Clinical trial NCT01331239
Conditions: Cushings Disease Cushing Disease
Keywords: Cushing Disease osilodrostat LCI699 Pituitary Gland Adrenocorticotropic Hormone
Sponsor: Novartis Pharmaceuticals
Start date: 2011-03-23; Completion date: 2019-10-22
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This exploratory study is a proof of concept study to determine whether LCI699 can safely reduce the level of urinary free cortisol in patients with Cushing's disease.

In addition, this study evaluated the long term efficacy and safety of LCI699 including an additional 12 week of treatment followed by a 12 month long term optional extension.

A second extension provided patients who were clinically benefitting from LCI699 an opportunity to continue to have access to the drug until LCI699 was commercially available and reimbursed or through the availability of a local access program.

Detailed description:
The Primary objective of this study was to assess the effect of 10-week treatment osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing's disease.

The study consisted of a screening period of up to 60 days (to allow an adequate washout period for any medications that modified cortisol levels), a 10-14-day baseline period, a 10-week sequential dose escalation treatment period and a 14-day washout period followed by a Study Completion evaluation approximately 14 days after the last drug administration. Twelve patients were recruited and completed Part l of the study.

Eligible patients were dosed at 2 mg b.i.d for the first two weeks, the dose could then be increased every two weeks as necessary (to doses of 5, 10, 20 and 50 mg b.i.d). If at anytime, the subject's UFC was \< Upper Limit of Normal (ULN), dose escalation was halted and the subject remained on the current, efficacious dose through Week 10, with continued monitoring of UFC responses every 2 weeks to allow continued dose adjustments if necessary. If at any time the subject experienced side effects which were either intolerable or met dose adjustment criteria, the prescribed dose was adjusted.

The primary endpoint (UFC ≤ ULN or ≥50% decrease at Day 70) was achieved by all patients. Subsequently, in order to confirm these observations, protocol was amended (Protocol amendment 4) and new patients were enrolled and investigated for a longer treatment period.

Following Protocol amendment 4, the study design was modified to include patients in Part II of the study for evaluating the long-term efficacy and safety of osilodrostat treatment for 22 weeks. Nineteen patients (15 who were treated in the expansion cohort in Part ll and 4 who participated in Part l) with Cushing's disease were enrolled as part of the Expansion cohort in Part II of the study. The 12 patients who had entered the study in Part I, were allowed to re-enter the study as the Core proof of concept (PoC) Follow-up cohort. At Day 70 ± 2 days (Week 10), all patients (both patients entering for the first time and those reentering the study) entered the 12-week assessment period. At Day 154, patients completed the End of Treatment-Core visit.

On Day 154 (Week 22), patients had the option to enter the 12-month extension phase (long-term extension 1). On Day 490, patients who continued in the study had the option to enter a second long term extension phase (extension-2) at the Investigator's discretion, provided they did not meet any of the study discontinuation criteria.

Arms: arm 1: Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part I of this study. 4 patients in this cohort moved to Part II of the study arm 2: Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Expansion of this study. These patients were all newly enrolled into the phase II part of the study arm 3: Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Follow-up of this study. These patients were patients who transferred from Part I Core phase of the study
Interventions: intervention 1: LCI699
Intervention descriptions: intervention 1: Osilodrostat 1 mg and 5 mg capsules, was prepared by Novartis and supplied to the Investigator. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 6. Osilodrostat was open labeled 1 mg, 5 mg, 10 mg and 20 mg tablets.

Protocol documents:
Prot_000.pdf: 
Translational Sciences/Oncology
LCI699 (osilodrostat)
Clinical Study Protocol CLCI699C2201 / NCT01331239
A proof-of concept, open-label, forced titration,
multi-center study to assess the safety/tolerability and 
efficacy of 10-weeks treatment of LCI699
followed by a 12 - week treatment period in patients with 
Cushing’s disease
Authors:
Document type:
Amended Protocol Version
EUDRACT number:
2010-022403-22
Version number:
09 (Clean)
Development phase:
II
Release date:
03-May-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols...........................................................................8
Glossary of terms.................................................................................................................9
Amendment 9 (03-May-2018)...........................................................................................10
Amendment 8 (11-Jul-2017) .............................................................................................11
Amendment 7 ....................................................................................................................13
Amendment 6 ....................................................................................................................15
Amendment 5 ....................................................................................................................17
Amendment 4 ....................................................................................................................22
Amendment 3 ....................................................................................................................28
Amendment 2 ....................................................................................................................28
Amendment 1 ....................................................................................................................29
Protocol synopsis...............................................................................................................31
Assessment schedules........................................................................................................36
1
Introduction .......................................................................................................................42
1.1
Background............................................................................................................42
1.1.1
Relevant data summary.........................................................................43
1.2
Study purpose ........................................................................................................48
2
Study objectives.................................................................................................................49
2.1
Primary objective(s)...............................................................................................49
2.2
Secondary objective(s)...........................................................................................49
49
3
Investigational plan ...........................................................................................................50
3.1
Study design...........................................................................................................50
3.2
Rationale of study design.......................................................................................53
3.3
Rationale of dose/regimen, duration of treatment .................................................54
3.4
Rationale for choice of comparator .......................................................................55
3.5
Risk/ benefit for this study.....................................................................................55
3.6
Purpose and timing of interim analyses/design adaptations..................................59
4
Population..........................................................................................................................59
4.1
Inclusion criteria ....................................................................................................60
4.2
Exclusion criteria...................................................................................................61


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5
Treatment...........................................................................................................................62
5.1
Investigational treatment .......................................................................................62
5.2
Treatment arms......................................................................................................63
5.3
Treatment assignment............................................................................................63
5.4
Treatment blinding.................................................................................................63
5.5
Treating the patient................................................................................................63
5.5.1
Patient numbering .................................................................................63
5.5.2
Dispensing the study treatment.............................................................64
5.5.3
Supply, storage and tracking of study treatment...................................64
5.5.4
Permitted dose adjustments and interruptions of study treatment ........65
5.5.5
Dose modification and dose delay ........................................................65
5.5.6
Follow up on potential drug-induced liver injury (DILI) cases ............67
5.5.7
Rescue medication ................................................................................68
5.5.8
Concomitant treatment..........................................................................68
5.5.9
Prohibited treatment..............................................................................69
5.5.10
Concomitant medication to be use with caution ...................................70
5.5.11
Discontinuation of study treatment .......................................................70
5.5.12
Withdrawal of Consent .........................................................................71
5.5.13
Lost to follow-up...................................................................................71
5.5.14
Emergency unblinding of treatment assignment...................................71
5.5.15
Study completion and post-study treatment..........................................72
5.5.16
Early study termination.........................................................................72
6
Visit schedule and assessments .........................................................................................72
6.1
Screening ...............................................................................................................73
6.2
Dietary, fluid and other restrictions.......................................................................73
6.3
Patient demographics/other baseline characteristics .............................................73
6.4
Treatment exposure and compliance .....................................................................73
6.5
Efficacy / pharmacodynamic assessments.............................................................74
6.5.1
Mean urinary free cortisol and creatinine .............................................74
6.5.2
Plasma ACTH, plasma cortisol, 11-deoxycortisol and renin................74
6.5.3
Plasma and urine aldosterone and 11-deoxycorticosterone ..................75
6.5.4
Serum and urine sodium and potassium................................................75
6.5.5
Salivary cortisol and aldosterone ..........................................................75
6.5.6
Other pharmacodynamic laboratory evaluations ..................................76
6.6
Safety.....................................................................................................................76
6.6.1
Physical examination ............................................................................76


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6.6.2
Vital signs..............................................................................................76
6.6.3
Height and weight .................................................................................77
6.6.4
Laboratory evaluations..........................................................................77
6.6.5
Electrocardiogram (ECG) .....................................................................78
6.6.6
Pituitary MRI ........................................................................................81
6.6.7
Pregnancy..............................................................................................81
6.6.8
Meal record ...........................................................................................82
6.7
Pharmacokinetics...................................................................................................82
6.7.1
Pharmacokinetics ..................................................................................82
6.7.2
Urine collection and processing............................................................84
6.7.3
Pharmacokinetic analytical method(s)..................................................84
85
85
7
Safety monitoring..............................................................................................................85
7.1
Adverse events.......................................................................................................85
7.2
Serious adverse event reporting.............................................................................87
7.3
Pregnancies............................................................................................................87
8
Data review and database management.............................................................................88
8.1
Site monitoring ......................................................................................................88
8.2
Data collection.......................................................................................................88
8.3
Database management and quality control............................................................89
9
Data analysis......................................................................................................................89
9.1
Analysis sets ..........................................................................................................89
9.2
Demographics and other baseline characteristics..................................................90
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................90
9.4
Analysis of the primary variable(s) .......................................................................90
9.4.1
Variable.................................................................................................91
9.4.2
Statistical model, hypothesis, and method of analysis..........................91
9.4.3
Handling of missing values/censoring/discontinuations.......................91
9.4.4
Supportive analyses...............................................................................91
9.5
Analysis of secondary variables ............................................................................92
9.5.1
Pharmacodynamics ...............................................................................92
9.5.2
Escape analysis......................................................................................92
9.5.3
Safety.....................................................................................................93
9.5.4
Health-related quality of life.................................................................93


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9.5.5
Pharmacokinetics ..................................................................................93
94
9.5.7
Other biomarkers...................................................................................94
9.5.8
PK/PD ...................................................................................................94
9.6
Sample size calculation..........................................................................................94
9.7
Power for analysis of key secondary variables......................................................95
9.8
Interim analyses.....................................................................................................95
10 Ethical considerations........................................................................................................95
10.1
Regulatory and ethical compliance........................................................................95
10.2
Informed consent procedures.................................................................................96
10.3
Responsibilities of the investigator and IRB/IEC..................................................96
10.4
Publication of study protocol and results...............................................................97
11 Protocol adherence ............................................................................................................97
11.1
Protocol Amendments ...........................................................................................97
12 References (available upon request)..................................................................................98
13 Appendices ........................................................................................................................99
13.1
Appendix 1: Sample Log table - all matrices ........................................................99
13.2
Appendix 2: Sample labeling and shipping information.....................................106
13.3
Appendix 3: Possible drug-drug interactions with LCI699.................................107
13.4
Appendix 4: Determination of body mass index (weight[kg] / height[m]2)........109
13.5
Appendix 5: Summary of Common Toxicity Criteria for Adverse Events v4.0 
(CTCAE)..............................................................................................................113
13.6
Appendix 6: Medications with a “known risk to cause TdP” and with a 
“possible risk to cause TdP”................................................................................114
13.7
Appendix 7: List of drugs to be used with caution with LCI699 ........................115


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List of tables
Table 1-1
Safety multiples for 50 mg bid and 30 mg bid dose based on 
toxicology studies..................................................................................45
Table 3-1
NOAEL determining toxicology...........................................................55
Table 3-2
Safety multiple for 50 mg bid dose based on reprotoxicity studies ......58
Table 5-1
Criteria for interruption and re-initiation of LCI699 for abnormal 
liver function.........................................................................................66
Table 6-1
Non-compartmental pharmacokinetic parameters for LCI699 .............82
Table 6-2
PK blood sampling for LCI699.............................................................83
Table 9-1
Precision level (95% confidence interval for each response rate) in 
the study ................................................................................................95
Table 13-1
List of strong CYP3A4/5 and CYP2D6 inhibitors and inducers ........115
List of figures
Figure 1-1
Effects of LCI699 on ACTH-stimulated cortisol and aldosterone 
synthesis in rats .....................................................................................44
Figure 3-1
Study design..........................................................................................53
Figure 6-1
Sequence of cardiovascular data collection ..........................................79
Figure 6-2
QT Prolongation Monitoring Flow Chart .............................................81


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List of abbreviations
ACTH
Adrenocorticotropic Hormone
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
b.i.d.
twice a day
CD
Cushing’s disease
(e)CRF
(electronic) Case Report/Record Form
CNS
Central Nervous System
CPO
Country Pharma Organization
CRH
Corticotropin Releasing Hormone
CRO
Contract Research Organization
CS
Cushing’s syndrome
CYP
Cytochrome P450
DILI
Drug-induced liver injury
CMO&PS
Chief Medical Office and Patient Safety
ECG
Electrocardiogram
EDC
Electronic Data Capture
FPG
Fasting Plasma Glucose
HbA1c
Glycosylated Hemoglobin
HOMA
Homeostasis Model of Assessment
HPA(-Axis)
Hypothalamic Pituitary Adrenal
IC50
Half Maximal Inhibitory Concentration
ICH
International Conference on Harmonization 
IEC
Independent Ethics Committee
i.v.
intravenous
IRB
Institutional Review Board
LDH
Lactate dehydrogenase
LFT
Liver function test
LLN
Lower limit of normal
MDRD
Modification of Diet in Renal Disease
MEN-1
Multiple Endocrine Neoplasia Type 1
MRI
Magnetic Resonance Imaging
NOAEL
No Observable Adverse Effect Level
p.o.
oral
q.d.
once a day
SAE
serious adverse event
TdP
Torsades de Pointes
TBIL
Total Bilirubin
UFC
Urinary Free Cortisol
ULN
Upper Limit of Normal


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Pharmacokinetic definitions and symbols
AUC0-6hr,ss
AUC at steady state 0-6hr post dose (ng.hr/mL)
AUC0-12hr,ss
The AUC from time zero to 12 hours post dose at steady state, calculated by using the pre-
dose concentration (Ctrough,ss) as the 12 hr concentration, assuming steady-state has 
been reached (hr*ng/mL).
Cmax,ss
Maximum plasma drug concentration at steady state (ng/mL)
Tmax,ss
Time to reach maximum plasma drug concentration at steady-state (hr)
T1/2,ss (HL)
Elimination half-life associated with the terminal slope of a semi logarithmic concentration-
time curve at steady-state (hr)
Ctrough, ss
Steady-state plasma concentration at the pre-dose time for b.i.d. dosing (ng/mL)


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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study subject or study patient
Control drug
A study drug used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate comparative effects of 
the investigational drug.
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol).
Investigational drug
The study drug whose properties are being tested in the study; this definition is consistent 
with US CFR 21 Section 312.3 and is synonymous with “investigational new drug.”
Medication number
A unique identifier on the label of each study drug package in studies that dispense study 
drug using an IVR system.
Subject number
A number assigned to each patient who enrolls in the study. When combined with the 
center number, a unique identifier is created for each patient in the study.
Period
A minor subdivision of the study timeline; divides phases into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial. This data includes subject identifier information, 
study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized patient, corresponding to a specific 
treatment arm assignment.
Stage
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc.
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit or when study drug was 
discontinued whichever is later.
Study drug
Any drug administered to the patient as part of the required study procedures; includes 
investigational drug and any control drugs.
Study drug 
discontinuation
Point/time when patient permanently stops taking study drug for any reason; 
Subject
An individual who has consented to participate in this study. The term Subject may be used 
to describe either a healthy volunteer or a patient.
Variable
Information used in the data analysis; derived directly or indirectly from data collected using 
specified assessments at specified timepoints.
Withdrawal of 
Consent
Withdrawal of consent occurs only when a patient does not want to participate in the study 
any longer, and does not want any further visits or assessments, and does not want any 
further study related contact


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Amendment 9 (03-May-2018)
Amendment Rationale
Of the 19 patients initially enrolled under Amendment 4, 10 patients are still ongoing as of 
03 May 2018.
The purpose of this amendment is to extend the study end date from 31 December 2018 to 31 
December 2019 to allow continued access to the study drug for those patients benefitting from 
the treatment until a separate long-term safety follow-up study (roll-over study) is set up at 
participating sites. 
Additional updates were made to the Protocol glossary and withdrawal of informed consent 
section to align with the new Personal Data and Withdrawal of Consent language requirement.
Due to the extension of the study duration, this amendment is classified as substantial. 
Changes to the protocol and the ICF

Protocol synopsis and Sections 3.1, 5.5.15, and 6: Long Term Extension-2 end day 
changed from 31 December 2018 to 31 December 2019 

Glossary: Updated Personal Data and Withdrawal of Consent language 

Section 5.5.12 Updated Withdrawal of Consent language

Updates to the ICF include updating the study end date from 31 December 2018 to 31 
December 2019 throughout the document and the implementation of General Data 
Protection Regulation (“GDPR”) language for sites in the European Union.
IRB/IEC
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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Amendment 8 (11-Jul-2017)
Amendment Rationale
Of the 19 patients initially enrolled under Amendment 4, 11 patients are still ongoing in the 
trial as of 14 June 2017.
The main purpose of this amendment is to provide continued access to the study drug for 
those patients benefitting from the treatment into a separate long-term safety follow-up study 
(roll-over study) is set up at participating sites. Based on this, the end of study definition has 
been updated.
This protocol amendment introduces the following changes:
1. The End of study (EOS) definition was changed throughout the protocol from “until 
LCI699 is commercially available and reimbursed or through the availability of a local 
access program” to “patient treatment in Long Term Extension-2 will end at each site 
within 4 months after a separate roll-over study is opened at their site, or by 31 December 
2018 (whichever occurs earlier). The roll-over study will provide an opportunity of 
continued treatment for patients who are still ongoing at that time and who are clinically 
benefitting from LCI699. For sites where a separate roll-over study is not an option, the 
patient may be offered a local alternative treatment option. In addition, the option of an 
earlier End of Trial (EOT) visit (i.e. earlier than the 6 month interval visits in Long Term 
Extension-2) has been implemented to allow seamless transition of patients into the 
separate rollover study.
2. 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 LCI699 (Section 3.5).
3. In view of the results of the thorough QT study CLCI699C2105, which showed that the 
increase in QTcF caused by LCI699 at therapeutic doses is below the threshold of 
regulatory concern, the QT-specific concomitant medication guidance for LCI699 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®).
4. Section 9.8 (Interim Analysis) was updated to allow for an additional database lock in 
support of future market authorization applications for LCI699.
Due to the updated EOS definition, this amendment is classified as substantial. Updates to the 
ICF include addition of EOS definition, information on possible continuation into roll over 
protocol and updated Novartis wording on data use and protection.
Changes to the protocol

Protocol Synopsis: Clarification of end of patient study participation.

Assessment Schedule: New Footnote #6 and #7 under “Long Term Extension-2”


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
Section 3.1 Optional Long Term Extension-2: clarification of end of patient participation, 
option of entry into roll over protocol and EOT/EOS visit completion.

Section 3.5 Risk/benefit for this study: Update to effects on QTc interval, based on 
information from LCI699C2105 thorough QT study. Added reference to LCI699 
Investigator brochure, for up to date information.

Section 3.5 Risk/benefit for this study: Update to effects on adrenal hormones.

Section 5.5.15 Study completion and post-study treatment: clarification for patient’s 
completing LCI699C2201 study or entering roll-over protocol. Added clarification of 
EOT/EOS visit completion.

Section 9.8 Interim Analysis: updated to allow for an additional database lock in support 
of future market authorization applications for LCI699.

Appendix 6: Removal of table listing medications with a known risk of QTcF 
prolongation. Provision of e-link to list of drugs to provide access to most up to date 
information.
IRB/IEC
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 7
Of the 19 patients initially enrolled under protocol Amendment 4, 12 patients are still ongoing 
in the trial under the open-ended long term extension as of 30 November 2015.
This protocol amendment introduces the following changes:

The primary purpose of this protocol amendment is to ensure 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 LCI699 to date, these criteria are added in the event that a case of 
suspected DILI arises in the future.

