Conditions: Cushing's Syndrome Ectopic Corticotropin Syndrome Adrenal Adenoma Adrenal Carcinoma AIMAH PPNAD
Keywords: Cushing's syndrome osilodrostat LCI699 ectopic corticotropin syndrome adrenal adenoma adrenal carcinoma ACTH-Independent Macronodular Adrenal Hyperplasia AIMAH Primary Pigmented Nodular Adrenal Dysplasia PPNAD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
The study aim was to investigate the efficacy and safety of Osilodrostat in patients with Cushing's syndrome due to causes other than Cushing's disease in Japan.

Detailed description:
This was a Phase II, single arm, open-label, dose titration, multi-center study which consisted of two distinct Study Periods plus an optional extension period in non-CD patients with CS. The 3 Study Periods (two distinct Study Periods plus an optional extension period) were as follows:

Study Period I \[Week 0 (Day 1) to Week-12\]: Study Period I was the dose titration period to achieve a stable therapeutic dose and to assess the efficacy and safety of osilodrostat.

The dosing regimen of osilodrostat in this study was titrated according to the following escalation sequence: osilodrostat 2 mg bid, 5 mg bid, 10 mg bid, 20 mg bid, and 30 mg bid. Dose adjustments were based on the serum cortisol values measured by the local lab at each site. Osilodrostat titration was done weekly for the initial 4-weeks, up to a maximum dose of 10 mg bid.

The mean of three 24-hour UFC (mUFC) values were measured to evaluate the efficacy in this period.

Study Period II (After Week-12 to Week-48): Study Period II was the period to assess the sustainability of efficacy and long term safety.

During Study Period II, only patients who tolerated and agreed to continue osilodrostat treatment continued on the study. The patient was administered with the stable therapeutic dose which was achieved in the Study Period I.

Optional extension period (After Week-48): Patients who continued to receive clinical benefit, as assessed by the study Investigator and who wished to enter the extension period were reconsented at Week-48. Patients who entered the extension period continued to be treated with the study drug without interruption to be assessed for efficacy and safety. Patients who continued to benefit from study treatment as assessed by the study investigator and who completed Week-72 were offered to participate in a separate long-term safety follow-up study. The optional extension period ended after all patients had completed Week-72 or had discontinued early.

Post-treatment Follow-up: All patients had 30 days safety follow-up after the last dose of study treatment.

Arms:
arm 1: Patients in this arm took the study drug, osilodrostat.

Interventions: intervention 1: Osilodrostat
Intervention descriptions: intervention 1: Osirodrostat 1mg, 5mg \& 10mg in the form of film-coated tablets was used for oral administration.

Protocol document:
Prot_000.pdf: 
Clinical Development
Osilodrostat (LCI699)
Oncology Clinical Trial Protocol CLCI699C1201 / NCT02468193
A Phase II, open-label, dose titration, multi-center study to 
assess the safety/tolerability and efficacy of osilodrostat in 
patients with all types of endogenous Cushing’s syndrome 
except Cushing’s disease
Document type
Amended protocol version
EUDRACT number
Not applicable
Version number
04 (Clean)
Development phase
II
Document status
Final
Release date
31-Jul-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 6-Apr-2017


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Amendment 4 (31-Jul-2018) ...............................................................................................9
Summary of previous amendments ...................................................................................10
Amendment 3 (07-Aug-2017)...........................................................................................10
Amendment 2 (11-Nov-2016)...........................................................................................11
Amendment 1 (29-Feb-2016)............................................................................................14
Protocol summary:.............................................................................................................16
1
Background........................................................................................................................18
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............18
1.1.1
Epidemiology and pathogenesis of Cushing’s syndrome (CS).............18
1.1.2
Current treatment modalities.................................................................18
1.2
Introduction to investigational treatment(s) and other study treatment(s).............19
1.2.1
Overview of osilodrostat (LCI699).......................................................19
2
Rationale............................................................................................................................25
2.1
Study rationale and purpose...................................................................................25
2.2
Rationale for the study design ...............................................................................25
2.3
Rationale for dose and regimen selection..............................................................26
2.4
Rationale for choice of combination drugs............................................................27
2.5
Rationale for choice of comparators drugs............................................................27
2.6
Benefit-Risk Assessment of osilodrostat in study population...............................27
28
3
Objectives and endpoints...................................................................................................29
4
Study design ......................................................................................................................32
4.1
Description of study design ...................................................................................32
4.2
Timing of interim analyses and design adaptations...............................................33
4.3
Definition of end of the study................................................................................33
4.4
Early study termination..........................................................................................33
5
Population..........................................................................................................................34
5.1
Patient population..................................................................................................34
5.2
Inclusion criteria ....................................................................................................34
5.3
Exclusion criteria...................................................................................................36
6
Treatment...........................................................................................................................38
6.1
Study treatment......................................................................................................38


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6.1.1
Dosing regimen.....................................................................................38
6.1.2
Ancillary treatments..............................................................................39
6.1.3
Rescue medication ................................................................................39
6.1.4
Guidelines for continuation of treatment ..............................................39
6.1.5
Treatment duration................................................................................39
6.2
Dose escalation guidelines.....................................................................................40
6.3
Dose modifications................................................................................................40
6.3.1
Dose modification and dose delay ........................................................40
6.3.2
Follow-up for toxicities.........................................................................44
6.3.3
Anticipated risks and safety concerns of the study drug.......................45
6.4
Concomitant medications ......................................................................................45
6.4.1
Permitted concomitant therapy .............................................................45
6.4.2
Prohibited concomitant therapy ............................................................46
6.5
Patient numbering..................................................................................................47
6.6
Study drug preparation and dispensation...............................................................47
6.6.1
Study drug packaging and labeling.......................................................48
6.6.2
Drug supply and storage........................................................................48
6.6.3
Study drug compliance and accountability ...........................................48
6.6.4
Disposal and destruction .......................................................................49
7
Visit schedule and assessments .........................................................................................49
7.1
Study flow and visit schedule................................................................................49
7.1.1
Screening...............................................................................................58
7.1.2
Run-in period ........................................................................................59
7.1.3
Treatment period...................................................................................59
7.1.4
Discontinuation of study treatment .......................................................59
7.1.5
Follow up for safety evaluations...........................................................61
7.1.6
Lost to follow-up...................................................................................61
7.2
Assessment types...................................................................................................61
7.2.1
Efficacy assessments.............................................................................61
7.2.2
Safety and tolerability assessments.......................................................62
7.2.3
Pharmacokinetics ..................................................................................70
71
7.2.5
Resource utilization...............................................................................72
7.2.6
Patient reported outcomes.....................................................................72
8
Safety monitoring and reporting........................................................................................73
8.1
Adverse events.......................................................................................................73
8.1.1
Definitions and reporting ......................................................................73


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8.1.2
Laboratory test abnormalities................................................................74
8.1.3
Adverse events of special interest.........................................................75
8.2
Serious adverse events...........................................................................................76
8.2.1
Definitions.............................................................................................76
8.2.2
Reporting...............................................................................................76
8.3
Pregnancies............................................................................................................77
8.4
Warnings and precautions......................................................................................77
8.5
Data Monitoring Committee..................................................................................78
8.6
Steering Committee ...............................................................................................78
9
Data collection and management.......................................................................................78
9.1
Data confidentiality ...............................................................................................78
9.2
Site monitoring ......................................................................................................78
9.3
Data collection.......................................................................................................79
9.4
Database management and quality control............................................................79
10 Statistical methods and data analysis ................................................................................80
10.1
Analysis sets ..........................................................................................................80
10.1.1
Full Analysis Set ...................................................................................80
10.1.2
Safety Set ..............................................................................................80
10.1.3
Pharmacokinetic analysis set.................................................................80
10.2
Patient demographics/other baseline characteristics .............................................81
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................81
10.4
Primary objective...................................................................................................81
10.4.1
Variable.................................................................................................81
10.4.2
Statistical hypothesis, model, and method of analysis..........................81
10.4.3
Handling of missing values/censoring/discontinuations.......................81
10.4.4
Supportive analyses...............................................................................82
10.5
Secondary objectives .............................................................................................82
10.5.1
Key secondary objective(s)...................................................................82
10.5.2
Other secondary efficacy objectives .....................................................82
10.5.3
Safety objectives ...................................................................................83
10.5.4
Pharmacokinetics ..................................................................................84
85
10.5.6
Resource utilization...............................................................................85
10.5.7
Patient-reported outcomes.....................................................................85
85
85


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85
10.7
Interim analysis......................................................................................................85
10.8
Sample size calculation..........................................................................................86
10.9
Power for analysis of key secondary variables......................................................86
11 Ethical considerations and administrative procedures ......................................................86
11.1
Regulatory and ethical compliance........................................................................86
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................86
11.3
Informed consent procedures.................................................................................87
11.4
Discontinuation of the study..................................................................................87
11.5
Publication of study protocol and results...............................................................87
11.6
Study documentation, record keeping and retention of documents.......................88
11.7
Confidentiality of study documents and patient records .......................................89
11.8
Audits and inspections...........................................................................................89
11.9
Financial disclosures..............................................................................................89
12 Protocol adherence ............................................................................................................89
12.1
Amendments to the protocol..................................................................................89
13 References (available upon request)..................................................................................90
14 Appendices ........................................................................................................................91
14.1
Appendix 1: Summary of Common Toxicity Criteria for Adverse Events v4.0 
(CTCAE)................................................................................................................91
14.2
Appendix 2: List of drugs to be used with caution with osilodrostat....................92
14.3
Appendix 3: Medications with a “Known risk to cause TdP” and with a 
“Possible risk to cause TdP”..................................................................................94
14.4
Appendix 4: Patient Quality of Life questionnaires ..............................................95
List of tables
Table 3-1
Objectives and related endpoints ..........................................................30
Table 6-1
Dose Modification Guidelines for osilodrostat-suspected toxicities ....41
Table 6-2
Criteria for interruption and re-initiation of osilodrostat for 
abnormal liver function.........................................................................42
Table 6-3
Preparation and dispensing ...................................................................48
Table 7-1
Visit evaluation schedule – Study period I (dose titration period) 
and Study period II................................................................................50
Table 7-2
Visit evaluation schedule – Study extension period (Year 1)...............53
Table 7-3
Visit evaluation schedule – Study extension period (After Year 1)......55
Table 7-4
Disease assessment collection plan.......................................................61


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Table 7-5
Central clinical laboratory parameters collection plan..........................63
Table 7-6
Local clinical laboratory parameters collection plan ............................63
Table 7-7
ECG collection plan..............................................................................66
Table 7-8
Pharmacokinetic blood collection log...................................................70
72
Table 14-1
List of summary of Common Toxicity Criteria for Adverse Events 
v4.3 (CTCAE).......................................................................................91
Table 14-2
List of medications with potential drug-drug interactions with 
osilodrostat – to be used with caution...................................................92
List of figures
Figure 1-1
Mechanism of action of osilodrostat (LCI699) in Cushing’s disease...20
Figure 1-2
Arithmetic mean and SE plots for fold ULN of mUFC (PD analysis 
set).........................................................................................................23
Figure 1-3
Mean (+/-SE) mUFC (nmol/24h) over time by cohort .........................23
Figure 4-1
Study period 1 .......................................................................................32
Figure 6-1
Appearance of osilodrostat tablets by strength .....................................38
Figure 7-1
Sequence of cardiovascular data collection ..........................................68
Figure 7-2
QT Monitoring Flow Chart (except for Day 1).....................................69


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List of abbreviations
ACTH
Adrenocorticotropic Hormone
AE
Adverse Event
AESI
Adverse events of special interest
AIMAH
ACTH-Independent Macronodular Adrenal Hyperplasia
AIP
Aryl hydrocarbon receptor interacting protein
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
BDI®-II
Beck Depression Inventory®-II
b.i.d.
bis in diem/twice a day
BIPSS
Bilateral inferior petrosal sinus sampling
BMI
Body mass index
CD
Cushing’s Disease
CMO&PS
Chief Medical Office and Patient Safety
CNS
Central Nervous System
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRH
Corticotropin Releasing Hormone
CRO
Contract Research Organization
CS
Cushing’s Syndrome
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DDI
Drug-Drug interaction
DEX
Dexamethasone
DILI
Drug-Induced Liver Injury
ECG
Electrocardiogram
EEA
European Economic Area
EoT
End of Treatment
FSH
Follicle stimulating hormone
GDPR
General Data Protection Requirements
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
LDH
lactate Dehydrogenase
LFT
Liver Function Test
LH
Luteinizing Hormone
LLN
Lower Limit of Normal
LLOQ
Lower Limit Of Quantification
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation
(m)UFC
(mean) Urine Free Cortisol
pCO2
Partial pressure of carbon dioxide
PHI
Protected Health Information
PK
Pharmacokinetic
p.o.
per os/by mouth/orally
PoC
Proof of Concept


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ACTH
Adrenocorticotropic Hormone
PPNAD
Primary Pigmented Nodular Adrenal Dysplasia
QTcF
QT interval Corrected according to Friderica’s formula
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RBC
Red Blood Cells
REB
Research Ethics Board
RoW
Rest of World
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
TBIL
Total Bilirubin
TdP
Torsades de Pointes
ULN
Upper Limit of Normal
WBC
White Blood Cells


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Amendment 4 (31-Jul-2018)
Amendment rationale
Study status: As of 12 Jul 2018, 9 patients have been enrolled into the study, received study 
drug and only one patient continues study treatment. The study enrollment has been completed.
The data cut-off date for the primary analysis was 7 Jun 2018 when all 9 patients had completed 
study period I (Week 12). The primary analysis is on-going.
The main purpose of this amendment is to accommodate the remaining patient to be able to 
continue study treatment until the next surgery or local alternative treatment options is available 
beyond Week 72.
The other purpose of this amendment is to remove the planned second analysis at completion 
of study period II (Week 48).
Originally, this study was planned to be analyzed at least 3 times, at completion of study period 
I (Week 12), at completion of study period II (Week 48), and at the final analysis after all 
patients complete the study in the protocol.
No second analysis is required as primary analysis (first analysis) contains data through Week 
48.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 2.2, Section 4.1, Section 4.3, Section 6.1.5: revised to update the duration of the 
optional extension period and end of study definition and to exclude the long term safety 
follow-up study modalities.

Section 7.1.4.1: the definition of Withdrawal of Consent has been updated in line with the 
latest Novartis protocol template updated following the release of the General Data 
Protection Requirements (GDPR) in the European Economic Area (EEA).

Section 10: removed the description of second analysis at completion of study period II 
(Week 48).
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Summary of previous amendments
Amendment 3 (07-Aug-2017)
Amendment rationale 
Study status: As of 14 Jul 2017, 6 patients have been enrolled into the study and received study 
drug.
The main purpose of this amendment is to clarify the duration of the optional extension period 
in order to collect long-term safety and efficacy data as well as to provide continued access to 
the study drug for those patients benefitting from the treatment until a separate long-term safety 
follow-up study is set up at participating sites. Based on this extension, the end of study 
definition has been updated. In addition, the long-term safety follow-up study modalities have 
been detailed.
Other protocol changes include:

In view of the results of the thorough QT study CLCI699C2105, which showed that the 
increase in QTcF caused by osilodrostat at therapeutic doses is below the threshold of 
regulatory concern, the QT-specific concomitant medication guidance for osilodrostat was 
revised to limit the list of prohibited drugs to medications with a “Known risk to cause 
TdP” and “Possible risk to cause TdP”, instead of all drugs known to prolong QT. This 
change is also in alignment with the terminology used in the QT Drug Lists 
(CredibleMeds®).

The risks section was updated to include neutropenia, which is a known effect related to 
the decrease of cortisol in patients with Cushing’s disease, in line with cases observed in 
clinical trials with osilodrostat.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Protocol synopsis: edited to be consistent with the changes made throughout the protocol.

Section 2.2, Section 4.1, Section 4.3, Section 6.1.5: revised to update the duration of the 
optional extension period and end of study definition and to include the long term safety 
follow-up study modalities.

Section 2.6: updated to include the possibility of neutropenia based on observed cases 
with LCI699

Table 3-1, definition of the partial responder has been updated to be consistent throughout 
the protocol.

Section 6.4.2, Section 6.4.2.1, Appendix 3: revised to update the QT-specific concomitant 
medication guidance for LCI699 limiting the list of prohibited drugs to medications with a 
“Known risk to cause TdP” and “Possible risk to cause TdP” instead of all drugs known to 
prolong QT

Figure 7-2: added QT Monitoring Flow Chart

Section 7.2.1: added to collect 24-hour UFC as required by investigators.


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
Section 7.2.3: revised to clarify the serial PK sampling if osilodrostat administration was 
interrupted prior to a planned visit.

Section 13: Reference added.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Amendment 2 (11-Nov-2016)
Amendment rationale
Study status: As of 3 October 2016, 2 patients have been enrolled into the study and received 
study drug
The primary purpose of this protocol amendment is to facilitate enrollment by amending some 
of the inclusion/exclusion criteria based on feedback from the study investigators.
This amendment included the following changes:
1. Inclusion criterion #1: Change upper limit age from 75 years old to 85 years old
2. Inclusion criterion #2: Remove mandatory wash-out of steroidogenesis inhibitors before 
mean Urine Free Cortisol (mUFC) evaluation at screening (See Inclusion criterion #4a 
for the steroidogenesis inhibitors)
3. Exclusion criterion #3: Allow patients who have an inherited syndrome causing 
hypercortisolism
The rationale for these changes are presented below:
Inclusion criterion #1: Include Male or female patients aged 18 - 85 years 
(Change upper limit age from 75 years old to 85 years old)
There is the potential for a decrease in liver/renal/heart function or an increase in underlying 
disease with advancing age. However these patients are excluded by the following exclusion 
criteria. Therefore the patients’ safety is considered to be adequate even if the age ceiling is 
increased from 75 years old to 85 years old

Patients with insufficient liver/renal/heart function are excluded (exclusion criteria 6, 8, 9 
and 10).

Patients who have underlying disease that can interfere with the conduct or evaluation of 
study is also excluded (exclusion criteria 7 and 15).


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Inclusion criterion #2: 24-hour urine samples can be collected during screening 
without washout of steroidogenesis inhibitors to confirm mUFC > 1.3 x ULN 
(See Inclusion criterion #4a for the steroidogenesis inhibitors)
In this amendment, 24-hour urine samples can be collected during screening without washout 
of steroidogenesis inhibitors to confirm mUFC > 1.3 x ULN. However, washout before baseline 
laboratory evaluation will remain mandatory so that reference values for mUFC and other 
parameters at pre-dose will be collected to evaluate efficacy assessment.
At screening, confirmation of mUFC > 1.3 x ULN with or without washout increases patient 
convenience and avoids unnecessary exposure to elevated cortisol levels since patients who 
meet the mUFC inclusion criteria without washout will also be required to meet mUFC criteria 
with washout, thus confirming the diagnosis of Cushing’s syndrome.
In the case of patients who do not meet the mUFC criteria without washout, rescreening after 
washout is recommended to eliminate the possibility of inappropriate screen failure.
Exclusion criterion #3: Include patients who have an inherited syndrome 
causing hypercortisolism:
Previously, the rare inherited syndromes causing hormone over secretion (i.e. Carney Complex, 
McCune-Albright syndrome, Multiple endocrine neoplasia-type 1 [MEN-1], and aryl 
hydrocarbon receptor interacting protein [AIP]) were excluded to limit the heterogeneity of the 
study population.
In this amendment, these patients will be included because the target population of C1201 study 
is already a heterogeneous population of various types of Cushing’s syndrome [i.e. ectopic 
corticotropin 
syndrome, 
adrenal 
adenoma, 
adrenal 
carcinoma, 
ACTH-Independent 
Macronodular Adrenal Hyperplasia (AIMAH), or Primary Pigmented Nodular Adrenal 
Dysplasia (PPNAD)] from the beginning of study. In fact, most cases of PPNAD occur in 
patients with the inherited syndrome Carney Complex.
The inclusion of patients with the inherited syndromes may impact the study population in the 
following ways: on the one hand, heterogeneity will increase, thereby requiring additional 
caution in interpreting the results; on the other hand, this amendment would reflect more 
broadly the natural heterogeneity of Cushing’s syndrome as it presents in clinical practice.
Other protocol changes are: 

To provide more information regarding the study drug, the results of the thorough 
QT/QTc study (CLCI699C2105) of osilodrostat in healthy volunteers has been added.

To reduce the risk of overdosing error, the 20 mg tablet strength will no longer be 
available for use in this study.

To distinguish between recommended and mandatory dose interruptions or reduction, 
language has been added for clarification.

Inclusion of updated and more conservative hepatic safety-related discontinuation criteria.
The duration of the optional extension period is increased in order to collect additional long-
term safety data as well as to provide continued access to the study drug for those patients 
benefitting from the treatment. The reason for collecting a long term safety data is valuable 
because the drug is intended to be used as a long term treatment in these patients. The reason 


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for collecting a long term data is not because of the new safety reasons. The optional extension 
period will end when seamless transition to a long-term safety follow-up study is possible or 
osilodrostat is commercially available, whichever is earlier. In the first case, patients who 
continue to benefit from the treatment will be offered participation in the separate long-term 
safety follow-up study.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined font for insertions.

Protocol Summary: Changes in the main body of the protocol are also implemented in the 
relevant sections of the protocol synopsis.

Section 1.2.1, 6.1 and 6.6: Added a description that the 20 mg tablet strength will no 
longer be used.

Section 1.2.1.2.4: Added the cardiac repolarization (QT/QTc) data of osilodrostat in 
healthy volunteers.

Section 2.2, 4.1, 4.3, 6.1.5, 7.1, 7.1.3, Table 7-1, 7-2 and 7-3: Updated to include the 
changes due to the increase in duration of the optional extension period and the study 
period.

Section 5.1: Provided explanation about adjustment of target patient number based on 
enrollment status.

Section 5.2:

Inclusion criterion #1: Changed upper limit of age from 75 to 85 years old.

Inclusion criterion #2: Changed wash-out of steroidogenesis inhibitors to not 
mandatory before mUFC evaluation at screening.

Section 5.3:

Exclusion criterion #3: Changed to allow patients who have a known inherited 
syndrome.

Section 6.1.1: Added a description of guidance on dose adjustments.

Section 6.3.1, Table 6-1 and Table 6-2: Clearly distinguished between recommended and 
mandatory dose interruptions and/or dose reduction.

Table 6-2: Updated discontinuation criteria for patients with AST or ALT > 10.0 x ULN.

Table 7-3: Added visit schedule for the optional extension period of more than one year.

Section 7.1.4: Added hepatic safety-related discontinuation criteria.

Section 8.1.3: Added definition of adverse events of special interest.

Section 8.1.3.1: Added results of the thorough QT/QTc study (CLCI699C2105) data of 
osilodrostat in healthy volunteers and removed preliminary clinical data.

Section 10 and 10.8: Provided explanation of certain parts of data analysis.

Appendix 2: Updated to remove the corticosteroids (budesonide, fluticasone) as use of 
glucocorticoids is prohibited except under certain conditions as specified in Section 6.4.2.


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A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein affect the Informed Consent. Sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes 
described in this protocol amendment.
Amendment 1 (29-Feb-2016)
Amendment rationale
The primary purpose of this protocol amendment is to improve patient safety by adding specific 
criteria for the identification and management of patients with potential drug-induced liver 
injury (DILI).  Although there are no known cases of suspected DILI in patients treated with 
osilodrostat to date, these criteria are added in the event that a case of suspected DILI arises in 
the future.
Additional changes include;

Addition of the benefit-risk assessment of osilodrostat

Clarification of the correct procedures for dose adjustment and drug dispensation to 
emphasize the education of sites and patients

Implementation of partial pressure of carbon dioxide (pCO2) is added as an alternative lab 
assessment to bicarbonate for evaluation of acid-base status at study sites that are not able 
to measure bicarbonate directly.
In addition, editorial changes and clarifications were made at various places in the protocol.
As of 30 October 2015, 2 patients have provided written informed consent for the study and 1
patient has received osilodrostat.
Changes to the protocol
Section 2.6: Addition of the benefit-risk assessment of osilodrostat
Section 5.3 Item 10: Implement the new criteria for exclusion of patients with liver disease
Section 6.3.1: Implement the dose modification criteria for abnormal liver function.
Section 6.3.2.1: Implement the follow up procedure for potential drug-induced liver injury cases
Section 6.1, Figure 6-1, Section 6.6, Table 6-3: Clarification of the correct procedures for dose 
adjustment and drug dispensation
Section 7.2.2.4.2, Table 7-5: Implement pCO2 as an alternative option of bicarbonate
Section 8.2.2: Updated to introduce new protocol template


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Section 10.5.3.3: Add analysis plan of laboratory test for liver function.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Protocol summary:
Title
A Phase II, open-label, dose titration, multi-center study to assess the 
safety/tolerability and efficacy of osilodrostat in patients with all types of 
endogenous Cushing’s syndrome except Cushing’s disease
Brief title
Study of efficacy and safety osilodrostat in Cushing’s syndrome.
Sponsor and Clinical 
Phase
Novartis, phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to investigate the efficacy and safety of osilodrostat in 
patients with Cushing’s syndrome (CS) due to causes other than Cushing’s disease 
(CD) in Japan.
In Japan, the proportion of patients with CD in the population of CS patients is lower 
compared to Western countries. In Western countries, the proportion of CS patients 
with CD is around 70%, while in Japan, the proportion of CS patients with CD is 
approximately 35%. Therefore, the development of osilodrostat for the population of 
patients with CD only will not satisfy the medical needs of all patients with 
endogenous CS in Japan.
Primary Objective(s) 
and Key Secondary 
Objective
To assess the percent change from baseline in the mean Urine Free Cortisol 
(mUFC) at the individual patient level at Week 12
Secondary Objectives
To assess the percent change from baseline in the mean urine free cortisol (mUFC)
at the individual patient level at Week 24 and Week 48
To assess the absolute and percent change from baseline in mUFC at Week 12, 
Week 24 and Week 48
To assess the complete, partial, and overall response rate at Week 12, Week 24 
and Week 48
To assess the absolute and percent change from baseline in morning serum 
cortisol at the individual patient level at Week 12, Week 24 and Week 48
To assess the absolute and percent change from baseline in morning serum 
cortisol at Week 12, Week 24 and Week 48
To assess the absolute and percent change from baseline in steroid hormones at 
the individual patient level at Week 12, Week 24 and Week 48
To assess the change from baseline in cardiovascular-related metabolic 
parameters associated with CS at Week 12, Week 24 and Week 48
To assess the general safety of osilodrostat
To assess the change from baseline in Patient-Reported Outcome (Health Related 
Quality of Life) at Week 12, Week 24 and Week 48
To evaluate PK of osilodrostat in patients with CS
Study design
This is a phase II, single arm, open-label, dose titration, multi-center study 
consisting of two distinct study periods (12 weeks and 36 weeks) plus an optional 
extension period.
Population
The patient aged 18 - 85 years, non-CD patients with CS who have persistent or 
recurrent hypercortisolism after primary surgery and/or irradiation and/or 
chemotherapy, and patients de novo CS who are not surgical candidates for 
medical reasons, or refuse to undergo surgery.
Inclusion criteria
● Patients must have confirmed CS [i.e. ectopic corticotropin syndrome, adrenal 
adenoma, adrenal carcinoma, ACTH-Independent Macronodular Adrenal 
Hyperplasia (AIMAH), or Primary Pigmented Nodular Adrenal Dysplasia (PPNAD)].
● Patients are expected to remain in stable condition for at least 5 months.
● For patients on medical treatment for hypercortisolism due to CS the washout 
periods must be completed prior to baseline efficacy assessments.


