Visit:  date will be imputed with the medication start date assuming the 
month and day are JAN the 1st.
•
Missing start date
The start date will be imputed with the date of first IMP in Period B
Medication with incomplete end date where the day is missing, the date will be imputed with 
the minimum of the last day for the reported month and year and the end of study date. If 
month and day are missing for an end date, the date will be imputed with the minimum of 
medication end date assuming month and day are Dec 31, and the end of study date. If the 
medication end date is missing and the medication is not reported as ongoing, the end date 
will be imputed with the end of study date.
19.3.5
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 date, or for ongoing 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.
• Patients not in APTS_PC: 
•
Incomplete start dates where the day is missing
The start date will be imputed with the latest of adverse event start date assuming the 
day is the 1st of the month (e.g. if year=2017, and month=MAY, the start date would
assume to be 01MAY2017), and date of Visit 1
•
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 1:st, and date of Visit 1 
• Patients in APTS_PC that are not randomized or randomized patients not 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 Period A: 
the date will be imputed with the latest of adverse event start date assuming the day 
is the 1:st of the month, and Visit 1
•
If the start year and month are at or after the year and month of first IMP in Period A 
and at or before the last visit in Period A:  date will be imputed with the latest 


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adverse event start date assuming the day is the 1:st of the month, and the date of 
first IMP
•
If the start year and month are after the year and month of the last visit in Period A:  
date will be imputed with the latest of adverse event start date assuming the day is 
the 1:st of the month, and the day after last visit in Period A
•
Incomplete start date where month and day are missing
•
If the year is equal to the year of first IMP in Period A:  the date will be imputed with 
the date of first IMP
•
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 the 1st, and date of 
Visit 1
• 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 Period A: 
date will be imputed with the latest of adverse event start date assuming the day is 
the 1:st of the month, and date of Visit 1
•
If the start year and month are at or after the year and month of first IMP in Period A 
and before first IMP in Period B:  date will be imputed with latest of adverse event 
start date assuming the day is the 1st of the month, and the date of first IMP in Period 
A. 
•
If the start year and month are at or after the year and month of first IMP in Period B 
and at or before last visit in Period B:  date will be imputed with latest of adverse 
event start date assuming the day is the 1st of the month, and the date of first IMP in 
Period B.
•
If the start year and month are after the year and month of the last visit in Period B:  
date will be imputed with the latest of adverse event start date assuming the day is 
the 1:st of the month, and the day after last visit in Period B. 
•
Incomplete start date where month and day are missing
•
If the year is equal to the year of first IMP in Period B:  date will be imputed with the 
date of first IMP in Period B. 
•
If the year is equal to the year of first IMP in Period A and before the year of the first 
IMP in Period B:  date will be imputed with the date of first IMP in Period A. 


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•
If the year is before the year of first IMP in Period A:  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 1. 
Adverse events with incomplete end date 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 the minimum of 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 be 
imputed using the same algorithm as for incomplete start date 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:
• If the adverse event start date of the original event was 15MAY2017, the date of first IMP 
in Period B 17MAY2017, and the incomplete date for change in intensity 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 Period B 02MAY2017, and the incomplete date for change in intensity 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 Period B 13APR2017, and the incomplete date for change in intensity 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 an intensity change that come after, 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 come after.
19.4
Data with Multiple Records
19.4.1
Medication Dose Changes
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 section 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.
19.4.2
Adverse Events Changing in Intensity or Seriousness
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 


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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 
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 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 (e.g. for an adverse 
event originally reported as being mild and non-serious is reported as having changed to 
severe and serious on the same date, there will be one additional row in data). 
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 one 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. 