Update to the requirement for contraception by male study participants. For male subjects 
participating in clinical trials, contraception is not required. The rationale is that the safety 
margin for causing embryo-fetal toxicity and teratogenicity through seminal fluid transfer 
is > 100-fold. Based on the FDA guidance for Industry (2011), if the compound is 
teratogenic and/or embryolethal and the safety margin is >25, then male condom use is not 
required. Given the fact that at the proposed clinical doses of LCI699, there is a sufficient 
safety margin in causing reproductive, embryofetal, and teratogenic effects via seminal 
transfer of LCI699 to the potential female partner, male patient contraception is no longer 
required.

Clarification of protocol language regarding withdrawal of consent, study drug 
discontinuation, and discontinuation procedures
In addition, minor editorial changes were applied in the List of Abbreviations.
Changes to the protocol

List of Abbreviations: Revised to include new terminology introduced in Amendment 7

Assessment Schedule: Correction to Footnote #2 under “Extension Study” and to Footnote 
X under “Long Term Extension-2”

Section 3.5 Risk/benefit for this study: Reference to males was deleted from the “Effects 
of sex hormones” section

Section 5.5.5: Added section on Dose modification and dose delay

Section 5.5.6: Added section “Follow up on potential drug-induced liver injury (DILI) 
cases

Section 5.5.9 Prohibited Treatment: Removed “premature” to clarify study discontinuation

Section 5.5.11 Discontinuation of study treatment: Updated language to define withdrawal 
of consent and clarify process of discontinuation

Section 5.5.12 Withdrawal of Consent: Added section to clarify Withdrawal of Consent 
procedures

Section 5.5.13 Lost to Follow-Up: Updated template language regarding patients lost to 
follow-up


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
Section 5.5.14 Early Study Termination: Updated template language for clarification

Section 6: Removed “premature” to clarify study discontinuation
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.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Boards (IRBs), 
Independent Ethics Committees (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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Amendment 6
As of 01 March 2014, 19 patients have been enrolled under protocol Amendment 4 of the 
protocol. A total of 17 patients completed the 22 week core phase of the study and 2 patients 
were discontinued. Of the 17 patients who completed the core phase, 16 patients are enrolled 
in the optional long term extension-1 of the study.
Amendment Rationale
The purpose of this protocol amendment is to continue the study to monitor patients for long-
term safety and efficacy, and to provide continued access to LCI699 to patients who have 
completed long term extension-1. As there are only 16 patients currently participating in 
extension-1, and the clinical development program of LCI699 is still in its early stage, it is 
important to continue to collect long-term safety and efficacy data over a longer period of 
time. In addition, considering that currently available alternative treatment options have 
limitations to their efficacy and safety profiles, this additional extension (extension-2) will 
provide patients who are clinically benefitting from LCI699 an opportunity to continue to 
have access to the drug until LCI699 is commercially available and reimbursed or through the 
availability of a local access program.
At day 490, the end of long term extension-1, patients will be evaluated by their investigator 
for clinical benefit. Provided that the investigator’s assessment is that the patient would 
benefit from continued treatment with LCI699, and does not meet the protocol’s termination 
criteria, the patient will have the option to enter a second long term extension period 
(extension-2), which will continue until LCI699 is commercially available and reimbursed or 
through the availability of a local access program.
In addition, the protocol has been updated to indicate that the formulation of LCI699 will be 
changed from capsules to tablets during long term extension-2. The reason for this change is 
that the tablet formulation will be used in the pivotal Phase III studies of LCI699 and other 
clinical trials for the treatment of patients with Cushing’s disease. LCI699 is considered a 
BCS class I compound, characterized by its high solubility, high permeability and extensive 
absorption. For these compounds, as long as the dosage forms have rapid and similar in vitro 
dissolution profiles, the rate and extent of drug absorption are not expected to be different. 
Therefore, the two LCI699 formulations (capsule and tablet) are expected to have similar 
pharmacokinetic properties. Comparative in vitro dissolution data will be included in the 
quality information for the tablets, and no patient will be allowed to switch to the tablet 
formulation until any necessary approvals are received.
Changes to the protocol
Protocol synopsis: Edited to be consistent with changes throughout the protocol.
Assessment Schedules: Revised to include the additional visits for long term extension-2.
Section 3.1 Study Design: A description of the optional long term extension-2 was added
Figure 3-1: Revised to include the second optional long term extension (extension-2)


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Sections 3-2, 3-3 and 3-5: Revised to include the second optional long term extension 
(extension-2)
Section 5-1: Revised to add the 1, 5, 10 and 20 mg tablets
Section 6.5.1: Revised to include the second optional long term extension (extension-2)
Section 6.5.5: Salivary cortisol and aldosterone: Additional assessment days added during 
long term extension-2.
6.6.5: Revised to add long –term extension-2
Appendix 1: Revised to be consistent with the long term extension -2 assessments
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.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Boards (IRBs), 
Independent Ethics Committees (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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Amendment 5
As of 01 Apr 2013, 12 patients have been enrolled under protocol Amendment 4 of the 
protocol and 7 have started treatment. Six patients are still under treatment, 3 patients are 
under screening, 2 are screen failed and 1 patient has withdrawn due to adverse event.
Amendment rationale
Cardiac safety
1.
ECG Monitoring
With this amendment, ECG monitoring will be intensified during the study. The reason for 
this change is to further enhance patient safety and collect additional safety information 
because new pre-clinical and preliminary clinical results indicate a potential risk of QTc 
prolongation in humans. Of note, there have been no QT-related Adverse Events (AEs)
reported in the clinical development program of LCI699 to date, in which a total of 659 
subjects have been exposed to the drug, and with exposures as single doses of 200 mg, and 
repeated doses as 50 mg bid.
Preclinical Data
New results from a monkey telemetry study show QTc prolongation, conduction 
abnormalities, and cardiac arrhythmias at very high exposures to LCI699. In this study, a total 
of 6 monkeys (3 males and 3 females) sequentially received single oral doses of LCI699 of 
10mg/kg, 30mg/kg, and 100mg/kg, while ECG was continuously monitored for a total of 24
hours post-dose.
No ECG abnormalities were observed after the 10mg/kg dose. However, QTc prolongation 
was observed in 2 male and 1 female animals at an LCI699 dose of 30mg/kg. The lowest 
plasma free-drug concentration (Cmax) that resulted in QTc prolongation was 13.1 µM, which 
is approximately 16-times the free-drug steady-state Cmax (0.81 µM) estimated in healthy 
volunteers at the currently proposed maximum clinical dose of 30 mg bid. Conduction 
abnormalities, including aberrant ventricular conduction were observed in 1 male animal at 
100mg/kg (Cmax 91.1µM, or 112-times the human exposure at the 30 mg dose). PVCs, non-
sustained ventricular tachycardia, and a brief, reversible episode of Torsade de Pointe (TdP)
were observed in another individual male animal at 100mg/kg (Cmax 176.4 µM, or 217-times 
the human exposure at the 30 mg dose).
The new results are consistent with prior pre-clinical cardiac safety data. An in vitro hERG
assay showed evidence of inhibition with IC25=18.9 µM, and IC50=54µM. In vitro isolated 
rabbit heart had an APD60 prolongation at ≥ 1μM, and proarrhythmic indices indicative of a 
torsadogenic potential at 10 µM.
In vivo cardiovascular safety in dogs showed no QTc change at single or repeat oral doses up 
to 10mg/kg. However, in a 2-week intravenous LCI699 infusion in dogs at 50mg/kg/day, 
there was a variable increase in the QRS complex and QTc interval (17% in males, 22% in 


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females). At 50 mg/kg, the Css was 12.4 µM free-drug, or approximately 15 times the Cmax 
of 0.81 µM after 30 mg oral dosing in healthy human volunteers.
Preliminary Clinical Data
The new findings in the monkey telemetry study prompted a careful review of all prior ECG 
data in the LCI699 program. There have been no QTc-related AEs reported in the clinical 
development program of LCI699 to date, in which a total of 659 subjects have been exposed 
to the drug. This includes the 12 patients with Cushing’s disease that received LCI699 at the 
10-week interim analysis of the current study [LCI699C2201]. Although the current study 
[LCI699C2201] was not designed to control adequately for changes in the QT interval, locally 
read 12-lead ECGs were performed at baseline and the end of study (EOS) visit. In the 10-
week interim analysis, the mean (± SD) for QTcB at screening was 388.60 ± 62.803 msec, 
and at the end of study (2 weeks after the last dose of LCI699 was administered) was 412.31 ± 
28.861 msec. No conclusion can be drawn from these data because of the high variability of 
results, the absence of correlation with LCI699 plasma concentration, and the potential for 
several concomitant risk factors for QT prolongation.
Preliminary results from an exploratory post-hoc analysis of data from the Phase I study 
[LCI699A2101] in healthy volunteers showed evidence of significant QTcF prolongation (> 
30ms in some patients) after single doses of 100mg and 200mg, particularly at 2 hours and 4 
hours post-dose. However, no QTcF prolongation was observed after a single 30mg dose.
These results should be interpreted with caution, because study [LCI699A2101] was not 
designed to control adequately for changes in the QTcF interval. Nonetheless, it appears that 
LCI699 does cause QTcF prolongation in humans at least at doses of 100 mg or higher.
Intensive Cardiac Monitoring
Based on the preclinical cardiac safety data, and preliminary clinical data -on QT prolongation 
from study [LCI699A2101] and [LCI699C2201]-, it is necessary to assess the risk of QT 
prolongation in patients with Cushing’s disease. Therefore patients in the present study will 
have intensive ECG monitoring to collect additional important safety data and to further 
enhance patient safety in the clinical trial setting. In addition, a “thorough QT” (TQT) study 
[LCI699C2105], designed according to the ICH E14 and FDA Guidance (2005), is planned in 
healthy volunteers. As mentioned above, no QTc-related adverse events have been reported in 
clinical trials of LCI699 to date.
Intensive cardiac monitoring will include standard 12-lead Safety ECGs and 24-hour 
continuous 12-lead Holter recordings, as described in Section 6.6.5:

Safety ECGs will be the primary method of monitoring cardiac safety, and will be 
performed at each study visit day that LCI699 is administered, as described in section 
6.6.5. The safety ECGs are timed to coincide with the Cmax for LCI699 (1.5 hours post-
dose), and enable a real-time assessment of QTc at the time the risk of QTcF prolongation 
is highest. Safety ECGs are to be read by a qualified physician (e.g., the investigator or 
another qualified physician, such as a consulting cardiologist) immediately to screen for
significant abnormalities. A safety algorithm is initiated for any instance that the QTc is > 
500ms.


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
24-hour Holter recordings will be performed on 5 days during the study. The data are 
electronically submitted to a central lab for subsequent analysis. The Holter recordings are 
NOT intended for real-time feedback of the cardiac rhythm, but instead are for the 
collection of large amounts of ECG data. When the Holter is performed on the same day 
that PK profiling is also performed, the PK data will be correlated to the ECG data to 
evaluate the drug exposure-QTc effect relationship.
2.
Concomitant medications that increase QTc
This protocol amendment also provides a list of drugs (see Appendix 6) that are known to 
cause QT prolongation. With the exception of temporary interruption of study drug therapy 
because of a short-term need to use a QT-prolonging drug (e.g., certain antibiotics), these 
drugs are prohibited as concomitant medications in this study, because there is a potential risk 
of additive QT prolongation with LCI699.
3
Reduction of maximum LCI699 study dose
Another change to enhance patient safety is to remove the highest dosing regimen (50 mg bid) 
from the dose titration schedule, and add a dose of 30 mg bid for those patients who do not 
have normalization of UFC at 20 mg bid. The rationale for this change is that the results of the 
exploratory post hoc analysis of QTcF in relation to LCI699 dose from the phase I study 
[LCI699A2101] found no evidence of a QTcF prolongation effect after a single 30 mg dose, 
but did find substantial QTcF changes (some patients with QTcF prolongation > 30 ms) at 
single doses of 100 mg and 200 mg. Since it is not yet clear at which dose or plasma 
concentration of LCI699 the threshold for a QT prolongation effect is, the 50 mg bid dose was 
removed as a precaution.
If at the time this protocol Amendment 5 is implemented, any patients are already treated by
the 50 mg bid dose, the dose must be reduced to the new maximum dose of 30 mg bid.
Inclusion and Exclusion Criteria
Radiation therapy
Pituitary irradiation can be used as second-line therapy when trans-sphenoidal surgery has 
failed to control hypercortisolism. Either conventional pituitary radiation or radiosurgery 
(gamma-knife therapy) are often effective in this clinical situation. Pituitary irradiation results 
in slowly declining ACTH secretion by corticotroph adenomas. Based on published data by 
Estrada et al (1997); Minniti et al (2007); and Losa et al (2010), the time course to 
normalization of UFC is often within 2-5 years after post-irradiation in about 80% of cases 
(Estrada et al 1997; Minniti et al 2007; and Losa et al 2010). Some, but relatively few patients 
respond more than 5 years post-irradiation, and this can be observed up to 10 years post 
irradiation (Losa et al 2010). In one study (Minniti et al 2007; N=40 patients), normalization 
of plasma cortisol was seen in 28% of patients at 1 year, 78% at 5 years and 84% at 10 years. 
Pituitary irradiation often results in permanent hypopituitarism in about 20-40% of patients 
post-radiation.


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Since the effect of radiation has the potential to contribute to the decline and control of the 24-
hour urine-free cortisol (UFC), at the same time that the evaluation of this effect by the study 
drug LCI699 is being assessed, radiation could be a confounding factor in interpreting the 
primary analysis of the study. Consequently, patients with a history of pituitary irradiation 
within 5 years prior to study entry are excluded.
Modified definition of escape
One of the secondary objectives is to assess escape (Section 2.2). The definition of escape has 
been modified to include its relation to the highest tolerated dose of LCI699. The concept of 
escape refers to loss of control of UFC after having attained normalization of UFC on LCI699 
therapy at an earlier time point. In this study, it is permitted to increase the dose of LCI699 
not only during the dose titration phase (weeks 1-10), but also during the treatment period 
(weeks 11-22) of the core study, and during the extension study if applicable. This is intended 
to mimic clinical practice. The additional requirement to have uncontrolled UFC at the highest 
tolerated dose of LCI699 is also intended to reflect anticipated clinical use of the drug. The 
highest tolerated dose is the highest dose without a drug-suspected adverse event (AE), up to 
the maximum LCI699 dose of 30mg bid.
The requirement of uncontrolled UFC on two consecutive visits is intended to ensure that the 
elevated UFC is not due to lab error or variations just above the upper limit of the normal 
reference range. Escape events will be described by a Kaplan-Meier analysis of “time to 
escape,” i.e., the time (in weeks) from the first normalization of UFC to the first of two 
consecutive uncontrolled UFC levels (Section 9.5.2).
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 changes throughout the protocol.
Assessment Schedules: Table has been updated to reflect the intensive cardiac monitoring 
(ECG and Holter) and the additional interim visits when dose escalation should occur if 
needed.
Section 1.1.1.1 (Table 1-1): Safety margin multiples for the 30 mg bid dose have been added 
to Table 1-1.
Section 1.1.1.4: This section has been updated to include estimation of PK exposure at 30 mg 
bid, and added background on emerging preclinical data regarding LCI699 metabolism.
Section 2.2: Secondary objective on escape, and the definition of escape, were modified.
Section 3.1: Addition of the interim dose escalation visits and update of Figure 3-1 to reflect 
new design with interim visits. Section updated (including Figure 3-1) to reflect the change of 
the maximum dose strength of 30 mg.
Section 3.5: Risk/benefit section updated including effect on QTc interval, minor editorial 
changes and providing clarification regarding effects of sex hormones.


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Section 4.1: Inclusion criteria for confirmation of pituitary origin of excess ACTH has been 
modified with respect to Inferior Petrosal Sinus Sampling (IPSS).
Section 4.2: Exclusion criteria were added (pituitary irradiation and risk factors for QTc 
prolongation or Torsade de Pointes).
Section 5.5.7: Addition of a list of prohibited treatments related to potential risk of QTc 
prolongation.
Section 5.5.8: Based on emerging preclinical data, CYP3A4/5 and CYP2D6 may be involved 
in the metabolism of LCI699. As such, a list of comedications to be used with caution with 
LCI699 due to potential risk of drug-drug interactions is added.
Section 5.5.9: Addition of discontinuation criteria.
Section 6: Clarification on sequence of assessments and addition of visit window.
Section 6.5: Missing assessments were added to list.
Section 6.6.5: Section has been updated to reflect the details of intensive cardiac monitoring 
(12-lead Safety ECG and 24-hour Holter recording) as well as to include the QT prolongation 
algorithm.
Section 6.7.1.1: A few PK collection times referenced in this section and in Table 6-2 were 
incorrect. These have now been corrected.
Section 9.5.2: Missing escape analysis has been added to analysis of secondary variables.
Section 9.5.8: QTcF has been added to PK/PD correlation analysis.
Appendix 1: Time for visit 2 sample log has been extended to baseline period (day-14 to day0) 
in order to have all results available to check inclusion/exclusion criteria before day1.
Appendix 6: Appendix 6 was added to list drugs with a known risk of causing QT 
prolongation.
Appendix 7: Appendix 7 was added to list drugs that are strong CYP3A4/5 and CYP2D6 
inhibitors and inducers, to be used with caution as concomitant medications with LCI699
IRB/IEC
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, the changes herein affect the Informed Consent and 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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Amendment 4
Amendment rationale
As of 10 Feb 2012, 12 patients have been enrolled in the study and 11 have completed the 
core period of 10 weeks. One patient is ongoing and is scheduled to complete the 10 weeks in 
March 2012.
Preliminary data as of Dec 2011 from the present study in 11 out of the 12 subjects with 
Cushing’s disease were evaluated. Of these, 9 had completed and 2 were still ongoing. 
LCI699 normalized UFC on at least 1 assessment in 11 out of 11 subjects during the study 
(baseline UFC range of 1.6-17.0xULN). The primary endpoint was achieved by all 9 subjects 
who had completed the active treatment phase (10 weeks), 8 of whom had normal UFC levels 
on day 70. A mean increase in plasma ACTH (2-3 fold) was observed from baseline to 
week10.
The dose at which patients achieved normalization of UFC varied; Overall, all 11 patients had 
at least one UFC <ULN in recorded visits. One patient had normal UFC with a dose of 2 mg 
bid, 3 patients had normal UFC with a dose of 5 mg bid, 3 patients had normal UFC with a 
dose of 10 mg bid, one patient had normal UFC with a dose of 15 mg bid, two patients had 
normal UFC with a dose of 20 mg bid and one patient had a normal UFC with a dose of 50 
mg bid.
LCI699 was generally well tolerated. There were no discontinuations due to adverse events or 
serious AEs of suspected drug relationship reported. Eleven patients reported at least one AE. 
Additional information from the data cut is presented in Section 1.1.1.3.
The purpose of this protocol amendment is to confirm the preliminary observations from this 
proof of concept (PoC) study by enrolling a new cohort (Expansion cohort) of patients and 
evaluating the long-term efficacy and safety of LCI699 treatment for a total duration of 22 
weeks. This longer treatment period will help address questions on the sustainability of the 
cortisol reductions and longer term safety (e.g. potential on ACTH levels and off-target 
effects on the mineralocorticoid and androgen pathways). At the end of the 22 weeks, patients 
will have the option to enter into the long term extension for duration up to 12 months.
With this amendment, approximately 15 new patients (not previously enrolled) with 
Cushing’s disease will be enrolled as the “Expansion Cohort”. Patients who previously 
completed the trial prior to Amendment 4 and benefited from the treatment with LCI699 will 
also be allowed to re-enter the study as the “Core PoC Follow-up Cohort”. These patients will 
start the study over again at screening and follow through the visit schedule the same as new 
patients. Core PoC Follow-up patients can reenter if their UFC is > ULN and all other 
eligibility criteria have been met.
Rationales for changes in this amendment are presented below:
Sample size
To confirm the preliminary observations, additional patients will be enrolled. In view of the 
rarity of Cushing’s disease 15 additional patients was chosen based on practical 


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considerations. The 12 patients who participated in the trial prior to Amendment 4 are also 
allowed to restart the study at screening and will be in addition to the 15 new patients.
Treatment duration
The original protocol limited treatment duration of 10 weeks. In order to better understand the 
long-term efficacy and safety profile of LCI699 the total treatment duration with LCI699 will 
be extended to 22 weeks.
PK blood sampling
Current multiple dose PK data of LCI699 are limited to healthy volunteers who received 
significantly lower doses (3 mg qd and 1 mg bid) than doses being used in Cushing’s disease 
in the core PoC study (2, 5, 10, 20 and 50mg bid). In addition, PK sampling in Cushing’s 
disease patients prior to Amendment 4 was limited to trough samples only. Therefore, further 
PK sampling (0 to 6 hrs post-dose) is needed to determine steady state PK parameters such as 
Cmax, Tmax, AUC0-6hr, AUC0-12hr (utilize Ctrough at steady state as concentration at 12hr 
post dose), T1/2 and Ctrough at doses that are more relevant in the target population (i.e., 2-
50mg bid), particularly in view of over-proportionality findings in healthy volunteers. In 
addition, PK/PD analysis based on those PK parameters will be better than using trough 
concentrations to define the dose/exposure and exposure/efficacy relationship, and eventually 
to facilitate the design of future registration trial as well as to build a population PK/PD model 
of LCI699 in Cushing’s disease patients. Therefore, the 6-hr PK blood sampling will be added 
during the initial 10-week dose titration phase to characterize the steady-state
pharmacokinetics of LCI699 at each dose level in Cushing’s disease patients.
LCI699 starting dose
Preliminary results from this study showed that the median dose of LCI699 associated with 
UFC normalization was between 5 and 10mg bid. In view of the need to obtain more rapid 
control in patients with severe hypercortisolism, patients with baseline mUFC > 3xULN will 
not undergo the initial 2 week treatment with LCI699 2 mg bid, and will instead be started on 
the 5 mg bid dose.
Study assessments
Additional study assessments and changes include the use of a central lab, Pituitary MRI, and 
plasma lipid profile. Further, home BP monitoring and salivary assessments have been 
modified.
Central lab

Use of a central laboratory is deemed necessary to standardize key assessments related to 
LCI699 action across the study sites and will be done for the following analytes: UFC, 
plasma cortisol, plasma ACTH, salivary cortisol and aldosterone, 11-deoxycortisol, 
plasma and urine deoxycorticosterone, plasma and urine aldosterone, plasma renin, PK, 
testosterone and estradiol, LH, FSH, IGF-1. Local labs can be used throughout the study 
for dose titrations and/or if a faster turnaround time is needed for safety reasons.