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Exclusion criteria
● Patients with Cushing’s disease
● History of hypersensitivity to osilodrostat or to drugs of similar chemical classes
● History of malignancy of any organ system [with the exception of: a) malignancy 
causing ectopic corticotropin syndrome, or b) localized basal cell carcinoma of the 
skin], treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases
● Patients receiving treatment for malignancy (e.g., cytotoxic chemotherapy, 
molecular targeting drugs, somatostatin analogue) within 4 weeks or ≤5 x half-life 
of the agent (whichever is longer) before first dose of osilodrostat
● Patients with risk factors for QTc prolongation or Torsades de Pointes
Investigational and 
reference therapy
Osilodrostat (LCI699) at 2 mg b.i.d., 5 mg b.i.d., 10 mg b.i.d., 20 mg b.i.d. and 
30 mg b.i.d.
Efficacy assessments
● 24-hour urine to test for Urine Free Cortisol and creatinine
Safety assessments
● Adverse events
● Laboratory evaluations (biochemistry, hematology, coagulation, thyroid panel, 
fasting glucose, urinalysis and pregnancy test)
● ECG, vital signs and physical exam
Other assessments
● PK evaluation 
Data analysis
The primary objective is to assess the percent change from baseline in the mean 
Urine Free Cortisol (mUFC) in individual patient level data at week 12. The primary 
endpoint defined as the patients level percent change from baseline in mUFC will 
be listed. No statistical analysis including descriptive summary will be performed for 
the primary analysis. The assessment of the efficacy will be based on the review of 
individual patient listing and figures due to very small sample size and expected 
variability in response caused by various patient background and disease. 
Therefore, no statistical hypothesis is set up for this study.
Key words
Cushing’s syndrome, osilodrostat, LCI699, ectopic corticotropin syndrome, adrenal 
adenoma, adrenal carcinoma, AIMAH, PPNAD


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Epidemiology and pathogenesis of Cushing’s syndrome (CS)
Cushing’s syndrome (CS) is rare: the reported incidence of either endogenous CS or Cushing’s 
disease (CD) in the U.S., European countries (Spain, Denmark, Belgium, and Iceland) and New 
Zealand has been estimated to be 1.2 to 2.4 cases per million persons per year (Etxabe and 
Vazquez 1994, Lindholm et al. 2001, Daly et al. 2006, Arnardottir and Sigurjonsdottir 2011,
and Bolland et al. 2011). The endogenous CS is classified into Adrenocorticotropic hormone
(ACTH)-dependent and ACTH-independent etiologies based on cause of disease. The most of 
CS is ACTH-dependent in the U.S. and European countries, and the most common cause of 
ACTH-dependent CS is CD which occurs is due to an ACTH-secreting pituitary corticotroph 
adenoma. The other main cause of ACTH-dependent CS is ectopic ACTH secretion from 
non-pituitary tumors (e.g., small cell lung cancer). The ACTH-independent etiologies of CS are 
adrenal diseases such as adrenal tumors (adenomas or carcinomas) or bilateral adrenal 
hyperplasia. In U.S., the reported incidence of CD was 70% of CS. The incidences of ectopic 
corticotropin syndrome and cortisol-secreting adenoma were 12% and 18% of CS, respectively 
(Porterfield et al. 2008).
In Japan, Ministry of Health, Labour and Welfare working group has conducted a survey in 
1997 and the prevalence of CS was estimated as 1250 cases. In the 417 cases of CS which were 
actually reported, 35.8% had CD, 47.1% had adrenal adenoma, 17.1% had other cause of CS 
(Nawada et al. 1999).
Endogenous CS is characterized by chronic hypercortisolism, which results in a variety of 
metabolic abnormalities and co-morbidities that collectively lead to an overall 4-fold higher 
mortality rate than age-
and gender-matched subjects in the general population 
(Etxabe and Vazquez 1994 and Arnaldi et al. 2003). The increased cardiovascular risk is related 
to the following clinical manifestations of CS: metabolic syndrome, insulin resistance, visceral 
obesity, glucose intolerance, hypertension, dyslipidemia, and hypercoagulation. Other clinical 
signs and symptoms of CS include: supraclavicular and dorsal fat pads; proximal muscle 
weakness; osteoporosis with increased risk of fractures; skin changes (wide purple striae, 
hirsutism, acne); impaired immune function with increased risk of infection; neuropsychiatric 
disorders (depression, mood changes, and cognitive impairment), hypogonadism, and menstrual 
disorders in women (Newell-Price et al. 2006).
1.1.2
Current treatment modalities
For any types of CS the first line therapeutic option is surgical resection. However, patient may 
be treated with medical therapy during the pre-surgery period to control the hypercortisolism. 
The recurrence of CD after the surgical resection of the pituitary tumor is reported to be more 
than 20%. Radiation therapy at pituitary gland is used as an option to those who have recurred 
CD after surgery but the remission rate is less than 50% and takes long time to gain the effect. 
The surgery is a primary option for patients with the adrenal adenoma in principle but the drug 
therapy is used to patients who are not eligible for the surgery. Surgical resection of the cancer 


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or chemotherapy is used for the treatment of ectopic ACTH producing tumor. If the surgery is 
not applicable, the drug therapy for the hypercortisolemia or a bilateral adrenal resection is 
applied. For ACTH-independent macronodular adrenal hyperplasia (AIMAH) and primary 
pigmented nodular adrenal dysplasia (PPNAD) which causes the hyperplasia of bilateral 
adrenal, the bilateral adrenal resection is used as the curative therapy but depending on the 
disease condition, subtotal resection is applied. The drug therapy is applied as a part of the 
preoperative procedure or for those who are not eligible for the surgery. There’s no major 
difference in the treatment option between Japan and US/EU.
In Japan, mitotane, trilostane, and metyrapone are approved for CS. Mitotane has the cytotoxic 
effect which induces the adrenal cortex cytotoxicity and the inhibitory effect on the steroid 
synthase. The occurrence rate of adverse event (AE) by mitotane is 80% and the gastrointestinal 
manifestation, the central nerve manifestation, and adrenal failure are reported as common AEs. 
Trilostane inhibits the 3β-hydroxysteroid dehydrogenase and inhibits the synthesis of cortisol 
and aldosterone. Nausea, vomiting, liver deficiency, and rash are reported as the side effect. 
Metyrapone has the inhibitory effect on 11β-hydroxylase and inhibits the synthesis of cortisol 
and aldosterone. Metyrapone was approved for CS by the public domain submission under the 
scheme by “the committee for the unapproved/off-label drug with the high unmet medical needs”
in Japan. As the safety profile of metyrapone is milder than the mitotane profile, and the 
inhibitory effect of cortisol synthesis is stronger compared to the effect of trilostane, metyrapone 
is used widely in Japan for the treatment of CS. However, there are patients who have 
suboptimal effect with Metyrapone, the proportion of patients not adequately controlled is in 
the range of 20 - 40% (Feelders et al. 2010, Valassi et al. 2012), In addition, there is a drug 
compliance issue due to the need of drug administration 1-4 times per day.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of osilodrostat (LCI699)
Osilodrostat is a new chemical entity with the chemical structure 4-[(5R)-6,7-Dihydro-5H-
pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile phosphate.
Osilodrostat is a potent, oral inhibitor of 11β-hydroxylase (CYP11B1), the enzyme that 
catalyzes the last step in the biosynthesis of cortisol. This provides the rationale for investigating 
the use of osilodrostat in endogenous causes of CS. This drug also inhibits aldosterone synthase 
(CYP11B2), and therefore is a dual inhibitor of both cortisol and aldosterone synthesis. It is 
manufactured as a phosphate salt and available in film-coated tablets of 1 mg, 5 mg, 10 mg and 
20 mg for this phase II study: On 22 Aug 2016 (before Amendment #2), the 20 mg tablet 
strength was discontinued for use in the trial, in order to reduce the risk of dosing error in which 
the patient took more than the prescribed dose. Remaining supplies of the 20 mg tablets were 
to be collected from the sites.
The mechanism of action of osilodrostat is depicted in Figure 1-1 below.


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Figure 1-1
Mechanism of action of osilodrostat (LCI699) in Cushing’s disease
1.2.1.1
Non-clinical experience
For detailed non-clinical pharmacokinetics and toxicity findings, please refer to the 
[Investigator’s Brochure].
1.2.1.1.1 Non-clinical pharmacology
The oral absorption of In vivo osilodrostat in rat and dog was rapid with complete bioavailability 
indicating a minimal first-pass effect. The plasma half-life of osilodrostat in rat and dog was 
short (~ 2 h). Exposure was dose-proportional within the dose range investigated in the rat but 
over-proportional in dogs and mice. No accumulation or gender differences were observed in 
either species. Protein binding of osilodrostat in animals and humans was low (26.6-36.4%). 
osilodrostat rapidly and extensively distributed to rat tissues. The highest tissue-to-blood ratios 
(≥9) were observed in the uveal tract, skin, eye, glandular stomach, small intestine, liver, and 
adrenal cortex. Drug-related radioactivity showed a significant affinity to melanin in the skin 
and uveal tract. Drug-related radioactivity showed a moderate distribution to brain, spinal cord 
and the testis with tissue-to-blood concentration ratio of 0.73-1.7. The elimination of 
osilodrostat is mainly through metabolism and excretion in urine (~79% in rats and ~90% in 
dogs; unchanged osilodrostat ~ 5-10% in urine and < 3% in feces). Based on in vitro CYP P450 
inhibition profile and predicted steady state maximum concentration of 1.54 µM at 30 mg twice 
daily in humans, there is potential of drug- drug interaction for osilodrostat. Results from a 
clinical drug-drug interaction study are summarized in Section 1.2.1.2.1. It is unlikely for 
osilodrostat to increase in the systemic exposure of co-medications whose clearance is mediated 
by P-gp, BCRP, OAT1, OAT3, OCT1, and OCT2 transport activity.


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1.2.1.1.2 Preclinical safety
Safety pharmacology:
In safety pharmacology studies, proarrhythmic indices and QTc interval prolongation were 
observed in in vitro study in isolated rabbit heart and in vivo studies in dog and monkey with 
osilodrostat. Proarrhythmic indices were observed at 10 µM in isolated rabbit heart assay. QTc 
interval prolongation was noted at 50 mg/kg after 2 weeks of intravenous dosing in dogs, at 
30 mg/kg oral (gavage) after single dose, and at 10 mg/kg/day in a two week study in monkeys.
Toxicology:
No acute toxicity was observed in mice following administration of oral doses up to 125 mg/kg. 
In repeated dose general toxicity studies up to 26-weeks in duration in the rat, and up to 
39-weeks in the dog, the main target organs were central nervous system (CNS), liver, female 
reproductive organs, and adrenal gland. Reversible CNS effects were seen at very high doses 
in dogs (≥10 mg/kg) and mice (doses ≥30 mg/kg). Hepatocellular hypertrophy and vacuolation 
were seen in 13-week and 26-week rat studies at doses ≥5 mg/kg and in a 13-week study in 
mice at doses ≥10 mg/kg (partially reversible). In female dogs, transient increases in ALT and 
AST were observed at week 5 during the 13-week study at 0.1 and 10 mg/kg. Effects on female 
reproductive organs (ovary, uterus and vagina) were seen in rats at doses ≥5 mg/kg (reversible) 
and in mice at doses ≥30 mg/kg. Male reproductive organ changes were limited to a decrease 
in prostate weights (no microscopic correlate) in the 26-week rat study at 20 mg/kg. No effects 
on female or male reproductive organs were found in dogs. In the adrenal cortex, morphological 
alterations were observed in dogs (zona glomerulosa) and at much higher exposure in rats (zona 
fasciculata/glomerulosa). They may be a result of the inhibition of adrenocortical steroid 
biosynthesis leading to an adaptive induction of the aldosterone/cortisol synthase pathway. In 
the chronic toxicity studies, the NOAEL was 2 mg/kg in the rat (26-week), and was 10 mg/kg 
in the dog (39-week).
In genetic toxicology studies, no evidence of mutagenic activity was observed in the Ames test, 
and no evidence of chromosomal damage in the in vitro micronucleus test. Clastogenic effects 
at high concentrations with and without metabolic activation were reported in cultured human 
peripheral blood lymphocytes. In vivo genotoxicity tests in rats (micronucleus test and comet 
assay) were clearly negative and it is therefore concluded that osilodrostat has no relevant 
genotoxic potential in humans.
In reprotoxicity studies (embryo fatal developmental study in rats and rabbits, fertility and early 
development study in rats), embryo/fetal toxicity was observed at doses that produced maternal 
toxicity in the rat and the rabbit, and increased incidence of fetal malformation was observed in 
rats (only occurred at the maternally toxic dose).
1.2.1.2
Clinical experience
1.2.1.2.1 Clinical pharmacokinetics
The pharmacokinetics of osilodrostat has been studied in healthy volunteers, patients with 
hypertension, and patients with hyperaldosteronism, as well as in an ongoing proof-of-concept 
study in CD patients. For detailed information, please refer to the [Investigator’s Brochure].


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Following single oral doses of 0.5 mg to 200 mg to healthy volunteers under fasting conditions, 
osilodrostat was rapidly absorbed with a Tmax of approximately 1 hour. The elimination 
half-life of osilodrostat was 3-5 hours across all doses examined. The pharmacokinetics of 
osilodrostat were over-dose proportional in the dose range of 0.5 to 200 mg (single dose); for a 
2-fold increase in dose, the AUC increase would be about 2.4-fold, and Cmax increase would 
be 2.1-to 2.4-fold [CLCI699A2101]. Metabolism was the major clearance pathway for 
osilodrostat in humans with renal clearance making only a minor contribution. Metabolism of 
osilodrostat was extensive in humans via multiple pathways (and combination of pathways) 
[CLCI699C2101]. Results from a cocktail drug-drug interaction study [CLCI699C2102] 
showed that osilodrostat is a weak inhibitor for CYP3A4/5 and CYP2D6 (increased AUCs of 
midazolam and dextromethorphan ~1.5-fold), and a moderate inhibitor for CYP1A2 and 
CYP2C19 (increased AUC of caffeine and omeprazole ~2.5- and ~1.9-fold, respectively).
Impact of ethnic origin on osilodrostat pharmacokinetics was investigated in Caucasian and 
Japanese healthy male subjects following single and multiple doses of osilodrostat (0.25, 0.5, 
1, 2 mg). Osilodrostat exposure (AUC) was 18%, 44%, and 66% higher in Japanese healthy 
volunteers in comparison to Caucasians after single dose of 0.5 mg, 1 mg and 2 mg osilodrostat. 
Body weight difference (mean body weight: 64.6 to 68.6 kg for Japanese vs. 70.7 to 77.6 kg for 
Caucasians) was not shown to be a major determinant of the race effect on exposure 
[CLCI699A2102].
1.2.1.2.2 Results of CLCI699C2201 study in Cushing’s disease
The purpose of the CLCI699C2201 study was to determine whether the ability of osilodrostat 
to inhibit 11β-hydroxylase could safely reduce urinary free cortisol (UFC) in patients with CD. 
This was initially studied over a 10-week treatment duration Proof-of Concept (Part I). Part II 
of the study aimed to further evaluate the observations from the Part I by enrolling a cohort of 
patients who participated in Part I and a new cohort (Expansion cohort) of patients and 
evaluating the long-term efficacy and safety of osilodrostat treatment for a total duration of 22 
weeks.
In Part I, osilodrostat was effective in controlling cortisol production in all 12 patients studied. 
At daily osilodrostat doses between 2 mg b.i.d. and 50 mg b.i.d., 24-hour mean UFC (mUFC) 
decreased rapidly and normalized at least once in all patients studied. In general at 5 mg b.i.d. 
patients showed mUFC reduction after 2 weeks (at first mUFC measurement after dose titration).
The primary endpoint, defined as mUFC ≤ULN or ≥50% decrease from baseline at day 70, 
was achieved by all patients. Overall, the mean time to response (UFC normalization or ≥50% 
reduction from baseline) was 34.3 ± 14.1 days. The mean daily dose (± SD) of osilodrostat 
required to reach the primary endpoint was 13.5 ± 13.9 mg b.i.d. with 75% of patients 
normalizing mUFC on ≤10 mg b.i.d. At Day 84, two weeks after osilodrostat was withdrawn, 
mUFC levels increased to a mean of 4-fold above upper limit of normal (ULN) (Figure 1-2).


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Figure 1-2
Arithmetic mean and SE plots for fold ULN of mUFC (PD analysis set)
Source: In-text Figure 11-2, 10-week interim CSR study [CLCI699C2201]
Significant decreases in mean plasma cortisol and aldosterone from baseline (-60% and -70%, 
respectively) and marked increases in their precursors from baseline (11-deoxycortisol [13-fold] 
and 11-deoxycorticosterone [42-fold], respectively) and ACTH [2.4-fold] were observed at 
Day 70.
In Part II, 17 out of 19 patients completed the 22 weeks treatment period and 15 had normal 
mUFC levels at week 22 (79%). During treatment with osilodrostat, the mean mUFC levels 
decreased quickly and stabilized to a normal level (11 to 138 nmol/24h) at Week 4 (Figure 1-
3). After Week 4, normal mean mUFC levels were observed through the study up to Week 22. 
All patients attained UFC normalization at least once during the study, and no patient “escaped” 
UFC control.
Figure 1-3
Mean (+/-SE) mUFC (nmol/24h) over time by cohort
Source: In-text Figure 11-1, 22-week interim CSR study [CLCI699C2201]


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1.2.1.2.3 Overview of safety
In the clinical trials for the treatment of hypertension or primary hyperaldosteronism, 
osilodrostat was tolerated with the overall incidence of adverse events being similar to placebo. 
AEs were generally of mild to moderate intensity. Both SAEs and discontinuations due to AE 
were infrequent, and were reported at a rate similar to placebo in the hypertension studies. The 
most common AEs across these studies were: headache, dizziness (including postural dizziness), 
nausea, diarrhea and fatigue. There were also AEs of hyperkalemia and impaired 
ACTH-stimulated cortisol response in these trials, which are consistent with the potential for 
hypocortisolism and hypoaldosteronism.
In Part I of CLCI699C2201 study, all 12 patients (100%) experienced adverse events but these 
were generally mild to moderate in severity (NCI CTC grade 1 or grade 2). Fatigue, muscle 
cramps, dizziness and gastrointestinal events were the most common events suspected to be 
drug related. Four patients reported AEs consistent with cortisol and/or aldosterone withdrawal; 
dose reductions or temporary dose interruption in these patients improved the symptoms. There 
were no discontinuations related to study drug and no serious adverse events of suspected drug 
relationship.
In Part II, osilodrostat was generally well tolerated. Except for one patient in the expansion 
cohort, all patients experienced AEs, grade 1/2 in most of the cases. Adrenal insufficiency, 
nausea, fatigue and increased levels of oxycorticosteroids, blood corticotrophin, blood 
testosterone in females were the most common AEs suspected to be drug related (by preferred
term).
Two patients experienced a total of 3 SAEs.
One patient experienced grade 3 pituitary-dependent CS (preferred term). The SAE resulted in 
hospitalization/prolonged hospitalization and was not suspected to be related to the study drug. 
This SAE was continuing at the time of the data cut-off date.
Another patient experienced 2 SAEs concurrently: grade 3 gastroenteritis (preferred term) and 
grade 1 Electrocardiogram QT prolongation (preferred term). The gastroenteritis resulted in 
hospitalization/prolonged hospitalization, was not suspected to be related to the study drug and 
resolved with concomitant medication. The Electrocardiogram QT prolongation was suspected 
to be related to the study drug by the investigator, but causality is not clear. There were no 
cardiac symptoms or arrhythmia reported. The SAE “electrocardiogram QT prolongation” was 
ongoing at the time of the data cut-off date.
One patient discontinued the study drug due to AEs. This patient reported (by preferred term) 
grade 3 papule, and grade 1 diarrhea, malaise, muscular weakness and nausea. All the AEs were 
suspected to be related to study drug and the patient discontinued the study drug after two weeks 
treatment
In reviewing the clinical trial experience with osilodrostat to date, AEs have been identified that 
are consistent with the mechanism of action of the drug as an inhibitor of both cortisol and 
aldosterone synthesis. These can be summarized as follows:

Changes in adrenal hormones: cortisol decreased, aldosterone decreased, and their 
precursors (11-deoxycortisol, 11-deoxycorticosterone) increased

Change in pituitary hormone: ACTH increased


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
Changes in electrolytes: potassium increased or decreased

Changes in body weight and blood pressure: potentially increased by mineralocorticoid 
effect of the aldosterone precursor 11-deoxycorticosterone

Changes in sex hormones: testosterone and estradiol increased (testosterone more than 
estradiol, and more pronounced in women than in men)
A more detailed list of potential AEs related to the mechanism of action of osilodrostat can be 
found in Section 8.1.3 Adverse events of special interest. For a comprehensive review of clinical 
safety data with osilodrostat, see the [Investigator’s Brochure].
1.2.1.2.4 Study CLCI699C2105: QT/QTc data in healthy volunteers
For detailed information, please refer to the [Investigator’s Brochure].
The cardiac repolarization liability of osilodrostat was assessed in the definitive ICH E14 
compliant thorough QT/ QTc Study (TQT) study [CLCI699C2105] in 86 healthy male and 
female subjects.
The final results showed that the predicted mean QT effect of osilodrostat was below the 
threshold of regulatory concern (i.e., an upper boundary of the 90% CI < 10 ms) and fully 
support the use of osilodrostat doses up to 30 mg.
2
Rationale
2.1
Study rationale and purpose
Osilodrostat is a potent inhibitor of 11β-hydroxylase, the enzyme that catalyzes the last step in 
the biosynthesis of cortisol. This provides the rationale for investigating the use of osilodrostat
in endogenous causes of CS.
The effect of osilodrostat in patients with CD and recurrent or persistent hypercortisolism, was 
investigated in the Proof-of-Concept (PoC) study [CLCI699C2201] and demonstrated a 
response rate of 100% after 10 weeks, and approximately 80% after a new treatment period of 
22 weeks of osilodrostat treatment.
A Phase III study [CLCI699C2301], intended to support the registration of osilodrostat for the 
treatment of patients with CD is ongoing.
In Japan, the proportion of patients with CD in the population of CS patients is lower compared 
to Western countries. In Western countries, the proportion of CS patients with CD is around 
70%, while in Japan, the proportion of CS patients with CD is approximately 35%. Therefore,
the development of osilodrostat for the population of patients with CD only will not satisfy the 
medical needs of all patients with endogenous CS in Japan. Hence, it is necessary to investigate 
the efficacy and safety of osilodrostat in patients with CS due to causes other than CD in Japan.
2.2
Rationale for the study design
This is a Phase II, single arm, open-label, dose titration, multi-center study consisting of two 
distinct study periods plus an optional extension period with non-CD patients with CS.