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References
1. 
Siddiqui O, Hung HMJ, O’Neill R. MMRM vs. LOCF: A comprehensive comparison based on 
simulation study and 25 NDA datasets. J Biopharm Stat. 2009; 19: 227-246.
2.
United States Food and Drug Administration (FDA). Guidance for Industry: Drug-induced liver 
injury: Premarketing Clinical Evaluation. July 2009.
3. 
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-76
4. 
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: 16-23.
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 LD, Summerfelt A, Lann H, Muller RJ. The Negative Symptom Assessment: A new 
instrument to assess negative symptoms in schizophrenia. Psychopharmacology Bulletin. 1989; 
25: 159-163.
7.
Naber D, Moritz S, Lambert M, Pajonk F, Holzbach R, Mass R, et al. Improvement of 
schizophrenic patients’ subjective well-being under atypical antipsychotic drugs. Schizophr Res. 
2001; 50: 79-88.
8. 
Keefe, R.S.E.¸ Goldberg, T.E., Harvey, P.D., Gold, J.M., Poe, M., Coughenour, L.  The Brief 
Assessment of Cognition in Schizophrenia:  Reliability, sensitivity, and comparison with a 
standard neurocognitive battery.  Schizophrenia Research. 2004; 68(2-3): 283-297.
9. 
Keefe, R.S.E, Poe, M., Walker T.M., Harvey P.D. The relationship of the Brief Assessment of 
Cognition in Schizophrenia (BACS) to functional capacity and real-world functional outcome.  
Journal of Clinical and Experimental Neuropsychology. 2006; 28: 260-269.  
10. Keefe RSE, Harvey PD, Goldberg TE, Gold JM, Walker TM, Kennel C, et al.   Norms and 
standardization of the Brief Assessment of Cognition in Schizophrenia (BACS). Schizophr Res. 
2008; 102: 108-115.
11. Cannon-Spoor HE, Potkln SG, Wyatt RJ. Measurement of Premorbid Adjustment in Chronic 
Schizophrenia. Schizophrenia Bulletin. 1982; 8(3): 470-484.


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Appendix I
Statistical Analysis Plan 
Authentication and Authorization


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Statistical Analysis Plan
Authentication and Authorization
Study title:
Interventional, randomized, double-blind, active-controlled study of the efficacy of 
Lu AF35700 in patients with early-in-disease or late-in-disease treatment-resistant 
schizophrenia
SAP date:
13 March 2013
This document has been signed electronically. The signatories are listed below.
Authentication
Biostatistician:
, Biostatistics
CRS:
, Clinical Affairs
& Operations
Authorization
Head of Biostatistics:


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Appendix II
Study Flow Chart