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Pituitary MRI

Pituitary MRIs are added to assess potential corticotroph tumor progression in patients 
with Cushing’s disease as a result of cortisol synthesis inhibition/adrenal blockade with 
LCI699 monotherapy. MRIs will be performed at screening/baseline and at week 22. 
MRI’s will be read locally. Digital images are to be kept at the site in the event Novartis 
requests transfer of the files at a later date. Details on images and acquisition can be found 
in the Study Imaging Manual.
BP and Salivary assessments

Daily home BP monitoring is no longer deemed necessary based on the initial PoC results 
and is being removed to reduce undue burden on patients.

In addition, the twice daily determinations of salivary cortisol and aldosterone are not 
deemed necessary and therefore the frequency has been reduced to weekly.
Lipid Assessments

Due to the potential androgenic effect of LCI699 (and atherogenic lipid changes), a full 
lipid profile has been added to each visit and will include TC, TG, HDL-cholesterol and 
LDL-cholesterol.
Optional study extension

Considering that no approved medical therapy exists and alternative treatment options are 
limited due to lack of response and/or side effects, the extension provides these patients, 
responding to LCI699, an opportunity to continue treatment while generating long term 
safety and efficacy data.

At the end of week 22, patients will be evaluated for clinical benefit and have the option to 
enter the 12 month long term extension phase at the investigators discretion provided they 
do not meet discontinuation criteria.
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. The 
changes being made to the protocol due to this amendment are incorporated in the following 
sections:

Throughout the protocol, the term subject has been updated to the term patient for 
consistency. The term subject was left only if discussing a healthy volunteer.

Title Page: The title has been updated to show the longer treatment period.

List of abbreviations, Pharmacokinetic definitions and symbols, and Glossary of terms: 
these tables have been updated based on changes throughout the protocol.

Amendment 4 section: Added to describe changes introduced with amendment 4

Protocol Synopsis: edited to be consistent with changes throughout the protocol.

Assessment Schedules: A new assessment schedule has been created to avoid confusion. 
The additional visits and the 12 month extension have been added as well as the PK and 
MRI.


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
Section 1.1: editorial changes made as well as addition of preliminary data from this study.

Section 1.1.1.1: editorial changes made.

Section 1.1.1.3: addition of preliminary data from this study.

Section 1.1.1.5: addition of preliminary data from this study.

Section 1.2: study purpose updated to include addition of new cohorts and 12 month 
extension.

Section 2.2: secondary objectives added for the new cohorts.

Section 3.1: the study design was updated with instructions for the 2 different cohorts and 
for the additional visits.

Figure 3-1: updated for the new design and additional visits.

Section 3.2: Rationale added for the additional 12-week treatment period and for the 12-
month extension.

Section 3.3: Rationale added for the additional 12-week treatment period, the 12-month 
extension and the 5mg starting dose in severe patients.

Section 3.5: The potential benefits and risks sections have been updated with preliminary 
data from this study.

Section 3.6: the interim analysis plans have been updated.

Section 4: this section has been updated to include information on the 2 new cohorts.

Section 4.1: The inclusion criteria 3 was updated to include criteria for patients in the core 
PoC follow-up criteria, criteria 4 was added to include patients with de novo only when 
non candidates for surgery and mifepristone was added as a washout medication to criteria 
5.

Section 4.2: Exclusion criteria 5 and 6 for the pregnancy guidelines have been updated 
based on standard practice at Novartis. Criteria 11 has been updated to include specific 
information for excluding pseudo-Cushing’s syndrome.

Section 5.2: The starting dose has been updated to include 5 mg for severe patients.

Section 5.5.1: Addition of the Patient number for the 2 new cohorts.

Section 5.5.5: sentence deleted stating rescue medication recording process as there is no 
rescue medication.

Section 5.5.6: language clarified for capture of concomitant medications starting at signing 
of informed consent.

Section 5.5.9: removed the symptomatic hypotension criteria and added hypokalemia 
criteria.

Section 5.5.11: removed sentence referring to treatment continuation in a separate protocol.

Section 6: statement added for visit times to be consistent, added end of treatment visit 
and end of study visit.

Section 6.1: added procedures for screening visit.

Section 6.2: added fasting information and PK-profile meal timing.

Section 6.5: added parameters assessed by the central laboratory.


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
Section 6.5.1: mean Urinary free cortisol assessment timing changed and reference to the 
assessment schedule added.

Section 6.5.1.1: Central laboratory added.

Section 6.5.1.2: Central laboratory added.

Section 6.5.2: reference to the assessment schedule added.

Section 6.5.3: reference to the assessment schedule added.

Section 6.5.4: reference to the assessment schedule added.

Section 6.5.5: timing of the salivary samples updated and reference to the assessment 
schedule added.

Section 6.5.6: reference to the assessment schedule added.

Section 6.6.1: reference to the assessment schedule added.

Section 6.6.2: reference to the assessment schedule added and the home blood pressure 
monitoring removed.

Section 6.6.3: reference to the assessment schedule added.

Section 6.6.4.2: lipid parameters added.

Section 6.6.5: reference to the assessment schedule added.

Section 6.6.6: added section to discuss MRI procedures.

Section 6.6.7: reference to the assessment schedule added.

Section 6.7.1: updated section to include instructions on the PK profiling.

Section 6.7.3: statement regarding remaining samples added.

Section 7.1: adverse event reported changed to start from informed consent signing.

Section 7.3: statement added regarding pregnancy outcomes for female partners of male 
patients.

Section 8.3: Obvious error correction removed as this is no longer performed. Also 
removed reference to paper CRFs as the study uses EDC.

Section 9.1: analysis sets defined for the additional cohorts.

Section 9.2: analysis further defined for demographic data.

Section 9.3: analysis further defined regarding treatment.

Section 9.4: Primary variable clarified for applicable cohort.

Section 9.4.1: analysis further defined by controlled and partially controlled.

Section 9.4.2: statistical method updated.

Section 9.5.1: additional cohorts added.

Section 9.5.3: analysis defined for the cohorts.

Section 9.5.5: stead state PK parameters added.

Section 9.5.8: statistical method updated and added that PK/PD analyses may be done 
separately.


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
Section 9.6: statement regarding expansion cohort effect on the precision of the responder 
rate added.

Section 9.8: Interim analyses updated.

Appendix 1: updated based on additional visits and samples.

Appendix 2: updated to incorporate labels being provided by the central laboratory.
IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, the changes herein affect the Informed Consent, and 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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Amendment 3
Amendment rationale
The purpose of this protocol amendment is to revise and clarify the statistical analysis that 
will occur at the end of the study. In addition, the need for a urinary free cortisol measurement 
at screening has also been removed to reduce undue burden to the patients.
Changes to the protocol

Removal of the urinary free cortisol measurement at screening. This will be implemented 
throughout the protocol.

Clarification of the statistical method of analysis, the handling of missing values and the 
sample size calculation. This will be implemented throughout 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.
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.
This amendment will take effect after study start.
Amendment 2
Amendment rationale
The purpose of this protocol amendment is to update the blood log with regards to the amount 
of blood taken. The original optimal testing blood volume estimates received from the central 
labs were plasma/serum volumes instead of whole blood estimates. Due to the expected yield 
of plasma/serum from the collected blood, the amount of blood taken has increased from 244
ml to 454 ml per subject. This blood will be collected over a period of approximately 3
months.
This amendment will take effect prior to study start.
Changes to the protocol

Changes in blood volume required for Pharmacodynamic assessments. See Appendix 1.


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Amendment 1
Amendment rationale
The purpose of this protocol amendment is to amend the inclusion criteria to ensure that only 
Cushing’s disease patients are enrolled. Given the exploratory nature of this study, the 
definition of a positive response to LCI699 has been revised to include a ≥50% decrease in 
urine free cortisol (UFC) in addition to normalization of UFC. The study stopping rules for 
the study have also been amended to minimize premature termination of a subject from the 
study for AEs that are expected in this population or are efficacy related. In addition, the 
interim analysis for lack of efficacy has been removed to allow collection of more data for 
adequate evaluation of LCI699 in this small study. To maximize the utilization of all available 
data, the Last Observation Carried Forward (LOCF) method has been added to impute 
missing data for the primary endpoint. The opportunity has also been taken to remove minor 
inconsistencies between the protocol text and Schedule of Assessments as well as the addition 
of a Saliva log.
This amendment will take effect prior to study start.
Changes to the protocol

Clarification that only subjects with a confirmation of pituitary origin of excess ACTH 
will be included. See Section 4.1

Additional exclusion criteria concerning subjects with adrenal Cushing’s syndrome and 
pseudo-Cushing’s syndrome. See Section 4.1

Responders will now be defined as having a normalization of UFC or a ≥50% decrease in 
UFC. This will be implemented throughout the protocol.

Addition of a dose adjustment decrease for subjects with symptomatic hypocortisolism. 
See Section 5.5.4

Changes in study stopping rules to unexpected drug related AEs. See Section 5.5.9.

The assumptions and power calculations to support the study sample size have been 
revised. Consequently, the originally planned interim analysis has been removed. This will 
be implemented throughout the protocol.

Removal of the Karnofsky performance status as not deemed relevant upon further 
reflection. This will be implemented throughout the protocol.

Addition of saliva sample collection throughout the baseline and wash-out periods of the 
study. This will be implemented throughout the protocol.

Removal of an extension study. This will be implemented throughout the protocol.

Removal of the PK sample at Day 84 as trough sample collection not needed 14 days after 
last dose of study drug. This will be implemented throughout the protocol.

Clarification on timing of PD sample collection and additional PD parameters to allow 
further analysis surrounding secondary objectives. This will be implemented throughout 
the protocol.

Clarification of the urine and blood sample log to reflect PD sample numbering and 
addition of a saliva log to allow for sample numbering.


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
Increase in total blood volume from 196.5ml to 244ml due to addition of 
pharmacodynamic samples.

Missing data will now be imputed using LOCF. See Section 9.4.3


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Protocol synopsis
Title of study: A proof-of concept, open-label, forced titration, multi-center study to assess the 
safety/tolerability and efficacy of 10-weeks treatment of LCI699 followed by a 12-week treatment 
period in patients with Cushing’s disease.
Purpose and rationale: This exploratory study is designed as a proof of concept of LCI699 in patients 
with Cushing’s disease. The purpose of this study is to determine whether the ability of LCI699 to 
inhibit 11β-hydroxlase can safely reduce urinary free cortisol (UFC) in patients with Cushing’s disease. 
In addition, this study will evaluate an optional 12 month long term extension (long term extension-1) 
and a second optional long term extension (long term extension-2).
Objectives:
Primary Objective:
To assess the effects of 10 weeks treatment of LCI699 on 24 hour urine free cortisol (UFC) in patients 
with Cushing’s disease.
Secondary Objectives:

To assess the 10 week safety and tolerability of multiple doses of LCI699 in patients with 
Cushing’s disease

To assess the 22 week safety and tolerability of multiple doses of LCI699 in patients with 
Cushing’s disease.

To assess the effect of LCI699 on steroid hormones of the HPA-axis in plasma, urine and saliva

To assess the effects of LCI699 on improving the metabolic abnormalities (hypertension, 
dyslipidemia, obesity, insulin sensitivity, HbA1c and FPG) of Cushing’s disease

To assess the steady state pharmacokinetics of LCI699 in patients with Cushing’s disease.

To assess the effect of 22 weeks of treatment with LCI699 monotherapy on 24 hour urine free 
cortisol (UFC) in patients with Cushing’s disease. The proportion of patients with controlled or 
partially controlled will be determined as follows:

Controlled UFC: defined as a mean UFC level ≤ ULN

Partially controlled UFC: defined as a mean UFC level > ULN but with ≥50% reduction from 
baseline.

To assess escape. Escape is defined as loss of UFC control (i.e. UFC > ULN) on at least 2 
consecutive visits at the highest tolerated dose, after previously attaining UFC normalization.
Study design: This is a proof of concept, open-label, single arm, sequential dose-escalation, multi-
center study to assess the safety/tolerability and efficacy of 10-weeks treatment of LCI699 followed by 
a 12 week treatment period in patients with Cushing’s disease.
The study will consist of a screening period of up to 60 days (to allow an adequate washout period for 
any medications that modify cortisol levels), a 10-14-day baseline period, a 10-week treatment period 
with sequential dose escalation, a 12 week LCI699 BID treatment period where patients will continue 
to receive LCI699 at the last efficacious dose. Patients will also have the option to enter two long term 
extensions (long term extension-1 and long term extension-2). Patients will have a Study Completion 
evaluation approximately 28 days after the last drug administration.


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*Note: Patients with baseline UFC > 3xULN will start at 5 mg bid (in lieu of 2 mg bid)
Long Term Extension-2 will end at each site within 4 months after a separate roll-over study is opened 
at their site, or by 31 December 2019 (whichever occurs earlier). The roll-over study will provide an 
opportunity of continued treatment for patients who are still ongoing at that time and who are clinically 
benefitting from LCI699. Sites with the separate roll-over study option available, should arrange their 
patient’s End of Treatment (EOT) visit within 4 months of the roll-over study being opened at their site 
(i.e. earlier than the 6 month visit intervals in Long-Term Extension-2), to allow their patients to 
continue their LCI699 dose on this new study.
Patients not continuing into the roll-over protocol will complete an EOT visit upon stopping treatment, 
and an EOS visit 28 days after the last dose administration, must be completed by 31 December 2019.
Population:
The study population will be comprised of male and female patients with endogenous hypercortisolism 
due to increased ACTH production from the pituitary (Cushing’s disease). Approximately 15 patients 
(not previously enrolled into the trial) with Cushing’s disease will be enrolled to participate in the study. 
At least 8 patients are expected to complete the study. Patients who previously completed the study 
prior to Amendment 4 and benefited from treatment with LCI699 will be allowed to re-enter the study at 
screening if their UFC is > ULN and all other eligibility criteria have been met.
Inclusion/Exclusion criteria:
Inclusion:
1.
Written informed consent must be obtained before any assessment is performed.
2.
Male or female patients aged 18 - 75 years
3.
Patients must have confirmed Cushing’s Disease that is persistent or recurrent as evidenced by:

UFC >1.5XULN (Mean value of three 24-hour urine samples collected within 14 days) [For 
Patients who completed the first 10 weeks of treatment prior to Amendment 4, the appropriate 
washout of medical treatment for Cushing’s disease has to be followed per inclusion criteria 5. 
These patients must have UFC >1 X ULN (Mean value of three 24-hour urine samples 
collected within 14 days).]

Morning plasma ACTH above lower limit of normal

Confirmation of pituitary origin of excess ACTH by at least one of the following three:
i) History of MRI confirmation of pituitary adenoma (greater than or equal to 6 mm) with 
positive dynamic test (e.g. CRH or high dose dexamethasone suppression test)
or
ii) History of inferior petrosal sinus sampling in patients with a tumor less than 6 mm that 
meet any of the following criteria with either CRH or DDAVP (desmopressin) stimulation:
a) Central to peripheral ACTH ratio ≥ 2 at pre-stimulation baseline, or
b) Central to peripheral ACTH ratio ≥ 3 after CRH stimulation.
or
iii) Prior pituitary surgery with histopathology confirming an ACTH staining adenoma


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
Patients are permitted to washout current drug therapy to meet these entry criteria if 
they have a known diagnosis of Cushing’s disease.
4.
Patients with de novo Cushing’s disease can be included only if they are not considered a 
candidate for surgery (e.g. poor surgical candidates, surgically unapproachable tumors, patients 
who refuse to have surgical treatment or surgical treatment is not available)
5.
For patients on medical treatment for Cushing’s disease the following washout periods must be 
completed before baseline efficacy assessments are performed

Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week

Dopamine agonists (bromocriptine, cabergoline), PPAR-gamma agonists (rosiglitazone or 
pioglitazone): 4 weeks

Octreotide LAR, Pasireotide LAR and Lanreotide autogel: 8 weeks

Mifepristone, Lanreotide SR: 4 weeks

Octreotide and Pasireotide (immediate release formulation): 1 week

Other experimental therapy: at least 5 half-lives
Exclusion:
1.
Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of 
enrollment, whichever is longer; or longer if required by local regulations, and for any other 
limitation of participation in an investigational trial based on local regulations.
2.
History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
3.
History of malignancy of any organ system (other than 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.
4.
Pregnant or nursing (lactating) women
5.
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 after completion of dosing. 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) 
or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment

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,
d) In case of use of oral contraception women should have been stabile on the same pill for 
a minimum of 3 months before taking study treatment.
6.
Fertile males, defined as all males physiologically capable of conceiving offspring UNLESS they 
use a condom during intercourse while taking the study medication and for 1 week after stopping 
study medication and should not father a child in this period. A condom is required to be used also 
by vasectomized men in order to prevent delivery of the drug via seminal fluid (criterion no longer 
applicable as of Protocol Amendment 07).