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Three periods are Study period I, Study period II and Optional extension period. Study period 
I (12-weeks duration) is a dose titration period to achieve individual stable therapeutic dose and 
to assess the efficacy and safety. Individual dose titration is required based on the available data 
due to high inter-subject variability in effective dose and narrow therapeutic window (risk of 
hypocortisolism-related adverse events including acute adrenal insufficiency). Study period II 
(36-weeks duration) is to assess the sustainability of efficacy and to assess the long term safety 
for the patients who tolerate and agree to continue the study treatment and the aim of the 
optional extension period is the same as Study period II for the patients who are willing to enter 
this period. The optional extension period will end after all patients have completed Week 72 
or discontinued early (prior to Week 72). The patient can either be offered a local alternative 
treatment option or stay in the study until the study end (9 months after the last patient completes 
Week 72) 
Based on the very small sample size and expected variability in response caused by various 
patient background and disease, the primary analysis will report the individual patient data.
2.3
Rationale for dose and regimen selection
The rationale for b.i.d. dosing of osilodrostat is based on its half-life of 3-5 h. This regimen was 
used in the PoC study [CLCI699C2201] as well. Originally modeling of PK exposure estimated 
that a dose of 4-5 mg b.i.d. is expected to achieve a plasma concentration above the in vitro
IC50 for CYP11B1 (2.5 nM) for a full 24 hours for efficacy consideration; however, 2 mg b.i.d 
was chosen to be the starting dose in the PoC study based on safety considerations, i.e., to reduce 
the risks associated with potential hypocortisolism-related adverse events:

Glucocorticoid withdrawal due to rapid correction of elevated serum cortisol

Biochemical hypocortisolism [UFC < Lower limit of normal (LLN)]

Symptomatic hypocortisolism or adrenal insufficiency (potentially life-threatening)
There were four events of suspected hypocortisolism (glucocorticoid withdrawal) that improved 
with dose reduction or dose interruption during the 10-week PoC study [CLCI699C2201]. Since 
these events occurred during the 10-week dose titration period, they support a conservative 
approach to the starting dose of osilodrostat. In addition, since the 10-week analysis, 2 patients
in the ongoing study [CLCI699C2201] had adrenal insufficiency on 2 mg b.i.d., and their 
osilodrostat dose was reduced to 1 mg b.i.d..
The 10-week analysis of the PoC study [CLCI699C2201] showed that the dose of osilodrostat
required the normalization of mUFC ranged from 2 mg b.i.d. to 50 mg b.i.d. after individual 
dose titration, with nearly all patients (11/12) achieving UFC normalization at > 2 mg b.i.d. 
Trough concentrations at mUFC normalization also varied widely, ranging from 0.3-49 ng/mL. 
This indicates that there is a broad range (up to 25-fold in osilodrostat dose) of between-patient 
sensitivity to osilodrostat with respect to normalization of mUFC, and there was no apparent 
relationship between the therapeutic dose or exposure (trough concentrations) and the baseline 
mUFC.
Thus, it appears that individual dose titration starting at 2 mg b.i.d. is appropriate to assess the 
efficacy and safety of osilodrostat. Fixed-dose comparisons of osilodrostat doses would carry 
the risk of hypocortisolism if a relatively high dose is administered to a patient who is very 


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sensitive to osilodrostat; in extreme cases, such a complication could present as a potentially 
life-threatening adrenal crisis.
This study will therefore start with individual patient dose titration period during the first 12 
weeks with the following dose escalation sequence 2 mg b.i.d., 5 mg b.i.d., 10 mg b.i.d., 20 mg 
b.i.d., and 30 mg b.i.d.. The dose of osilodrostat is titrated on the basis of the serum cortisol
levels that are collected every week for initial 4 weeks, up to maximum dose of 10 mg b.i.d.. 
Thereafter, the dose can be further increased, if needed, at 2-week intervals in the dose titration 
period. In CLCI699C2201, mUFC was used for dose titration. In this study, serum cortisol will 
be used since patients with causes of endogenous CS other than CD are expected to have 
persistently elevated serum cortisol levels, without a daily circadian rhythm. In addition the 
turnaround time of serum cortisol is expected to be shorter than UFC. Based on the 2 patients
(see above) in the ongoing study [CLCI699C2201] who had adrenal insufficiency on 2 mg b.i.d., 
the dose can be lowered to 1 mg b.i.d. if this occurs in the present study. Further dose reductions 
to 1 mg once daily must be discussed with the sponsor before implementation.
Please refer to Section 6.1.1 for more detailed information regarding dose adjustment.
2.4
Rationale for choice of combination drugs
Not applicable
2.5
Rationale for choice of comparators drugs
Not applicable
2.6
Benefit-Risk Assessment of osilodrostat in study population
Appropriate eligibility criteria, as well as specific dose modification and stopping rules, are 
included in this protocol. Recommended guidelines for supportive management of study-drug 
induced adverse events are provided in Section 6.3.1.
Potential patient benefits
There is an unmet medical need in CS patients which is a rare and serious disease with limited 
options for medical therapy. Phase II data demonstrated normalization of mean UFC in 11/12 
patients after 10 weeks of therapy (LCI699C2201, Part 1) and 15/19 patients after 22 weeks of 
therapy (LCI699C2201, Part II Core). There was a trend toward improved fasting glucose and 
HbA1c in patients with diabetes at baseline, and an improved fasting lipid profile in patients 
with dyslipidemia at baseline. Based on these results osilodrostat is a promising potential new 
therapy in CS patients.
Study-specific risks
Study-specific risks in study LCI699C1201 include the potential for prolonged periods of 
uncontrolled hypercortisolism during washout and dose titration with a maximum combined 
duration of under-treatment of 4 months.
To mitigate the risk of uncontrolled hypercortisolism, specific exclusion criteria and criteria for 
discontinuation of study treatment with regard to blood pressure and diabetes control are used. 


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For patients who require washout periods of 4 weeks or longer, treatment with drugs that require 
a short washout period (e.g., 1 week) is recommended.
Risks of osilodrostat treatment in study population
The risks of treatment with osilodrostat in CS patients include: QT prolongation, adrenal 
insufficiency, AEs related to the accumulation of precursor molecules, including: increased or 
decreased blood pressure, hypokalemia or hyperkalemia, hyponatremia, weight gain, edema, 
and increase in the synthesis of sex steroids (primarily adrenal androgens in women) that may 
lead to menstrual changes and hirsutism in women and acne in men and women. Skin rash has 
also been observed.
In addition, treatment with osilodrostat can potentially result in neutropenia, which is 
considered to be an indirect effect of cortisol reduction, as reported in the literature. During 
hormonal control, a significant decrease of neutrophil count, which is commonly elevated in 
patients with Cushing’s disease, has been reported demonstrating the effect of glucocorticoids 
on these blood cells (Masri-Iraqi et al. 2014). This effect has also been observed with 
osilodrostat in the Cushing’s disease trials and has included cases of neutropenia which were 
associated with mUFC levels that were either below normal or have had a rapid and substantial 
decline from baseline. In the cases observed, neutropenia has rapidly reversed with 
discontinuation of osilodrostat, and has also reversed when osilodrostat was continued, typically 
with decreasing doses.
Mitigation of the risks related to osilodrostat treatment include: frequent study visits with 
careful monitoring for adverse events and toxicities including those that have been observed in 
previous studies with osilodrostat; vital signs, blood chemistry including urine, serum, and 
, plasma ACTH, electrolytes, renal and liver function, fasting lipid 
profiles, HbA1c, sex steroid levels (testosterone, estradiol, adrenal androgens), aldosterone and 
immediate precursor levels, safety ECGs at the time of Cmax and bone metabolism marker.
In addition, the protocol provides specific guidance for safety follow-up for liver toxicity 
(increased transaminases, increased total bilirubin) and an algorithm for monitoring and 
management of QT prolongation. 
 
 
Conclusion
Based on current data, and the planned risk mitigation processes, the overall benefit-risk of trial 
participation is expected to be positive for all trial subjects


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To assess the percent change from baseline in the
mean Urine Free Cortisol (mUFC) at the individual 
patient level at Week 12
Percent change from baseline to Week 12 in the mUFC
Refer to Section 10.4.
secondary
To assess the percent change from baseline in the
mUFC at the individual patient level at Week 24 and 
Week 48
Percent change from baseline to Week 24 and Week 48 in the mUFC
Refer to Section 10.4.4.
To assess the absolute and percent change from 
baseline in mUFC at Week 12, Week 24 and Week 48
Absolute and percent change from baseline to Week 12, Week 24, and 
Week 48 in mUFC
Refer to Section 10.4.4.
To assess the complete, partial, and overall response 
rate at Week 12, Week 24 and Week 48
Complete response rate: proportion of patients with mUFC ≤ULN at Week 12, 
Week 24 and Week 48
Partial response rate: proportion of patients with ≥50% reduction from baseline 
in mUFC, but mUFC > ULN at Week 12, Week 24 and Week 48
Overall response rate: proportion of patients with mUFC ≤ULN or at least 50% 
reduction from baseline; complete responders or partial responders at
Week 12, Week 24 and Week 48
Refer to Section 10.5.2.
To assess the absolute and percent change from 
baseline in morning serum cortisol at the individual 
patient level at Week 12, Week 24 and Week 48
Absolute and percent change from baseline to Week 12, Week 24, and 
Week 48 in morning serum cortisol
Refer to Section 10.5.2.
To assess the absolute and percent change from 
baseline in morning serum cortisol at Week 12, 
Week 24 and Week 48
Absolute and percent change from baseline to Week 12, Week 24, and 
Week 48 in serum cortisol
Refer to Section 10.5.2.
To assess the absolute and percent change from 
baseline in steroid hormones at the individual patient 
level at Week 12, Week 24 and Week 48
Absolute and percent change from baseline to Week 12, Week 24, and 
Week 48 in: serum aldosterone, serum 11-deoxycorticosterone, serum 
11-deoxycortisol, serum testosterone, serum estradiol and plasma ACTH
Refer to Section 10.5.2.
To assess the change from baseline in cardiovascular-
related metabolic parameters associated with CS at
Week 12, Week 24 and Week 48
Absolute and percent change from baseline to Week 12, Week 24, and 
Week 48 in : fasting glucose, HbA1c, fasting lipid profile, blood pressure, body 
weight, body mass index (BMI) and waist circumference
Refer to Section 10.5.2.


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Objective
Endpoint
Analysis
To assess the general safety of osilodrostat
Adverse events and laboratory abnormalities will be assessed using the 
Common Terminology Criteria for Adverse Events (CTCAE) grading scale 
(version 4.03).
AEs as reported by the investigator, or by laboratory evaluation, ECG, and 
Holter recording
Refer to Section 10.5.3.
To assess the change from baseline in Patient-Reported 
Outcome (Health Related Quality of Life) at individual 
patient level at Week 12, Week 24 and Week 48
Change in standardized score of CushingQoL and Beck Depression Inventory-
II from baseline to Week 12, Week 24 and Week 48
Refer to Section 10.5.7.
To evaluate PK of osilodrostat in patients with CS
Plasma concentrations (at the scheduled time point) of osilodrostat
Refer to Section 10.5.4.


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4
Study design
4.1
Description of study design
This is a phase II, single arm, open-label, dose titration, multi-center study consisting of two 
distinct study periods plus an optional extension period in non-CD patients with CS who have 
persistent or recurrent hypercortisolism after primary surgery and/or irradiation and/or 
chemotherapy, and patients de novo CS who are not surgical candidates for medical reasons, or 
refuse to undergo surgery.
Study period I (Week 1 to Week 12):
Study period I is the dose titration period to achieve a stable therapeutic dose and to assess the 
efficacy and safety of osilodrostat.
Figure 4-1
Study period 1
Dose adjustments are based on the serum cortisol values measured by the local lab at each site. 
Osilodrostat titration can be done weekly for the initial 4 weeks, up to a maximum dose of
10 mg b.i.d. Two-week interval must be taken to increase from 10 mg b.i.d. to 20 mg b.i.d., 
even if in initial 4 weeks. After Week 4, the dose can be further increased, if needed, at 2-week 
intervals (Figure 4-1). The dose is increased if morning serum cortisol is above normal (> ULN
of each site). The dose is reduced if serum cortisol is below normal (< LLN of each site), or if 
the patient is symptomatic and serum cortisol is in the lower part of the normal range. The dose 
should be maintained if serum cortisol is within the normal range and the patient does not have 
signs or symptoms of hypocortisolism or adrenal insufficiency.
The mean of three 24-hour UFC (mUFC) values will be measured to evaluate the efficacy in 
this period.
Study period II (Week 12 to Week 48):
Study period II is the period to assess the sustainability of efficacy and to assess long term 
safety. For this study period II, only the patients who tolerate and agree to continue osilodrostat
treatment will continue study treatment during period II. The patient will be administered with 
the stable therapeutic dose which will be achieved in the study period I. The dose level could 
be modified according to the patient condition (refer to Section 6.1 and Section 6.3). The mUFC 
will also be measured to evaluate the efficacy in this period.


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Optional extension period (after Week 48):
Patients who continue to receive clinical benefit, as assessed by the study investigator and who 
wish to enter the extension period must be re-consented at week 48. Patients who enter the 
extension period will do so without interruption of study drug or assessments. The extension 
period will end after all patients have completed Week 72 or discontinued early (prior to 
Week 72).
Study CLCI699C1201 ends when all ongoing patients have been offered local alternative 
treatment options; this period will not exceed 9 months after all ongoing patients have 
completed Week 72. 
The patient can either be offered a local alternative treatment option or stay in the study until 
the study end (i.e. 9 months after the last patient completes Week 72) Patients will complete an 
EoT visit, and a Follow-up visit (30 days after the last dose administration).
The patient will continue to receive stable therapeutic dose. The dose level could be modified 
according to the patient condition (refer to Section 6.1 and Section 6.3).
Follow-up
All patients will be contacted for safety evaluation during the 30 days following the last dose 
of study treatment.
4.2
Timing of interim analyses and design adaptations
The study will have no interim analysis. The data to be reported based on a data cut-off 
corresponding to the time point where all patients have completed at 12 weeks treatment or 
discontinued the study for any reason, whichever comes first (including the follow-up period).
4.3
Definition of end of the study
Completion of the study as a whole (last patient last visit) will occur after all patients have 
completed all assessments as per Table 7-1, Table 7-2 and Table 7-3 or have discontinued early. 
Study CLCI699C1201 ends when all ongoing patients have been offered local alternative 
treatment options; this period will not exceed 9 months after all ongoing patients have 
completed Week 72.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the patient’s interests. The investigator will be responsible for 
informing IRBs and/or ECs of the early termination of the trial.


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5
Population
5.1
Patient population
The study population targets enrollment of 10 adult male or female non-CD patients with CS 
who have persistent or recurrent hypercortisolism after primary surgery and/or irradiation 
and/or chemotherapy, and patients with de novo CS who are not surgical candidates for medical 
reasons, or refuse to undergo surgery. This target sample size will be monitored and could be 
adjusted on the basis of the enrollment status.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following general criteria and 
the criteria applicable for the specific disease causing CS:
Written informed consent must be obtained prior to any screening procedures.
1. Male or female patients aged 18 - 85 years.
2. Patients must have confirmed CS as evidenced by:
a. For ectopic corticotropin syndrome, patients must have confirmed ectopic 
corticotropin syndrome by all of the following criteria:
1. mUFC > 1.3 x ULN [mean of three 24-hour urine samples collected during 
screening after washout is completed (if patient received medical treatment for 
hypercortisolism due to CS*) and within a 14-days duration]
* In case a patient receives steroidogenesis inhibitors and the investigator 
presumes the patient may meet this mUFC criterion without washout, washout 
before screening is not mandatory. In case that patient doesn’t meet this mUFC 
criterion without washout, the patient is recommended to be rescreened after 
washout.
2. Morning plasma ACTH above lower limit of normal
3. Low dose (0.5 mg or 1.0 mg p.o. at 23:00) dexamethasone (DEX) suppression 
test dose not suppress the serum cortisol level at about 8:00 the next morning (i.e. 
serum cortisol level > 5 µg/dL or > 138 nmol/L for 0.5 mg DEX suppression test, 
> 3 µg/dL or > 83 nmol/L for 1.0 mg DEX suppression test).
4. Patients meet any of the following criteria with either i. or ii.:
i.
High dose (8 mg p.o. at 23:00) DEX suppression test dose not suppress the serum 
cortisol level at about 8:00 the next morning by more than 50%.
ii. Plasma ACTH does not exceed 1.5 times than pre-dose after corticotropin 
releasing hormone (CRH) stimulating test.
5. To exclude pituitary adenoma, patients must meet all of the following criteria:

MRI does not confirm pituitary adenoma when MRI data available.

Bilateral inferior petrosal sinus sampling (BIPSS) with either CRH or DDVAP 
stimulation. When the BIPSS data available, the criteria for a non-confirmatory 
BIPSS test are any of the following:


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i.
Pre-dose central to peripheral ACTH gradient < 2
ii. Post-dose central to peripheral ACTH gradient < 3
b. For adrenal adenoma, patients must have confirmed adrenal adenoma by all of the 
following criteria:
1. mUFC > 1.3 x ULN [mean of three 24-hour urine samples collected during 
screening, after washout is completed (if patient received medical treatment for 
hypercortisolism due to CS*), and within a 14-days duration]
* In case a patient receives steroidogenesis inhibitors and the investigator 
presumes the patient may meet this mUFC criterion without washout, washout 
before screening is not mandatory. In case that patient doesn’t meet this mUFC 
criterion without washout, the patient is recommended to be rescreened after 
washout.
2. Low plasma ACTH level (< 10 pg/ml or < 2.2 pmol/L)
3. High dose (8 mg p.o. at 23:00) DEX suppression test dose not suppress the serum 
cortisol level at about 8:00 the next morning (i.e. serum cortisol level > 5 µg/dL 
or > 138 nmol/L) when high dose DEX suppression test result available.
4. Evidence of adrenal tumor by CT and/or MRI
5. Patients meet any of the following criteria with either i. or ii. :
i.
Patients are not considered for surgery.
ii. Patients need to control of hypercortisolism before surgery and who can receive 
12 weeks treatment.
c. For adrenal carcinoma, patients must have confirmed adrenal carcinoma by all of the 
following criteria:
1. mUFC > 1.3 x ULN [mean of three 24-hour urine samples collected during 
screening, after washout is completed (if patient received medical treatment for 
hypercortisolism due to CS*), and within a 14-days duration]
* In case a patient receives steroidogenesis inhibitors and the investigator 
presumes the patient may meet this mUFC criterion without washout, washout 
before screening is not mandatory. In case that patient doesn’t meet this mUFC 
criterion without washout, the patient is recommended to be rescreened after 
washout.
2. Evidence of adrenal carcinoma by CT and/or MRI and diagnosed as adrenal 
carcinoma by pathologically and/or clinically
3. Patients are not considered for surgery.
d. For AIMAH or PPNAD, patients must have confirmed AIMAH or PPNAD by all of 
the following criteria:
1. mUFC > 1.3 x ULN [mean of three 24-hour urine samples collected during 
screening, after washout is completed (if patient received medical treatment for 
hypercortisolism due to CS*), and within a 14-days duration]
* In case a patient receives steroidogenesis inhibitors and the investigator 
presumes the patient may meet this mUFC criterion without washout, washout 
before screening is not mandatory. In case that patient doesn’t meet this mUFC 
criterion without washout, the patient is recommended to be rescreened after 
washout.


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2. Low plasma ACTH level (< 10 pg/ml or 2.2 pmol/L)
3. High dose (8 mg p.o. at 23:00) DEX suppression test dose not suppress serum 
cortisol level at about 8:00 the next morning (i.e. serum cortisol level > 5 µg/dL 
or > 138 nmol/L) when high dose DEX suppression test result available.
4. Evidence of bi-lateral adrenal multiple hyperplasia by CT and/or MRI (large 
nodules for AIMAH and small nodules for PPNAD).
5. Patients are not considered for surgery.
3. Patients are expected to remain in stable condition for at least 5 months. [e.g. controlled 
condition for the primary disease (i.e. tumor of the patients. )]
4. For patients on medical treatment for hypercortisolism due to CS the following washout 
periods must be completed prior to baseline efficacy assessments:
a. Steroidogenesis inhibitors (metyrapone, trilostane, ketoconazole): 1 week
b. Mitotane: 6 months
c. Mifepristone: 4 weeks
d. Other experimental therapy: at least 5 half-lives or 30 days, whichever is longer
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients with Cushing’s disease
2. History of hypersensitivity to osilodrostat or to drugs of similar chemical classes
3. Patients who have a known inherited syndrome as the cause for hormone over secretion 
[i.e. Carney Complex, McCune-Albright syndrome, multiple endocrine neoplasia I 
(MEN-1), aryl hydrocarbon receptor interacting protein (AIP)]. This exclusion criterion 
is retired as of Amendment #2.
4. History of malignancy of any organ system [with the exception of: a) malignancy causing 
ectopic corticotripin syndrome, or b) localized basal cell carcinoma of the skin], treated or 
untreated, within the past 5 years, regardless of whether there is evidence of local 
recurrence or metastases
5. Patients receiving treatment for malignancy (e.g., cytotoxic chemotherapy, molecular
targeting drugs, somatostatin analogue) within 4 weeks or ≤5 x half-life of the agent 
(whichever is longer) before first dose of osilodrostat
6. Patients with risk factors for QTc prolongation or Torsades de Pointes, including:

Patients with a baseline QTcF > 450 ms for males and QTcF > 460 ms for females, 
personal or family history of long QT syndrome, or concomitant medications known 
to prolong the QT interval

Hypokalemia, hypocalcaemia, or hypomagnesaemia, if NOT corrected before pre-
dose Day 1
7. Diabetic patients with poorly controlled diabetes as evidenced by HbA1c > 9%
8. Patients who have a history of: congestive heart failure (NYHA Class III or IV), unstable 
angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced 
heart block, acute myocardial infarction less than one year prior to study entry, or 
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9. Patients with moderate to severe renal impairment [estimated glomerular filtration rate
(GFR) < 60 mL/min by the MDRD formula, or serum creatinine > 2.0 x ULN]
10. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent 
hepatitis, or patients with any of the following laboratory abnormalities;

Total bilirubin > 1.5 x ULN

Aspartate transaminase (AST) > 3.0 x ULN

Alanine transaminase (ALT) > 3.0 x ULN
11. Patients who are not euthyroid judged by the investigator
12. Patients who have undergone major surgery within 1 month prior to screening
13. Pregnant or nursing (lactating) women
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 1 week of study medication. Highly effective contraception methods 
include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of bilateral oophorectomy, documentation is required (e.g. 
operative report, pelvic ultrasound or other reliable imaging method).

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject.

Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
< 1%), for example hormone vaginal ring or transdermal hormone contraception
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal 
ligation at least six weeks ago. In the case of bilateral oophorectomy, documentation 
is required (e.g. operative report, pelvic ultrasound or other reliable imaging method).
15. Patients who have any current or prior medical condition that can interfere with the 
conduct of the study or the evaluation of its results in the opinion of the investigator or the 
sponsor’s medical monitor
16. Patients who have a history of alcohol or drug abuse in the 6 months period prior to study 
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17. Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will be unable to complete the entire study
6
Treatment
6.1
Study treatment
Study treatment: osilodrostat 1 mg, 5 mg, 10 mg, 20 mg in the form of film-coated tablets for 
oral administration: On 22-Aug-2016 (before Amendment #2), the 20 mg tablet strength was 
discontinued for use in the trial, in order to reduce the risk of dosing error in which the patient 
took more than the prescribed dose. Remaining supplies of the 20 mg tablets were to be 
collected from the sites.
Each strength has a unique size and color (Figure 6-1). The osilodrostat 1 mg, 5 mg, 10 mg and 
20 mg film coated tablets are approximately 6 mm, 7 mm, 9 mm, and 11 mm respectively in 
diameter and pale yellow, yellow, pale orange brown and light brown respectively in color.
Figure 6-1
Appearance of osilodrostat tablets by strength
Legend: Each strength of osilodrostat has a unique size and color to aid in recognition. The 
appearance of the actual tablets may vary slightly from the picture.
6.1.1
Dosing regimen
The dosing regimen of osilodrostat in the planned study will be titrated according to the 
following escalation sequence: osilodrostat 2 mg b.i.d., 5 mg b.i.d., 10 mg b.i.d., 20 mg b.i.d., 
and 30 mg b.i.d.. If hypocortisolism occurs at 2 mg b.i.d., the dose can be lowered to 1 mg b.i.d.. 
The maximum dose of osilodrostat in this study is 30 mg b.i.d..
Dose adjustments are based on the serum cortisol values as measured by the local lab at each 
site. The osilodrostat dose is increased if the morning serum cortisol is above normal (> ULN
of each site). The dose titration based on the mUFC value from central analysis could be 
considered with the same scheme (> ULN). Osilodrostat titration can be done weekly for the 
initial 4 weeks, up to a maximum dose of 10 mg b.i.d.. Two-week interval must be taken to 
increase from 10 mg b.i.d. to 20 mg b.i.d., even if in initial 4 weeks. After Week 4, the dose can 
be further increased, if needed, at 2-week intervals. The osilodrostat dose will be reduced if the 


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serum cortisol value is < LLN of each site or the patient has signs and symptoms of 
hypocortisolism or adrenal insufficiency and the serum cortisol value is in the lower part of the 
normal range. The osilodrostat dose will be maintained if the serum cortisol value is in the 
normal range and the patient does not have signs or symptoms of hypocortisolism or adrenal 
insufficiency.
If hypocortisolism occurs at 2 mg b.i.d., the dose can be decreased to 1 mg b.i.d. or lower, e.g., 
1 mg q.d. (once a day) or 1 mg q.o.d. (every other day), if needed. Any lower dose other than 
1 mg bid is not a standard dose and as mentioned below must be discussed with the sponsor on 
a case-by-case basis before implementation.
Once the patient is controlled following the dose titration period, if intermediate doses (doses 
that are not specified in the titration sequence) are deemed necessary, the same dose should be 
used in the a.m. and the p.m., as a b.i.d. regimen, if possible, to ensure consistent drug exposure.
Permitted intermediate dose levels are: 3, 7 and 15 mg b.i.d.
Outside of the planned doses for the escalation sequence and permitted intermediate doses, any 
dosing regimen not following the above must be discussed with the sponsor on a case-by-case 
basis.
Osilodrostat should be administered at approximately the same time each day, about 12-hours 
apart for the twice-daily regimen. Osilodrostat can be administered regardless of food or fast 
condition.
On study visit days, patients should be reminded not to take the study treatment prior to the site 
visit in order to ensure compliance with the pre-dose PK sampling procedure. The morning dose 
on the visit days should be taken at the site after the pre-dose PK sampling.
Dose reductions and temporary dose interruptions for safety reasons are permitted at any time 
during the study.
6.1.2
Ancillary treatments
Not applicable
6.1.3
Rescue medication
Not applicable
6.1.4
Guidelines for continuation of treatment
Osilodrostat therapy is continued unless it must be interrupted, discontinued for safety or other 
reason, or completion of study treatment. See Section 6.1.5 “Treatment duration” and 
Section 6.3 “Dose modifications” for details.
6.1.5
Treatment duration
The primary endpoint is assessed at Week 12 but treatment duration is 48 weeks in patients who 
agree to continue after Week 12. In addition, patients will have the option to continue in the 
extension phase; patients who wish to enter the extension period must be re-consented at 
week 48. The optional extension period will end when all patients have completed Week 72 or 
discontinued early (prior to Week 72).