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g
This visit is only for patients that withdraw from Period B of the study before the scheduled Primary 
Outcome Visit (Week 14). Patients withdrawn during Period B (except those withdrawing due to withdrawal 
of consent) will be asked to attend an Efficacy Follow-up Visit at the date of their last scheduled visit of 
Period B (Week 14) for the assessment of efficacy, safety and concomitant medication. If patient attends the 
Withdrawal Visit 5 days prior to week 14 (planned Primary Outcome Visit) the patient should not be asked to 
come for an Efficacy Follow-up Visit.
h
If the date of a patient visit does not conform to the study plan, subsequent visits must be planned to maintain 
the visit schedule relative to the Baseline 1 Visit.
i
Includes Premorbid Adjustment Scale.
j
The patient's demographics information (age, sex, race) is to be recorded in the eCRF at Informed Consent 
Form signature date.
k
Informed Consent process for in-study pharmacogenetic testing is covered in section 4.2 of the protocol. For 
patients not qualifying for study Period B this sample must be discarded. 
l
BACS is applicable for US and Europe only.
m The blood samples for Lu AF35700 and metabolite or olanzapine, risperidone and 9-hydroxy-risperidone 
analysis should be drawn in association to the blood sampling for clinical safety laboratory tests (as 
applicable). Lu AF35700 and the major metabolite Lu AF36152 will only be analysed in samples from Visits
8, 9, and 11. Olanzapine, risperidone and 9-hydroxy-risperidone will be analysed in all six samples.
n
Exploratory gene expression profiling (RNA) and metabolomics/proteomics are an integrated part of the 
study and are covered by the main Patient Information Sheet.
o
Sampling for pharmacogenetics is optional and a separate Patient Information Sheet and Informed Consent 
Form covers this analysis. See protocol section 4.2. Sampling may be scheduled to another visit if needed.
p
Sampling for PBMC collection (US only) for possible future generation of induced pluripotent stem cells 
lines is optional and a separate Patient Information Sheet and Informed Consent Form covers this. Sampling 
may be scheduled to another visit if needed.
q
Sampling for Infectious Disease Testing refer only to patients enrolled for PBMC collection for which this is 
mandatory and will be addressed in the separate Patient Information Sheet/Informed Consent Form referring 
to the PBMC collection.
r
Signs and symptoms present at the Screening and/or Baseline 1 Visits (before IMP intake) must be recorded 
on an Adverse Event Form.
s
Only for adverse events ongoing at Primary Outcome/Withdrawal Visit and new SAEs.
t
Only to be taken if the laboratory test was clinically significantly abnormal at the Primary 
Outcome/Withdrawal Visit.
u
Results will remain blinded throughout the study.
v
One week supply will be provided for down-titration of blinded IMP
w The dose of IMP can be increased for efficacy or decreased for tolerability at scheduled or unscheduled visits 
during weeks 3 and 4. Last possible time point for dose adjustment is at Visit 5.
x
Urine drug screen tests can be repeated any time during the study at the discretion of the investigator.
y
S-βhCG pregnancy test should be performed at the Screening and the Primary Outcome/Withdrawal Visits 
for women of childbearing potential. Urine pregnancy test should be performed at Baseline 2 Visit and can be 
performed any time during the study at the discretion of the investigator. Any positive urine pregnancy test 
must be confirmed by a S-βhCG pregnancy test.
[Country-specific Protocol Amendment 1 for UK:
y
S-βhCG pregnancy test should be performed at the Screening and the Primary Outcome/Withdrawal Visits 
for women of childbearing potential. Urine pregnancy test should be performed at Baseline 1 (Visit 2), Visit 
5, Baseline 2 (Visit 6) and Visit 9 and can be performed any time during the study at the discretion of the 
investigator. Any positive urine pregnancy test must be confirmed by a S-βhCG pregnancy test.]


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Appendix III
SAS® Code


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SAS® Code
Primary analysis
The SAS code for the primary analysis of the primary endpoint described in section 12.3.1
will be:
proc mixed data = xxx noclprint order = internal method = reml;
class NOMWEEK2 STRATA TRT02P USUBJID;
model CHG = 
TRT02P STRATA NOMWEEK2 NOMWEEK2*TRT02P BASE1
BASE2 BASE1*NOMWEEK2 BASE2*NOMWEEK2 / ddfm = kr;
repeated NOMWEEK2 / subject = USUBJID type = un;
lsmeans NOMWEEK2*TRT02P / diff cl;
quit;


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Appendix IV
PCS Criteria


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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 GSTAL
µg/L
≥ 20
(alpha-GST)
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
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


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Laboratory Test
CDISC Term
Unit
PCS LOW
PCS HIGH
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
Urine
Urinary pH
PH
≤ 4
≥ 9
S=serum; B=whole blood; U=urine


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Table 2
PCS Criteria for Vital Signs, Weight/BMI and Waist Circumference
Parameter
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
C
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
PRAG
Msec
≥ 260
QRS interval
QRSAG
Msec
≥ 150
QT interval
QTAG
Msec
≥ 500
Derived Time Interval
Heart rate
EGHRMN
beats/min
< 50 and
decrease ≥ 15 
≥ 120 and
increase ≥ 15
QTcB interval
QTCBAG
Msec
< 300
> 500 or
increase > 60 
QTcF interval 
QTCFAG
Msec
< 300
> 500 or
increase > 60
Increase/decrease is relative to the baseline value