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7.
Patients who have been treated with mitotane during the last 6 months prior to Visit 1.
8.
Patients with compression of the optic chiasm, in order to exclude patients with a tumor causing 
chiasmal compression requiring surgery.
9.
Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. 
Carney Complex, McCune-Albright syndrome, MEN-1, AIP)
10. Patients with Cushing’s syndrome due to ectopic ACTH secretion or adrenal Cushing’s syndrome
11. Patients with pseudo-Cushing’s syndrome (for patients with a mean UFC< 3x ULN further testing 
to rule out this condition will be required unless Cushing’s disease is confirmed by histopathology. 
At least 2 of 3 tests should be abnormal in order to exclude pseudo-Cushing’s: low-dose 
dexamethasone suppression test, dexamethasone-CRH test or late-night salivary or serum 
cortisol.
12. Patients with renal impairment (estimated creatinine clearance < 60 mL/min by the MDRD formula), 
serum creatinine >2.0 X ULN.
13. Patients who are not biochemically euthyroid.
14. Patients who have undergone major surgery within 1 month prior to screening.
15. Diabetic patients with poorly controlled diabetes as evidenced by HbA1C >9%.
16. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained 
ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute MI 
less than one year prior to study entry or clinically significant impairment in cardiovascular function.
17. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, 
or patients with ALT/AST more than 3 X ULN, serum bilirubin >2.0 X ULN.
18. 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.
19. Patients who have a history of alcohol or drug abuse in the 6 month period prior to treatment.
20. 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.
21. Patients who have received pituitary irradiation within five years prior to Visit 1.
22. Patients with risk factors for QTc prolongation or Torsade de Pointes, i.e. patients with a baseline 
QTcF > 470ms, hypokalemia, hyperkalemia, hypomagnesemia, uncontrolled hypothyroidism, 
personal or family history of long QT syndrome, or concomitant medications known to prolong the 
QT interval.
Investigational and reference therapy: This study has only one treatment arm; LCI699. Patients will 
start on a dose of either 2 mg bid if baseline mUFC is ≤ 3 x ULN or 5 mg bid if baseline mUFC 
is >3xULN and they will increase their dose every 2 weeks until week 10. Patients who previously 
completed the trial prior to Amendment 4 will start at the penultimate dose and uptitrate as needed 
over 1 week and then will continue treatment adjusting the dose as needed until week 10. All patients 
will continue LCI699 treatment from week 10-22.
Efficacy / pharmacodynamic assessments: Efficacy assessments will include urinary free cortisol, 
plasma ACTH, cortisol, 11-deoxycortisol and renin, plasma and urine deoxycorticosterone, plasma and 
urine aldosterone, serum and urine sodium and potassium, salivary cortisol and aldosterone, 
testosterone and estradiol, LH, FSH, IGF-1, TSH, free T4, HbA1c and plasma insulin.
Safety assessments: Safety assessments will include physical examinations, 12-lead Safety ECGs,
24-hour continuous 12-lead Holter recordings, vital signs, standard clinical laboratory evaluations 
(hematology, blood chemistry, serum lipids, urinalysis), blood and urine hormones, adverse events, 
serious adverse event monitoring and pituitary MRIs.
Pharmacokinetic assessments: Pharmacokinetic assessments for LCI699 will include 0 to 6-hr PK 
samples at the steady state of each dose escalation up to week 10, as well as trough samples up to 
week 22.


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Data analysis: The primary variable is defined as the proportion of responders to LCI699 at Week 10. 
A patient is considered to be a responder if the mean UFC level from the Week 10 24-hour urine 
samples is ≤ ULN or represents a ≥50% decrease from baseline. Patients who discontinue for a 
disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or 
whose mean Week 10 24-hour UFC levels are higher than the normal limit and whose decrease in 
UFC is < 50%, are classified as non-responders. Patients who have <2 baseline or post-baseline 24-
hour UFC measurement will not be included in the primary analyses.
The proportion of responders and the associated 95% confidence interval will be estimated using the 
Exact Binomial Test.


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Assessment schedules
Core study
Category
Screening
Baseline
Dose Escalation Period
12 week 
treatment 
period
EOT 
CORE
EOS 28 
days 
post last 
dose8
Visit Number
V1
V2
V3
V4
V5
V505
V6
V605
V7
V705
V8
V805
V9
V10
V11
V777
V778
Days
D-74
to -15
D-14 
to 0
D1
D7
D14
D21
D28
D35
D42
D49
D56
D63
D70
D98
D126
D154
Weeks
1
2
3
4
5
6
7
8
9
10
14
18
22
Informed consent
D
x
Inclusion/Exclusion criteria
D
x
x
Relevant medical History/Current medical 
conditions
D
x
Demography
D
x
Physical examination
S
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test7
D
x
x
x
x
x
x
x
x
x
x
x
x
Drug administration record - LCI699
D
x
x
x
x
x
x
x
x
x
x
x
x
Body height
D
x
Body weight
D
x
x
x
x
x
x
x
x
x
x
x
x
Body temperature
D
x
x
x
x
x
Blood pressure/Pulse rate1
D
x
x
x
x
x
x
x
x
x
x
x
x
12 Lead safety ECG assessment
D
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
12-Lead 24-hour Holter ECG recording 
D
x
x
x
x
x
Pituitary MRI
D
x
x
Hematology, Blood chemistry, Urinalysis
D
x
x
x
x
x
x
x
x
x
x
x
x
IGF-1, TSH, free T4, LH, FSH
D
x
x
x
x
x
x


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Category
Screening
Baseline
Dose Escalation Period
12 week 
treatment 
period
EOT 
CORE
EOS 28 
days 
post last 
dose8
Visit Number
V1
V2
V3
V4
V5
V505
V6
V605
V7
V705
V8
V805
V9
V10
V11
V777
V778
Days
D-74
to -15
D-14 
to 0
D1
D7
D14
D21
D28
D35
D42
D49
D56
D63
D70
D98
D126
D154
Weeks
1
2
3
4
5
6
7
8
9
10
14
18
22
HbA1C
D
x
x
x
Testosterone/estradiol
D
x
x
x
x
x
x
x
x
x
x
x
LCI699 PK blood collection
D
x4
x5
x5
x5
x5
x6
x6
x6
Urinary Free Cortisol and urine creatinine3
D
x
x
x
x
x
x
x
x
x
x
x
Plasma ACTH, cortisol, 11-deoxycortisol 
and renin
D
x
x
x
x
x
x
x
x
x
x
Plasma and urine aldosterone
D
x
x
x
x
x
x
x
x
x
x
Urine sodium/potassium
D
x
x
x
x
x
x
x
x
x
x
x
Salivary Cortisol and aldosterone2
D
x
x
x
x
x
x
x
x
x
x
x
x
Plasma and urine Deoxycorticosterone
D
x
x
x
x
x
x
x
x
x
x
Insulin
D
x
x
x
x
x
x
x
x
x
x
Adverse Events
D
As required
Prior and Concomitant meds/Therapies
D
As required
Study completion information
D
x
End of Treatment information
D
x
Visit assessments window is ± 2 days.
1= Blood pressure to be measure in seated position after 3 mins resting.
2= To be collected every week in the morning and evening. See Section 6.5.5.
3= Three 24-hour urine collections should be taken within the 4 days prior to visit day (except for baseline: samples should be taken within 7 days prior to day-7).
4= PK samples to be collected at pre-dose(0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose.
5= PK samples to be collected at (1) pre-dose(0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or (2) pre-dose (trough) for maintained dose.
6= PK sample to be collected at trough (pre-dose) only
7= Pregnancy test at screening, baseline and EOS to be serum.
8= This visit is only for patients not entering the extension.


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Extension study
Category
LONG TERM EXTENSION-1
EOT 
EXTENSION-
1
EOS
28 days 
post last 
dose6
Visit Number
V12
V13
V14
V15
V16
V17
V18
V19
V777
V778
Days
D154
D182
D210
D238
D266
D294
D322
D406
D490
Weeks
22
26
30
34
38
42
46
58
70
Physical examination
S
x
x
x
x
x
x
x
x
x
Pregnancy test 4
D
x
x
x
x
x
x
x
x
x
Drug administration record - LCI699
D
x
x
x
x
x
x
x
x
Body weight
D
x
x
x
x
x
x
x
x
x
Body temperature
D
x
x
Blood pressure/Pulse rate 1
D
x
x
x
x
x
x
x
x
x
12 Lead safety ECG assessment
D
x
x
x
x
x
x
Pituitary MRI
D
x5
x
Hematology, Blood chemistry, Urinalysis
D
x
x
x
x
x
x
x
x
x
IGF-1, TSH, free T4, LH, FSH
D
x
x
x
x
x
x
x
x
x
HbA1C
D
x
x
x
x
x
Testosterone/estradiol
D
x
x
x
x
x
x
x
x
x
Urinary Free Cortisol and urine creatinine 3
D
x
x
x
x
x
x
x
x
x
Plasma ACTH, cortisol, 11-deoxycortisol and renin
D
x
x
x
x
x
x
x
x
x
Plasma and urine aldosterone
D
x
x
x
x
x
x
x
x
x
Urine sodium/potassium
D
x
x
x
x
x
x
x
x
x
Salivary Cortisol and aldosterone 2
D
x
x
x
x
x
x
x
x
x
Plasma and urine Deoxycorticosterone
D
x
x
x
x
x
x
x
x
x
Insulin
D
x
x
x
x
x
x
x
x
x
Adverse Events
D
As required


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Category
LONG TERM EXTENSION-1
EOT 
EXTENSION-
1
EOS
28 days 
post last 
dose6
Visit Number
V12
V13
V14
V15
V16
V17
V18
V19
V777
V778
Days
D154
D182
D210
D238
D266
D294
D322
D406
D490
Weeks
22
26
30
34
38
42
46
58
70
Concomitant meds/Therapies
D
As required
Comments
D
As required
EOT Extension -1
D
                                                                               x
Study completion information
D
  x
Visit assessments window is ± 2 days.
1= Blood pressure to be measure in seated position after 3 mins resting.
2= To be collected every 28 days until D322 and then every 3 months at D406 and D490 in the morning and evening. See Section 6.5.5.
3= Two 24-hour urine collections should be taken prior to visit day, 24-hr urine collections.
4= Pregnancy test at EOS to be serum.
5= Macroadenoma patients only.
6 = This visit is only for patients that have completed long term extension-1 and are not entering long term extension-2.
Category
LONG TERM EXTENSION-2x
EOT 
EXTENSION-26
EOS 
28 days post last dose7
Visit Number
20
21-26
27,28,29…
V777
V778
Monthsx
16
Every 3 months
Every 6 months
Physical examination
S
x
x
x
X
Pregnancy test 4
D
x
x
x
X
Drug administration record - LCI699
D
X
x
x
Body weight
D
x
x
x
X


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Category
LONG TERM EXTENSION-2x
EOT 
EXTENSION-26
EOS 
28 days post last dose7
Visit Number
20
21-26
27,28,29…
V777
V778
Monthsx
16
Every 3 months
Every 6 months
Body temperature
D
x
x
x
X
Blood pressure/Pulse rate 1
D
x
x
x
X
12 Lead safety ECG assessment
D
x
x
x
X
Pituitary MRI5
D
X5
X5
x
Hematology, Blood chemistry, 
Urinalysis
D
x
x
x
X
IGF-1, TSH, free T4, LH, FSH
D
x
x
x
X
HbA1C
D
x
x
x
Testosterone/estradiol
D
x
x
x
X
Urinary Free Cortisol and urine 
creatinine 3
D
x
x
x
X
Plasma ACTH, cortisol, 11-
deoxycortisol and renin
D
x
x
x
X
Plasma aldosterone
D
x
x
x
X
Urine sodium/potassium
D
x
x
x
X
Salivary Cortisol and aldosterone 2
D
X
x
x
X
Plasma and urine Deoxycorticosterone
D
x
x
x
X
Insulin
D
x
x
x
X
Adverse Events
D
As required
As required
As required
As required
Concomitant meds/Therapies
D
As required
As required
As required
As required


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Category
LONG TERM EXTENSION-2x
EOT 
EXTENSION-26
EOS 
28 days post last dose7
Visit Number
20
21-26
27,28,29…
V777
V778
Monthsx
16
Every 3 months
Every 6 months
Comments
D
As required
As required
As required
As required
End of Treatment (Extension-2)
D
X
Study Completion
D
X
Visit assessments window is ± 2 days.
1= Blood pressure to be measure in seated position after 3 mins resting.
2= To be collected every 3 months for the first 18 months and every 6 months until EOT Extension-2 in the 
morning and evening. See Section 6.5.5.
3= Two 24-hour urine collections should be taken prior to visit day, 24-hr urine collections.
4= Pregnancy test at EOS to be serum.
5 = MRIs will be performed once per year.
6 = For patient’s entering the roll-over study, should complete an EOT visit within 4 months of the roll-over study 
being opened at the site.
7 = Not applicable to patients entering the roll-over study.
X=Assessments to be completed every 3 months for the first 18 months during Extension-2, and every 6 months 
until EOT Extension-2. 


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1
Introduction
1.1
Background
Cushing’s syndrome (CS) is defined by chronic excess cortisol secretion, which results in a 
plethora of metabolic abnormalities leading to an increased cardiovascular risk and higher 
mortality rates than the normal population. The clinical symptoms of Cushing’s syndrome 
include: obesity, insulin resistance, dyslipidaemia, severe fatigue and muscle weakness, 
hypertension, skin changes (striae, ulcers, hirsutism, acne), hypercoagulation, reduced 
immune response, CNS effects (depression, mood changes, and cognitive impairment), and 
menstrual disorders in women.
The most common cause of endogenous Cushing’s syndrome is Cushing’s disease, in which a 
pituitary tumor (usually benign) secretes excess adrenocorticotropic hormone (ACTH). The 
resulting increased levels of ACTH stimulate the adrenal glands to produce excess cortisol. 
Cushing’s disease is a relatively rare (<10 cases/million people/year; prevalence of ~ 10-60 
million), and most commonly affects adults aged 20-50, with a marked female preponderance.
The diagnosis of Cushing’s disease is challenging, so patients often suffer for many years 
before receiving appropriate therapy. Diagnosis generally requires a 3 step process: (1)
confirmation of hypercortisolemic state using 24 hour urine collections. Evening serum or 
saliva cortisol measurement and a low dose dexamethasone test may also aid in this 
confirmation; (2) identification of the source of excess cortisol (e.g. Cushing’s disease, 
adrenal adenomas, carcinomas or hyperplasia, or an ectopic ACTH producing tumor) using 
plasma ACTH levels; (3) confirmation of a pituitary source of the elevated ACTH can be 
confirmed by either magnetic resonance imaging (MRI) or bilateral inferior petrosal sinus 
sampling (BIPSS) with a CRH stimulation test.
The primary treatment and standard of care for Cushing’s disease is surgical removal of the 
pituitary tumor via transsphenoidal adenectomy. However, if the tumor is small or in a 
difficult location, resection can be challenging. Post-surgical remission rates of 70-80% have 
been reported, however long-term follow-up of patients in remission shows a significant 
incidence of recurrence - approximately 25% at 10 years (Bochicchio et al 1995, 
Sonino et al 1996). For patients whom surgery is not indicated or has not been successful, 
radiotherapy is a possible alternative; however, it is curative in only about 15-45% of patients. 
Thus, medical therapy, although not usually curative, is required for better control of excess 
cortisol levels in a substantial proportion of patients. A number of drugs are currently used off 
label for the treatment of patients with Cushing’s disease, including metyrapone, ketoconazole, 
mitotane, and cabergoline. However, most elicit limited efficacy and work only in a minority 
(~ 30% or less) of patients mainly due to dose limiting toxicities of the drugs. Consequently, 
new medical therapies with improved safety profiles are a desirable alternate treatment for 
patients with Cushing’s disease.
LCI699 is a potent inhibitor of 11β-hydroxylase, the enzyme that catalyzes the last step in the 
synthesis of cortisol. In this respect, it is similar to metyrapone, which is occasionally used to 
treat patients with Cushing’s disease. Although metyrapone has an in vitro IC50 of ~7.5 nM 
against recombinant human CYP11B1 (i.e. 3 fold less than LCI699) it has a half-life of < 2


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hours. As a result, doses of 1-2 g t.i.d of metyrapone are often needed for efficacy, and can 
cause significant gastrointestinal (nausea, vomiting, abdominal pain) and central nervous 
system (headache, dizziness and sedation/drowsiness) issues that limit patients tolerability to 
the drug.
Preliminary LCI699 data (as of Dec 2011) in Cushing’s disease patients (baseline UFC range 
of 1.6-17.0xULN) from this proof of concept study demonstrated normalization of UFC on at 
least 1 assessment in 11 out of 11 subjects during the study. The primary endpoint was 
achieved by all 9 subjects who have completed the active treatment phase (10 weeks), 8 of 
whom had normal UFC levels on day 70. Geometric mean increase in plasma ACTH levels 
from baseline to week 10 was 2-3 fold. Increased ACTH levels could lead to the following 
undesirable effects: 1) Up regulation of 11B hydroxylase gene resulting in escape, 2) 
Overstimulation of adrenal androgen pathway resulting in virilization-related adverse events 
and 3) Accumulation of mineralocorticoid precursors resulting in hypokalemia, fluid retention 
and hypertension.
Amendment 4 will further explore the safety and efficacy of LCI699 in patients with 
Cushing’s disease.
1.1.1
Relevant data summary
Preclinical toxicology studies up to 26-weeks in duration in the rat, and up to 39 -weeks in the 
dog have been completed. Clinical studies in healthy subjects (up to 2 weeks) and 
hypertensive patients (up to 8 weeks) have been conducted with LCI699. A summary of both 
preclinical and clinical findings are given below. A more detailed version of these results is 
available in the [LCI699 Investigator’s Brochure].
1.1.1.1
Preclinical data
LCI699 has been tested preclinically in a number of in vivo and in vitro mechanistic models. 
LCI699 inhibited recombinant human CYP11B1 (11β-hydroxylase; cortisol synthase) and 
aldosterone synthase (CYP11B2) in vitro in a dose-dependent manner (IC50 = 2.5 nM and 0.7
nM, respectively). In addition, LCI699 shows weak inhibitory activity towards human 
aromatase (IC50 = 1.7 µM); however, the enantiomer of LCI699, LCI698, is detectable at low 
levels in the drug product (<0.1%) and is a potent inhibitor of aromatase (IC50 = 9 nM).
The in vivo effects of LCI699 on inhibition of CYP11B1 and B2 were evaluated using a rat 
model where corticosterone and aldosterone synthesis were stimulated with a 9 hr ACTH 
infusion (Figure 1-1). LCI699 treatment resulted in a dose-dependent decrease in both 
corticosterone and aldosterone (ED50 = 73 and 1.1 mg/kg, respectively).


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Figure 1-1
Effects of LCI699 on ACTH-stimulated cortisol and aldosterone 
synthesis in rats
Preclinical studies evaluated the safety pharmacology, general toxicity, and genotoxicity of 
LCI699 in rodents and dogs. No data of concern were obtained from in vitro or in vivo safety 
pharmacology studies including cardiac electrophysiology. No acute toxicity was observed in 
mice following administration of a single oral dose 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. The no observable adverse effect level (NOAEL) was 2 mg/kg in the rat (mean 
AUC of 5660 ng*hr/mL; estimated human equivalent dose of 50 mg bid based on exposure) 
based on liver findings in male rats, ovarian findings and clinical signs in females at a dose of 
5 mg/kg/day in the 13-week rat study, and by liver findings in both sexes, adrenal gland and 
ovarian findings at doses of 20 mg/kg in the 26-week rat study. The NOAEL of 1 mg/kg in 
dogs (mean AUC of 659 ng*hr/mL; estimated human equivalent dose of 8 mg b.i.d. based on 
exposure) is based on clinical findings and adrenocortical changes at 10 mg/kg (mean AUC of 
33750 ng*hr/mL) in the 13-week dog study.
Safety multiples for a 50 mg bid dose and 30 mg bid dose are summarized in Table 1-1.