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Study CLCI699C1201 ends when all ongoing patients have been offered local alternative 
treatment options; this period will not exceed 9 months after all ongoing patients have 
completed Week 72. 
The patient can either be offered a local alternative treatment option or stay in the study until 
the study end (i.e. 9 months after the last ongoing patient completes Week 72). Patients will 
complete an EOT visit and a Follow-up visit (30 days after the last dose administration).
In the absence of premature discontinuation, patients will receive osilodrostat for a minimum 
of 12 weeks.
6.2
Dose escalation guidelines
Not applicable. This is not a dose escalation study. Please refer to Section 6.1.1 for dose titration 
procedure.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment.
These dose modifications are summarized in Table 6-1 and Table 6-2. Deviations to mandatory 
dose modifications are not allowed. Permanent treatment discontinuation is mandatory for 
specific events indicated as such in Table 6-2 or listed in Section 7.1.4.
During treatment with osilodrostat in patients with Cushing’s syndrome and regardless of 
suspected drug causality, an AE may require not only interruption of study drug, but also 
replacement or stress doses of glucocorticoids until the AE has resolved.
Please refer to Section 4.1 “Description of study design” and Section 6.1.1 “Dosing regimen” 
for further information about dose and dosing regimen during various periods during the trial.
Symptomatic hypocortisolism or adrenal insufficiency is suspected on the basis of clinical 
signs/symptoms, which may include gastrointestinal symptoms (nausea, vomiting), fatigue, 
weakness, failure to thrive, morning headache, symptoms consistent with hypoglycemia, 
dizziness. When symptomatic hypocortisolism is suspected, the investigator may order urgent 
local laboratory testing, including serum cortisol to help differentiate glucocorticoid withdrawal 
symptoms from adrenal insufficiency.
For patients whose dose needs to be fine-tuned to provide the requested efficacy or are unable 
to tolerate the protocol-specified dosing schedule, dose adjustments to other than standard dose 
levels (2, 5, 10, 20 and 30 mg respectively b.i.d) are permitted in order to keep the patient on 
study drug. The following guidelines (Table 6-1 and Table 6-2) need to be applied. These 
changes must be recorded on the Dosage Administration Record CRF.


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Table 6-1
Dose Modification Guidelines for osilodrostat-suspected toxicities
Toxicity
Actions
Symptomatic hypocortisolism 
or adrenal insufficiency
Recommendation: If the investigator at any time suspects symptomatic 
hypocortisolism or adrenal insufficiency, they can immediately interrupt study 
drug and initiate replacement with glucocorticoids. Upon recovery as assessed 
by the investigator*, glucocorticoid therapy can be tapered as tolerated, and 
study drug can be re-started. The decision to restart study drug will be made 
by the investigator. The AE and associated treatments need to be 
appropriately documented in the eCRF.
* Recovery is assessed clinically by the investigator.  A general guideline is 
that glucocorticoid taper can begin when serum cortisol or mUFC is in the 
upper part of the normal range or > ULN, and study drug can be re-started if 
the patient is clinically stable off glucocorticoid therapy for at least one week, 
and the serum cortisol or mUFC is normal or > ULN.
Persistent asymptomatic 
hypocortisolism (serum 
cortisol or mUFC < LLN) at 
the lowest dose of 
osilodrostat (1 mg every 
other day)
Recommendation: The investigator can interrupt study drug and restart at the 
same dose as clinically indicated.
Glucocorticoid withdrawal 
syndrome
Recommendation: The investigator can reduce or interrupt dose until improved
Hypotension (mild, 
reversible)
Recommendation: The investigator can reduce or interrupt dose until 
improved.
Hypertension
Recommendation: The investigator can reduce or interrupt dose until 
improved; consider ACE inhibitors for treatment of hypertension, or 
spironolactone as second line treatment, particularly if hypokalemia is present.
ACE inhibitors and spironolactone should not be used in combination.
Weight gain, edema
Recommendation: The investigator can reduce or interrupt dose until 
improved; consider spironolactone for treatment of edema.
Hypokalemia
Recommendation: The investigator can reduce or interrupt dose until 
improved; replace potassium; consider spironolactone or eplerenone for 
prevention and treatment of hypokalemia
Hyperkalemia
Recommendation: The investigator can reduce or interrupt dose until 
improved; if on spironolactone or eplerenone, reduce or interrupt; treat with 
kayexalate and other therapies as needed.
Hirsutism (women only)
Recommendation: The investigator can reduce or interrupt dose until 
improved; review testosterone level; consider spironolactone, cyproterone 
acetate or finasteride per local guideline.
Acne (women or men)
Recommendation: The investigator can reduce or interrupt dose until 
improved; review testosterone level; consider spironolactone, cyproterone 
acetate or finasteride per local guideline.
Abbreviations: UFC, 24-hour urine free cortisol; ULN, upper limit of the normal reference range; LLN, lower limit 
of the normal reference range.
Instructions for monitoring liver function, and the criteria for interrupting, re-initiating, 
reducing dose or discontinuation of study medication are provided in Table 6-2 below.


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Table 6-2
Criteria for interruption and re-initiation of osilodrostat for abnormal 
liver function
Isolated total Bilirubin elevation
> ULN – 1.5 x ULN
Recommendation: Maintain dose level
> 1.5 - 3.0 x ULN
Recommendation: lnterrupt study drug dose. Monitor liver function tests 
(LFTs)a  weekly, or more frequently if clinically indicated, until resolved to ≤1.5
x ULN:
If resolved in ≤14 days, restart study drug and maintain dose level 
If resolved in > 14 days, restart study drug and decrease by one dose level
> 3.0 - 10.0 x ULN*
Recommendation: Interrupt study drug. Monitor LFTsa weekly, or more 
frequently if clinically indicated, until resolved to ≤1.5 x ULN:
If resolved in ≤14 days, restart study drug and decrease by one dose level 
Mandatory: If resolved in > 14 days, then discontinue patient from study drug 
treatment. The patient should be monitored weekly (including LFTsa), or more 
frequently if clinically indicated, until total bilirubin has returned to baseline or 
stabilized over 4 weeks.
> 10.0 x ULN*
Mandatory: Discontinue patient from study drug treatment
The patient should be monitored weekly (including LFTsa), or more frequently if 
clinically indicated, until total bilirubin has returned to baseline or stabilized 
over 4 weeks.
Isolated AST or ALT elevation
> ULN - 3.0 x ULN
Recommendation: Maintain dose level
> 3.0 - 5.0 x ULN
Recommendation: Maintain dose level. Repeat LFTsa as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; if 
abnormal lab values are confirmed upon the repeat test, then monitor LFTsa
weekly, or more frequently if clinically indicated, until resolved to ≤3.0 x ULN
> 5.0 - 10.0 x ULN
Recommendation: Interrupt study drug. Repeat LFTsa as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; monitor 
LFTsa weekly, or more frequently if clinically indicated, until resolved to ≤3.0 x 
ULN. Then:
If resolved in ≤14 days, restart study drug and maintain dose level
If resolved in > 14 days, restart study drug and decrease dose by one level
Mandatory: If not resolved after 4 weeks, discontinue patient from study drug
> 10.0 x ULN
Mandatory: Discontinue study drug. Repeat LFTsa as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; monitor 
LFTsa weekly, or more frequently if clinically indicated, until resolved to ≤3 x 
ULN.


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Isolated total Bilirubin elevation
Combined b,c elevations of AST or ALT and total bilirubin
For patients with normal 
baseline ALT and AST and 
total bilirubin value:
AST or ALT > 3.0 x ULN 
combined  with total bilirubin 
> 2.0 x ULN without 
evidence of cholestasisc
OR 
For patients with elevated 
baseline AST or ALT or total 
bilirubin value: 
[AST or ALT > 2 x baseline 
AND > 3.0 x ULN] OR [AST 
or ALT > 8.0 x ULN], 
combined with [total bilirubin 
> 2 x baseline AND > 2.0 x 
ULN]
Mandatory: Permanently discontinue patient from study drug treatment. 
Repeat as soon as possible, preferably within 48 hours from awareness of the 
abnormal results, then with weekly monitoring of  LFTsa, or more frequently if 
clinically indicated, until AST, ALT, or bilirubin have returned to baseline or 
stabilized over 4 weeks.
Refer to Section 6.3.2.1 for additional follow-up evaluations as applicable.
All dose modifications should be based on the worst preceding toxicity.
a. Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x 
ULN), and alkaline phosphatase (ALP) (fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x 
ULN.)
b. “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase 
to the defined threshold.
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue study drug at the situation when interrupt study 
drug is needed for one parameter and discontinue study drug is required for another parameter). After all 
elevations resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the 
same dose or at one dose lower if meeting a criterion for dose reduction
c. “Cholestasis” defined as: ALP elevation (> 2 x ULN and R value (ALT/ALP in x ULN) < 2) in patients without 
bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It 
denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤2), hepatocellular 
(R ≥5), or mixed (R > 2 and < 5) liver injury
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and 
haptoglobin determination), then ↓1 dose level and continue treatment at the discretion of the investigator.
In addition, any AE, regardless of suspected drug causality, may require interruption of
osilodrostat and replacement or stress doses of glucocorticoid therapy until resolution of the 
event.

Upon recovery from the AE, the investigator may consider re-starting osilodrostat if the 
dose interruption has been ≤14 days.

If the dose interruption has been > 14 days, then the patient should be observed. If mUFC 
rises to above the ULN, and has been off glucocorticoid therapy for at least one week, 
osilodrostat may be re-started.
If the patient has interruption of osilodrostat for more than 4 weeks, the investigator should 
consider early discontinuation from the study. Patients that had interruption of osilodrostat and 
mUFC remains ≤ULN off osilodrostat should remain on study for observation.
These changes must be recorded on the Dosage Administration Record CRF.


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6.3.2
Follow-up for toxicities
Please refer to Section 6.3.1 and Section 8.1.3.
6.3.2.1
Follow-up on potential drug-induced liver injury (DILI) cases
Transaminase increase combined with total bilirubin (TBIL) increase may be indicative of 
potential DILI, and should be considered as clinically important event.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤2), hepatocellular (R ≥5), or mixed (R > 2 and < 5) liver injury.
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/ international normalized ratio (INR)
and alkaline phosphatase.

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.

Obtain PK sample, as close as possible to last dose of study drug.

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly
documented.


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6.3.3
Anticipated risks and safety concerns of the study drug
Anticipated drug-related risks are summarized in Section 2.6. Recommended guidelines for 
supportive treatment for expected toxicities, including management of study-drug induced 
adverse events, are provided in Section 6.3.1.
Additional anticipated risks are summarized in Section 8.1.3 “Adverse events of special 
interest.” Two of these AEs are described in greater detail: the potential for QT prolongation 
(Section 8.1.3.1), and hypocortisolism (glucocorticoid withdrawal/adrenal insufficiency) 
(Section 8.1.3.2). Recommendations for QT prolongation monitoring and management are 
provided in Section 7.2.2.7. Other AEs of special interest for osilodrostat (either reported or 
anticipated based on the mechanism of action of the drug) include cardiac arrhythmia. These 
particular AEs may require premature discontinuation from the study (see Section 7.1.4).
Refer to preclinical toxicity and or clinical data found in the [Investigator’s Brochure].
6.4
Concomitant medications
Stable doses of concomitant medications (except those for hypercortisolism) are allowed during 
the study. All pre-existing concomitant medications should be recorded at study start. The 
investigator should instruct the patient to notify the study site about any new medications he/she 
takes after the start of the study. All medications and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the patient signs the informed 
consent through 30 days after the last dose of osilodrostat must be listed on the CRF. If the 
patient receives the new treatment for Cushing’s syndrome within 30 days from the study 
treatment discontinuation, from that point, only the concomitant medication and significant 
non-drug therapies which are used for adverse events should be recorded.
All prescription medications and over-the-counter drugs taken within the timeframe defined in 
the entry criteria prior to the start of the study, must be recorded on the prior medication page 
of the CRF. Medication entries should be specific to trade name, the single dose and unit, the 
frequency and route of administration, the start and discontinuation dates and the reason for 
therapy.
All concomitant medications received during the study should be reported on the CRF, and 
include the drug name (specific trade name), start and discontinuation dates and the reason for 
therapy. Medications used for the treatment of hypertension, diabetes or impaired glucose 
tolerance, and hyperlipidemia, in particular, require this detailed information as part of the 
efficacy assessment.
6.4.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug including 
herbal/natural medications) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered during the study must be listed on the concomitant 
medications or the surgical and medical procedures CRF.
Spironolactone and eplerenone are permitted for the treatment or prevention of study 
drug-related edema or hypokalemia. The use of these drugs should be done with close 


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monitoring for the risk of severe hyperkalemia, which is further increased if renal insufficiency 
is present.
Medications that are metabolized by CYP450 enzymes
In vitro drug metabolism studies show that osilodrostat is a potential inhibitor of CYP1A2, 
CYP2C19, CYP2D6, CYP3A4/5 and CYP2E1, and may consequently increase exposure to 
drugs metabolized by this enzyme.
In a clinical drug-drug interaction (DDI) study, osilodrostat was found to be a moderate 
inhibitor of CYP1A2 (2.5-fold increase in substrate exposure), a weak to moderate inhibitor of 
CYP2C19 (1.9-fold increase in substrate exposure), and a weak inhibitor of CYP2D6 and 
CYP3A4/5 (1.5-fold increase in substrate exposure). Therefore concomitant medications that 
are known substrates of these enzymes (see Appendix 2) should be used with caution.
The patient and the Investigator should be aware of potential signs of overdose of the 
concomitant medication and in the event of suspected toxicities; administration of either the 
substrate or osilodrostat should be discontinued according to investigators’ judgement.
6.4.2
Prohibited concomitant therapy
Use of the following concomitant medications are prohibited during the study:

Other drug treatments for Cushing’s syndrome

Medications with a “known risk to cause Torsades des Pointes (TdP)” and “possible risk 
to cause TdP”

Eplerenone and glucocorticoids, except under certain conditions:

Eplerenone may be used if necessary in acute post-myocardial infarction 
management, and in the event of refractory hypokalemia in patients with hypertension 
or edema

Glucocorticoids (e.g., prednisone, prednisolone, and dexamethasone) may be used as 
required for the short-term treatment of symptomatic hypocortisolism or adrenal 
insufficiency. If glucocorticoids are used in stress doses, or as replacement therapy, 
for > 4 weeks, then the investigator should consider temporary interruption of 
osilodrostat, weaning and discontinuation of glucocorticoid therapy, or early 
discontinuation from the study.
Topical and ophthalmic administrations are acceptable to use during the study.
6.4.2.1
Concomitant medications with a “Known risk to cause TdP” and drugs 
with a “Possible risk to cause TdP”
Preclinical and clinical data indicate that there is a risk of QTc prolongation in humans (see 
Section 8.1.3.1). Therefore, the use of medications with a “known risk to cause TdP” and with 
a “possible risk to cause TdP” concomitantly with osilodrostat is prohibited.
If a patient requires a long-term medication from the two categories mentioned above, and there 
is no appropriate alternative medication available, then they should be discontinued from the 
study.


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However, if a patient requires such a drug for short-term therapy, e.g., antibiotics for active 
infection, then the osilodrostat may be interrupted temporarily while this drug is administered
after a thorough risk-benefit assessment. This does not require the patient to discontinue from 
the study prematurely. Washout periods for osilodrostat and the short-term prohibited drug in 
many cases may not be possible; this is acceptable if the benefit of the drug outweighs the risk 
of withholding osilodrostat therapy in the investigator’s judgment. In such cases, a discussion 
with the Novartis medical monitor is recommended.
Please refer to Appendix 3 for an e-link to a list of medications that have a “known risk to cause 
TdP” and “possible risk to cause TdP”. Investigators are advised to utilize this website when 
considering the addition of a new concomitant medication, as the lists are periodically updated. 
If necessary, a discussion can be held with the Novartis Medical Monitor when considering the 
use of medications with a “known risk to cause TdP” and with a “possible risk to cause TdP”.
6.5
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF.
Study drug use in this study includes 1 mg, 5 mg, 10 mg and 20 mg tablets: On 22 Aug 2016 
(before Amendment #2), the 20 mg tablet strength was discontinued for use in the trial, in order 
to reduce the risk of dosing error in which the patient took more than the prescribed dose. 
Remaining supplies of the 20 mg tablets were to be collected from the sites. There is a unique 
size and color for each dose strength (see Figure 6-1). Study drug is dispensed in a set of kits 
(bottles) for each patient at each visit. Osilodrostat is dispensed in separate bottles for each dose 
strength. The label on each bottle indicates the dose strength.
Patients may be dispensed bottles of more than one tablet strength at the same visit. For 
example, if a patient is on the preferred intermediate dose of 7 mg b.i.d., the patient would be 
provided with both 1 mg and 5 mg tablet strengths and instructed to take 2 x 1 mg tablets and a 
1 x 5 mg tablet, twice a day. Consequently, to ensure patient safety, it is very important that 
site staff educate the patient on how to recognize the tablet strength dispensed at each visit, both 
on the bottle labels, and by the appearance of tablets by dose strength. Patients are given a 
dosing card that includes general instructions and an image displaying the color and size of each 
tablet strength. Clear, simple, written instructions must be provided to the patient at the visit; 
these instructions must include the dose and the number of tablets of each strength to be taken 
in the morning and in the evening. The site ensures that enough study drug is dispensed to treat 


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the patient until the next scheduled visit by specifying the set of kits (bottles) for each patient 
at each visit. A minimal number of strengths will be dispensed at any one visit, as feasible.
Patients requiring a different tablet strength to implement a dose change between scheduled 
study visits, will need to return to the site (unscheduled visit) to collect the new study drug 
supplies. The site will dispense the corresponding kit(s) to the patient, to provide drug supply 
until the next study visit.
Table 6-3
Preparation and dispensing
Study treatments
Dispensing
Preparation
Osilodrostat (1 mg, 
5 mg, 10 mg and 
20 mg)
Tablets including instructions for administration are dispensed by 
study personnel on an outpatient basis.
Patients will be provided with adequate supply of study drug for self-
administration at home until at least their next scheduled study visit 
(including any dose change required in between visits). More than 
one tablet strength may be dispensed to patients at the same 
visit.
Not applicable
6.6.1
Study drug packaging and labeling
Osilodrostat will be supplied as 1 mg, 5 mg, and 10 mg film coated tablets (the 20 mg tablet 
strength was discontinued for use), and will be given orally twice a day.
Each study site will be supplied by Novartis with study drug. Medication labels will be in the 
local language and comply with the legal requirements of Japan. They will include storage 
conditions for the drug (for details, see study drug handling procedure which is provided by 
Novartis).
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the osilodrostat should be stored according to the 
instructions specified on the drug labels and in the [Investigator’s Brochure].
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the drug accountability 
form. This information must be captured in the source document at each patient visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.


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At study close-out and as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, drug supply group or third 
party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1, Table 7-2 and Table 7-3 list all of the assessments and indicates with an “X”, the 
visits when they are performed. All data obtained from these assessments must be supported in 
the patient’s source documentation.
No CRF will be used as a source document.
The table indicates which assessments produce data to be entered into the clinical database (D) 
or remain in source documents only (S) (“Category” column). Patients who discontinue study 
treatment except for planned discontinuation of study treatment at Week 12 or Week 48, should 
be scheduled for a visit as soon as possible. Whenever patients discontinue study treatment 
(before or at Week 12 [during study period I], before or at Week 24 [during study period II] or 
during optional extension period), all of the assessments listed for the EoT visit will be 
performed.


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
Table 7-1
Visit evaluation schedule – Study period I (dose titration period) and Study period II
Screening 
Phase
Treatment phase
Category
Protocol 
Section
Screening
Baseline
Study period I (dose titration period)
Study period II
Day
-35 ~ 
-8
-7 ~ 
-1
1
8
15
22
29
43
57
71
85
113
141
169
183
211
239
253
281
309
337
Week
-5 ~-
2
-1
0
1
2
3
4
6
8
10
12
16
20
24
26
30
34
36
40
44
48
Obtain informed consent
D
7.1.1
X
X
X
Patient history
Demography
D
7.1.1.3
X
Inclusion/exclusion criteria
D
5.2, 5.3
X
X
Medical History
D
7.1.1.3
X
CS History
D
7.1.1.3
X
Prior treatments for CS
D
7.1.1.3
X
Concomitant medications
D
7.1.1.3
As required
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body height
D
7.2.2.3
X
Body weight
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
Body temperature
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure/Pulse rate
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.4.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
Screening 
Phase
Treatment phase
Category
Protocol 
Section
Screening
Baseline
Study period I (dose titration period)
Study period II
Day
-35 ~ 
-8
-7 ~ 
-1
1
8
15
22
29
43
57
71
85
113
141
169
183
211
239
253
281
309
337
Week
-5 ~-
2
-1
0
1
2
3
4
6
8
10
12
16
20
24
26
30
34
36
40
44
48
Thyroid Panel
D
7.2.2.4.5
X
X
X
X
X
Luteinizing Hormone (LH) 
and Follicle stimulating 
hormone (FSH)
D
7.2.2.4.6
X
X
X
X
X
Coagulation
D
7.2.2.4.4
X
X
X
Bone metabolism marker
D
7.2.2.4.7
X
X
X
X
X
Urinalysis
D
7.2.2.4.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test (serum)
D
7.2.2.4.8
X
X
Pregnancy test (urine)
D
7.2.2.4.8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy assessments
24-hour urinary free 
cortisol and creatinine
D
7.2.1
X
X
X
X
X
X
X
Serum testosterone and 
estradiol
D
7.2.2.4.6
X
X
X
X
X
Serum cortisol (central 
and local)
D
7.2.2.4.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma ACTH
D
7.2.2.4.6
X
X
X
X
X
X
X
X
X
X
X
X
Serum 11-deoxycortisol
D
7.2.2.4.6
X
X
X
X
X
X
Serum aldosterone
D
7.2.2.4.6
X
X
X
X
X
X
X
X
Serum 11-
Deoxycorticosterone
D
7.2.2.4.6
X
X
X
X
X
X


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
Screening 
Phase
Treatment phase
Category
Protocol 
Section
Screening
Baseline
Study period I (dose titration period)
Study period II
Day
-35 ~ 
-8
-7 ~ 
-1
1
8
15
22
29
43
57
71
85
113
141
169
183
211
239
253
281
309
337
Week
-5 ~-
2
-1
0
1
2
3
4
6
8
10
12
16
20
24
26
30
34
36
40
44
48
Fasting serum insulin
D
7.2.2.4.7
X
X
X
X
X
HbA1C
D
7.2.2.4.7
X
X
X
X
X
X
Safety
Adverse events
D
8.1
As required
12-lead safety ECG 
assessment
D
7.2.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead 24-hour Holter 
ECG recording
D
7.2.2.6
X
X
X
X
X
CT/MRI for ectopic 
corticotropin syndrome
D
7.2.2.5
X
X
X
Questionnaires of health 
related quality of life
D
7.2.6
X
X
X
X
X
X
Study drug administration
D
6.1.1
Continuous b.i.d. dosing
PK sampling
D
7.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
Table 7-2
Visit evaluation schedule – Study extension period (Year 1)
Treatment phase
Category
Protocol 
Section
Optional extension period
Day
365
393
421
449
477
505
589
673
Week
52
56
60
64
68
72
84
96
Obtain informed consent
D
7.1.1
Patient history
Concomitant medications
D
7.1.1.3
As required
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
Body weight
D
7.2.2.3
X
X
X
X
X
X
X
X
Waist circumference
D
7.2.2.3
X
X
X
X
X
X
X
X
Vital signs
Body temperature
D
7.2.2.2
X
X
X
X
X
X
X
X
Blood pressure/Pulse rate
D
7.2.2.2
X
X
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.4.1
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.4.2
X
X
X
X
X
X
X
X
Thyroid Panel
D
7.2.2.4.5
X
X
X
X
Luteinizing Hormone (LH) and Follicle stimulating hormone 
(FSH)
D
7.2.2.4.6
X
X
X
X
Coagulation
D
7.2.2.4.4
X
X
X
X
Bone metabolism marker
D
7.2.2.4.7
Urinalysis
D
7.2.2.4.3
X
X
X
X
Pregnancy test (urine)
D
7.2.2.4.8
X
X
X
X
Efficacy assessments
24-hour urinary free cortisol and creatinine
D
7.2.1
Serum testosterone and estradiol
D
7.2.2.4.6
X
X
X
X


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
Treatment phase
Category
Protocol 
Section
Optional extension period
Day
365
393
421
449
477
505
589
673
Week
52
56
60
64
68
72
84
96
Serum cortisol (central and local)
D
7.2.2.4.6
X
X
X
X
Plasma ACTH
D
7.2.2.4.6
X
X
X
X
Serum 11-deoxycortisol
D
7.2.2.4.6
X
X
X
X
Serum aldosterone
D
7.2.2.4.6
X
X
X
X
Serum 11-Deoxycorticosterone
D
7.2.2.4.6
X
X
X
X
Fasting serum insulin and HbA1C
D
7.2.2.4.7
X
X
X
X
Safety
Adverse events
D
8.1
As required
12-lead safety ECG assessment
D
7.2.2.6
X
X
X
X
12lead 24-hour Holter ECG recording
D
7.2.2.6
X
CT/MRI for ectopic corticotropin syndrome
D
7.2.2.5
X
Questionnaires of health related quality of life
D
7.2.6
X
X
Study drug administration
D
6.1.1
Continuous b.i.d dosing
PK sampling
D
7.2.3


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
Table 7-3
Visit evaluation schedule – Study extension period (After Year 1)
Treatment phase
EoT
Follow-up
Category
Protocol 
Section
Optional extension period
Day
757
841
925
1009
1093, 1177, 
1261, ...
85/337/NA
30 days from 
last dose
Week
108
120
132
144
156, 168, 
180, ...(every 
12 weeks)
12/48/premature withdrawal
Obtain informed consent
D
7.1.1
Patient history
Concomitant medications
D
7.1.1.3
As required
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
Body weight
D
7.2.2.3
X
X
X
X
X
X
Waist circumference
D
7.2.2.3
X
X
X
X
X
X
Vital signs
Body temperature
D
7.2.2.2
X
X
X
X
X
X
X
Blood pressure/Pulse rate
D
7.2.2.2
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.4.1
X
X
X
X
Same 
Extension 
assessments 
will be 
performed with 
same 
frequency.
X
X
Chemistry
D
7.2.2.4.2
X
X
X
X
X
X
Thyroid Panel
D
7.2.2.4.5
X
X
X
Only up to Week 48
X
Luteinizing Hormone (LH) and Follicle stimulating 
hormone (FSH)
D
7.2.2.4.6
X
X
X
Only up to Week 48
X
Coagulation
D
7.2.2.4.4
X
X
X
X
X
X
Bone metabolism marker
D
7.2.2.4.7
X
Only at Week 6, 12, 24 or 48
Urinalysis
D
7.2.2.4.3
X
X
X
X
X
X


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
Treatment phase
EoT
Follow-up
Category
Protocol 
Section
Optional extension period
Day
757
841
925
1009
1093, 1177, 
1261, ...
85/337/NA
30 days from 
last dose
Week
108
120
132
144
156, 168, 
180, ...(every 
12 weeks)
12/48/premature withdrawal
Pregnancy test (urine)
D
7.2.2.4.8
X
X
X
X
Same 
Extension 
assessments 
will be 
performed with 
same 
frequency.
X
X
Efficacy assessments
24-hour urinary free cortisol and creatinine
D
7.2.1
Same 
Extension 
assessments 
will be 
performed with 
same 
frequency.
X
Only up to Week 48
Serum testosterone and estradiol
D
7.2.2.4.6
X
X
X
X
Serum cortisol (central and local)
D
7.2.2.4.6
X
X
X
X
X
X
Plasma ACTH
D
7.2.2.4.6
X
X
X
X
X
X
Serum 11-deoxycortisol
D
7.2.2.4.6
X
X
X
Only up to Week 48
X
Serum aldosterone
D
7.2.2.4.6
X
X
X
Only up to Week 48
X
Serum 11-Deoxycorticosterone
D
7.2.2.4.6
X
X
X
X
X
Only up to Week 48
X
Fasting serum insulin and HbA1C
D
7.2.2.4.7
X
X
X
Only up to Week 48
X
Safety


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
Treatment phase
EoT
Follow-up
Category
Protocol 
Section
Optional extension period
Day
757
841
925
1009
1093, 1177, 
1261, ...
85/337/NA
30 days from 
last dose
Week
108
120
132
144
156, 168, 
180, ...(every 
12 weeks)
12/48/premature withdrawal
Adverse events
D
8.1
As required
12-lead safety ECG assessment
D
7.2.2.6
X
X
X
X
Same 
Extension 
assessments 
will be 
performed with 
same 
frequency.
X
X
12lead 24-hour Holter ECG recording
D
7.2.2.6
X
X
CT/MRI for ectopic corticotropin syndrome
D
7.2.2.5
X
Same 
Extension 
assessments 
will be 
performed with 
same 
frequency.
X
Questionnaires of health related quality of life
D
7.2.6
X
Study drug administration
D
6.1.1
Continuous b.i.d dosing
PK sampling
D
7.2.3
X
Only up to Week 48


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
7.1.1
Screening
Written main informed consent must be obtained before any study specific assessments are 
performed.
The screening assessments must be performed within 35 days before planned patient’s 
eligibility confirmation and before the start of the first study drug dose of osilodrostat at Day 1.
Based on the central laboratory turnaround time, it is highly recommended to send the three 
24-hour urinary free cortisol samples to the central Laboratory at least 14 days prior to Day 1 
in order to ensure that sufficient time is allowed for central laboratory results to become 
available.
Eligibility is assessed based on the screening results collected at the screening visit.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. If the 
repeated laboratory result does not meet the criteria, the patient will be considered a screening 
failure. In this case, the subject will not be required to sign another ICF.
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed. The rescreening should be documented in the source files and using 
the same Patient Number.
An individual patient may only be rescreened once for the study. Once the number of patients 
screened and enrolled is likely to ensure target enrollment, the Sponsor may close the study to 
further screening. In this case the patients who screen failed will not be permitted to re-screen. 
For details of assessments, refer to Table 7-1.
 
7.1.1.1
Eligibility screening
Patient eligibility will be checked by the sponsor once all screening procedures are completed.
The eligibility check form will be sent from the site to the sponsor for evaluation. Upon
confirmation of eligibility, the Sponsor will return the signed eligibility check form to the site.
The investigator site will then be allowed to assign treatment to the patient.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
screening phase disposition page. The demographic information, informed consent, and 
inclusion/exclusion pages must also be completed for screen failure patients. No other data will 
be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a serious adverse event during the screening phase.


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201
7.1.1.3
Patient demographics and other baseline characteristics
Standard demographic information and medical history will be collected. Baseline assessments 
will be collected as per Table 7-1. For the CS history, the listed items in the inclusion criteria 
will be collected.
7.1.2
Run-in period
Although there is no run-in period, washout requirements as described in inclusion criteria 
(Section 5.2) must be followed.
7.1.3
Treatment period
Treatment period is divided into 3 study periods (Study period 1, Study period 2 and Extension 
period). For details of assessments, refer to Table 7-1, Table 7-2 and Table 7-3.
Patients should be seen for all visits on the designated day with a visit window of ± 3 days and 
in a fasting state except for Day 1.
During Study period 1, patient will come to site every week for initial 4 weeks and every 2 
weeks thereafter. During Study period 2 and Extension period, patient will come to site 
according to the schedule indicated in Table 7-1, Table 7-2 and Table 7-3.
7.1.4
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision 
and record this information in the patient’s chart and on the appropriate CRF pages. They may 
be considered withdrawn if they state an intention to withdraw, fail to return for visits, or 
become lost to follow-up for any other reasons.
The investigator may discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances (Refer to Table 6-1
and Table 6-2):

Emergence of the following adverse events:

hypertension defined as office mean sitting systolic BP > 180 mmHg or mean sitting 
diastolic BP > 110 mmHg (confirmed and persistent*)
* Persistent is defined as unresolved with osilodrostat dose or other concomitant medication 
changes.

Any of the following laboratory abnormalities (confirmed):

hyperkalemia (serum potassium > 6.0 mmol/L)

hypokalemia (serum potassium < 2.8 mmol/L)

Any of the following laboratory abnormalities (confirmed and persistent*):

hyperkalemia (serum potassium > 5.5 mmol/L)

hypokalemia (serum potassium < 3.0 mmol/L)

hyponatremia (serum sodium < 130 mmol/L)


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Amended Protocol Version 04 (Clean)
Protocol No. CLCI699C1201

Isolated total Bilirubin elevation > 10.0 x ULN, or > 3.0 - 10.0 x ULN not resolved 
after 14 days

Isolated AST or ALT elevation > 10.0 x ULN, or > 5.0 - 10.0 x ULN not resolved 
after 4 weeks

For patients with normal baseline ALT and AST and total bilirubin value: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN without evidence of 
cholestasis

For patients with elevated baseline AST or ALT or total bilirubin value: [AST or 
ALT > 2 x baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined 
with [total bilirubin > 2 x baseline AND > 2.0 x ULN]

QTcF > 500 msec, if confirmed by cardiologist review (see Section 7.2.2.7)

QTcF > 480 msec, if the investigator determines it is no longer safe for the patient to 
continue in the study, based on ECGs, cardiac examination, and recommendation from a 
cardiologist (Section 7.2.2.7)

QTcF increase > 60 msec from mean baseline measurement (pre-dose measurement on 
Day 1), if confirmed by cardiologist review

Mean increase in QTcF > 30 ms from the mean baseline measurement (pre-dose 
measurement on Day 1). value at 1.5 hour post-dose or mean QTcF > 480 ms at Day 1 
(see Section 7.2.2.7), if confirmed by cardiologist review

Pregnancy

Use of prohibited treatment (refer to Section 6.4.2)

Initiation of  new medical treatment for hypercortisolism due to CS

Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Table 7-2. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be made to 
contact them as specified in Section 7.1.6.
Patients who discontinue study treatment should undergo an end of study visit and then be 
discontinued from the trial.
7.1.4.1
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.


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Protocol No. CLCI699C1201
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until their time of withdrawal) according to applicable 
law.
For United States and Japan: All biological samples not yet analyzed at the time of withdrawal 
may still be used for further testing/analysis in accordance with the terms of this protocol and 
of the informed consent form.
For European Union and RoW (Rest of World, i.e. all countries except the United States, Japan 
and the member states of the European Union): All biological samples not yet analyzed at the 
time of withdrawal will no longer be used, unless permitted by applicable law. They will be 
stored according to applicable legal requirements.
7.1.5
Follow up for safety evaluations
All patients must have safety evaluations for 30 days after the last dose of study treatment.
Data collected should be added to the Adverse Events CRF and the Concomitant Medications
CRF. New therapies for Cushing’s syndrome will be captured on the appropriate eCRF page 
following the last study treatment.
7.1.6
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Efficacy assessments includes mUFC, steroid hormones, and ACTH. For steroid hormones and 
ACTH, please refer Section 7.2.2.4.
Table 7-4
Disease assessment collection plan
Procedure
Screening/Baseline
During Treatment/Extension
24-hour urine to test for urine free 
cortisol and creatinine by central lab
Mandated at screening 
and baseline
Mandated, at week 4, 8, 12, 24 and 48. 
Three 24-hour samples at each time point


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Urinary free cortisol
The primary efficacy parameter will be urinary free cortisol (UFC) and will be assessed using 
a central laboratory. UFC will be measured in three 24-hour urine samples. The three samples 
will be averaged to obtain the mean UFC (mUFC) level.
Throughout the study, patients will collect three 24-hour UFC samples according to the Table 
7-1, Table 7-2 and Table 7-3. An additional 24-hour UFC sample (unscheduled) may be 
collected as required by investigators.
Screening: three 24-hour UFC samples should be collected and sent to central laboratory at
least 14 days prior to Day 1 in order to ensure that sufficient time is allowed for central 
laboratory results to become available. These samples will be used to assess eligibility of the 
patient. A repeated evaluation within the screening window is permitted for screening results 
out of the defined range. If the repeated laboratory result meets the criteria, that result may be 
used to determine eligibility. If the repeated laboratory result does not meet the criteria, the 
patient will be considered a screening failure.
Baseline: another three 24-hour UFC samples will be collected within 7 days prior to first day 
of treatment to serve as baseline value.
Treatment period: patient will collect three 24-hour UFC samples within 7 days prior to the 
next visit and with the last urine sample preferably collected the day prior to the visit at site as 
defined in Table 7-1, Table 7-2 and Table 7-3.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, laboratory evaluations, 
cardiac assessments, as well as collecting of the adverse events at every visit. For details on AE 
collection and reporting, refer to Section 8.
7.2.2.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and/or pelvic exams may be performed. This will be conducted 
at visits according Table 7-1, Table 7-2 and Table 7-3.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF.
7.2.2.2
Vital signs
Vital signs include body temperature, blood pressure and pulse measurements, and will be 
assessed according to Table 7-1, Table 7-2 and Table 7-3.
After the patient has been sitting for five minutes, with back supported and both feet placed on 
the floor, systolic and diastolic blood pressure will be measured three times using an automated 
validated device, with an appropriately sized cuff. The repeat sitting measurements will be made 
at 1 - 2 minute intervals and the three measurements will be reported.


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7.2.2.3
Height, weight and waist circumference
Height in centimeters (cm) and body weight [to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes] will be measured. Body height will be measured at screening and body 
weight and waist circumference will be measured at visits according to Table 7-1, Table 7-2
and Table 7-3.
To measure the waist circumference, patients should remove clothing from around the waist to 
ensure the measuring tape is correctly positioned. Using e.g. a cosmetic pencil, make a mark at 
the “natural waist” midway between the palpated iliac crest and the palpated lowest rib margin 
in the left and right mid-axillary lines. Place the non-strechable tape evenly around the natural 
waist covering the left and right natural waist marks. The measurement scale should face 
outward, and there should be no twists in the tape. Ensure that the tape is just touching the skin 
but not compressing the soft tissue. Instruct patients to stand erect with abdomen relaxed, arms 
at sides, feet together, and weight divided equally over both legs.
7.2.2.4
Laboratory evaluations
Clinical laboratory analyses (hematology, chemistry, coagulation, urinalysis, thyroid panel and 
additional tests mentioned in Table 7-5 and Table 7-6 below) are to be performed by the central 
or local laboratory. Visit windows of +/- 3 days are allowed.
At any time during the study, abnormal laboratory parameters which are clinically significant 
and require an action to be taken with study treatment (e.g. require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
CRF page. Laboratory data will be summarized using the CTCAE version 4.03. Additional 
laboratory evaluations are left to the discretion of the investigator.
Table 7-5
Central clinical laboratory parameters collection plan
Test Category
Test Name
Steroid 
hormones and 
ACTH
Serum testosterone and estradiol
Plasma ACTH, serum cortisol, serum 11-deoxycortisol,
Serum aldosterone, Serum 11-Deoxycorticosterone,
Table 7-6
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, WBC Morphology 
with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT (GPT), AST (GOT), Bicarbonate or pCO2, Glucose, 
Calcium, Chloride, Creatinine, Creatine kinase, GGT, Lactate dehydrogenase (LDH), 
inorganic phosphorus, lipase, amylase, magnesium, potassium, sodium, Total Bilirubin, 
Direct Bilirubin, Indirect Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
pH, Protein, Specific Gravity,)
Coagulation
Prothrombin time (PT) or INR, Activated partial thromboplastin time (APTT)
Thyroid Panel
Serum TSH, free T4


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Test Category
Test Name
Additional tests
Serum cortisol
Pregnancy test (serum / urine)
Fasting serum insulin and HbA1C
LH, FSH
Serum Type I collagen cross-linked N-telopeptide (NTX) and Serum bone-specific alkaline 
phosphatase (BAP)
7.2.2.4.1 Hematology
Hematology tests are to be performed by the local laboratory according to the schedule of 
assessments and collection plan outlined respectively in Table 7-1, Table 7-2 and Table 7-3. 
The Hematology panel includes hematocrit, hemoglobin, platelets, red blood cells (RBC), white 
blood cells (WBC), WBC morphology with differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils).
7.2.2.4.2 Clinical chemistry
Chemistry tests are to be performed by the local laboratory according to the schedule of 
assessments and collection plan outlined respectively in Table 7-1, Table 7-2 and Table 7-3.
The Chemistry tests should be analyzed under the fasting condition.
The chemistry panel includes albumin, alkaline phosphatase, ALT (GPT), AST (GOT), 
bicarbonate or pCO2, glucose, calcium, chloride, creatinine, creatine kinase, gamma-glutamyl 
transferase (GGT), lactate dehydrogenase (LDH), inorganic phosphorus, lipase, amylase, 
magnesium, potassium, sodium, total bilirubin, direct bilirubin, indirect bilirubin, total 
cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), total protein, 
triglycerides, Blood Urea Nitrogen (BUN) or urea, uric acid.
7.2.2.4.3 Urinalysis
Urinalysis tests are to be performed according to the schedule of assessments and collection 
plan outlined respectively in Table 7-1, Table 7-2 and Table 7-3.
A semi-quantitative "dipstick" evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes esterase and blood.
7.2.2.4.4 Coagulation
Prothrombin time (PT) or INR, activated partial thromboplastin time (APTT) will be assessed 
by the local laboratory according to Table 7-1, Table 7-2 and Table 7-3.
7.2.2.4.5 Thyroid panel
Serum thyroid stimulating hormone (TSH) and free T4 will be assessed by the local laboratory 
according to Table 7-1, Table 7-2 and Table 7-3.
7.2.2.4.6 Additional hormones
Serum cortisol, luteinizing hormone (LH), and follicle stimulating hormone (FSH) will be 
assessed by the local laboratory according to Table 7-1, Table 7-2 and Table 7-3.


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Serum testosterone and estradiol, plasma ACTH, serum cortisol, serum 11-deoxycortisol, serum 
aldosterone, 
 and serum 11-deoxycorticosterone will be assessed by 
the central laboratory according to Table 7-1, Table 7-2 and Table 7-3. Serum cortisol will be 
assessed by both central and local laboratories.
 
7.2.2.4.7 Other laboratory parameters
Serum fasting insulin, HbA1C and bone metabolism marker [serum Type I collagen cross-
linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP)] will be 
assessed by the local laboratory according to Table 7-1, Table 7-2 and Table 7-3.
7.2.2.4.8 Pregnancy and assessments of fertility
Serum pregnancy tests will be performed at screening and baseline. Urine or serum pregnancy 
testing will be performed as indicated in Table 7-1, Table 7-2 and Table 7-3.
If a urine pregnancy test is performed and is found to be positive, this will require immediate 
interruption of study drug until serum β-hCG is performed and found to be negative. If positive, 
the patient must be discontinued from the trial.
When performed at screening, the result of this test must be received before the patient may be
dosed.
7.2.2.5
Radiological examinations
MRI or CT scanning will be performed only for ectopic corticotropin syndrome patient at visit 
according to Table 7-1, Table 7-2 and Table 7-3. If the tumor will not be detected at baseline 
evaluation, the following evaluations are not mandatory. The same imaging technique should 
be used throughout the trial, as much as possible.
The following steps should be used to assess tumors causing syndrome:
1. For baseline, imaging by using CT or MRI should be performed to confirm location of the 
tumors (if detectable).
2. In case of detecting tumors at baseline, locations of tumors will be recorded. The biggest 
tumor (i.e. tumor with the longet diameter) will be monitored for the size.
a. The size should be captured in terms of longest perpendicular diameters.
b. If any of the perpendicular diameters cannot be reliably measured because of its small
size, the minimum limit of detection as the diameter size (e.g. 7.5 mm for CT) should
be entered.
c. A value of 0 mm X 0 mm should be entered in case of disappearance of the tumor.
The size of the tumor causing the syndrome is defined as the product of the crossdiameter of 
the tumor using the longest perpendicular diameters.
CT and MRI should be performed with slice thickness ≤7.5 mm.
7.2.2.6
Cardiac assessments
Cardiac monitoring will include 12-lead safety ECGs, which are the primary assessment of 
safety at study visits, and 24-hour continuous 12-lead Holter recordings, which provide large 


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amounts of additional ECG data with central reading, but are not intended to provide real-time 
assessment of cardiac intervals and cardiac rhythm.
Table 7-7
ECG collection plan
Week
Day
Time
ECG Type
Central or 
Local
-5 to -2
-35 to -8
NA
12 Lead
Local
-1
-7 to -1
NA
12 Lead
Local
-1
-7 to -1
24-hour
24-hour Holter
Central
0, 1, 2, 3, 4, 6, 8, 10, 
12, 16, 20, 24, 26, 30, 
34, 36, 40, 44, 48
1, 8, 15, 22, 29, 43, 57, 71, 
85, 113, 141, 169, 183, 
211, 239, 253, 281, 309, 
337
Pre-dose and Post-
dose 1.5 hours
12 Lead
Local
2, 12, 24, 48
15, 85, 169, 337
24-hour
24-hour Holter
Central
Optional Extension: 
60, 72, 84, 96, 108, 
120, 132, 144, 
subsequently with
same frequency (i.e. 
every 12 weeks)
421, 505, 589, 673, 757, 
841, 925, 1009, 
subsequently with same 
frequency
Pre-dose and Post-
dose 1.5 hours
12 Lead
Local
Optional Extension: 
72, 120,  subsequently 
with same frequency 
(i.e. every 48 weeks)
505, 841, subsequently with
same frequency
24-hour
24-hour Holter
Central
EoT: 12 a, 48 a, EoT
85a, 337a, EoT
NA
12 Lead
Local
EoT: 12 a, 48 a, EoT
85a, 337a, EoT
24-hour
24-hour Holter
Central
Follow-up
30 days from last dose
NA
12 Lead
Local
Unscheduled assessment
Anytime
12 Lead
Local
a: Required when patient finish the study.
7.2.2.6.1 24-hour Holter electrocardiogram
Twenty-four hour continuous 12-lead Holter recording with central reading of data are done on 
each patient according to the Table 7-1, Table 7-2, Table 7-3 and Table 7-7.
7.2.2.6.2 Electrocardiogram (ECG)
Twelve-lead safety ECGs are collected at the study sites according to Table 7-1, Table 7-2, 
Table 7-3 and Table 7-7.
Twelve-lead safety ECGs are collected at the study site using ECG equipment provided by 
vendor. This ECG must be read on site by a qualified physician (e.g. the investigator or another 
qualified physician such as a consulting cardiologist) at the time they are collected and 
documented on the ECG CRF.
Each 12-lead Safety ECG tracing should be labeled with the:

study number

patient initials

patient number

date and time


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and kept in the source documents at the study site. The clock on the ECG machine should be 
synchronized with the central clock on a daily basis.
The CRF will contain:

date and time of ECG

heart rate

PR interval

QT and QTcF interval

QRS duration
The Fredericia QT formula (QTcF) to correct for variations in heart rate should be used for 
clinical decisions.
The purpose of the safety ECG is to identify patients with clinically significant ECG 
abnormalities. On the day of the first study drug administration (Day 1), pre-dose ECGs must 
be done in triplicate. The mean of the QTcF from these 3 tracings is used as the baseline QTcF 
to be compared with subsequent ECGs.
ECGs with clinically significant abnormalities should be reported on the CRF. The overall 
interpretation will be collected with a Yes/No statement to confirm if any clinically significant 
abnormalities are present which need to be specified further.
A “notable ECG abnormality” is defined as:

Day 1 only: an increase in QTcF > 30 msec at 1.5 hours post-dose, compared to the mean 
pre-dose baseline QTcF from the same day. It is to eliminate subjects who experience 
large QT increases early and exclude them from further participation for safety.

QTcF > 480 msec with acute cardiovascular risk, as assessed by a consulting cardiologist

Any QTcF > 500 msec, confirmed by a consulting cardiologist

QTcF increase > 60 msec from baseline. The 60 ms threshold at all other times excluding 
post 1.5 hours at Day 1 is set for the following two reasons. QTc fluctuates during normal 
life, and the absolute risk of Torsades des Pointes is related to the actual QTcF value 
(> 500 ms) and not the change from baseline.
Notable ECG abnormalities should be recorded on the Adverse Events CRF page. If there is a 
notable abnormality, then a cardiology consult should be called, and the Novartis medical 
monitor for this trial notified of the event.
For any ECGs with clinically significant or notable ECG abnormalities, two additional 12-lead 
ECGs should be performed to confirm the safety finding and the triplicate ECGs collected 
should be transferred for central review.
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline.
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and then blood sampling for osilodrostat pharmacokinetic (PK) 
assessment (Figure 7-1). ECG procedure may also be performed 30 minutes after PK sampling.


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Figure 7-1
Sequence of cardiovascular data collection
Original ECG tracings, appropriately signed, will be archived at study site.
7.2.2.7
QT monitoring
QT monitoring will occur as follows:

On the first day of the first administration of osilodrostat (Day 1), pre-dose baseline ECGs 
must be done in triplicate. The mean of the QTcF values from these three ECG tracings is 
used to determine the mean baseline QTcF.

On Day 1, if the safety ECG (1.5 hours post-first dose of osilodrostat) shows a mean 
increase in QTcF > 30 ms from the mean baseline value, or the mean QTcF is > 480 ms, 
then the patient must be discontinued from the study drug according to the discontinuation 
procedure described in Section 7.1.4 and an unscheduled triplicate ECGs collected at 
approximately 1-2 hours and a PK sample collected. The patient must remain under 
observation until the QTcF is < 480 msec and serum electrolytes, calcium, and magnesium 
are measured and the results normal.

If at any follow up visit, a QTcF > 480 msec is observed or an increase of the QTcF 
of > 60 msec compared to baseline QTcF assessment, then two additional ECGs, each 2-3 
minutes apart, need to be taken after the initial ECG. The mean QTcF from the triplicate 
ECGs will be determined. If the mean QTcF is > 480 msec or the mean QTcF increase 
is > 60 msec compared to baseline, the patient has to interrupt study treatment while an 
urgent cardiology consultation is obtained to re-evaluate the ECG and perform a clinical 
consultation. If immediate treatment is required for patient safety, this should be initiated 
at the study site without delay and without waiting for confirmation by a cardiologist.
Based on the cardiologist consultation, the following should occur:

If a mean QTcF > 480 msec is NOT confirmed, no further action needs to be taken. If the 
cardiologist confirms a mean QTcF > 500 msec, the patient has to discontinue according 
to the discontinuation procedure described in Section 7.1.4 and an unscheduled PK sample 
collected. The patient must remain under observation until the QTcF is < 480 msec and 
serum electrolytes, calcium, and magnesium are measured and the results normal. This 
observation may be done at the site, in an emergency room, or a cardiology clinic, as 
appropriate and depending upon local resources.
a. If the cardiologist confirms that QTcF > 480 msec, osilodrostat treatment is 
temporarily interrupted and a thorough evaluation is performed to assess the patient 
for acute cardiovascular risk, and for possible underlying heart disease that needs 
additional evaluation and management. In addition, an unscheduled PK sample will 
be collected.


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b. If based upon the assessment by the cardiologist, the investigator considers that there 
is an acute cardiovascular safety risk and that the patient should not continue with 
study medication, the patient needs to be discontinued immediately (discontinuation 
criteria described in Section 7.1.4).
c. If based upon the assessment by the cardiologist, the investigator considers that there 
is not an acute cardiovascular safety risk; the patient can continue to receive study 
medication.
Figure 7-2
QT Monitoring Flow Chart (except for Day 1)
* Please refer to Section 7.1.4, study treatment must be discontinued under this circumstance.


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7.2.3
Pharmacokinetics
Blood samples for osilodrostat PK evaluation will be collected from all patients who receive at 
least one dose of study treatment as indicated in the Visit Evaluation Schedule (Table 7-1, Table 
7-2 and Table 7-3).
Time points of blood sample collection are outlined in Table 7-8.
If osilodrostat administration was interrupted prior to a planned visit and no study treatment is 
administered on the day of the planned visit, blood draw for PK sampling will not be required. 
All ECG procedures should be taken prior to and/or 30 minutes after any PK blood draws since 
sampling for PK impacts ECG measurements.
Complete dosing information, including the date and time of actual blood draw and time of the 
last study treatment dose prior to the sampling (24-h clock time), should be obtained on all 
sampling days and recorded on the PK CRF and/or Contract Research Organization (CRO) 
requisition form(s). Sampling problems will be noted in the relevant field in the CRF.
An additional blood sample (unscheduled) should be collected in the event that a patient 
experiences an AE which requires premature termination from the study treatment.
 