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Table 1-1
Safety multiples for 50 mg bid and 30 mg bid dose based on 
toxicology studies
Species 
(weeks of 
treatment)
Sex
NOAEL
(mg/kg)
AUC0-24h
(ng.hr/mL)a
Cmax
(ng/ml)a
Exposure multiple for 
50 mg bid b
Exposure multiple for 30 
mg bid
AUC0-24h
Cmax
AUC0-24h
Cmax
Mouse
M
30
61500
14000
9.2
32.1
19.5
49.0
(13 wk)
F
30
52000
13300
7.7
30.5
16.5
46.5
Rat (4 wk)
M
5
17700
2670
2.6
6.1
5.6
9.3
F
1
2290
581
0.3
1.3
0.7
2.0
(13 wk)
M
0.5
816
208
0.1
0.5
0.3
0.7
F
0.5
726
232
0.1
0.5
0.2
0.8
(26 wk)
M
2
6170
869
0.9
2.0
2.0
3.0
F
2
5150
931
0.8
2.1
1.6
3.3
Dog (4 wk)
M
10
39200
5640
5.8
12.9
12.4
19.7
F
10
28300
6340
4.2
14.5
9.0
22.2
(13 wk)
M
1
713
372
0.1
0.9
0.2
1.3
F
1
605
357
0.1
0.8
0.2
1.2
(39 wk)
M
10
22200
3770
3.3
8.6
7.0
13.2
F
10
20300
3850
3.0
8.8
6.4
13.5
a Mean values obtained at end of dosing period from 13, 26 or 39 week oral studies
b Estimated human exposure data of mean AUC0-24h (6716 ng.hr/mL) and Cmax (436 ng/ml) values at steady 
state after administration of 50 mg LCI699 bid
c Estimated human exposure data of mean AUC0-24h(3159 ng*h/mL) and Cmax (286 ng/mL) values at steady 
state after administration of 30 mg LCI699 bid
Reversible CNS effects were seen at very high doses in dogs (≥10 mg/kg; mean AUC of 
33750 ng*hr/mL) and mice (doses ≥30 mg/kg; mean AUC of 56750 ng*hr/mL)). 
Hepatocellular hypertrophy (reversible) and vacuolation (partially reversible) were seen in 13
week and 26-week rat studies at doses ≥5 mg/kg (mean AUC of 17700 ng*hr/mL) and in a 
13-week study in mice at doses ≥10 mg/kg (mean AUC of 8460 ng*hr/mL). Correlating 
increases (~2 -fold) in serum alanine aminotransferase activities were present in the mouse but 
not the rat. 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 rat female reproductive organs were 
present in the ovary (microscopic follicular degeneration at 4 weeks; prominent ovarian 
corpora lutea at 26-weeks), uterus (weight decrease and slight atrophy) of and vagina 
(mucification) 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 which were also reversible. Effects in rat 
female and male reproductive organs are consistent with effects seen after aromatase 
inhibition. No effects on female or male reproductive organs were found in dogs. In the 
adrenal cortex, morphological alterations were observed in dogs (zona glomerulosa; reversible) 
and at much higher exposure in rats (zona fasciculata/glomerulosa; partially reversible). They 
may be a result of the inhibition of adrenocortical steroid biosynthesis leading to an adaptive 
induction of the aldosterone/cortisol synthase pathway.
Estimated exposure multiples based on the NOAEL in repeated dose general toxicity studies 
and the estimated human exposure based on 50 mg twice daily dose are approximately 1 in 


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rats (based on NOAEL of 2 mg/kg) and 0.1 in dogs (based on NOAEL of 1 mg/kg) for AUC, 
and ≥2.0 and ≥ 0.9 for Cmax, respectively.
In vivo genotoxicity tests in rats (micronucleus test and comet assay) were clearly negative 
and it is therefore concluded that LCI699 has no relevant genotoxic potential in humans.
1.1.1.2
Teratogenicity and reproductive toxicity data
In reprotoxicity studies (EFD in rats and rabbits, FEED study in rats), embryo/fetal toxicity 
was observed at doses that produced maternal toxicity in the rat (50 mg/kg; AUC (0-24h)
=100000 ng*hr/mL) and the rabbit (10 mg/kg; AUC0-24h=11800 ng*hr/mL). Safety margins at 
the no observed effect level (NOEL) are 0.1 in rat (0.5 mg/kg; AUC0-24h=749 ng*hr/mL) and 
rabbit (3 mg/kg; AUC0-24h=850 ng*hr/mL) EFD studies (AUC at NOEL vs. AUC at 50 mg 
b.i.d. in humans). LCI699 appears to be teratogenic in the rat at high doses that also produced 
maternal toxicity (50 mg/kg; AUC0-24h=100000 ng*hr/mL). The safety margin at the NOEL 
for malformations (5 mg/kg; AUC (0-24h)=12800 ng*hr/mL) is approximately 2 relative to a 50
mg b.i.d. dose. Reproductive performance in female rats was affected at 50 mg/kg 
(NOAEL=5 mg/kg; safety margin 1.7 relative to a 50 mg bid dose).
1.1.1.3
Human safety and tolerability data
LCI699 was studied in healthy male volunteers following administration of single doses up to 
200 mg and following daily administration of up to 10 mg for 14 days. It was also evaluated 
in an ethnic sensitivity study of Caucasian and Japanese male healthy subjects. In addition, 
LCI699 has been studied in more than 500 patients with essential hypertension, resistant 
hypertension or primary hyperaldosteronism for up to 8 weeks of treatment, at doses ranging 
from 0.25 mg q.d. up to 1 mg bid.
Overall, LCI699 was well tolerated with the overall incidence of adverse events being similar 
to placebo. The most common AEs across all studies were headache, dizziness (including 
postural dizziness), nausea, diarrhea and fatigue. In general, these adverse events were not 
dose-related and most were mild to moderate in severity. Discontinuations due to an AE were 
infrequent, had no consistent pattern, and occurred at only a slightly higher rate with LCI699 
treatment in comparison to placebo. Serious adverse events (SAEs) were infrequent and 
occurred at a rate similar to placebo. The incidence of hyperkalemia (>5.5 mmol/L was more 
common in the LCI699 and eplerenone groups in both the essential hypertension study (3-5% 
for active vs 0% for placebo) and the resistant hypertension study (5.6-6.1% for active vs 0% 
for placebo. In the study in patients with essential hypertension, there was a 20% incidence of 
an impaired ACTH-stimulated cortisol response (<500 nmol/L) with a daily dose of 0.5 mg 
b.i.d. or 1 mg q.d. LCI699, with no abnormal tests for lower doses of LCI699, eplerenone or 
placebo. There was no reduction in basal cortisol levels and there were no signs/symptoms of 
adrenal insufficiency observed across the dose range of LCI699 studied.
Preliminary data (as of Dec 2011) from this PoC study (n=11) showed that LCI699 was 
generally well tolerated; the most frequently reported adverse events were fatigue (5/11), 
nausea (4/11) and headache (3/11). Five of 11 subjects experienced ACTH levels >2 x 
baseline. Three of 11 subjects experienced study drug-related hypokalemia (K+<3.5mmol/L; 
min 3.1 mmol/L). A tendency for decreases in mean systolic and diastolic blood pressure was 


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observed (mean change at day 70 was -13.1 and -9.3 mmHg for SBP and DBP respectively)
although the sample size is too small to make an appropriate estimate of the effect.
There were no study drug related discontinuations, deaths or serious AEs of suspected drug 
relationship.
The dose at which patients had a normalization of UFC varied. Overall, all 11 patients had at 
least one UFC <ULN in recorded visits. One patient had normal UFC with a dose of 2 mg bid, 
3 patients had normal UFC with a dose of 5 mg bid, 3 patients had normal UFC with a dose of 
10 mg bid, one patient had normal UFC with a dose of 15 mg bid, two patients had normal 
UFC with a dose of 20 mg bid and one patient had a normal UFC with a dose of 50 mg bid.
LCI699 was generally well tolerated. There were no discontinuations due to adverse events or 
serious AEs of suspected drug relationship reported. Eleven patients reported at least one AE. 
Four patients experienced AEs consistent with cortisol withdrawal and they all improved upon 
dose reduction.
1.1.1.4
Human pharmacokinetic data
Following single oral doses of 0.5 mg to 200 mg to healthy volunteers under fasting 
conditions, LCI699 was rapidly absorbed with a Tmax of approximately 1 hour. Tmax 
remained constant with increasing doses. Half-life was 3-5 hours across all doses examined. 
The pharmacokinetics of LCI699 displayed over-proportional increase in exposure with 
increasing dose over the 0.5 – 200 mg range. Consistent with its short half-life, LCI699 does 
not accumulate in plasma following multiple dosing at low doses, but is expected at 50 mg bid. 
Based on model-derived PK parameters, 50 mg b.i.d. is predicted to give a Cmax,ss of 436 
ng/mL and AUC0-24hr,ss of 6716 ng.hr/mL at steady state. Additionally, based on the current 
proposed maximum clinical dose of 30 mg b.i.d, the predicted mean Cmax,ss and AUC0-
24h,ss at 30 mg bid are 286 ng/mL and 3159 ng*h/mL at steady state, respectively.
Administration of 100 mg LCI699 with a high fat meal resulted in a reduction in both AUC 
and Cmax by 14% and 25%, respectively. The median Tmax was delayed from 1 hr to 2.5 hr 
after high fat meal. AUC was 47-68% higher in Japanese healthy volunteers in comparison to 
Caucasians (body weight difference was not a major determinant of race effect on exposure).
Formal drug-drug interaction studies have not been conducted with LCI699. However, based 
on in vitro CYP P450 inhibition profile (Ki values: CYP1A2 = 0.78 µM, CYP2D6 = 1.97 µM, 
CYP2E1 = 0.48 µM), steady state maximum concentrations at doses >20 mg b.i.d (e.g. 50 mg 
b.i.d: Cmax,ss = 436 ng/mL or 1.92 µM) and FDA regulatory guidance, LCI699 is likely to 
cause drug-drug interaction via inhibition of CYP1A2, CYP2D6 and CYP2E1 at these high 
doses.
Based on emerging preclinical data, CYP3A4/5 and CYP2D6 may be involved in LCI699 
metabolism. The relative contributions of these enzymes on LCI699 metabolism is currently
under investigation.
1.1.1.5
Human pharmacodynamic data
In healthy male volunteers ([CLCI699A2101]), LCI699 (0.5-200 mg once daily) reduced 
plasma and urine aldosterone levels. In response to inhibition of aldosterone, RAAS counter-


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regulation was observed as evidenced by increases in plasma renin activity (PRA). After 
repeated once daily administrations, an increase in aldosterone above baseline values was 
evident upon termination of LCI699. LCI699 had no effect on basal (morning) cortisol after 
repeated doses of ≤ 3 mg, however, there was a significant dose- and time-dependent 
inhibition of ACTH-stimulated cortisol synthesis at doses ≥ 3 mg. Subsequent trials in healthy 
volunteers and patients with hypertension confirmed and refined these effects of LCI699 on 
the RAAS and hypothalamic-pituitary-adrenal-axis. In these trials, treatment with LCI699 
caused a dose- and time-dependent inhibition of cortisol synthesis (ACTH-stimulated cortisol 
test), with the moderate inhibition at total daily doses 0.5 mg and increasing suppression to 10 
mg (highest dose tested). As observed in healthy volunteers, basal morning cortisol 
concentrations were unaffected by LCI699 at these doses and no patients experienced the 
overt signs or symptoms of adrenal insufficiency. Full recovery of the ACTH-stimulated 
cortisol response was observed within a week after LCI699 was withdrawn.
The blood pressure lowering effects of LCI699 have been evaluated in four clinical trials. 
Treatment with LCI699 was associated with modest reductions in mean sitting systolic 
(MSSBP) and diastolic (MSDBP) blood pressure in patients with resistant hypertension and 
primary hyperaldosteronism. Greater reductions in MSSBP/MSDBP were observed in patients 
with essential hypertension. Despite its relatively short half-life, ambulatory BP monitoring 
indicated that the blood pressure lowering effects of LCI699 were sustained for 24 hours. No
BP effects were observed in normotensive patients.
Preliminary data (as of Dec 2011) from this PoC study in Cushing’s disease subjects (n=11) 
with a baseline UFC range of 1.6-17.0 x ULN showed that LCI699 normalized UFC on at 
least 1 assessment in 11 out of 11 subjects during the study. The primary endpoint was 
achieved by all 9 subjects who have completed the active treatment phase (10 weeks), 8 of 
whom had normal UFC levels on day 70. After treatment discontinuation, UFC was >ULN in 
6 subjects with measurements at day 84. The median dose of LCI699 associated with UFC 
normalization was between 5 and 10mg bid. Geometric mean increase in plasma ACTH levels 
from baseline to week 10 was 2-3 fold. These data support further evaluation of LCI699 in 
Cushing’s disease.
1.2
Study purpose
This exploratory study is designed as a proof of concept of LCI699 in patients with Cushing’s 
disease. The purpose of this study is to determine whether the ability of LCI699 to inhibit 
11β-hydroxlase can safely reduce urinary free cortisol (UFC) in patients with Cushing’s 
disease. With the introduction of Amendment 4 this study aims to confirm the preliminary 
observations from this proof of concept (PoC) study by enrolling a new cohort (Expansion 
cohort) of patients and evaluating the long-term efficacy and safety of LCI699 treatment for a 
total duration of 22 weeks. This longer treatment period will help address questions on the 
sustainability of the cortisol reductions and potential longer term safety issues (e.g. increases 
in ACTH levels and off-target effects on the mineralocorticoid and androgen pathways).
With Amendment 4, approximately 15 new patients (not previously enrolled) with Cushing 
disease will be enrolled as the Expansion Cohort. Patients who previously completed the trial 
prior to Amendment 4 and benefited from the treatment with LCI699 will also be allowed to 
re-enter the study as the Core PoC Follow-up Cohort. These patients will start the study over 


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again at screening and follow through the visit schedule the same as new patients with certain 
differences described in Section 3.1. Core PoC Follow-up patients can reenter if their UFC is > 
ULN and all other eligibility criteria have been met.
2
Study objectives
2.1
Primary objective(s)

To assess the effect of 10 week treatment LCI699 on 24 hour urine free cortisol (UFC) in 
patients with Cushing’s disease.
2.2
Secondary objective(s)

To assess the 10 week safety and tolerability of multiple doses of LCI699 in patients with 
Cushing’s disease.

To assess the 22 week safety and tolerability of multiple doses of LCI699 in patients with 
Cushing’s disease.

To assess the effect of LCI699 on steroid hormones of the HPA-axis in plasma, urine and 
saliva.

To assess the effects of LCI699 on improving the metabolic abnormalities (hypertension, 
dyslipidaemia, obesity, insulin sensitivity, HbA1c and FPG) of Cushing’s disease.

To assess the steady state pharmacokinetics of LCI699 in patients with Cushing’s disease.

To assess the effect of 22 weeks of treatment with LCI699 monotherapy on 24 hour urine 
free cortisol (UFC) in patients with Cushing’s disease. The proportion of patients with 
controlled or partially controlled will be determined as follows:

Controlled UFC: defined as a mean UFC level ≤ ULN.

Partially controlled UFC: defined as a mean UFC level > ULN but with ≥ 50% 
reduction from baseline.

To assess escape Escape is defined as loss of UFC control (i.e. UFC > ULN) on at least 2 
consecutive visits at the highest tolerated dose after previously attaining UFC 
normalization.


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3
Investigational plan
3.1
Study design
This is a proof of concept, open-label, single arm, sequential dose-escalation, multi-center 
study to assess the safety/tolerability and efficacy of 10-weeks treatment of LCI699 followed 
by a 12-week treatment period in patients with Cushing’s disease.
The study will consist of a screening period of up to 60 days (to allow an adequate washout 
period for any medications that modify cortisol levels), a 10-14-day baseline period, a 10-
week sequential dose escalation treatment period, a 12-week treatment period on the last 
efficacious dose, an End of Treatment-Core evaluation and two optional extensions. Patients 
are to have an end of study (EOS) visit 28 days after the last drug administration.
With Amendment 4, approximately 15 new patients (not previously enrolled) with Cushing 
disease will be enrolled as the expansion cohort. Patients who previously completed the trial 
prior to Amendment 4 and benefited from the treatment with LCI699 will also be allowed to 
re-enter the study as the core PoC follow-up cohort. These patients will start the study over 
again at screening and follow through the visit schedule the same as new patients with certain 
differences described below. Core PoC follow-up patients can reenter if their UFC is > ULN 
and all other eligibility criteria have been met.
Screening and baseline period:
Patients who meet the eligibility criteria at screening and are either not on medications that 
effect cortisol levels or have completed the required washout period of these medications, will 
proceed to baseline evaluations. Patients will be instructed in the proper method for collecting 
24 hour urine and saliva. Every 7 days during the baseline period, patients will collect a 
morning and evening saliva sample (upon waking and just prior to bedtime e.g. 6-8:00 and 
23-24:00, respectively). In addition, the patient will perform at least three 24 hour urine 
collections. Patients will bring in their urine collection bottles on Day -7. At this time, 
baseline safety and PD samples will be collected. All baseline evaluation results must be 
reviewed, and confirmation of inclusion/exclusion criteria determined prior to the patient 
starting dosing with LCI699. Patients will receive medication for the next 2 weeks on Day 1.
Dose escalation period:
Patients that meet all inclusion/exclusion criteria at baseline will begin taking their first dose 
of LCI699 the morning of Day 1. Due to the circadian rhythm nature of steroid levels 
(including cortisol), patients are advised to come to the clinic on a fixed time window (such as 
± 2 hrs) for each of the visit and best efforts should be made to keep consistent throughout the 
study.
Expansion cohort:
Patients will continue to take their prescribed medication every morning and evening. Patients 
with a baseline UFC ≤3 x ULN will start at 2 mg bid on Day 1. Patients with baseline UFC > 
3xULN will start at 5 mg bid on Day 1. On Day 7, the patient will be contacted by the site 
staff to ensure patients are taking their study medication and to record any adverse events. 