 
7.2.3.1
Pharmacokinetic blood collection and handling
Refer to the [CLCI699C1201 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.
Table 7-8
Pharmacokinetic blood collection log
Week
Day
Scheduled time point a
Dose Reference 
ID
PK Sample No
Sample volume [mL]
0
1
Pre-dose/ 0 h
1
1
2.6
0
1
Post-dose 0.25 - 0.75 h
1
2
2.6
0
1
Post-dose 1 - 2 h
1
3
2.6
0
1
Post-dose 3 - 4 h
1
4
2.6
1
8
Pre-dose/ 0 hb
2/102
5
2.6
1
8
Post-dose 1 - 2 h
2
6
2.6
2
15
Pre-dose/ 0 hb
3/103
7
2.6
2
15
Post-dose 0.25 - 0.75 h
3
8
2.6
2
15
Post-dose 1 - 2 h
3
9
2.6
2
15
Post-dose 3 - 4 h
3
10
2.6
3
22
Pre-dose/ 0 hb
4/104
11
2.6
3
22
Post-dose 1 - 2 h
4
12
2.6
4
29
Pre-dose/ 0 hb
5/105
13
2.6
4
29
Post-dose 1 - 2 h
5
14
2.6
6
43
Pre-dose/ 0 hb
6/106
15
2.6
6
43
Post-dose 1 - 2 h
6
16
2.6
8
57
Pre-dose/ 0 hb
7/107
17
2.6


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Week
Day
Scheduled time point a
Dose Reference 
ID
PK Sample No
Sample volume [mL]
8
57
Post-dose 1 - 2 h
7
18
2.6
10
71
Pre-dose/ 0 hb
8/108
19
2.6
10
71
Post-dose 1 - 2 h
8
20
2.6
12
85
Pre-dose / 0 hb
9/109
21
2.6
12
85
Post-dose 0.25 – 0.75 h
9
22
2.6
12
85
Post-dose 1 - 2 h
9
23
2.6
12
85
Post-dose 3 - 4 h
9
24
2.6
16
113
Pre-dose / 0 hb
10/110
25
2.6
16
113
Post-dose 1 - 2 h
10
26
2.6
20
141
Pre-dose / 0 hb
11/111
27
2.6
20
141
Post-dose 1 - 2 h
11
28
2.6
24
169
Pre-dose / 0 hb
12/112
29
2.6
24
169
Post-dose 1 - 2 h
12
30
2.6
48
337
Pre-dose / 0 hb
13/113
31
2.6
EoT
---
NA
1001
2.6
Unscheduled 
sample
---
NA
2001+
2.6
a The following PK assessment windows are acceptable: predose sample within 0.5 h before dose 
administration.
b For the PK predose (trough) samples, the actual date and time of administration of the previous dose of study 
medication should also be recorded with appropriate Dose Reference ID as indicated in the above table. The 
Dose Reference ID series “1, 2, 3…” is for the osilodrostat dose administered on study visit day, while Dose 
Reference ID series “102, 103, 104…” is for last osilodrostat dose the patient received prior to the collection of 
the PK predose (trough) sample.
7.2.3.2
Analytical method
The plasma samples from all patients will be assayed for osilodrostat concentrations using a 
validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower 
limit of quantitation (LLOQ) will be 0.10 ng/mL for osilodrostat; values below LLOQ will be 
reported as zero ng/mL, and missing samples will be labeled accordingly. Concentrations of 
osilodrostat will be expressed in mass per volume units (ng/mL). A further refinement of this 
bioanalytical method may be conducted during the course of the study.


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7.2.5
Resource utilization
Not applicable
7.2.6
Patient reported outcomes
Two patient reported outcome instruments, CushingQoL and Beck Depression Inventory-II, 
will be used to assess the impact of treatment on patient quality of life and symptom burden 
(see Appendix 4). Patients must be asked to complete each questionnaire prior to clinical 
assessments being undertaken, and these must be completed in accordance with the schedules 
listed in Table 7-1, Table 7-2 and Table 7-3. Patient Questionnaires should be completed in the 
sequence from specific to general; CushingQoL followed by Beck Depression Inventory-II. 
Patient’s refusal to complete all or any part of a questionnaire should be documented in the 
study data capture system and should not be captured as a protocol deviation. Patient 
questionnaires should be completed in the language most familiar to the patient. The patient 
should be given sufficient space and time to complete the questionnaire. The site personnel 
should check the questionnaire for completeness and ask the patient to complete any missing 
responses. The original questionnaire will be kept with the patient’s file as the source document.
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 


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SAEs before any clinical study examinations. This assessment should be documented in study 
source records. If AEs or SAEs are confirmed, study investigators should not encourage the 
patient to change responses reported in the completed questionnaires. Study investigators must 
follow reporting instructions outlined in Section 8 (e.g. reference “Adverse Events” section) of 
the study protocol.
7.2.6.1
CushingQoL
The Cushing’s Disease Health-Related Quality of Life Questionnaire (CushingQoL) (version 
1.0) that was developed to evaluate quality of life in patients with Cushing’s syndrome (Webb
et al. 2008). The CushingQoL is comprised of 12 items that capture patient responses on seven 
concepts: daily activities, healing and pain, mood and self-confidence, social concerns, physical 
appearance, memory and concern about the future. Content reliability, sensitivity to change and 
psychometric properties have been validated in patients with Cushing’s disease (Nelson et al.
2013).
For this study, the CushingQoL has been modified from the standard four-week recall to a 
one-week recall in order to be more sensitive to the changes in patient quality of life.
7.2.6.2
BDI-II
The Beck Depression Inventory® II (BDI®-II) is a patient reported instrument that consists of 
21 items designed to assess the intensity of depression in clinical and normal patients in the 
preceding two weeks. Each item is a list of four statements arranged in increasing severity about 
a particular symptom of depression.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate adverse 
event.


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Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, 
the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will 
be used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though a death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (start and end dates)
3. Its relationship to the study treatment (reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for adverse events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 


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investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.1.3
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are of scientific and medical concern specific to the sponsor’s product or program, for which 
ongoing monitoring may be appropriate. Such events may require further investigation in order 
to characterize and understand them. Adverse events of special interest are defined on the basis 
of an ongoing review of the safety data. AESI are discussed in detail in the Investigator 
Brochure.
In addition to the AEs listed earlier (Section 1.2.1.2.2 and Section 1.2.1.2.3), other AEs are 
predicted by the underlying disease or the mechanism of action (MoA) of osilodrostat, 
specifically in patients with Cushing’s disease. Many, but not all, of these AEs have been 
observed in preclinical and/or clinical studies.
These “AEs of Special Interest” include the following mechanistic groups:

Adrenal Hormone Precursor Accumulation-related AEs 

Hypocortisolism related AEs

QT-prolongation-related AEs

Arrhythmogenic potential AEs

Pituitary tumor enlargement related AEs
Two of the AEs of special interest, the potential for QT prolongation and hypocortisolism 
(glucocorticoid withdrawal/adrenal insufficiency) are described in greater detail below.
8.1.3.1
Risk of QT prolongation
Preclinical cardiac safety studies have revealed a signal of QT prolongation with osilodrostat
that is consistent across in vitro and in vivo studies. The risk was quantified in an ICH E-14 
compliant thorough QT/QTc study conducted in healthy volunteers (see Section 1.2.1.2.4 for a 
summary of the results). The results support the use of osilodrostat in doses up to 30 mg
[CLCI699C2105].
8.1.3.2
Hypocortisolism (glucocorticoid withdrawal/adrenal insufficiency)
Important and closely related AEs of special interest are hypocortisolism-related adverse events 
including glucocorticoid withdrawal and adrenal insufficiency. These AEs are a consequence 
of the potent activity of osilodrostat to inhibit cortisol synthesis. In patients Cushing’s disease, 
the relatively rapid correction of hypercortisolism can result in symptoms of glucocorticoid 
withdrawal. If the inhibition of cortisol synthesis is excessive, hypocortisolism-related adverse 
events including adrenal insufficiency may develop.
The patient should be questioned on the signs and symptoms of hypocortisolism (glucocorticoid 
withdrawal/adrenal insufficiency) at each visit. If any potential signs or symptoms are reported, 
they should be graded for severity and reported as an AE.


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8.1.3.3
Definitions and reporting
Groupings of adverse event of special interest will be considered and the number of patients 
with at least one event in each grouping will be reported. Such groups consist of AEs for which 
there is a specific interest in connection with osilodrostat treatment (i.e. where osilodrostat may 
influence a common mechanism of action responsible for triggering them) or adverse event that 
are very similar although not identical. The groups will be defined according to criteria 
described in MedDRA.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 


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thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form and submit the completed form within 24 hours to Novartis. Detailed instructions
regarding the SAE submission process and requirements for signatures are to be found in the 
investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each 
re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.


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8.5
Data Monitoring Committee
Not applicable
8.6
Steering Committee
Not applicable
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.


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The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
The designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs and, allow modification or verification of the entered 
data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
Pharmacokinetic (PK) 
 collected during the course of the study will be 
collected from the investigator sites and analyzed by Novartis or a central laboratory contracted 
by Novartis. The site staff designated by the investigator will enter the information required by 
the protocol onto the PK 
 Collection CRFs, as well as onto the designated 
CRO’s requisition form. One copy of the requisition form will be sent to the CRO with the 
relevant information (including study number, patient ID, etc.) and one copy will be retained 
by the site.
ECG tracings of every Holter ECG and 12-Lead ECG if needed will be transferred to central 
readers. Method for data collection will be described in respective manuals. A [Laboratory 
Manual] will also be available for Central laboratory.
9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.


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Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
The study will be analyzed at least 2 times, at completion of study period I (Week 12), and at 
the final analysis after all patients complete the study. The initial analysis will be performed 
when all enrolled patients have completed the dose titration period of study (study period I) or 
have prematurely withdrawn from the study, whichever comes first. This first analysis will be 
the primary analysis. Additionally analyses plan to follow up patient long time safety profiles 
and updates.
Novartis or designated CRO will analyze all data using the SAS System for data analysis V9.3 
or higher. Any data analyses carried out independently by an investigator should be submitted 
to Novartis before publication or presentation.
The data from all centers participating in the trial will be combined when required, so that an 
adequate number of patients will be available for analysis. The statistical analysis methods 
described in this section will focus on the analysis of the data in the first  analysis of the study 
(study period I). Similar methods will be applied to the analyses in the extension phase as 
appropriate.
Given the sample size which is reflective of the rarity of this condition, data will be primarily 
described in individual basis except for a few endpoints including “mUFC response rate” and 
“Change from baseline in mUFC” and may require extra cautions in their interpretation. Details 
will be discussed in the statistical analysis plan (SAP).
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all enrolled patients who received at least one dose of 
osilodrostat. This is the default analysis set for efficacy.
10.1.2
Safety Set
The safety analysis set (SAS) includes all patients who received at least one dose of osilodrostat
and had at least one valid post-baseline safety assessment.
10.1.3
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of osilodrostat and had at least one evaluable PK concentration at any visit (post-first-dose).
Additional definition of an evaluable PK blood sample will be further specified in the report 
and analysis plan (RAP).


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10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data will be summarized descriptively for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented. 
All data will be listed.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
All patients will be classified into a single dose of osilodrostat for FAS, SAS and PAS.
Exposure to osilodrostat will be summarized descriptively and listed using FAS.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized by anatomical therapeutic chemical (ATC) class 
and preferred term for SAS.
10.4
Primary objective
The primary objective is to assess the percent change from baseline in the mean Urine Free 
Cortisol (mUFC) in individual patient level data at Week 12.
10.4.1
Variable
The primary endpoint is the percent change from baseline in mUFC in individual patient level 
data. No statistical analysis including descriptive summary will be performed for the primary 
analysis. Assessment of the efficacy endpoint will be based on the review of individual patient 
listing and figures due to very small sample size and expected variability in response caused by 
various patient background and disease.
The percent change will be plotted over time by individual patient. Since the Week 12 analysis 
will be performed when the last patient completed Week 12 assessment or discontinued earlier, 
data will be reported up to data cut-off point. For patients who discontinued prior to Week 12, 
data will not be imputed and only actual data will be provided.
10.4.2
Statistical hypothesis, model, and method of analysis
No statistical hypothesis is set up for this study.
10.4.3
Handling of missing values/censoring/discontinuations
The mUFC will be determined at a central laboratory from three 24-hour urine specimens 
collected within 7 days from scheduled visit date. The mean of the results from the 3 samples 
will be used to obtain the corresponding mUFC level for a given assessment. If a patient has 
two or more missing UFC values for a particular visit, the mUFC assessment for that patient at 
that visit will be considered missing. Otherwise, the mean of UFC samples for a given patient 
and timepoint will be considered as the mUFC level for that visit.


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10.4.4
Supportive analyses
As a supportive analysis to the primary analysis, the absolute and percent change from baseline 
will be summarized at each visit through Week 24 for overall and by the status of prior 
experience of metyrapone, if applicable.
Individual patient level data of change from baseline in mUFC beyond Week 12 (e.g. Week 24, 
Week 48) will be plotted over time and listed in the same manner as those for the primary 
analysis.
10.5
Secondary objectives
There is no key secondary endpoint set up in this study. All secondary endpoints are to support 
individual patient response to osilodrostat.
10.5.1
Key secondary objective(s)
Not applicable
10.5.2
Other secondary efficacy objectives
Response rate (complete response rate, partial response rate and overall 
response rate)
Point estimates of the complete, partial and overall response rates with exact 95% confidence 
interval (Clopper-Pearson method) will be provided at Week 12, 24 and 48, respectively. 
Complete response rate is defined as the proportion of enrolled patients who has mUFC ≤ULN. 
Partial response rate is defined as the proportion of enrolled patients who has mUFC > ULN 
and at least 50% reduction from baseline in mUFC. Overall response rate is defined as the 
proportion of enrolled patients who has mUFC ≤ULN or at least 50% reduction from baseline.
Change from baseline in serum cortisol
The percent change from baseline in morning serum cortisol which will be assessed by central 
laboratory will be reported up for each patient over time. Additionally, descriptive summary of 
the absolute and the percent change will be provided at Week 12, 24 and 48.
Additionally serum cortisol will be assessed by local laboratory for dose confirmation purpose. 
These will be listed only.
Change from baseline in steroid hormones
Both absolute and percent change from baseline in steroid hormones in the HPA-axis will be 
listed over time.
Serum hormones include aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, testosterone 
and estradiol. Plasma hormone includes ACTH.


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Change from baseline in cardiovascular-related metabolic parameters 
associated with Cushing syndrome
The absolute and percent change from baseline in cardiovascular related metabolic parameters 
will be listed.
Parameters include fasting glucose, HbA1c, fasting lipid profile, blood pressure, body weight 
body mass index (BMI) and waist circumference.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 30+1 after last dose of study medication
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include AEs that started or worsened during the 
on-treatment period, the treatment-emergent AEs. However, all safety data (including those 
from the pre and post-treatment periods) will be listed and those collected during the pre-
treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.
Deaths and non-fatal serious adverse events will be listed by patient and tabulated by type of 
adverse event.
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment.
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, the study’s biostatistical and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-
missing values not graded as 1 or higher. Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.


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The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4 (see below for details)

listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges
Additionally, laboratory tests related to liver function will be summarized, which includes total 
bilirubin (TBIL), AST, ALT and alkaline phosphatase (ALP) and the combinations.
Absolute and percent change in hormones for bone metabolism will be also listed over time, 
which includes luteinizing hormone (LH) and follicle stimulating hormone (FSH).
10.5.3.4 Other safety data
ECG

listing of ECG evaluations for all patients with at least one abnormality

shift table baseline to the worst on-treatment result for overall assessments
Vital signs
Definitions of notably abnormal results have to part of the CDP, MAP, CSP and RAP.

table with descriptive statistics at baseline, one or several post-baseline time points and 
percent change from baseline
10.5.3.5 Supportive analyses for secondary objectives
Not applicable
10.5.3.6 Tolerability
Tolerability will be studied in terms of dose reductions or drug interruption due to an AE.
10.5.4
Pharmacokinetics
The PAS will be used in all pharmacokinetic data analysis and summary statistics.
As sparse pharmacokinetic sampling is performed in this study, traditional non- compartmental 
analysis will not be performed to calculate pharmacokinetic parameters. Plasma concentration 
data of osilodrostat will be listed by subject, visit, incident dose and nominal sampling times. 
Descriptive statistics of plasma concentrations will be provided by incident dose, visit and 
nominal sampling times. Graphical depiction (arithmetic mean and individual) for osilodrostat 
concentrations over time during the course of the study will be performed by incident dose. PK 
data generated from this study will be used in conjunction with PK data from other clinical 
studies in population PK assessment. Patient demographics (e.g. age, gender, ethnicity, weight) 
will be explored as covariates, if appropriate. The broad principles outlined in the FDA 
“Guidance for Industry: Population Pharmacokinetics” will be followed during the population 
PK analysis. The results of population PK assessment will be presented in a separate report. 
 
 After database lock, merge PK 
dataset with actual elapsed time will be used for analysis.


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10.5.4.1 Data handling principles
Plasma concentrations of osilodrostat will be expressed in ng/mL. Missing concentration values 
will be labeled as such in data listings. Concentrations below the lower limit of quantitation 
(LLOQ) will be treated as zero in summary statistics and reported as zero in data listings.
10.5.6
Resource utilization
Not applicable
10.5.7
Patient-reported outcomes
The CushingsQoL score is identified as the primary patient reported outcome variable of 
interest. Beck Depression Inventory®-II (BDI®-II) total score is identified as secondary PRO 
variables of interest. Missing items data in a scale will be handled based on each instrument
manual. Additional details for handling missing items data will be specified in the analysis plan 
for instruments with no missing data handling criteria in the instrument manual.
No imputation will be applied if the total scores are missing at a visit. All available data until 
completion or early discontinuation during study period I and II will be listed only due to very 
small sample size. Details will be specified in the RAP.
10.7
Interim analysis
The study has no planned interim analysis for efficacy which requires consideration of 
multiplicity.


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10.8
Sample size calculation
Based on medical and operational feasibility, 10 patients plan to be enrolled in this study 
because of the following reasons:

According to epidemiology survey in 1997 in Japan, the incidence of CS was estimated as 
1250 cases. In the 417 cases of CS which were actually reported, 35.8% had CD, 47.1% 
had adrenal adenoma, 17.1% had other cause of CS (Nawada et al 1999).

Only less than 50 patients are those who need medically treatment in CS because the 
success rate of surgeon is very high (about 95% in adrenal adenoma can be treated by only 
surgery). The number of ectopic corticotropin syndrome, AIMAH and PPNAD who need 
medically treatment is low as well.

Metyrapone is approved in Japan for Cushing syndrome. Therefore, some enrolled 
patients are expected to be inadequately controlled with metyrapone.
As a heterogeneous population will be enrolled, the effects of osilodrostat on each patient is 
expected to vary. Therefore, the primary analysis will be based on the percent change from 
baseline in mUFC at the individual patient level at Week 12.
Moreover, some of the currently planned analyses and/or data presentation may be modified if 
actual enrollment has not reached the original target. Detailed will be discussed in the statistical 
analysis plan (SAP).
10.9
Power for analysis of key secondary variables
Not applicable
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s informed consent was 
actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov before study start. In 
addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., Last patient last visit), those for interventional clinical trials 
involving pediatric patients within 6 months of study completion.
Novartis follows the International Committee of Medical Journal Editors (ICMJE) authorship 
guidelines (www.icmje.org) and other specific guidelines of the journal or congress to which 
the publication will be submitted.


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Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. For electronic CRFs an audit trail will be 
maintained by the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 


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permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
References (available upon request)
Arnaldi G, Angeli A, Atkinson AB, et al (2003). Diagnosis and Complications of Cushing’s 
Syndrome: A Consensus Statement. J Clin Endocrinol Metab; 88(12):5593-5602.
Arnardottir S, Sigurjonsdottir H (2011). The incidence and prevalence of Cushing’s disease 
may be higher than previously thought: results from a retrospective study in Iceland 1955 
through 2009. Clin Endocrinol. 74(6): 792-793.
Bolland M, Holdaway I, et al (2011). Mortality and morbidity in Cushing’s syndrome in New 
Zealand. Clin Endocrinol; 75: 436-442.
Daly A, Rixhon M, et al (2006). High Prevalence of Pituitary Adenomas: A Cross-Sectional 
Study in the Province of Lie`ge, Belgium. J Clin Endo and Met. 91(12): 4769-4775.
Etxabe J, Vazquez JA (1994). Morbidity and mortality in Cushing's disease: an 
epidemiological approach.Clin Endocrinol (Oxf) 40 (4):479-484.
Feelders RA, Hofland LJ, et al (2010). Medical treatment of Cushing's syndrome: adrenal-
blocking drugs and ketaconazole. Neuroendocrinology. 92 Suppl 1:111-5.
Lindholm J, Juul S, et al (2001). Incidence and Late Prognosis of Cushing’s Syndrome: A 
Population-Based Study*. J Clin Endo & Metab. 86(1): 117-123.
Masri-Iraqui H, Robenshtok E, et al. (2014). Elevated white blood cell counts in Cushing’s 
disease: association with hypercortisolim. Pituitary 2014 Oct; 17(5):436-40
Nawada H, Takayanagi R, Nakagawa H, et al (1999). Nationwide epidemiological survey of 
disorders of adrenal hormones in Japan. Annual report of the Ministry of Health and Welfare 
"Disorders of adrenal hormones" Research Committee, Japan: 11-55.
Nelson L, Forsythe A, McLeod L, et al (2013). Psychometric Evaluation of the Cushing’s 
Quality-of-Life. The Patient - Patient-Centered Outcomes Research; 6(2): 113-124.
Newell-Price J, Bertagna X, Grossman AB, et al (2006). Cushing’s syndrome. Lancet 2006; 
367(9522): 1605-17.
Porterfield JR, Thompson GB, et al (2008). Surgery for Cushing's syndrome: an historical 
review and recent ten-year experience. World J Surg. 32(5):659-77.
Valassi W, Crespo I, Gicht I, et al (2012). A reappraisal of the medical therapy with 
steroidogenesis inhibitors in Cushin’s syndrome. Clinical Endocrinology; 77:735-742.
Webb S, Badia X, Barahona M, et al (2008). Evaluation of health-related quality of life in 
patients with Cushing’s syndrome with a new questionnaire. European Journal of 
Endocrinology; 158: 623-630.


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14
Appendices
14.1
Appendix 1: Summary of Common Toxicity Criteria for Adverse 
Events v4.0 (CTCAE)
Table 14-1
List of summary of Common Toxicity Criteria for Adverse Events v4.3 
(CTCAE)
Grade
Definition of Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated
2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL*
3
Severe or medically significant but not immediately life-threatening hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL**
4
Life-threatening consequences; urgent intervention indicated
5
Death related to AE
Activities of Daily Living (ADL)
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.


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14.2
Appendix 2: List of drugs to be used with caution with 
osilodrostat
Table 14-2
List of medications with potential drug-drug interactions with 
osilodrostat – to be used with caution
CYP1A2 
substrates
CYP2C19 
substrates
CYP2D6 substrates
CYP3A4/5 substrates
CYP2E1 substrates
Atypical 
antipsychotics:
Clozapine
Olanzapine
Xanthines:
Caffaine1
Theophylline2
Others:
Nabumetone
Riluzole
Ropivacaine
Zolmitriptan
Alosetron1
Duloxetine1
Melatonin1
Ramelteon1
Tacrine1
Tizanidine1,2
Anti-epileptics:
Diazepam
Phenytoin
Phenobarbitone
S-mephenytoin1,2
Benzodiazepines:
Clobazam1
Proton pump 
inhibitors:
Lansoprazole1
Omeprazole1
Pantoprazole
Rabeprazole
Esomeprazole
Antidepressants:
Amitriptyline
Clomipramine
Others:
Clopidogrel
Moclobemide
Proguanil
Antipsychotics:
Aripiprazole
Chlorpromazine
Clozapine
Fluphenazine
Haloperidol
Iloperidone
Pimozide
Risperidone
Perphenazine1
Thioridazine2
Antiarrhythmics:
Encainide
Flecaninide
Mexilletine
Prajmaline
Procainamide
Propafenone
Sparteine
Vernakalant
Alpha/Beta-
adrenergic 
antagonists:
Metoprolol1
Nebivolol1
Carvedilol
Propranolol
Tamsulosin
Timolol
Serotonin 
modulators:
Venlafaxine1
Citalopram
Duloxetine
Fluoxetine
Fluvoxamine
Nefazodone
Ondansetron
Paroxetine
Repinotan
Trazodone
Tropisetron
Tricyclics/ 
tetracyclics:
Desipramine1
Amitriptyline
Clomipramine
Doxepin
Imipramine
Maprotiline
Mianserin
Mirtazapine
Antiarrhythmics:
Quinidine2
Dronedarone1
Antihistimines:
Astemizole2
Ebastine1
Terfenadine1,2
Benzodiazepines:
Brotizolam1
Midazolam1
Triazolam1
Alprazolam
Diazepam
Calcium channel 
blockers:
Felodipine1
Nisoldipine1
Amlodipine
Diltiazem
Nifedipine
Nitrendipine
Verapamil
Protease inhibitors:
Brecanavir1
Capravirine1
Darunavir1
Indinavir1
Lopinavir1
Saquinavir1
Tipranavir1
Boceprevir
Ritonavir
Telaprevir
HMG CoA reductase 
inhibitors:
Atorvastatin1 Lovastatin1
Simvastatin1
Antibiotics:
Clarithromycin
Erythromycin
Telithromycin
Antipsychotics:
Aripiprazole
Haloperidol
Lurasidone1
Perospirone1
Pimozide2
Quetiapine1
Immune Modulators:
Cyclosporine2
Everolimus1
Sirolimus1,2
Enflurane
Halothane
Isoflurane
Methoxyflurane
Sevoflurane
Acetaminophen
Chlorzoxazone
Ethanol
N, N-
Dimethylformamide
Theophylline


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CYP1A2 
substrates
CYP2C19 
substrates
CYP2D6 substrates
CYP3A4/5 substrates
CYP2E1 substrates
Nortriptyline
Trimipramine
Opiods:
Codeine
Dihydrocodeine
Hydrocodone
Methadone
Oxycodone
Tramadol
Others:
Atomoxetine1
Dextromethorphan1
Tolterodine1
Amiflamine
Brofaromine
Chlorpheniramine
Debrisoquine
Dexfenfluramine
Donepezil
Fesoterodine
Gefitinib
Lasofoxifene
Loratadine
Methamphetamine
Methoxyphenamine
Methylphenidate
Nicergolin
Pactimibe
Phenformin
Ranolazine
Ratonavir
Sabeluzole
Tamoxifen
Traxoprodil
Tacrolimus1,2
Tyrosine Kinase 
Inhibitors:
Dasatinib1
Neratinib1
Imatinib
Nilotinib
Opioids:
Alfentanil1,2
Fentanyl2
Levomethadyl1
Methadone
Others:
Quinine
Tamoxifen
Trazodone
Vincristine
Ergot derivatives:
Diergotamine/
Dihydroergotamin2
Ergotamine2
Erectile dysfunction 
agents:
Sildenafil1
Vardenafil1
Antiemetics:
Aprepitant1
Casopitant1
Others:
Alpha-
dihydroergocryptine1
Aplaviroc1
Buspirone1
Cisapride2
Conivaptan1
Darifenacin1
Eletriptan1
Eplerenone1
Lumefantrine1
Maraviroc1
Ridaforolimus1
Ticagrelor1
Tolvaptan1
Vicriviroc1
1 Sensitive substrates: drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with 
a known potent inhibitor.
2 Substrates with narrow therapeutic index: drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns.
This database of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; from the FDA’s “Guidance for Industry, Drug Interaction Studies” and from the University of 
Washington’s Drug Interaction Database.


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14.3
Appendix 3: Medications with a “Known risk to cause TdP” and 
with a “Possible risk to cause TdP”
The following e-link provides a list of medications with a “known risk to cause TdP” and with 
a “possible risk to cause TdP”. These medications are prohibited to be used concomitantly with 
osilodrostat: www.crediblemeds.org.
Investigators are advised to utilize this website when considering the addition of a new 
concomitant medication, as the lists are periodically updated. If necessary, a discussion can be 
held with the Novartis Medical Monitor when considering the use of medications with a “known 
risk to cause TdP” and with a “possible risk to cause TdP”.


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14.4
Appendix 4: Patient Quality of Life questionnaires
Cushing’s Syndrome Quality Of Life Questionnaire
The following sentences refer to what you may think or feel about your Cushing’s syndrome. 
Your answers will help us to know how you feel and how much your illness has interfered in 
your usual activities in the past 4 weeks.
Below each sentence you will find several response choices. Please read each sentence carefully. 
After reading each sentence, check the box next to the answer that best describes what you think 
is happening to you.
There are NO right or wrong answers. We are simply interested in what is happening to you 
because of your Cushing’s syndrome.
1. I have trouble sleeping (I wake up during the night; it takes me a long time to get to sleep, 
etc.).
Always
Often
Sometimes
Rarely
Never
2. I have pain that keeps me from leading a normal life.
Always
Often
Sometimes
Rarely
Never
3. My wounds take a long time to heal.
Always
Often
Sometimes
Rarely
Never
4. I bruise easily.
Always
Often
Sometimes
Rarely
Never


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5. I am more irritable, I have sudden mood swings and angry outbursts.
Always
Often
Sometimes
Rarely
Never
6. I have less self-confidence, I feel more insecure.
Always
Often
Sometimes
Rarely
Never
7. I’m worried about the changes in my physical appearance due to my illness.
Always
Often
Sometimes
Rarely
Never
8. I feel less like going out or seeing relatives or friends.
Always
Often
Sometimes
Rarely
Never
9. I have had to give up my social or leisure activities due to my illness.
Always
Often
Sometimes
Rarely
Never
10. My illness affects my everyday activities such as working or studying.
Always
Often
Sometimes
Rarely
Never


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11. It’s difficult for me to remember things.
Always
Often
Sometimes
Rarely
Never
12. I’m worried about my health in the future.
Always
Often
Sometimes
Rarely
Never


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Beck Depression Inventory Questionnaire
This depression inventory can be self-scored. The scoring scale is at the end of the questionnaire.
1.
0
I do not feel sad.
1
I feel sad
2
I am sad all the time and I can't snap out of it.
3
I am so sad and unhappy that I can't stand it.
2.
0
I am not particularly discouraged about the future.
1
I feel discouraged about the future.
2
I feel I have nothing to look forward to.
3
I feel the future is hopeless and that things cannot improve.
3.
0
I do not feel like a failure.
1
I feel I have failed more than the average person.
2
As I look back on my life, all I can see is a lot of failures.
3
I feel I am a complete failure as a person.
4.
0
I get as much satisfaction out of things as I used to.
1
I don't enjoy things the way I used to.
2
I don't get real satisfaction out of anything anymore.
3
I am dissatisfied or bored with everything.
5.
0
I don't feel particularly guilty
1
I feel guilty a good part of the time.
2
I feel quite guilty most of the time.
3
I feel guilty all of the time.
6.
0
I don't feel I am being punished.
1
I feel I may be punished.
2
I expect to be punished.
3
I feel I am being punished.
7.
0
I don't feel disappointed in myself.
1
I am disappointed in myself.
2
I am disgusted with myself.
3
I hate myself.
8.
0
I don't feel I am any worse than anybody else.
1
I am critical of myself for my weaknesses or mistakes.
2
I blame myself all the time for my faults.
3
I blame myself for everything bad that happens.


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9.
0
I don't have any thoughts of killing myself.
1
I have thoughts of killing myself, but I would not carry them out.
2
I would like to kill myself.
3
I would kill myself if I had the chance.
10.
0
I don't cry any more than usual.
1
I cry more now than I used to.
2
I cry all the time now.
3
I used to be able to cry, but now I can't cry even though I want to.
11.
0
I am no more irritated by things than I ever was.
1
I am slightly more irritated now than usual.
2
I am quite annoyed or irritated a good deal of the time.
3
I feel irritated all the time.
12.
0
I have not lost interest in other people.
1
I am less interested in other people than I used to be.
2
I have lost most of my interest in other people.
3
I have lost all of my interest in other people.
13.
0
I make decisions about as well as I ever could.
1
I put off making decisions more than I used to.
2
I have greater difficulty in making decisions more than I used to.
3
I can't make decisions at all anymore.
14.
0
I don't feel that I look any worse than I used to.
1
I am worried that I am looking old or unattractive.
2
I feel there are permanent changes in my appearance that make me look unattractive
3
I believe that I look ugly.
15.
0
I can work about as well as before.
1
It takes an extra effort to get started at doing something.
2
I have to push myself very hard to do anything.
3
I can't do any work at all.
16.
0
I can sleep as well as usual.
1
I don't sleep as well as I used to.
2
I wake up 1-2 hours earlier than usual and find it hard to get back to sleep.
3
I wake up several hours earlier than I used to and cannot get back to sleep.
17.
0
I don't get more tired than usual.
1
I get tired more easily than I used to.
2
I get tired from doing almost anything.
3
I am too tired to do anything.


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18.
0
My appetite is no worse than usual.
1
My appetite is not as good as it used to be.
2
My appetite is much worse now.
3
I have no appetite at all anymore.
19.
0
I haven't lost much weight, if any, lately.
1
I have lost more than five pounds.
2
I have lost more than ten pounds.
3
I have lost more than fifteen pounds.
20.
0
I am no more worried about my health than usual.
1
I am worried about physical problems like aches, pains, upset stomach, or constipation.
2
I am very worried about physical problems and it's hard to think of much else.
3
I am so worried about my physical problems that I cannot think of anything else.
21.
0
I have not noticed any recent change in my interest in sex.
1
I am less interested in sex than I used to be.
2
I have almost no interest in sex.
3
I have lost interest in sex completely.
INTERPRETING THE BECK DEPRESSION INVENTORY
Now that you have completed the questionnaire, add up the score for each of the twenty-one 
questions by counting the number to the right of each question you marked. The highest possible 
total for the whole test would be sixty-three. This would mean you circled number three on all 
twenty-one questions. Since the lowest possible score for each question is zero, the lowest 
possible score for the test would be zero. This would mean you circles zero on each question.
You can evaluate your depression according to the Table below.
Total Score ________Levels of Depression
1-10
___________These ups and downs are considered normal
11-16
___________Mild mood disturbance
17-20
___________Borderline clinical depression
21-30
___________Moderate depression
31-40
___________Severe depression
over 40 ___________Extreme depression
A PERSISTENT SCORE OF 17 OR ABOVE INDICATES THAT YOU MAY NEED 
MEDICAL TREATMENT. IF YOU HAVE ANY CARDIAC CONCERNS, PLEASE 
CONTACT CARDIOVASCULAR INTERVENTIONS, P.A. at 407-894-4880

SAP_001.pdf: 
Clinical Development
Osilodrostat (LCI699)
CLCI699C1201 / NCT02468193
A Phase II, open-label, dose titration, multi-center study to assess the 
safety/tolerability and efficacy of osilodrostat in patients with all types of 
endogenous Cushing’s syndrome except Cushing’s disease
RAP Module 3 – Detailed Statistical Methodology
Author:
, Trial Statistician
Document type:
RAP Documentation
Document status:
Amendment 3.0
Release date:
22-Jun-2018
Number of pages:
29
Property of Novartis
Confidential
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Document History – Changes compared to previous version of RAP module 3
Version
Time 
point
Date
Changes
1.0
Prior to 
DB lock
9-Sep-2015
Initial version
Amendment 
1.0
Prior to 
DB lock
19-Jan-2017
1. Section numbers were updated as previous version had 
section 7.3 for both PK and efficacy sections 
erroneously. Section numbers of subsequent sections 
were also updated.
2. In order to make summaries consistent with internal 
guideline as much and also reflect the recent protocol 
amendment, following changes are incorporated in the 
analysis plan:
Section 5 Data cutoff for analysis
Clarified that all assessments prior to data cut off 
will be included in the analysis.
Section 7.1.3 Demography and baseline disease 
characteristics
25th and 75th percentiles will not be presented to 
be consistent with standard
Baseline height and weight are added in the 
demography table.
Section 7.3 Efficacy evaluation
Described all efficacy listings will be presented by 
type of disease.
Section 7.3.1.1 Supportive analyses
Clarified summary of change from baseline in 
mUFC by subgroup of prior experience of 
metyrapone will be presented when at least 4 
subjects are included in either group.
Section 7.3.2.1 Response rate
Clarified that intention of 95% presentation in 
summary of response rate is not for 
statistical summary in this small study. In 
addition, this will be presented only when at 
least 4 subjects have been enrolled and 
stayed in the study through week 12. 
Section 7.5.1.4 Safety disclosure is newly inserted.
Section 7.5.2.1 Hematology, chemistry, urinalysis, 
coagulation and thyroid panel
A Typo in equation of corrected serum calcium 
was corrected.


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Version
Time 
point
Date
Changes
Clarified that all data up to data cut-off will be 
used for the on-treatment summary.
Section 7.5.3 Vital signs
Only absolute change will be summarized to be 
consistent with oncology standard instead of 
absolute and percent change from baseline.
Clarified that abnormal values will be flagged in 
the listing.
Table 7-2 clinically notable abnormal values is 
updated to be consistent with oncology 
standard.
Section 7.5.4 Electrocardiogram (ECG)
Summary table is modified to be consistent with 
internal oncology standard and Table 7-3 is 
modified with new category.
3. Section 8.6 Imputation rules for partial or missing dates is 
moved to newly created appendix 2.  Moreover, 
imputation method is modified to be consistent with 
oncology standard.
4. Section 8.6 Assessment time window is inserted for 
efficacy and safety. 
5. Section 9 Changes from planned analysis in the study 
protocol is updated with changes listed in the above.
Amendment 
2.0
Prior to 
DB lock
27-Sep-2017
1. Administrative change in change history by adding a 
column for time point. In addition, cosmetic corrections
are made across documents.
2. Section 2 Study design – Description has been updated 
for the end of optional extension period (after week 48) of 
the study.
3. Sections 7.1 patient studied and 7.2 study medication –
listing will be by disease type in similar to efficacy and 
safety.
4. Section 7.1.3 demography and baseline disease 
characteristics

Remove the description of metyrapone as for the 
use of previous medication, as another medication 
may have been used.


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Version
Time 
point
Date
Changes

Clarified best response to the previous medication
is listed. 
 
 
 
5. Section 7.2.1 exposure of study treatment – Inserted how 
to handle multiple different doses are given in a certain 
schedule. 
6. Section 7.3 efficacy evaluation – Clarified that AIMAH 
and PPNAD will be presented, respectively, and will not 
be grouped together for listing by subtype of Cushing’s 
syndrome. 
7. Section 7.3.2.3 – section title has been updated to 
change from baseline in ACTH and other adrenal steroid 
hormones
8. Section 7.5 Safety evaluation

Listing will be sorted by subtype of Cushing’s 
syndrome in similar to efficacy listing.

The definition of the on-treatment period is clarified 
as date from first dose of study medication through 
30 days after last dose of study medication, 
regardless of another therapy use for Cushing’s 
syndrome.

Section 7.5.1 Adverse events – Link to NCI CTCAE 
version 4.03 is removed as the analysis preparation 
is based on the internal guidance of EASE (End to 
end analysis standards from protocol to reporting) 
which is based and modified on CTCAE version 
4.03.

Section 7.5.2.1 hematology, chemistry, urinalysis, 
coagulation and thyroid panel is modified that WBC 
differentials will be based on absolute values when 
only percentage values are collected in alignment 
with standard methodology internally.


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Version
Time 
point
Date
Changes
 
 
Amendment 
3.0
Prior to 
DB lock
22-Jun-2018
1.
Administrative changes:

Section 9 Changes from planned analysis in 
the study protocol – typos are corrected.

Typos are corrected across document with 
Safety analysis set.
2.
Section 6.1.3 Pharmacokinetic analysis set (PAS) –
Clarified the conditions further regarding time window
allowance and missing incident dose.
3.
Section 7.1.2 Patient disposition – removed the wording 
of Week 96 restriction in the optional extension period.
4.
Section 7.2.1 Exposure to study treatment – derivation 
for dose with longest duration

Analysis set is corrected o SAS and added in 
the section 9 change from planned analysis 
as well.

It was inconsistent descriptions between this 
document and TFL shells about how to 
handle multiple doses with the longest.
duration, which is now consistently to choose 
the highest dose rather than average dose.

Clarified that sum of durations will be 
summarized at different occasions for a given 
dose.
5. Section 7.3 Efficacy evaluation 

Section 7.3.1 Primary efficacy analysis –
clarified that corresponding 95% CI will be 
presented for both mean change and mean % 
change.

Section 7.3.2.1 Response rate – clarified that 
denominator of response rate after study 
period II will be based on patients who 
entered into study period II and reached at a 
specific visit.

Section 7.3.2.2 change from baseline in 
serum cortisol - clarified that corresponding 
95% CI will be presented for both mean 
change and mean % change.


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Version
Time 
point
Date
Changes
6.
Section 7.4 Pharmacokinetic evaluation – Corrected to 
clarify graphical depiction over time will be performed 
by week 12 dose and visit.
7.
Section 8.6 Assessment window – Clarified that an 
unscheduled assessment may be used as an 
alternative assessment for safety summary by visit.


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Table of contents
Table of contents .................................................................................................................7
1
Introduction .......................................................................................................................10
2
Study design ......................................................................................................................10
3
Objectives..........................................................................................................................11
3.1
Primary objective...................................................................................................11
3.2
Secondary objectives .............................................................................................11
12
4
Sample size and power considerations..............................................................................12
4.1
Sample size calculation..........................................................................................12
4.2
Power for analysis of primary and secondary variables ........................................12
5
Data cutoff for analyses.....................................................................................................12
6
Analysis sets ......................................................................................................................13
6.1.1
Full Analysis Set ...................................................................................13
6.1.2
Safety Analysis Set ...............................................................................13
6.1.3
Pharmacokinetic analysis set.................................................................13
7
Statistical analyses.............................................................................................................13
7.1
Patients studied......................................................................................................14
7.1.1
Grouping for analyses ...........................................................................14
7.1.2
Patient disposition.................................................................................14
7.1.3
Demography and baseline disease characteristics.................................14
7.1.4
Medical history......................................................................................15
7.1.5
Prior medication....................................................................................15
7.1.6
Protocol deviations (PDs) .....................................................................15
7.2
Study medication ...................................................................................................15
7.2.1
Exposure to study treatment..................................................................15
7.2.2
Concomitant medication .......................................................................15
7.3
Efficacy evaluation................................................................................................16
7.3.1
Primary efficacy analysis ......................................................................16
7.3.2
Secondary efficacy analysis..................................................................16
7.3.3
Other efficacy analysis..........................................................................17
7.4
Pharmacokinetic evaluation...................................................................................17
7.4.2
Other biomarkers...................................................................................18
7.4.3
Patient-reported outcomes.....................................................................18
7.5
Safety evaluation ...................................................................................................19
7.5.1
Adverse events ......................................................................................19


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7.5.2
Laboratory abnormalities ......................................................................21
7.5.3
Vital signs..............................................................................................23
7.5.4
Electrocardiogram (ECG) .....................................................................23
24
8
Definitions .........................................................................................................................24
8.1
Study day ...............................................................................................................24
8.2
Baseline..................................................................................................................24
8.3
Calculating mUFC.................................................................................................25
8.4
Study day associated with a Urine Free Cortisol (UFC) assessment.....................25
8.5
Method for calculating confidence interval...........................................................25
8.6
Assessment window...............................................................................................25
9
Changes from planned analysis in the study protocol.......................................................25
10 References .........................................................................................................................27
11 Appendices ........................................................................................................................28
11.1
Appendix 1: Cushing’s Syndrome Quality of Life Questionnaire ........................28
11.2
Appendix 2: Imputation rules for partial or missing dates ....................................28
11.2.1
For exposure data..................................................................................28
11.2.2
For AE and concomitant medication.....................................................29


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Table 1-1
List of abbreviations
abbreviations
Meaning
ACTH
Adrenocorticotropic Hormone
AE
Adverse event
AIMAH
ACTH-Independent Macronodular Adrenal Hyperplasia
BDI-II
Beck Depression Inventory-II
b.i.d.
bis in diem/twice a day
BMI
Body mass index
CD
Cushing’s disease
CREDI
Clinical Research Documentation and Information system
CS
Cushing’s syndrome
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Drug administration record (CRF page)
ECG
Electrocardiogram
FAS
Full analysis set
(m)UFC
(mean) Urine Free Cortisol
LLOQ
Lower limit of quntitation
MedDRA
Medical Dictionary for Regulatory Activities
PAS
Pharmacokinetic analysis set
PD
Pharmacodynamics
PDs
Protocol deviations
PK
Pharmacokinetic
PPNAD
Primary Pigmented Nodular Adrenal Dysplasia
SAS
Safety analysis set
SSD
Study specific documentation


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1
Introduction
This document describes the planned statistical analysis and methodology for study 
LCI699C1201 CSR in patients with Cushing’s syndrome (CS). 
Data will be analyzed according to the data analysis section 10 of the study protocol, which is 
available in Appendix 16.1.1 of the CSR.  Important information is given in the following 
sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR.
2
Study design
This is a phase II, single arm, open-label, dose titration, multi-center study consisting of two 
distinct study periods plus an optional extension period in non-Cushing’s disease (CD) patients 
with CS who have persistent or recurrent hypercortisolism after primary surgery and/or 
irradiation and/or chemotherapy, and patients de novo CS who are not surgical candidates for 
medical reasons, or refuse to undergo surgery.
Study period I (Week1 to Week 12):
Study period I is the dose titration period to achieve a stable therapeutic dose and to assess the 
efficacy and safety of osilodrostat.
Figure 2-1
Study period 1
Dose adjustments are based on the serum cortisol values measured by the local lab at each site. 
Osilodrostat titration can be done weekly for the initial 4 weeks, up to a maximum dose of 10 
mg b.i.d.. Two-week interval must be taken to increase from 10 mg b.i.d. to 20 mg b.i.d., even 
if in initial 4 weeks. After Week 4, the dose can be further increased, if needed, at 2-week 
intervals (Figure 2-1). The dose is increased if morning serum cortisol is above normal (> ULN
of each site). The dose is reduced if serum cortisol is below normal (< LLN of each site), or if 
the patient has signs or symptoms of hypocortisolism or adrenal insufficiency and serum 
cortisol is in the lower part of the normal range. The dose should be maintained if serum cortisol
is within the normal range and the patient does not have signs or symptoms of hypocortisolism 
or adrenal insufficiency.
The mean of three 24-hour UFC (mUFC) values will be obtained to evaluate the efficacy in this 
period.
Study period II (Week 12 to Week 48):
Study period II is the period to assess the sustainability of efficacy and to assess long-term
safety. For this study period II, only the patients who tolerate and agree to continue osilodrostat


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treatment will continue study treatment during period II. The patient will be administered with 
the stable therapeutic dose, which will be achieved in the study period I. The dose level could 
be modified according to the patient condition (refer to [Sections 6.1 and 6.3 of the study 
protocol]. The mUFC will also be measured to evaluate the efficacy in this period.
Optional extension period (after Week 48):
Patients who continue to receive clinical benefit, as assessed by the study investigator and who 
wish to enter the extension period must be re-consented at week 48. Patients who enter the 
extension period will do so without interruption of study drug or assessments. The extension 
period will end after all patients have completed Week 72 or discontinued early (prior to Week 
72).
The patient will continue to receive stable therapeutic dose. The dose level could be modified 
according to the patient condition.
Follow-up
All patients will be contacted for safety evaluation during the 30 days following the last dose 
of study treatment.
3
Objectives
3.1
Primary objective
The primary objective is to assess the percent change from baseline in the mean Urine Free 
Cortisol (mUFC) at the individual patient level at Week 12.
3.2
Secondary objectives
The secondary objectives are as follow:

To assess the percent change from baseline in the mUFC at the individual patient level at 
Week 24 and Week 48.

To assess the absolute and percent change from baseline in mUFC at Week 12, Week 24
and Week 48.

To assess the complete, partial, and overall response rate at Week 12, Week 24 and Week 
48.

To assess the absolute and percent change from baseline in morning serum cortisol at the 
individual patient level at Week 12, Week 24 and Week 48.

To assess the absolute and percent change from baseline in morning serum cortisol at
Week 12, Week 24 and Week 48.

To assess the absolute and percent change from baseline in steroid hormones at the 
individual patient level at Week 12, Week 24 and Week 48.

To assess the change from baseline in cardiovascular-related metabolic parameters 
associated with CS at Week 12, Week 24 and Week 48.

To assess the general safety of osilodrostat.


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
To assess the change from baseline in Patient-Reported Outcome (Health Related Quality 
of Life) at individual patient level at Week 12, Week 24 and Week 48.

To evaluate PK of osilodrostat in patients with CS.
4
Sample size and power considerations
4.1
Sample size calculation
Based on medical and operational feasibility, 10 patients plan to be enrolled in this study 
because of the following reasons:

According to epidemiology survey in 1997 in Japan, the incidence of CS was estimated as 
1250 cases. In the 417 cases of CS which were actually reported, 35.8% had CD, 47.1% 
had adrenal adenoma, 17.1% had other cause of CS (Nawada et al 1999).

Only less than 50 patients are those who need medically treatment in CS because the 
success rate of surgeon is very high (about 95% in adrenal adenoma can be treated by only 
surgery). The number of ectopic corticotropin syndrome, AIMAH and PPNAD who need 
medically treatment is low as well.

Metyrapone is approved in Japan for Cushing syndrome. Therefore, some enrolled 
patients are expected to be inadequately controlled with metyrapone.
As a heterogeneous population will be enrolled, the effects of osilodrostat on each patient is 
expected to vary. Therefore, the primary analysis will be based on the percent change from 
baseline in mUFC at the individual patient level at Week 12.
4.2
Power for analysis of primary and secondary variables
Not applicable.
5
Data cutoff for analyses
The study will be analyzed at least 3 times, at completion of study period I (Week 12), at 
completion of study period II (Week 48), and at the final analysis after all patients complete the 
study. The initial analysis will be performed when all enrolled patients have completed the dose 
titration period of study (study period I) or have prematurely withdrawn from the study, 
whichever comes first. All assessments and/or events occurred on or prior to data cut off will 
be included in the analysis. 


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A patient who didn’t enter into study period II (After Week 12 through Week 48) or optional 
extension phase (after Week 48) will not be considered withdrawn from study. A patient in 
study period II or in optional extension phase will be analyzed in a report once the patient 
completed the period or discontinued earlier.
6
Analysis sets
6.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all enrolled patients who received at least one dose of 
osilodrostat. This is the default analysis set for efficacy.
6.1.2
Safety Analysis Set
The safety analysis set (SAS) includes all patients who received at least one dose of osilodrostat
and had at least one valid post-baseline safety assessment. Post-baseline safety assessments
include all assessments for safety endpoints including laboratory, ECG, vital signs and adverse 
events (AE)/SAEs.
6.1.3
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of osilodrostat and had at least one evaluable PK concentration at any visit (post-first-dose). A 
PK concentration may be considered non-evaluable as per scientific judgement of the clinical 
pharmacology expert and the reason of being non-evaluable will be documented.
Data that is considered non-evaluable including, but not limited to, by the below reasons will 
be flagged and excluded from the analysis set.

The patient didn’t receive the incident dose (last dose administered prior to PK collection) 
as planned per protocol, OR

PK concentration data after vomit occurring within 4 hours of dosing, OR

If the elapsed time between PK sample and prior dose didn’t fall within acceptable 
window.

Pre-dose samples within 0.5h before dose administration, and within 9h to 15h after 
the previous dose.

Post-dose samples with elapsed time window within protocol specified nominal time 
range (i.e. within 0.25h to 0.75h, 1h to 2h and 3h to 4h).
7
Statistical analyses
Novartis or designated CRO will analyze all data using the SAS System for data analysis V9.4
or higher. Any data analyses carried out independently by an investigator should be submitted 
to Novartis before publication or presentation.


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7.1
Patients studied
Summary statistics of data pertaining to subject disposition, demographics, baseline 
characteristics, medical history, prior medications and protocol deviations will be tabulated and 
displayed using grouping described below.
All listings will be generated by type of disease (ectopic corticotropin syndrome, adrenal 
adenoma, adrenal carcinoma, AIMAH and PPNAD) for full analysis set, unless otherwise 
specified.
7.1.1
Grouping for analyses
The data from all centers participating in the trial will be combined, so that an adequate number 
of patients will be available for analysis.
Data will be summarized only by a single arm name osilodrostat, as the level of dose 
administration will be adjusted depending on a subject response, which will be closely 
monitored by an investigator for safety/tolerability, and efficacy (expected dose level from 2 
mg b.i.d to 30 mg b.i.d).
7.1.2
Patient disposition
For overall study period as well as each period, counts of patients for the following items will 
be summarized for the Full analysis set:

The number of patients who discontinued at any time and primary reason for 
discontinuation at any time

The numbers of patients who entered into the Study period I (Day 1 to Week 12)

The numbers of patients who entered into the Study period II (Week 12 to Week 48)

The numbers of patients who entered into the Optional extension period (after Week 48)
A patient who did not enter into study period II (After Week 12 through Week 48) or optional 
extension phase (after Week 48) will not be counted as discontinuations in the corresponding 
period.
7.1.3
Demography and baseline disease characteristics
All demographic will be summarized and listed in detail for the Full analysis set.  Categorical 
data will be summarized by frequencies and percentages. For continuous data, mean, standard 
deviation, minimum, median and maximum will be presented. Demographic variables include 
Age (in year), Age (< 65 years/≥ 65 years), gender, race, ethnicity, baseline height, weight and 
BMI.
Baseline disease characteristics will be listed, including diagnosis date of Cushing’s syndrome, 
cause of disease (ectopic corticotropin syndrome, adrenal adenoma, adrenal carcinoma, 
AIMAH/PPNAD), use of previous medication  and the best response to the previous medication, 
Cushing’s syndrome status (de novo or persistent/recurrent) and previous surgery. 