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Every 7 days during the dose escalation period, patients will collect a morning and evening 
saliva sample (upon waking and just prior to bedtime e.g. 6-8:00 and 23-24:00, respectively). 
Patients will perform three 24 hour urine collections within 4 days of Day 14 ± 2 days. 
Patients will report to the site in a fasted state, the morning of Day 14 ± 2 days with their 
urine collection. A predose PK sample (12 hr post previous PM dose) will be collected and 
post-dose PK samples at 1, 1.5, 2, 4, and 6 hours post morning dose will be collected. A meal 
will be provided 4 hours after the AM dose. Patients will undergo safety/PD assessments and 
be sent home with medication for the next 2 weeks, with instructions to wait for confirmation 
of the dose to be taken pending the UFC results.
If UFC > ULN, the site will contact the patient to plan an interim escalation dose visit 7 days 
after the regular visit (on Day 21). At the interim visit, the patient will take the first escalated 
dose at the site, and remain for 1.5 hours in order to have a 12-lead Safety ECG. This ECG 
must be read on site by a qualified physician (e.g., the investigator, or another qualified 
physician such as a consulting cardiologist), who will decide whether or not there is a 
“notable abnormality”. Notable abnormality is defined as QTcF > 480msec with acute cardiac 
risk, QTcF > 500msec, or increase in QTcF > 60msec from baseline QTcF from the pre-dose 
ECG taken on the day of the first study drug administration (Day 1). If there is no notable 
abnormality, then the patient will be sent home to continue the higher dose until the next visit 
on the current schedule. 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.
This schedule of events will continue every 2 weeks (i.e. Day 28, 42, 56) with potential
interim dose escalation visits (on Days 35, 49, 63) during the dose escalation period, with the 
dose of LCI699 increasing according to Figure 3-1. If at any time, the patients UFC is < ULN, 
dose escalation will be halted and the patient will remain on the current, efficacious dose 
through the rest of the dose escalation period (Week 10), and if UFC remains normal, 
continue until Week 22. Monitoring of UFC responses will continue every 2 weeks to allow 
additional dose adjustments if necessary. Accordingly, only a predose PK sample will be 
required for patients that remain on the efficacious dose. If at any time the patient experiences 
side effects which are either intolerable or meet dose adjustment criteria, the prescribed dose 
will be adjusted as outlined in Section 5.5.4.
Between days 66-69, patients will perform three 24-hour urine collections. Patients will bring 
in their urine collection bottles to the site on Day 70 ± 2 days. A pre-dose PK sample only (12
hr post previous PM dose) will be collected for patients on their previous maintained dose 
(<30 mg bid). Pre-dose (12 hr post previous PM dose), 1, 1.5, 2, 4 and 6 hour PK samples will 
be collected for patients receiving 30 mg bid. Patients will undergo safety/PD assessments at 
the site on Day 70 ± 2 days.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, urinalysis,) adverse event and serious 
adverse event monitoring.
Core PoC follow-up cohort:
Patients who previously completed the study prior to Amendment 4 and reenter the study will 
be started at the penultimate LCI699 dose that was efficacious and well tolerated with the 


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possibility to up-titrate the dose within one week based on tolerability. Patients should be sent 
home with enough medication to allow for up titration on Day 7 with instructions to wait for 
confirmation of the dose to be taken pending tolerability as assessed by the Investigator. 
Additional dose titrations will be done as needed based on efficacy and tolerability. They are 
to complete all assessments during that phase as indicated in the Assessment Schedules. The 
6-hr PK profile blood samples (predose, 1, 1.5, 2, 4, and 6 hr post dose) will only be collected 
from these patients at day 14, and only pre-dose PK blood samples will be collected in the 
following visits.
12 -week assessment period:
At Day 70 ± 2 days (Week 10), all patients (both patients entering for the first time and those 
re-entering the study) will enter the 12 week assessment period. Three visits will be 
performed at Day 98, Day 126 and Day 154. Patients will continue the home saliva 
collections every 7 days twice daily (upon waking and just prior to bedtime e.g. 6-8:00 and 
23-24:00 respectively). Patients will perform three - 24 hour urine collections over 7 days 
prior to the next scheduled visit. Patients will report to the site in a fasted state, the morning of 
scheduled visits with their urine collections and undergo safety/PD assessments. In addition, a 
predose PK sample will be collected during their visits.
From Day 70 through Day 154, patients can have the LCI699 dose adjusted based on the 
criteria in Section 5.5.4). At Day 154, patients will complete the End of Treatment-Core visit. 
Patients not continuing into the optional long term extension-1 will also complete an End of 
Study visit 28 days after the last dose administration.
Optional long term extension-1
At Day 154, patients have the option to enter the 12 month extension phase at the 
investigators discretion provided they do not meet any discontinuation criteria. Dosing 
titration during the extension is to be based on efficacy (UFC control) and safety (Section
5.5.4). Patients will come in for monthly visits for the first 6 months (Day 154- Day 322) of 
the long-term extension and then will have visits every 3 months from month 6 through 12 
(Day 322 - Day 490). At the end of the extension phase, patients will complete and End of 
Treatment-Extension visit at Day 490 and an End of Study visit 28 days after the last dose 
administration, if not continuing into long term Extension-2.
Optional long term extension-2
At Day 490, patients have the option to enter a second long term extension phase (extension-2) 
at the investigator’s discretion, provided they do not meet any of the study discontinuation 
criteria. Dose adjustment during the extension is to be based on efficacy (UFC control) and 
safety (Section 5.5.4). Patients will come in for visits every 3 months during the first 18 
months of extension-2 (approximately 3 years into the study), and every 6 months thereafter. 
This additional long term extension (extension-2) will provide important long term safety and 
efficacy data of LCI699 in patients with Cushing’s disease.
1. Patient treatment in Long Term Extension-2 will end at each site within 4 months after a 
separate roll-over study is opened at their site, or by 31 December 2019 (whichever occurs 


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earlier). The roll-over study will provide an opportunity of continued treatment for 
patients who are still ongoing at that time and who are clinically benefitting from LCI699. 
For sites where a separate roll-over study is not an option, the patient may be offered a 
local alternative treatment option.
Patients entering the roll-over protocol will complete an EOT visit. For these patients the EOS 
visit is not applicable, as treatment on LCI699 will not be interrupted. Sites with the separate 
roll-over study option available, should arrange their patient’s End of Treatment (EOT) visit 
within 4 months of the roll-over study being opened at their site (i.e. earlier than the 6 month 
visit intervals in Long-Term Extension-2), to allow their patients to continue their LCI699 
dose on this new study.
Patients not continuing into the roll-over protocol will complete an EOT visit upon stopping 
treatment, and an EOS visit 28 days after the last dose administration, must be completed by 
31 December 2019.
Figure 3-1
Study design
*Note: Patients with baseline UFC > 3xULN will start at 5 mg bid (in lieu of 2 mg bid) at Day 1
3.2
Rationale of study design
The design of this study addresses the primary objective of reduction of UFC in patients with 
Cushing’s disease, and takes into account the rarity of this disease and the objective nature of 
the measurement. A dose titration design was chosen for this proof-of-concept study because 
it provides a fast yet reasonable first approximation of dose-response, and allows 
individualization of therapy for this disease. Cushing’s disease patients are scarce and 
compared to a parallel dose-response study, this design uses fewer patients, yet allows the 
testing of multiple doses. In addition, as the level of cortisol can be extremely varied in 
patients with Cushing’s disease due to tumor size and degree of compensatory mechanisms, 
dose titration to efficacy will reduce unwanted side effects and also reflects clinical practice 
for the treatment of this disease. While such a design inherently shows that higher doses are 
the most effective, especially if the pharmacodynamic response is time-dependent, this design 
can provide valuable data to aide dose selection for a subsequent parallel dose-response study. 
Given the objective nature of the UFC measurement, an open-label, non-comparator design 
was chosen to further reduce patient numbers in this proof of concept study. Twenty-four hour 
UFC measurements were chosen for the primary outcome measure of the study as it is a well-
accepted measure of disease activity and allows for the circadian variability and pulsatile 


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nature of ACTH secretion in patients with Cushing’s disease. The mean of 3 UFC 
measurements will be used to account for the intra-patient variability in the 24-hour UFC 
measurement in patients with Cushing’s disease.
Amendment 4 introduces an additional 12 week treatment period following the 10 week dose-
escalation phase. The aim of Amendment 4 is to confirm the preliminary observations from 
the proof of concept evaluation and evaluate the long term efficacy and safety of LCI699 in 
patients with Cushing’s disease. In particular, this extended treatment with LCI699 will help 
address questions on the sustainability of cortisol reductions (or escape) and the effect of 
LCI699 therapy on steroid hormones of the HPA-axis and metabolic effects. Two consecutive, 
optional long-term extensions (extension-1 and extension-2) will further establish the safety 
and efficacy profile of LCI699 in patients with Cushing disease.
3.3
Rationale of dose/regimen, duration of treatment
Treatment duration of 10 weeks was chosen to allow for multiple dose escalations, if required, 
and to allow possible rebound or break through of the inhibition to be examined. The
inhibition of cortisol synthesis by LCI699 also appears to be time-dependent. Data to-date 
suggests that the maximal inhibition occurs by 2-4 weeks of treatment. Given this dose 
escalation every 2 weeks was chosen. Amendment 4 extends the evaluation of LCI699 for a 
total of 22 weeks in order to assess the sustainability of the cortisol reductions over time as 
well as potential off -target effects affecting the mineralocorticoid and androgen pathways and 
any effects on corticotroph tumor volume. The half-life of LCI699 is 4-5 hour and therapy 
will therefore be administered b.i.d. in this study. The two consecutive optional long term 
extensions (extension-1 and extension-2) have been added to generate further efficacy and 
safety data.
Inhibition of cortisol synthesis with LCI699 is dose-dependent. Looking across the 6 studies 
performed in patients with “normal” cortisol levels, a notable inhibition of cortisol synthesis 
(based on an ACTH-stimulation test) was at ~2 mg/day (2 mg qd or 1 mg bid) after 2-4 weeks 
of treatment. No notable change in basal (morning) cortisol levels were observed at these 
doses (likely due to the compensatory rise in ACTH to maintain the cortisol levels), but 
reduction in 24-hour urinary cortisol has been observed at 1 mg bid in patients with primary 
aldosteronism.
Based on modeling of PK and PD data, a dose of 4-5 mg bid is expected to achieve a plasma 
concentration above the IC50 for CYP11B1 (2.5 nM) for a full 24 hours. As the current study 
represents the first time LCI699 will be administered to patients with elevated levels of 
cortisol, a dose of 2 mg bid was chosen as the starting dose. This dose will transiently achieve 
plasma concentration above the IC50, but not for the full 24 hours and therefore, this dose is 
expected to be minimally effective at reducing UFC in these patients and have few side 
effects. Preliminary results from this study are consistent with the PK/PD simulations in that 
the starting 2 mg BID dose was a fully efficacious dose for only 1 of 12 patients. In view of 
the need to obtain more rapid control in patients with severe hypercortisolism patients with 
baseline mUFC > 3xULN will not undergo the initial 2-week treatment with LCI699 2 mg bid, 
and will instead be started on the 5 mg bid dose.


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Based on repeated dose toxicology studies, the NOAEL in rat has been set at 2 mg/kg (mean 
AUC of 5660 ng*hr/mL) based on the 26-week study. While lower NOAEL were identified in 
shorter term studies, in all cases, the NOAEL was determined based on reversible adverse 
effect observed at doses ≥5 mg/kg (Table 3-1). In the dog, the NOAEL has been set at 1
mg/kg (mean AUC of 659 ng*hr/mL) based on the 13-week study where reversible clinical 
signs of aggression were observed in 1 female at 10 mg/kg in this study. In both the 4- and 39-
week studies, the NOAEL was 10 mg/kg (mean AUC of 21250 ng*hr/mL for 39-wk study). 
Based on these data, we had originally planned to escalate to a maximum of 50 mg bid in this 
study.
However, at the time of protocol Amendment 5, on the basis of preliminary clinical data 
showing a potential risk of QTc prolongation, the maximum dose has been reduced to 30 mg 
bid. The rationale for this change is that the results of the exploratory post-hoc analysis of 
QTcF in relation to LCI699 dose from the phase-I study [LCI699A2101] found no evidence 
of a QTcF prolongation effect after a single 30 mg dose, but did find substantial QTcF 
changes (some patients with QTcF prolongation > 30ms) at single doses of 100 mg and 200
mg. Since it is not yet clear at which dose or plasma concentration of LCI699 the threshold for 
a QT prolongation effect is, the 50 mg bid dose was removed as a precaution.
The exposure at the 30 mg bid dose is estimated to be: Cmax = 286 ng/mL and AUC0-24= 
3159 ng*h/mL. Based on the NOAEL exposures in long term rat (26 week) and dog (39 week) 
studies safety margins would be ~ 1.6 – 7 at the 30 mg bid dose (see Table 1-1). Since the 
NOAEL defining toxicities (Table 3-1) were either monitorable and/or reversible, the ability 
to slowly dose escalate to the preclinical NOAEL is warranted in this proof-of-concept study.
Table 3-1
NOAEL determining toxicology
Species
Dose
NOAEL effects
Rat
2 mg/kg
Reversible adverse effects: female reproductive tract atrophy changes, liver hypertrophy 
and vacuolation, and adrenal cortex hypertrophy/vacuolation of the zona fasciculata at 
doses >/= 5 mg/kg
Dog
1 mg/kg
Clinical signs of aggression in one female at 10 mg/kg in the 13-week study, not seen in 
the 39 week study. This effect is clinically monitorable.
Mouse
30 mg/kg
No adverse effects at 30 mg/kg. Doses between 30 and 100 mg/kg have not been 
evaluated
3.4
Rationale for choice of comparator
Not applicable.
3.5
Risk/ benefit for this study
Potential benefits
Biochemical remission is a goal in the treatment of Cushing’s disease. Preliminary data from 
this PoC study in patients with Cushing’s disease clearly demonstrated that LCI699 can 
reduce and normalize plasma cortisol in this population. However, it is unknown whether 
patients responding to LCI699 will eventually loose UFC control. Patients will be 
discontinued from LCI699 treatment in case of unsatisfactory response.


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The primary treatment and standard of care for Cushing’s disease is surgical removal of the 
pituitary tumor via transsphenoidal adenectomy. Therefore, in order to avoid any potential 
delay in receiving first line treatment patients enrolled under Amendment 4 should have either 
failed standard therapy (including surgery) or can be de novo patients for whom surgery is not 
an option. Given LCI699’s potency to suppress cortisol synthesis, it is conceivable that 
patients may ameliorate some of the sequelae of their hypercortisolism state while on the drug 
for the planned duration of this study protocol following Amendment 4. Patients who are 
responding to LCI699 with good tolerability have the option to participate in optional two 
long term extension phases of the study.
Potential risks
Based on the preclinical and clinical experience with LCI699 the risks associated with this 
study are outlined below. The risks to patients will be minimized by strict inclusion/exclusion 
criteria, close clinical monitoring and predefined dose adjustment and dose termination 
criteria (see Section 5.5.4 and Section 5.5.9).
Effects on QTc interval
Final results from the completed ICH E14-compliant thorough QT Study LCI699C2105 
showed that the predicted mean QT effect of osilodrostat was below the threshold of 
regulatory concern for the currently investigated dose range (2-30 mg twice a day [bid]).
Effects on blood pressure
LCI699 has been shown to reduce BP of hypertensive patients in a dose dependent manner 
over 4-8 weeks. An acute decrease in BP has not been observed with LCI699 in healthy 
volunteers (up to 200 mg) or hypertensive patients (range tested = 0.25 mg - 2 mg/day). Doses 
used in this study will be higher than those where a BP effect was observed, and may 
therefore elicit larger decreases in BP than observed to-date. Patients with Cushing’s disease 
have a high prevalence of hypertension and effective treatment of hypercortisolism may result 
in reductions in blood pressure.
In the studies performed to-date, an increase in the precursor to aldosterone, 11-
deoxycorticosterone (DOC) has been observed. DOC is also a potent mineralocorticoid which 
may replace aldosterone on its receptor. The levels of DOC were further increased at doses 
that inhibited cortisol, presumably driven by the rise in ACTH. In patients with already 
elevated levels of ACTH, combination with aldosterone blockade may lead to high levels of 
11-DOC which could increase BP, decrease potassium, and cause fluid retention.
Preliminary data from this PoC study in CD patients (using doses higher than those tested in 
the hypertension studies) showed a tendency for decreases in mean systolic and diastolic 
blood pressure although the sample size is too small to make an appropriate estimate of the 
effect. During the extended treatment period introduced by Amendment 4, patients will be re-
educated on signs and symptoms of hypotension/ hypertension and BP will be monitored 
throughout the study.


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Effects on the serum electrolytes
Blockade of aldosterone may physiologically increase potassium levels (hyperkalemia) and 
reduce sodium levels (hyponatremia). While reports of these abnormal laboratory parameters 
have generally been infrequent, transient, and mild in the studies conducted to-date with 
LCI699, serum electrolytes will be monitored closely. In addition, inclusion/exclusion criteria 
for baseline sodium and potassium levels will be strictly enforced.
Furthermore, levels of DOC might further increase at doses of LCI699 that inhibit cortisol, 
presumably driven by the rise in ACTH. In patients with already elevated levels of ACTH (i.e.
Cushing’s disease) combination with aldosterone blockade may lead to high levels of DOC 
which could lower blood potassium.
Preliminary data from the PoC study in Cushing’s disease patients showed the following out 
of range potassium levels: 3 subjects had potassium levels < 3.5 mmol/L whereas 2 subjects 
had potassium levels > 5.3 mmol/L. Minimal or no changes were observed in plasma sodium.
Serum electrolytes will continue to be closely monitored during the extended study protocol.
Effects on adrenal hormones
Inhibition of both cortisol and aldosterone has the potential of rendering a patient adrenally 
insufficient. Patients will be provided with an instruction sheet surrounding adrenal 
insufficiency and details of rescue medications that can be taken. Clinical sign/symptoms of 
this condition include chronic fatigue, muscle weakness, nausea, vomiting, hypotension and 
hypoglycemia. Symptoms of frank adrenal insufficiency have not been observed to-date with 
LCI699 however symptoms suggestive of cortisol withdrawal were reported by 4 patients in 
the PoC study which were easily managed by dose adjustments of LCI699 with minimal 
clinical sequelae. Blood chemistry and clinical vital sign assessments will be reviewed every 2 
weeks for the first 10 weeks, monthly thereafter and as clinically needed. In addition, reported 
adverse events will be monitored.
Treatment with LCI699 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 LCI699 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 
LCI699, and has also reversed when LCI699 was continued, typically with decreasing doses.
Effects of sex hormones
General toxicology and reprotoxicology studies in rats/rabbits have identified reproductive 
organs (ovaries, uterus, vagina and prostate) as target organs of toxicity for LCI699 (Table 3-
2). These reversible findings may be attributed to off target effects of LCI699 to inhibit 
aromatase (enzyme that converts testosterone to estradiol and andstenedione to estrone). 
LCI699 has weak in vitro inhibition of human aromatase (IC50 = 1.7 µM), and the drug’s 