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For a patient with ectopic corticotropin syndrome, primary site of cancer, date of initial 
diagnosis and metastatic sites will be presented in a listing.
7.1.4
Medical history
Relevant medical history and ongoing medical conditions will be listed for the Full analysis set. 
7.1.5
Prior medication
Prior medication, prior radiation and prior surgery for Cushing’s syndrome will be listed for the 
Full analysis set.
7.1.6
Protocol deviations (PDs)
All CSR-reportable PDs up to data cutoff will be listed. The criteria for CSR-reportable protocol 
deviation are specified in the study specific documentation (SSD) and will be finalized prior to 
database lock.
7.2
Study medication
All listings will be generated by type of disease (ectopic corticotropin syndrome, adrenal 
adenoma, adrenal carcinoma, AIMAH and PPNAD), unless otherwise specified.
7.2.1
Exposure to study treatment
The exposure to study drug will be summarized overall and listed for the safety analysis set.
Duration of exposure (weeks) will be calculated as the earliest of (date of last administration of 
osilodrostat, date of data cut-off, date of death) minus date of first osilodrostat administration 
plus one. If drug administration is temporarily interrupted for a certain period, it is included in 
the calculation of duration.
The highest dose (mg/day), average dose (mg/day), and the dose with the longest duration of 
administration (mg/day) up to Week 12 and up to data cut-off will be summarized. For dose 
with the longest duration, the highest dose will be used if there are more than one dose with the 
same longest duration, and the sum of durations should be used if multiple different occasions 
are observed for a given dose. If multiple different doses are given in a certain period for a 
patient (e.g. 2 mg/day on Day 1 + 3 mg/day on Day 2), then daily dose for the period will be 
the mean of doses, but the detailed information will be presented in a listing.
Drug administration record (DAR) will be kept on the CRF DAR page along with details 
regarding dose interruption, dose reduction, and dose increase along with the reason for dose
modification. This information will be listed with the mUFC information.
7.2.2
Concomitant medication
Concomitant medications and significant non-drug therapies will be listed and summarized 
using frequency counts and percentages by ATC class and preferred term overall regardless of 
study period.
If the start date of a concomitant medication is missing, then it will be assumed to have the 
medication administered started on or after the first dose of study treatment.


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7.3
Efficacy evaluation
All efficacy analyses will be performed for full analysis set. All listings will be generated by 
type of underlying disease (ectopic corticotropin syndrome, adrenal adenoma, adrenal 
carcinoma, AIMAH and PPNAD) for full analysis set, unless otherwise specified.
7.3.1
Primary efficacy analysis
The primary objective is to assess the percent change from baseline in the mean Urine Free 
Cortisol (mUFC) in individual patient level data at Week 12.
The primary endpoint is the percent change from baseline in mUFC at the individual patient 
level. Due to the limited sample size and variabilities of patients, no statistical hypothesis is set 
up for this study. The percent and absolute change will be plotted over time along with dose 
administration data by individual patient for the Full analysis set. For patients who discontinued 
prior to Week 12, data will not be imputed and only actual data will be presented. Additionally, 
mean change and mean % change will be summarized along with corresponding 95% CIs.
The mUFC levels will be determined at a central laboratory from three 24-hour urine specimens 
collected within 7 days from the scheduled visit date. The mean of the results from the 3 samples 
will be used to obtain the corresponding mUFC level for a given assessment. If a patient has 
two or more missing UFC values for a particular visit, the mUFC assessment for that patient at 
that visit will be considered missing. Otherwise, the mean of UFC samples for a given patient 
and time point will be considered as the mUFC level for that visit.
7.3.1.1
Supportive analyses
Summary tables of overall mean change from baseline and the mean percent change from 
baseline in mUFC will be generated at Week 12, Week 24 and Week 48, descriptively for all 
patients. In addition, these parameters will be presented by status of prior treatment with
metyrapone. Summary by the status of prior treatment with metyrapone will be presented, if at 
least 4 patients are included in either group (patients with prior treatment with metyrapone or 
patients without prior treatment with metyrapone).
7.3.2
Secondary efficacy analysis
There is no key secondary endpoint pre-specified in this study. All secondary endpoints are to 
support individual patient response to osilodrostat.
7.3.2.1
Response rate (complete response rate, partial response rate and 
overall response rate)
Point estimates of complete, partial and overall response rates will be presented with exact 95% 
confidence interval (Clopper-Pearson method) at Week 12 (end of study period I), Week 24 and 
Week 48 (end of study period II), respectively, for the Full analysis set. Complete response (CR)
rate is defined as the proportion of enrolled patients who have mUFC ≤ ULN. Partial response
(PR) rate is defined as the proportion of enrolled patients who have mUFC>ULN and at least 
50% reduction from baseline in mUFC. Overall response rate (ORR) is defined as the 
proportion of enrolled patients with mUFC ≤ ULN or at least 50% reduction from baseline.


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Complete response at Week 12 is defined as a patient with mUFC≤ ULN at Week 12. A patient 
with missing mUFC assessment at Week 12 or a patient who discontinued study drug during 
study period I will be counted as a non-responder for the analysis. 
Similarly, complete response at Weeks 24 or Week 48 is defined as a patient with mUFC≤ ULN
at Week 24 or Week 48, respectively). A patient who entered into study period II and reached 
at a specific visit will be included in the denominator of the calculation of response rate at the 
visit. If a patient who entered into the period discontinued study drug prior to mUFC assessment
or had missing mUFC at the time of assessment, the patient will be considered a non-responder. 
.
Please note that the purpose of presentation of 95% CI is not for statistical inference in this 
small study. Moreover, this summary will be presented only when at least four subjects have 
been enrolled overall and stayed in the study through week 12.
7.3.2.2
Change from baseline in serum cortisol
Morning serum cortisol will be assessed at central laboratory. The percent change from baseline
in morning serum cortisol along with dose administration data will be plotted over time for each 
patient. Additionally, a descriptive summary of the mean change from baseline and the mean 
percent change from baseline in morning serum cortisol will be provided at Week 12, 24 and 
48. The corresponding 95% CIs will be provided in both mean change and mean % change.
Additionally serum cortisol will be assessed by local laboratory. These will be presented in a 
listing only.
7.3.2.3
Change from baseline in ACTH and other adrenal steroid hormones
Both mean change and mean percent changes from baseline in the following ACTH and adrenal 
steroid hormones will be listed over time by individual patient: plasma adrenocorticotropic 
hormone (ACTH), serum aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, testosterone 
and estradiol. 
7.3.2.4
Change from baseline in cardiovascular-related metabolic parameters 
associated with Cushing syndrome
The mean change and mean percent change from baseline in the following cardiovascular 
related metabolic parameters will be provided in a listing: Fasting glucose, HbA1c, fasting lipid 
profile, blood pressure, body weight body mass index (BMI) and waist circumference. BMI 
will be calculated as weight (kg)/ [height (m)]2 using the baseline weight and height.
7.3.3
Other efficacy analysis
Not applicable.
7.4
Pharmacokinetic evaluation
The PAS will be used in all pharmacokinetic data analysis and summary statistics.


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As sparse pharmacokinetic sampling is performed in this study, traditional non- compartmental 
analysis will not be performed to calculate pharmacokinetic parameters. Plasma concentration 
data of osilodrostat will be listed by subject, visit, incident dose and nominal sampling times. 
Descriptive statistics of plasma concentrations will be provided by incident dose, visit and 
nominal sampling times. Graphical depiction (mean and individual) for osilodrostat 
concentrations over time during the course of the study will be performed by Week 12 dose and 
visit. When Week 12 dose level is missing for a subject with an early withdrawal or temporary 
interruption, then corresponding patient data will not be plotted. 
7.4.1.1
Data handling principles
Plasma concentrations of osilodrostat will be expressed in ng/mL. Missing concentration values 
will be labeled as such in data listings. Concentrations below the lower limit of quantitation 
(LLOQ) will be treated as zero in summary statistics and reported as zero in data listings.
7.4.3
Patient-reported outcomes
The Cushing’s Disease Health-Related Quality of Life Questionnaire (CushingQoL) score is 
identified as the primary patient reported outcome variable of interest. Beck Depression 
Inventory-II (BDI-II) total score is identified as secondary PRO variables of interest. 
For CushingQoL, details for data handling and how to calculate standard scores are discussed 
in the Appendix 1. The score can be interpreted if the number of unanswered items does not 
exceed 3 (25% of the questions). If the number of unanswered items exceed 3, then the sum of 
total score and standardized score will not be calculated.
For BDI-II, each of 21 items corresponds to a symptom of depression and the sum of total score 
will be calculated where each item has a four-point scale ranging from 0 to 3, leading to a total 
score from zero to 63. Interpretation of the total score is described at the end of the 
questionnaires: score of 1 to 10 is considered normal, score of 11 to 16 is considered mild mood 
disturbance, score of 17 to 20 is considered borderline clinical depression, score of 21 to 30 is 
considered moderate depression, score of 31 to 40 is considered severe depression and score of 
over 40 is considered extreme depression.
No imputation will be applied if the total scores are missing at a visit. All available data of raw
scores and sums of scores for both questionnaires as well as standardized scores for 


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CushingQoL until completion or early discontinuation during study period I and II will be listed
only due to very small sample size. 
7.5
Safety evaluation
For all safety analyses, the safety analysis set will be used.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication, regardless of another therapy used for Cushing’s syndrome (e.g. 
metyrapone)
3. post-treatment period: starting at day 30+1 after last dose of study medication
Unless otherwise specified, summary tables present data during on-treatment period in addition 
to baseline data.  In listings, all data will be presented regardless of observation period and will 
be presented by type of disease (ectopic corticotropin syndrome, adrenal adenoma, adrenal 
carcinoma, AIMAH and PPNAD) for safety analysis set, unless otherwise specified.
7.5.1
Adverse events
Summary tables for treatment-emergent adverse events (AEs) will include AEs that started or 
worsened during the on-treatment period. However, all adverse events (including those from 
the pre and post-treatment periods) will be listed and those collected during the pre-treatment 
and post-treatment period are to be flagged.
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. The latest version available at the time of database lock will be used.
AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
The CTCAE represents a comprehensive grading system for reporting acute and late effects of 
cancer treatments. CTCAE v4.03 is graded by definition by a 5-point scale generally 
corresponding to clinical severity (mild, moderate, severe, life-threatening, and death). This 
grading system inherently places a value on the importance of an event although there is not 
necessarily proportionality among grades (a Grade 2 is not necessarily twice as bad as a Grade 
1). 
For adverse events for which CTCAE grades are not available, grades 1 – 4 corresponding to 
the severity of mild, moderate, severe, and life threatening will be used. CTCAE grade 5 (death) 
is not used in this study; rather, this information will be collected on the “End of Treatment” or 
“Study evaluation completion” eCRF pages.
7.5.1.1
General rule for AE reporting
AE summaries will include all AEs starting on or after study day 1 (i.e. on or after the day of 
the first administration of study drug) but no later than data cutoff or study withdrawal of each 


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patient, whichever comes first.  All AEs before data cutoff date will be listed, including those 
that start before study day 1. AEs starting prior to study day 1 will be identifiable based on the 
AE start date displayed in the listings and not summarized in tables. 
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, and having at least one AE in each body system/primary system organ class and for 
each preferred term using the most current MedDRA coding available prior to database lock
and maximum CTC grade. A subject with multiple occurrences of an AE will be counted only 
once in the AE category. A patient with multiple CTC grades for an AE will be summarized 
under the maximum CTC grade recorded for the event. AEs with missing CTC grade will be 
summarized under “missing”.
Any information collected (e.g. CTC grades, relationship to study drug, action taken etc.) will 
be listed as appropriate.
7.5.1.2
AE summaries
The following adverse event summaries will be produced:

Adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and maximum CTC grade (Any or Grade 3/4)

Adverse events, with suspected study drug relationship, by primary system organ class, 
preferred term and maximum CTC grade (Any or Grade 3/4)

On treatment deaths, by primary system organ class and preferred term 

Serious adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and maximum CTC grade  (Any or Grade 3/4)

Serious adverse events with suspected study drug relationship, by primary system organ 
class, preferred term and maximum CTC grade  (Any or Grade 3/4)

Adverse events leading to study drug discontinuation, regardless of study drug relationship, 
by primary system organ class and preferred term 

Adverse events requiring dose adjustment or study-drug interruption, regardless of study 
drug relationship, by primary system organ class and preferred term 

Adverse events requiring additional therapy, regardless of study drug relationship, by 
primary system organ class and preferred term
7.5.1.3
AE of special interest
Groupings of AEs of special interest consist of adverse events for which there is a specific 
clinical interest in connection with LCI699 treatment (i.e. where LCI699 may influence a 
common mechanism of action responsible for triggering them) or adverse events which are 
similar in nature (although not identical). 
An Excel file with the exact composition of the adverse events groupings is available in an 
internal repository system named CREDI (Clinical Research Documentation and Information 
system) which is to be used to map reported adverse events to the adverse events groupings. 
This file is updated periodically after MedDRA update and/or review of accumulating trial data. 


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Following summaries will be produced:

Adverse events of special interest, regardless of study drug relationship, by group name, 
preferred term, and maximum CTC grade  (Any or Grade 3/4)

Adverse events of special interest with suspected study drug relationship, by group name, 
preferred term, and maximum CTC grade  (Any or Grade 3/4)
7.5.1.4
Safety disclosure
For the legal requirements of ClinicalTrials.gov, two required tables on on-treatment adverse 
events which are not serious adverse events and on on-treatment serious adverse events and 
SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety analysis set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective.
7.5.2
Laboratory abnormalities
For analyzing laboratory results, data from all sites will be combined and reported. Table 7-1
provides the local laboratory information except for serum cortisol, which will be assessed by 
both local and central laboratories and reported, respectively.
Eligible laboratory data will be converted into values in SI units and classified into CTC grades 
according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03. In the 
unlikely case, a local laboratory normal range overlaps into the higher (i.e. non-zero) CTC grade, 
if the laboratory value is within local normal limits it will be assigned a CTC grade of zero.


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Table 7-1
Local clinical laboratory parameters
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, WBC 
Morphology with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT (GPT), AST (GOT), Bicarbonate, Glucose, 
Calcium, Chloride, Creatinine, Creatine kinase, GGT, Lactate dehydrogenase 
(LDH), inorganic phosphorus, lipase, amylase, magnesium, potassium, sodium, 
Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, Total Cholesterol, LDL, HDL, 
Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, pH, Protein, Specific Gravity,)
Coagulation
Prothrombin time (PT) or INR, Activated partial thromboplastin time (APTT)
Thyroid Panel
Serum TSH, free T4
Additional tests
Serum cortisol
Pregnancy test (serum / urine)
Fasting serum insulin and HbA1C
LH, FSH
Serum Type I collagen cross-linked N-telopeptide (NTX) and Serum bone-
specific alkaline phosphatase (BAP)
7.5.2.1
Hematology, chemistry, urinalysis, coagulation and thyroid panel
The summaries will include all on-treatment laboratory assessments up to data cut-off date. All 
laboratory assessments will be listed with corresponding CTC grades and/or normal ranges.
Both tables and listings will be presented for Safety analysis set.
For WBC differentials provided in percentage unit, values will be converted to absolute values 
with the below equation for grading including calculations of upper limit normal (ULN) and 
lower limit normal (LLN) as well:
WBC differential count = (WBC count) × (WBC 
differentials percentage values/100).
For grading of serum calcium, values will be adjusted for albumin by the following equation:
Corrected serum calcium (mg/dL) = total calcium (mg/dL) – 0.8 [albumin (g/dL)-4]
The following summaries will be presented:

Shift to the worst post-baseline up to data cut-off from baseline on CTC grade

Number and percentage of patients meeting categorical liver function test criteria, 
including Hy’s Law criteria for liver injury (ALT or AST > 3 x ULN and TBIL ≥2 x 
ULN and ALP < 2 x ULN). Each patient will be counted only for the worst grade 
observed post-baseline. All data up to data cut-off will be used.
7.5.2.2
Additional tests
Additional test information is listed in Table 7-1. Absolute and percent changes in these 
parameters will be listed over time, which include fasting serum insulin, HbA1c, luteinizing 
hormone (LH), follicle stimulating hormone (FSH) and bone metabolism markers (serum 


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Type I collagen crosslinked N-telopeptide (NTX) and serum bone-specific alkaline 
phosphatase (BAP)) . All other test results will be listed over time only for the Safety 
analysis set.
7.5.3
Vital signs
All vital signs data (height (cm), weight (kg), waist circumference (cm), body temperature (°C), 
supine pulse rate (beats per minute), and supine systolic/diastolic blood pressure (mmHg)) will 
be listed by patient and visit/time, and abnormalities will be flagged on listing. Summary 
statistics of absolute change from baseline will be presented over time.
The criteria for clinically notable abnormalities are defined in Table 7-2 below. Abnormal 
values will be flagged in the listing.
Table 7-2
clinically notable abnormal values
Abnormal criteria
Systolic BP (SBP) (mmHG)
180 mmHg and an increase 20 mmHg from baseline
90 mmHg and a decrease 20 mmHg from baseline
Diastolic BP (DBP) (mmHG)
105 mmHg and an increase 15 mmHg from baseline
50 mmHg and a decrease 15 mmHg from baseline
Supine pulse (bpm)
100 bpm with increase from baseline > 25 %
50 bpm with decrease from baseline > 25 %
Weight (kg)
Increase from baseline of 10%
Decrease from baseline of 10%
BMI (kg/m2)
<18.5 kg/m2
Waist Circumference (cm)
N.A.
7.5.4
Electrocardiogram (ECG)
Local 12-lead ECG evaluations will be listed with abnormality flag following criteria below in 
Table 7-3, regardless of scheduled/unscheduled assessments. The number and percentage of 
subjects with notable ECG will be presented up to week 12 and up to data cut-off, respectively. 
No imputation of missing data will be performed.
Table 7-3
ECG notable abnormal values
Abnormal criteria
QT and QTcF (msec)
Increase from baseline > 30 to ≤60 (msec)
Increase from baseline > 60 (msec)
New >450 and ≤480 (msec)
New >480 and ≤500 (msec)
New >500 (msec)
Heart rate  (beat per minute)
Decrease from baseline > 25% and post-baseline assessment < 50 
(bpm)
Increase from baseline > 25% and post-baseline assessment > 100 
(bpm)


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Abnormal criteria
PR interval (msec)
Increase from baseline > 25% and post-baseline assessment > 200 
(msec)
New > 200 (msec)
QRS duration (msec)
Increase from baseline > 25% and post-baseline assessment > 120 
(msec)
New >120 (msec)
Separately, if there are abnormalities, local data will be transferred to central laboratory for re-
read and adjudication by central laboratory, which will be listed separately. In addition, 24-hour
holter ECG data will be recorded and transferred from central laboratory. Central laboratory 
data will be listed separately from local laboratory data.
8
Definitions
8.1
Study day
Study Day 1 is the date of first administration of study drug.
The study day for an event that occurs prior to study Day 1 will be calculated as the date of 
event minus the date of first administration of study drug.
The study day for an event that occurs on or after study Day 1 will be calculated as the date of 
event minus the date of first administration of study drug plus one.
8.2
Baseline
For efficacy and safety evaluations (e.g. laboratory assessments and vital signs): the last 
available pre-dose assessment within 35 days prior to or on Study Day 1 (before the first dose 
of osilodrostat) is considered as the “baseline” assessment regardless of scheduled/unscheduled 
assessments. 
For ECG assessments, both 12-lead from local and central laboratories as well as 24-hour holder 
from central laboratory will be collected.  Baseline is defined as the average of all ECG 
measurements taken prior to the dose of study drug from local and central laboratory values 
separately per subject and type. Post-treatment assessments from local and central laboratories 
will be reported with corresponding laboratory baseline values.


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8.3
Calculating mUFC
To compute the mUFC (mean Urine Free Cortisol) for a patient at any particular visit, at least 
two UFC specimens are required at that visit. If there are less than two samples available then 
mUFC will be considered missing for that assessment.
8.4
Study day associated with a Urine Free Cortisol (UFC)
assessment
The study day associated with a UFC assessment at any particular visit is defined as the study 
day of the last UFC sample collection for that visit.
8.5
Method for calculating confidence interval
Two-sided 95% exact confidence intervals for proportions will be calculated using the exact 
Clopper-Pearson method, unless stated otherwise.
8.6
Assessment window
Efficacy assessments, e.g. mUFC, morning serum cortisol, steroid hormones, ACTH 
 
, at scheduled visit will be used for summary. If scheduled visit assessments are missing
but unscheduled/end of treatment(EoT) visit assessments exist within +/- 3 days from the 
originally planned visit date (within – 7 days through + 3 days for mUFC only), then those 
unscheduled/EoT visit assessments may be used for summary. For example, if a subject did not 
have an assessment at Week 12 but had those at EoT visit within specified time window, then 
EoT assessments will be used for efficacy summary, even though he may withdrew the study 
earlier after Week 10. 
Summary of safety assessments will be mainly based on scheduled visits only except for shift
tables and summary by visit. For summary of safety endpoint by visit, unscheduled/EoT 
assessment may be used when a scheduled assessment on treatment period is not available and 
unscheduled/EoT assessment was collected within +/- 3 days from the scheduled visit date. In 
shift tables, all post-treatment assessments on treatment period will be considered, unless 
otherwise specified.
9
Changes from planned analysis in the study protocol
The following changes have been made from the analysis planned in the protocol.
Table 9-1
Change from planned analysis
Section
Changes
Rationale
Section 7.2.1 Exposure to study 
treatment
Summary will be performed for 
Safety analysis set instead of 
full analysis set.
In order to see the impact for
safety assessment.
Section 7.5.2 Laboratory 
abnormalities
Summary of Hy’s Law criteria is 
added.
Further data look is required for 
liver related toxicity and to be 
consistent with safety guideline.


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Section
Changes
Rationale
Section 7.5.2.1 Hematology, 
chemistry, urinalysis, 
coagulation and thyroid panel
Frequency table for newly 
occurring on-treatment grades 
¾ is changed to shift table from 
baseline to worst pots-baseline
In order to be consistent with 
oncology standard
Section 7.5.3 Vital signs
% change from baseline is 
removed from the table  
changed
In order to be consistent with 
oncology standard
Section 7.5.4 ECG
Shift table is changed to 
summary of abnormal table
In order to be consistent with 
oncology standard


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10
References
[Nawada H (1999)] Nawada H, Takayanagi R, Nakagawa H, et al (1999). Nationwide 
epidemiological survey of disorders of adrenal hormones in Japan. Annual report of the 
Ministry of Health and Welfare "Disorders of adrenal hormones" Research Committee, Japan: 
11-55.
[S Webb (2008)] Webb S, Badia X, Barahona M, et al (2008). Evaluation of health-related 
quality of life in patients with Cushing’s syndrome with a new questionnaire. European 
Journal of Endocrinology; 158: 623–630.


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11
Appendices
11.1
Appendix 1: Cushing’s Syndrome Quality of Life Questionnaire
S Webb et al published scoring and standardization method (S Webb et al. 2008). Each 
questionnaire of the CushingQOL has a scale of 1-5 where `1` corresponding to `Always` or 
`Very much` and `5` to `Never` or `Not at all`. The lower the score, the greater the impact on 
HRQoL. The score is the sum of all the item response and can range from 12 (worst) to 60 
points (best).
To simplify interpretation of scores, standardization on a scale from 0 (worst) to 100 (best) can 
be calculated with the following formula:
Y={[(X) - min]/(max-min)}x 100
Where Y is the recalculated score, X is the sum of all the item responses within the study score, 
`min` is the minimum and `max` is the maximum possible score.
11.2
Appendix 2: Imputation rules for partial or missing dates
11.2.1
For exposure data
Partial dates will remain partial in the data listing. For the purpose of analysis, the following 
imputation rules will be used for exposure data.
If date of last administration is completely missing and there is no EoT CRF page, the subject 
is considered as on-going and cut-off date should be used as the last dosing date for interim 
report. 
If date of last administration is completely or partially missing and the EoT CRF page is 
available:

The date of last administration is completely missing and the EoT visit date is complete, 
then this latter date should be used.

Only Year (yyyy) of the dose end date is available and yyyy < the year of EoT date, then 
use Dec31yyyy

Only Year (yyyy) of the dose end date is available and yyyy = the year of EoT date, then 
use EoT date

Both Year (yyyy) and Month (mm) are available for the date of last administration and 
yyyy = year of the EoT date and mm < the month of EoT visit, then use the last day of 
the Month (mm)

After imputation, compare the imputed date with the start date of that specific record, if 
the imputed date is < start of that record, then use the start date of that record.
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations. Therefore, if the date of first administration is missing, then the date of last 
administration should not be imputed.


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11.2.2
For AE and concomitant medication
Partial dates will remain partial in the data listing. For the purpose of analysis, the following 
imputation rules will be used.

If year is completely missing, then no imputation will be performed. 

If year (yyyy) < treatment year 
o
If month (mm) is missing, then use 01Jul of the year (yyyyy).  
o
If month (mm) is known, then use 15th of the month (mm).

If year (yyyy) = treatment year 
o
If month (mm) is missing, then use treatment start date + 1.
o
If month (mm) < treatment month, then use 15th of the month (mm).
o
If month (mm)  >= treatment month, then  use max of (1st of the month (mm), 
treatment start day + 1)

If year (yyyy) > treatment year
o
If month (mm) is missing, then use 1Jan of the year (yyyy).
o
If month (mm) is non-missing, then use max of (1st of the month (mm), 
treatment start day + 1).