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enantiomer (LCI698; present at approximately 0.06% in the clinical batch) has considerably 
higher aromatase inhibitory activity (IC50 = 9 nM). Based on the predicted Cmax of 0.8µM
(free drug) in human at the dose of 30 mg b.i.d., aromatase inhibition may be of relevance in 
humans at the exposures to be achieved in this study.
In addition, inhibition of aldosterone and cortisol can lead to build up of precursors. As some 
of the early precursors in the synthesis pathways are also common to sex steroid synthesis (e.g. 
pregnenolone and 17-OH pregnenolone) and therefore could lead to increased synthesis of sex 
steroids, like testosterone and estradiol. Since patients with Cushing’s disease are typically 
hypogonadal, the increase in sex steroid levels may place them within the normal reference 
range. However, the magnitude of increase in sex steroids will need to be observed long-term 
to evaluate whether the levels become elevated above the normal range. Hirsutism and acne 
may result from increased androgen levels in female patients. These effects would be 
expected to reverse when the drug is withdrawn.
For these reasons, females that participate in the study will be asked to refrain from getting 
pregnant for the duration of the study. In addition, they must agree to use 2 forms of birth 
control. Furthermore, testosterone and estradiol levels will be measured every 2 weeks for the 
first 10 weeks and monthly thereafter.
Table 3-2
Safety multiple for 50 mg bid dose based on reprotoxicity studies
Study
Generation or 
gender
NOAEL 
(mg/kg)
AUC0-24h
(ng.hr/mL)b
Cmax
(ng/ml)b
Exposure multiple a
AUC0-24h
Cmax
EFD 
rabbit
Maternal
3
850
481
0.1
1.1
Fetal
3
850
481
0.1
1.1
EFD rat
Maternal
0.5
749
172
0.1
0.4
Fetal
5
12800
1920
1.9
4.4
FEED rat
Males
50
1E+05
11400
14.9
26.1
Females
5
11400
2260
1.7
5.2
a Estimated human exposure: AUC0-24h = 6716 ng.hr/mL, Cmax = 436 ng/ml at steady state after 50 mg bid 
LCI699
b measured in maternal blood, except for FEED study where values from 13-week study day 75 are used
In addition, due to the potential androgenic effect of LCI699 (and atherogenic lipid changes), 
a full lipid profile has been added to each visit as part of Amendment 4 and will include TC, 
TG, HDL-cholesterol and LDL-cholesterol.
Potential impact of discontinuing therapy
Some patients who enter this study may wash out current drug therapies in order to participate 
in this trial. It is to be expected that patients willing to consider washout of current therapies 
are those who are not responding to or tolerating their current therapies, and for whom the risk 
of a relatively short washout may be considered acceptable to test whether another therapy 
works better. There is a theoretical risk that if current effective therapy would be withdrawn, 
that cortisol levels would increase, and that patients would not respond well to LCI699. 
However, preliminary data from this PoC study indicate that all patients analyzed responded 
to LCI699. There is a risk that some patients may lose UFC control over time (“therapeutic 
escape”) while participating in the longer treatment evaluation. If a patient is not responding 


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to, or not tolerating an effective dose of, LCI699, they can be withdrawn from the study and 
resume their prior therapy.
Potential impact of delaying therapy
Some patients who enter this study may have a new diagnosis of Cushing’s disease. The
standard of care therapy for Cushing’s disease is surgical resection of the ACTH producing 
tumor.
Entry into this study may delay the time to the provision of standard effective therapy. If 
LCI699 is effective, initiation of medical therapy to reduce excess cortisol may improve 
patient symptoms and improve medical co-morbidities which can improve their ability to 
tolerate the surgery. If LCI699 is not effective, the patient may experience extra weeks of 
excess cortisol exposure. If a patient is not responding to, or not tolerating an effective dose of, 
LCI699 they can be withdrawn from the study and undergo surgical resection.
The standard of care therapy for Cushing’s disease is surgical resection of the ACTH 
producing tumor. Cushing’s disease patients enrolled under Amendment 4 should have either 
failed standard therapy (including surgery) or can be de novo patients for whom surgery is not 
an option.
Preliminary data from this PoC study demonstrated that LCI699 is an effective medical 
therapy to reduce hypercortisolism. If a patient is not responding to, or not tolerating an 
effective dose of, LCI699 they can be withdrawn from the study (Section 5.5.9).
3.6
Purpose and timing of interim analyses/design adaptations
Because this is an open label study, response to the therapy will be monitored as the study 
proceeds. In addition, an interim analysis will be performed after the first 12 patients complete
10 weeks of treatment and a CSR will be generated from this data. Additional interim 
analyses may be conducted for the expansion cohort and the core-PoC follow-up cohort.
4
Population
The study population will be comprised of male and female patients with endogenous 
hypercortisolism due to increased ACTH production from the pituitary (Cushing’s disease). 
Approximately 15 patients (not previously enrolled in the trial) with Cushing’s disease will be 
enrolled to participate in the study (expansion cohort). At least 8 patients are expected to 
complete the study. Patients who previously completed the trial prior to Amendment 4 and 
benefited from the treatment with LCI699 will also be allowed to re-enter the study (core PoC 
follow-up cohort). These patients will start the study over again at screening.
The investigator must ensure that all patients being considered for the study meet the 
following eligibility criteria. No additional exclusions should be applied by the investigator, in 
order that the study population will be representative of all eligible patients.
Patient selection is to be established by checking through all inclusion/exclusion criteria at 
screening and study baseline. A relevant record (e.g. checklist) must be stored with the source 
documentation at the study site.


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Deviation from any entry criterion excludes a patient from enrollment into the study.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria at the 
screening or baseline visit as described in the Assessment Schedules:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female patients aged 18 - 75 years
3. Patients must have confirmed Cushing’s Disease that is persistent or recurrent as 
evidenced by:

UFC >1.5XULN (Mean value of three 24-hour urine samples collected within 14 days) 
[For Patients who completed the first 10 weeks of treatment prior to 
Amendment 4 (Core PoC follow-up cohort), the appropriate washout of medical 
treatment for Cushing’s disease has to be followed per inclusion criteria 5. These 
patients must have UFC >1 X ULN (Mean value of three 24-hour urine samples 
collected within 14 days).]

Morning plasma ACTH above lower limit of normal

Confirmation of pituitary origin of excess ACTH by at least one of the following three:
1. History of MRI confirmation of pituitary adenoma (greater than or equal to 6 mm)
with positive dynamic test (e.g. CRH or high dose dexamethasone suppression test)
or
2. History of inferior petrosal sinus sampling in patients with a tumor less than 6 mm 
that meet any of the following criteria with either CRH or DDAVP (desmopressin) 
stimulation:

Central to peripheral ACTH ratio ≥ 2 at pre-stimulation baseline, or

Central to peripheral ACTH ratio ≥ 3 after CRH stimulation.
or
3. Prior pituitary surgery with histopathology confirming an ACTH staining adenoma

Patients are permitted to washout current drug therapy to meet these entry 
criteria if they have a known diagnosis of Cushing’s disease
4. Patients with de novo Cushing’s disease can be included only if they are not considered 
candidate for surgery (e.g. poor surgical candidates, surgically unapproachable tumors, 
patients who refuse to have surgical treatment or surgical treatment is not available)
5. For patients on medical treatment for Cushing’s disease the following washout periods 
must be completed before baseline efficacy assessments are performed

Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week

Dopamine agonists (bromocriptine, cabergoline), PPAR-gamma agonists 
(rosiglitazone, pioglitazone): 4 weeks

Octreotide LAR, Pasireotide LAR and Lanreotide autogel: 8 weeks

Mifepristone, Lanreotide SR: 4 weeks

Octreotide and Pasireotide (immediate release formulation): 1 week

Other experimental therapy: at least 5 half-lives


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4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of enrollment, whichever is longer; or longer if required by local regulations, and for 
any other limitation of participation in an investigational trial based on local regulations.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.
3. History of malignancy of any organ system (other than 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.
4. Pregnant or nursing (lactating) women.
5. 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 after completion of dosing. 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) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment.

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,
d. In case of use of oral contraception women should have been stabile on the same 
pill for a minimum of 3 months before taking study treatment.
6. Fertile males, defined as all males physiologically capable of conceiving offspring 
UNLESS they use a condom during intercourse while taking the study medication and for 
1 week after stopping study medication and should not father a child in this period. A 
condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid.
7. Patients who have been treated with mitotane during the last 6 months prior to Visit 1.
8. Patients with compression of the optic chiasm, in order to exclude patients with a tumor 
causing chiasmal compression requiring surgery.


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9. Patients who have a known inherited syndrome as the cause for hormone over secretion 
(i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP).
10. Patients with Cushing’s syndrome due to ectopic ACTH secretion or adrenal Cushing’s 
syndrome.
11. Patients with pseudo-Cushing’s syndrome (for patients with a mean UFC < 3xULN 
further testing to rule out this condition will be required unless Cushing’s disease is 
confirmed by histopathology.) At least 2 of 3 tests should be abnormal in order to exclude 
pseudo-Cushing’s: low-dose dexamethasone suppression test, dexamethasone-CRH test or 
late salivary or serum cortisol.
12. Patients with renal impairment (estimated creatinine clearance < 60 ml/min by the MDRD 
formula), serum creatinine >2.0 X ULN.
13. Patients who are not biochemically euthyroid.
14. Patients who have undergone major surgery within 1 month prior to screening.
15. Diabetic patients with poorly controlled diabetes as evidenced by HbA1c > 9 %.
16. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, 
history of acute MI less than one year prior to study entry or clinically significant 
impairment in cardiovascular function.
17. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent 
hepatitis, or patients with ALT/AST more than 3 X ULN, serum bilirubin >2.0 X ULN.
18. 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.
19. Patients who have a history of alcohol or drug abuse in the 6 month period prior to 
treatment.
20. 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.
21. Patients who have received pituitary irradiation within five years prior to Visit 1.
22. Patients with risk factors for QTc prolongation or Torsade de Pointes, i.e. patients with a 
baseline QTcF > 470ms, hypokalemia, hyperkalemia, hypocalcaemia, hypomagnesaemia, 
uncontrolled hypothyroidism, personal or family history of long QT syndrome, or 
concomitant medications known to prolong the QT interval.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Investigational treatment
The investigational drug, LCI699 1 mg and 5 mg capsules, will be prepared by Novartis and 
supplied to the Investigator as open labeled bulk medication.
In addition, LCI699 open labeled 1mg, 5mg, 10mg and 20mg tablets will be prepared by 
Novartis and supplied to the Investigator.


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5.2
Treatment arms
This study has only one treatment arm; LCI699. Patients will start on a dose of 2 mg b.i.d. if 
baseline mUFC is ≤ 3x ULN or 5 mg b.i.d. if baseline mUFC is > 3x ULN and increase their 
dose every 2 weeks as illustrated in Figure 3-1 up until week 10. From week 10 to week 22, 
the dose will be adjusted as needed based on efficacy and tolerability.
5.3
Treatment assignment
Treatment numbers will be assigned in ascending, sequential order to eligible patients in 
accordance with entry into the study. The treatment number becomes the definitive subject 
number as soon as a patient receives the first dose of the respective study treatment.
5.4
Treatment blinding
Not applicable as this study is open label.
5.5
Treating the patient
5.5.1
Patient numbering
Screening number
Each patient screened is assigned a unique screening number. The screening number is a 
combination of the center number, which is provided by Novartis, and a three digit number 
starting with 
 for each patient which is assigned by the Investigator. Therefore, if the 
center number is  (any leading zeros in the center number are dropped) the screening 
numbers will be assigned such as 
 in ascending order. If the center number is 
 the screening numbers will be 
 in an ascending order.
Starting with Amendment 4 each patient will be identified in the study by a Patient Number 
(Patient No.) which 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 study. 
The Patient No. consists of the Site Number (Center No.) (as assigned by Novartis to the 
investigative site) and patient number suffixed to it, so that each patient is numbered uniquely 
across the entire database. Upon signing the informed consent form, the patient is assigned to 
the next sequential Patient No. available to the investigator. Patients that previously 
completed Part I and reenter the study for Part II (core PoC follow-up cohort) are to be 
assigned a new patient number. A record of the old screening number and the new patient 
number is to be kept. If a patient is rescreened after being screen failed, then a new patient 
number is to be used. With Amendment 4, the patient number will also be captured on the 
eCRF.
Treatment number
If the patient is deemed eligible for enrollment into the study and will commence dosing, a 
treatment number will be assigned. Treatment numbers will be assigned in ascending, 
sequential order to eligible patients in accordance with entry into the study. The treatment 
number becomes the definitive subject number as soon as a patient receives the first dose of 


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the respective study treatment. Patients that previously completed the study and reenter the 
study after Amendment 4 (core PoC follow-up cohort) are to be assigned a new patient 
number. A record of the old treatment number and the new patient number is to be kept.
Once assigned to a patient, a treatment number will not be reused.
There should be a source document maintained at the site which links the screening number to 
the treatment assignment number (once assigned).
Patients will be assigned treatment numbers; each site will have a list of unique treatment 
numbers.
5.5.2
Dispensing the study treatment
Appropriate documentation of the patient specific dispensing process must be maintained.
Bulk medication labels will be in the local language, will comply with the legal requirements 
of each country, and will include storage conditions for the drug but no information about the 
patient.
5.5.3
Supply, storage and tracking of study treatment
Study drugs must be received at the study site by a designated person, handled and stored 
safely and properly, and kept in a secured location to which only the Investigator and 
designated staff have access. Upon receipt, the study drugs should be stored according to the 
instructions specified on the drug labels.
Storage conditions must be adequately monitored and appropriate temperature/humidity logs 
maintained as Source data.
The Investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Drug accountability will be noted by the Monitor during 
site visits and/or at the completion of the trial.
Patients will be asked to return all unused study drug and packaging at the end of the study or 
at the time of study drug discontinuation.
All drug supplies are to be used only for this protocol and not for any other purpose. Unless 
specifically instructed by Novartis, the Investigator must not destroy any drug labels, or any 
partly used or unused drug supply.
At the conclusion of the study, and, if allowed during the course of the study (e.g. an open 
label study or an un-blinded monitor), the Investigator will provide a copy of the drug 
accountability ledger to the Monitor.
Only after receiving a written authorization by Novartis, the Investigator will send all the 
unused and partly used drug supplies as well as the empty containers to the address provided 
at the time of authorization for destruction or have the unused and partly used drug supplies 
as well as the empty containers destroyed by the site’s pharmacist, providing a drug 
destruction certificate.


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5.5.3.1
Instructions for prescribing and taking study treatment
Patients will self-administer LCI699 p.o. b.i.d. in the morning and evening regardless of when 
they have eaten.
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed.
The patients will also be instructed to bring back used and unused medication at selected 
time-points for drug accountability checking.
Patients must be instructed not to chew the medication, but to swallow it whole. All dosages 
prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF.
5.5.4
Permitted dose adjustments and interruptions of study treatment
LCI699 dose will be titrated as outlined in Section 3.1 or until normalization of UFC (below 
upper limit of normal, as per local lab levels). For patients who are unable to tolerate the 
protocol-specified dose scheme, dose adjustments are permitted. The following guidelines 
should be followed:

If the patient has not reached normalization of UFC, but does not tolerate the current dose, 
administration of an intermediate dose between the current (untolerated) and preceding 
(tolerated) dose or repeated administration of the preceding, tolerated dose should be 
considered.

If the patient has reached normalization of their UFC, but the current dose is no longer 
tolerated, an intermediate dose between the current dose and previous dose should be 
considered.

If the patient had reached normalization of their UFC, but the current dose is no longer 
efficacious based on on-going UFC measurements, dose escalation should resume.

If the patient has low serum cortisol or UFC < LLN, and the patient has signs/symptoms 
of adrenal insufficiency, a dose reduction of LCI699 should be considered.
These changes must be recorded on the Dosage Administration Record eCRF.
5.5.5
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Instructions for 
monitoring liver function, and the criteria for withholding, re-initiating, reducing dose, or 
discontinuing study treatment are provided in Table 5-1 below.


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Table 5-1
Criteria for interruption and re-initiation of LCI699 for abnormal liver 
function
Isolated total Bilirubin elevation
> ULN – 1.5 x ULN
Maintain dose level
> 1.5 - 3.0 x ULN
Interrupt study drug dose. Monitor liver function tests (LFTs)a, 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, then restart study drug and decrease by
one dose level
> 3.0 - 10.0 x ULN*
Interrupt study drug. Monitor LFTsa weekly, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 x ULN:
If resolved in ≤ 14 days, then restart study drug and decrease by 
one dose level
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 resolved to baseline or stabilized over 4 weeks.
> 10.0 x ULN*
Discontinue patient from study drug treatment
The patient should be monitored weekly (including LFTsa), or more 
frequently if clinically indicated, until total bilirubin has resolved to 
baseline or stabilized over 4 weeks.
Isolated AST or ALT elevation 
> ULN - 3.0 x ULN
Maintain dose level
> 3.0 - 5.0 x ULN 
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
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
If not resolved after 4 weeks, discontinue patient from study drug.
>10.0 – 20.0 x ULN
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 restart study drug and decrease by one dose 
level.
> 20.0 x ULN
Discontinue patient from study drug treatment
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 returned to baseline or 
stabilized over 4 weeks.


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Combined b, d 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 > 2x 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
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 resolved to baseline or stabilization over 4 weeks.
Refer to Section 5.5.6 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 in the situation when interrupt study 
drug is required 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. See Section 5.5.6
* 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.
5.5.6
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
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.


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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 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.

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 7.2) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
5.5.7
Rescue medication
As this is the first study to evaluate LCI699 for Cushing’s disease there are no established 
rescue medications. If patients are not responding to, or not tolerating LCI699, they should be 
withdrawn from the study and other accepted therapies (surgical resection or other 
medications) should be initiated.
5.5.8
Concomitant treatment
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 must be listed on the Concomitant medications/Significant non-drug 
therapies after start of study (e)CRF.
Should a patient have an incidental and limited need for a medication to be taken within the 
restricted pre-dose timeframe (e.g. ibuprofen for a headache, antibiotic prophylaxis prior to 
dental surgery etc.), the sponsor should be advised, as administration of any concomitant 
medication may require the patient to be replaced. Decisions regarding replacements will be 


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discussed with the sponsor on a case-by-case basis. Administration of paracetamol, 
(acetaminophen) is acceptable, but must be documented.
All prescription medications and over-the-counter drugs taken within the timeframe defined in 
the entry criteria prior to the start of the study and during the study, must be recorded on the 
Concomitant Medications/ Non-Drug Therapies page of the e(CRF). Medication entries 
should be specific to trade name, the single dose and unit, the frequency and route of 
administration, the start and discontinuation date and the reason for therapy.
5.5.9
Prohibited treatment
Use of other drug treatments for Cushing’s disease is prohibited during this study. Patients on 
drugs for ailments other than Cushing’s disease will be checked by the Investigator against the 
list of known substrates of CYP1A2, CYP2D6 and CYP2E1 (see detailed list in Appendix 3). 
For any concomitant medications on this list, an alternate drug may be prescribed, dose 
adjusted of the concomitant medication as per the product label or dose limitation of LCI699 
should be considered by the Investigator.
Preclinical data and preliminary clinical data indicate that there is a potential risk of QTc 
prolongation in humans (see Amendment 5 Rationale). Therefore, the use of medications with 
a “Known risk to cause TdP” and drugs with a “Possible risk to cause TdP” concomitantly 
with LCI699 is prohibited.
If a patient requires a long-term medication from the two categories mentioned above, and 
there is no adequate alternative medication available, then they should be discontinued from 
the study.
However, if a patient requires such a drug for short-term therapy, e.g., antibiotics for active 
infection, then the LCI699 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. Washout periods for LCI699 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 
LCI699 therapy in the investigator’s judgment. In such cases, a discussion with the Novartis 
Medical Monitor is recommended.
Investigators are advised to refer to Appendix 6 and utilize the www.crediblemeds.org
website when considering the addition of a new concomitant medication, with risks of TdP, 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”.
In addition, the following drugs are prohibited: spironolactone, eplerenone, and 
glucocorticoids (e.g., prednisone, dexamethasone). Please note the following exceptions to 
these prohibitions: 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 may be used as required for the short-term treatment of adrenal 
insufficiency.


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If glucocorticoids are used in stress doses, or as replacement therapy, for > 4 weeks, then the 
investigator should consider temporary interruption of LCI699, weaning and discontinuation 
of glucocorticoid therapy, or early discontinuation from the study.
5.5.10
Concomitant medication to be use with caution
Emerging preclinical data suggest that CYP3A4/5 and CYP2D6 may be involved in LCI699 
metabolism; while relative contribution of these enzymes to LCI699 metabolism in vivo is not 
yet elucidated, risk exists for drug-drug interaction with medications that are strong 
CYP3A4/5 and CYP2D6 inhibitors and inducers (Appendix 7). Therefore concomitant 
medications that are known strong inhibitors or inducers of CYP3A4/5 and CYP2D6 are to be 
used with caution with LCI699.
5.5.11
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, email, 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 reason.
The investigator should 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 and according to 
Investigator discretion:

Withdrawal of informed consent.

Emergence of the following adverse events (compound specific):

hypertension defined as office mean sitting systolic BP > 180 mmHg or mean sitting 
diastolic BP > 110 mmHg (confirmed and persistent*).

Any of the following laboratory abnormalities:

hyperkalemia (serum potassium > 5.5 mmol/L; confirmed and persistent*).

hypokalemia (serum potassium < 3.5 mmol/L; confirmed and persistent*).

hyponatremia (serum sodium < 130 mmol/L; confirmed and persistent*).

QTcF > 500 msec, if confirmed by a cardiologist (see Section 6.6.5).

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 (see Section 6.6.5).

Pregnancy.

Use of any other therapy for Cushing’s disease.

Any other protocol deviation that results in a significant risk to the patient’s safety.
* Persistent is defined as unresolved with LCI699 dose or other concomitant medication 
changes


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Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Section 6. If they fail to return to 
return for these assessments for unknown reasons, reasonable effort (e.g. telephone, email, 
letter) should be made to contact them as specified in Section 5.5.13.
5.5.12
Withdrawal of Consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

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 subject’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. 
Further attempts to contact the subject 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 subject’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 subject’s samples until their time of withdrawal) according to 
applicable law.
For US 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 EU and RoW: 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.
5.5.13
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.
5.5.14
Emergency unblinding of treatment assignment
Not applicable as study is open-label.


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5.5.15
Study completion and post-study treatment
Patient treatment in Long Term Extension-2 will end at each site within 4 months after a 
separate roll-over study is opened at their site, or by 31 December 2019 (whichever occurs 
earlier). The roll-over study will provide an opportunity of continued treatment for patients 
who are still ongoing at that time and who are clinically benefitting from LCI699.
Sites with the separate roll-over study option available, should arrange an End of Trial (EOT) 
visit within 4 months of the roll-over study opening at their site (i.e. earlier than the 6 month 
interval visits in Long Term Extension-2), to allow their patients to continue their LCI699 
dose on this new study.
For sites where a separate roll-over study is not option, the patient may be offered a local 
alternative treatment option and must complete their Long-Term Extension-2 EOS visit by 31 
December 2019.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.5.16
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 treated as described in Section 6 for a 
discontinued 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.
The study will be stopped if any of the following criteria are met: and no further patients 
enrolled pending a full safety review:

At least 3 patients manifest a similar unexpected/off-target AE which is > CTCAE (v4) 
grade 2 (Appendix 5), suspected to be related to study drug and that does not resolve with 
drug reduction

At least 3 patients are withdrawn from the study for adverse events as described under the 
individual withdrawal rules below
6
Visit schedule and assessments
The full Assessment schedules is presented before Section 1.
Patients should be seen for all visits on the designated day with a visit window of ± 2 days. 
Due to the circadian rhythm nature of steroid levels (including cortisol), patients are advised 
to come to the site on a fixed time window (e.g. ± 2 hours) for each of the visits and best 
efforts should be made to keep consistent throughout the study.
Patients who discontinue study treatment before completing the study, and those who 
discontinue from the study for any reason, should be scheduled for a visit as soon as possible, 
at which time all of the assessments listed for the End of Treatment visit. In addition, an End 
of Study visit will be performed 28 days after the last dose administration. Every effort will be 
made to take the pharmacokinetic sample at the protocol specified time.


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Patients entering the roll-over protocol will complete an EOT visit. Their EOT visit should be 
arranged within 4 months of the roll-over study opening at their site. For these patients the 
EOS visit is not applicable, as treatment on LCI699 will not be interrupted.
Patients not continuing into the roll-over protocol will complete an EOT visit upon stopping 
treatment, and an EOS visit 28 days after the last dose administration, must be completed by 
31 December 2019. Any repeat assessments associated with this visit should be documented 
and followed-up appropriately by the Investigator.
6.1
Screening
Screening examinations (Visit 1) are to include the procedures found in the 
Assessment schedules and should occur within 74-15 days prior to Day 1. The informed 
consent must be signed prior to ANY screening procedure being performed. Patients that do 
not meet eligibility criteria are allowed to be rescreened and should be given a new patient ID 
number. The rescreening should be documented in the source files.
6.2
Dietary, fluid and other restrictions
During recruitment, screening/informed consent review, and baseline visit, the patients will be 
informed and reminded of the following restrictions:

Patient should maintain their normal exercise regime (i.e. no new strenuous physical 
exercise (e.g., weight training, aerobics, football) for 7 days before dosing until after 
Study Completion evaluation.

Patients should report to the site at each visit in an 8 hour fasted state. During a PK 
profile, patients will be provided lunch 4 hours post-dose.
6.3
Patient demographics/other baseline characteristics
Demographics
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, sex, race, predominant ethnicity.
Relevant medical history / current medical conditions
Relevant medical history and current medical conditions will be recorded on the in the CRF 
until the start of the study drug.
Where possible, diagnoses and not symptoms will be recorded. Cushing’s disease history 
together with the medication/treatment used will be collected.
Any event or change in the patient’s condition or health status occurring prior to the initial 
study drug administration will be reported in the Relevant medical history/Current medical 
conditions section of the CRF.
6.4
Treatment exposure and compliance
Treatment compliance will be determined by collecting a trough plasma PK sample at the end 
of the last dose (C12hr) of each b.i.d. regimen, as detailed in Section 6.7.


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6.5
Efficacy / pharmacodynamic assessments
The following efficacy/pharmacodynamic assessments will be done using a central laboratory: 
UFC, plasma cortisol, plasma ACTH, salivary cortisol and aldosterone, 11-deoxycortisol, 
plasma and urine 11-deoxycorticosterone, plasma and urine aldosterone, plasma renin, PK, 
testosterone and estradiol, LH, FSH, IGF-1, urinary creatinine, urine sodium and potassium, 
insulin, HbA1c, TSH, free T4. Local labs can be used throughout the study for dose titrations 
and/or if a faster turnaround time is needed for safety reasons. Local values for UFC, plasma 
ACTH, plasma and urine deoxycorticosterone, testosterone and estradiol will be captured in 
the eCRF as applicable.
6.5.1
Mean urinary free cortisol and creatinine
The primary efficacy parameter will be urinary free cortisol. UFC will be measured in three 
24-hour urine specimens collected within 7 days of day -7. The three samples will be 
averaged to obtain the baseline UFC level. Throughout the study, patients will collect three 
24-hour urine specimens within 4 days prior to the next visit according to the Assessment 
schedules. If at any time, the Patient’s UFC is < ULN on 2 consecutive measurements dose 
escalation will be halted and the patient will remain on the current efficacious dose through 
week 10. During the two long term extension phases, (extension-1 and extension-2) patients 
will collect two 24-hour urine specimens within 7 days prior to the next visit. Urine creatinine 
levels will also be measured to ensure validity of the 24-hour collection.
6.5.1.1
Pharmacodynamic collection and processing
Procedures for sample handling and storage will be supplied by the local and central 
laboratories. All sampling should have application of unique sample numbering within the 
sample log table contained within Appendix 1.
6.5.1.2
Pharmacodynamic analytical method(s)
Procedures for sample analysis will be supplied by the local and central laboratories and 
checked by Novartis personnel.
6.5.2
Plasma ACTH, plasma cortisol, 11-deoxycortisol and renin
Plasma ACTH, cortisol, 11-deoxycortisol and renin will be measured via blood samples taken 
at visits according to the Assessment schedules.
6.5.2.1
Pharmacodynamic collection and processing
Procedures for sample handling and storage will be supplied by the central laboratory. All
sampling should have application of unique sample numbering within the sample log table 
contained within the Appendix 1.
6.5.2.2
Pharmacodynamic analytical method(s)
Procedures for sample analysis will be supplied by the central laboratory and checked by 
Novartis personnel.


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6.5.3
Plasma and urine aldosterone and 11-deoxycorticosterone
Aldosterone and 11-deoxycorticosterone will be measured via blood and urine samples taken 
at visits according to the Assessment schedules.
6.5.3.1
Pharmacodynamic collection and processing
Procedures for sample handling and storage will be supplied by the central laboratory. All
sampling should have application of unique sample numbering within the sample log table 
contained within Appendix 1.
6.5.3.2
Pharmacodynamic analytical method(s)
Procedures for sample analysis will be supplied by the central laboratory and checked by 
Novartis personnel.
6.5.4
Serum and urine sodium and potassium
Sodium and potassium will be measured via blood and urine samples taken at visits according 
to the Assessment schedules.
6.5.4.1
Pharmacodynamic collection and processing
Serum sodium and potassium will be assessed as part of the clinical chemistry panel (see
Section 6.6.4.2 below) and will therefore be performed by the local lab. Procedures for sample 
handling and storage for urine will be supplied by the central laboratory. All sampling should 
have application of unique sample numbering within the sample log table contained within 
Appendix 1.
6.5.4.2
Pharmacodynamic analytical method(s)
Procedures for urine sample analysis will be supplied by the central laboratory and checked 
by Novartis personnel.
6.5.5
Salivary cortisol and aldosterone
Cortisol and aldosterone will be measured via saliva samples taken at baseline and weekly 
thereafter until Day 154. From Day 154 through Day 322 it will be collected every 28 days 
(Day 182, D210, D238, D266, D294 and D322) and from Day 322 through 490 it will be 
collected every 3 months (D406 and D490). During long term extension-2 samples will be 
collected every 3 months during the first 18 months, and every 6 months thereafter. Patients 
will collect a morning and evening saliva sample (upon waking and just prior to bedtime e.g., 
6-8:00 and 23-24:00 respectively)
6.5.5.1
Pharmacodynamic collection and processing
Procedures for sample handling and storage will be supplied by the central laboratory. All
sampling should have application of unique sample numbering within the sample log table 
contained within Appendix 1.


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6.5.5.2
Pharmacodynamic analytical method(s)
Procedures for sample analysis will be supplied by the central laboratory and checked by 
Novartis personnel.
6.5.6
Other pharmacodynamic laboratory evaluations
Insulin will be measured via blood samples taken at visits according to the 
Assessment schedules. HbA1c, IGF-1, TSH, free T4, LH, FSH will be collected at visits 
according to the Assessment schedules. Testosterone and estradiol will be collected at visits 
according to the Assessment schedules.
6.5.6.1
Pharmacodynamic collection and processing
Procedures for sample handling and storage will be supplied by the central laboratory. All
sampling should have application of unique sample numbering within the sample log table 
contained within Appendix 1.
6.5.6.2
Pharmacodynamic analytical method(s)
Procedures for sample analysis will be supplied by the central laboratory and checked by 
Novartis personnel.
6.6
Safety
6.6.1
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, 
and 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 to the Assessment schedules.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded the (e)CRF. Significant findings that are present prior to 
the start of study drug must be included in the Relevant Medical History/Current Medical 
Conditions screen on the patient’s (e)CRF. Significant findings made after the start of study 
drug which meet the definition of an Adverse Event must be recorded on the Adverse Event 
screen of the patient’s (e)CRF.
6.6.2
Vital signs
Vital signs include body temperature, BP and pulse measurements. After the patient has been 
sitting for 3 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. In case the cuff sizes available are not large enough for the 
patient's arm circumference, a sphygmomanometer with an appropriately sized cuff may be 
used.
Body temperature will be measured at visits according to the Assessment schedules. Blood 
pressure and pulse rate will be measured at visits according to the Assessment schedules. If 


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vital signs are out-of-range at screening or baseline, the Investigator should obtain two 
additional readings, so that a total of five (5) consecutive assessments are made, with the 
patient seated quietly for approximately five (5) minutes preceding each repeat assessment. At 
least the last reading must be within the ranges provided above in order for the patient 
to qualify.
6.6.3
Height and weight
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 will be measured at visits according to the Assessment schedules.
6.6.4
Laboratory evaluations
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening and/or at the initial baseline, the 
assessment may be repeated once (for the purpose of inclusion), and in any case, prior to 
enrollment, to rule out laboratory error. If the repeat value remains outside of protocol-
specified ranges, the patient should be excluded from the study.
The following laboratory evaluations for safety will be performed locally: hematology, 
clinical chemistry, urinalysis (Section 6.6.4.1 to Section 6.6.4.3).
In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range for the center at screening and/or initial baseline, a decision regarding whether 
the result is of clinical significance or not shall be made by the Investigator and shall be based, 
in part, upon the nature and degree of the observed abnormality. The assessment may be 
repeated 
once 
(for 
the 
purpose 
of 
inclusion) 
and 
in 
any 
case, 
prior 
to 
enrollment/randomization, to rule out laboratory error.
In all cases, the Investigator must document in the source documents, the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the patient to continue in the study.
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
6.6.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, 
(monocytes, eosinophils, basophils, neutrophils, lymphocytes), and platelet count will be 
measured.
6.6.4.2
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, total cholesterol, 
HDL-cholesterol, LDL-cholesterol, triglycerides, chloride, creatinine, CK, -GT, fasting 


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plasma glucose, LDH, inorganic phosphorus, lipase, amylase, magnesium, potassium, total 
protein, AST, ALT, sodium,, urea/BUN and uric acid.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.
6.6.4.3
Urinalysis
A midstream urine sample (approx 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments.
A semi-quantitative "dipstick" evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes and blood.
6.6.5
Electrocardiogram (ECG)
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 
amounts of additional ECG data with central reading, but are not intended to provide real-time 
assessment of cardiac intervals and cardiac rhythm.
Twenty-four hour continuous 12-lead Holter recording with central reading of data are done 
on each patient according to the Assessment schedules.
Twelve-lead safety ECGs are collected at the study sites according to the Assessment 
schedules. At each visit when a study drug dose is administered, the safety ECG should be
collected at 1.5 hours post-dose (approximately at the time of Cmax). If the patient chooses to 
enroll in long term extension-1 and long term extension-2 studies, 12-lead safety ECGs will 
also be done according to the Assessment schedules, and the timing will also be 1.5 hours 
post-dose if study drug is administered.
Twelve-lead safety ECGs are collected at the study site using local ECG equipment. 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 section of the CRF / eCRF.
Each 12-lead Safety ECG tracing should be labeled with the:

study number

patient initials

patient number

date and time
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 eCRF will contain:

date and time of ECG

heart rate

PR interval

QT and QTc interval


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
QRS duration
The Fridericia QT formula (QTcF) to correct for variations in heart rate should be used for 
clinical decisions (Fridericia 1920).
The purpose of the safety ECG is to identify patients with clinically significant (“notable”
ECG abnormalities. On the day of the first study drug administration (day 1), the pre-dose 
ECG must be done in triplicate. The mean of the QTcF from these 3 tracings is used as the 
baseline QTcF to be compared with the 1.5 hour post-dose ECG on Day 1 only.
Only ECGs with clinically significant (“notable”) abnormalities should be reported on the 
ECG tracing. A “notable abnormality” is defined as:

Day 1 only: an increase in QTcF > 30msec at 1.5 hours post-dose, compared to the mean 
pre-dose baseline QTcF from the same day

QTcF > 480msec with acute cardiovascular risk, as assessed by a consulting cardiologist

Any QTcF > 500msec, confirmed by a consulting cardiologist
Notable ECG abnormalities should be recorded on the Adverse Events e(CRF) page. 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.
For any ECGs with patient safety concerns, two additional 12-lead ECGs should be performed 
to confirm the safety finding. 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.
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 LCI699 pharmacokinetic (PK) 
assessment (Figure 6-1).
Figure 6-1
Sequence of cardiovascular data collection
Original ECG tracings, appropriately signed, will be archived at study site.
QT prolongation monitoring
On the day of the first administration of LCI699 (day 1), the pre-dose baseline ECG must be 
done in triplicate. The mean of the QTcF values from these three ECG tracings is used to 
determine the mean baseline QTcF for that day only. If the safety ECG (1.5 hours post-first 
dose of LCI) shows an increase in QTcF > 30ms from the mean baseline value, or the QTcF 
is > 480ms, then the patient should be discontinued from study drug. Any ECG in doubt 


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should be reviewed promptly by a consulting cardiologist before discontinuing the patient 
from LCI699 therapy.
If at any follow up visit, a QTcF > 500msec is observed on the 1.5 hour post-dose safety ECG, 
then triplicate 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 > 500msec, 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.
If the cardiologist confirms a mean QTcF > 500msec, the patient has to discontinue according 
to the discontinuation procedure described in Section 5.5.9. The patient must remain under 
observation until the QTcF is < 480msec 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.
Otherwise, and if the cardiologist confirms, that at least one ECG shows a QTcF > 480msec, 
the cardiac assessments described for a confirmed QTcF > 480msec need to be followed.
If at any follow up visit a 480msec < QTcF ≤ 500msec is observed on the 1.5 hour post-dose 
safety ECG, the following steps need to be taken (described in Figure 6-2):
The patient has to interrupt study treatment while an urgent cardiology consultation is 
obtained to re-evaluate the ECG. 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.

If a QTcF > 480msec is NOT confirmed, no further action needs to be taken;

If a QTcF > 480msec is confirmed, a cardiologist must perform a thorough clinical 
evaluation to assess the patient for acute cardiovascular risk, and for possible underlying 
heart disease that needs additional evaluation and management.
a. If based upon the assessment by the cardiologist, the investigator considers that there 
is an acute cardiovascular safety risk and that the subject should not continue with 
study medication, the subject needs to be discontinued immediately (discontinuation 
criteria described in Section 5.5.9).
b. If based upon the assessment by the cardiologist, the investigator considers that there 
is not an acute cardiovascular safety risk, the subject can continue to receive study 
medication.
The patient must remain under observation until the QTcF is < 480msec and serum 
electrolytes, calcium, and magnesium are measured and the results are normal. This 
observation may be done at the site, in an Emergency Room, or a cardiology clinic, as 
appropriate and depending upon local resources. The results of the ECGs, cardiac examination 
and the recommendation by the cardiologist must be evaluated by the investigator to 
determine whether the subject should continue in the trial or not.


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Figure 6-2
QT Prolongation Monitoring Flow Chart
6.6.6
Pituitary MRI
Pituitary MRI scanning with gadolinium enhancement will be performed at visits according to 
the Assessment schedules. These will be assessed locally to determine tumor volume and 
longest diameter and recorded in the eCRF. If MRI intravenous contrast is contraindicated for 
a patient, a non-contrast MRI scan should be performed. If MRI cannot be performed at all 
then a CT (with i.v. contrast if not contraindicated) may be performed. Digital copies of all 
imaging should be kept on site in the event Novartis requests their transfer for 
review/adjudication. Please see the study imaging manual for further information.
6.6.7
Pregnancy
Pregnancy 
tests 
are 
required 
of 
all 
female 
patients 
regardless 
of 
reported 
reproductive/menopausal status.
Serum pregnancy tests will be performed at screening, baseline and End of Study visit. Urine 
or serum pregnancy testing will be performed as indicated in the Assessment schedule.
Perform ECG
QTcF > 500 msec?
Perform triplicate ECG,
each 2-3 min apart
Mean QTcF > 500 msec?
(≥1 ECG with)
QTcF > 480 msec?
Patient is observed
until QTcF < 480 msec, and 
electrolytes, calcium and 
magnesium are normal, 
then can continue on 
study
Patient is observed until
QTcF < 480 msec, and electrolytes, 
calcium and magnesium are normal,
then discontinued from study
Interrupt study treatment and obtain 
cardiology consultation on ECG
Clinical cardiology consultation as 
needed
Acute cardiovascular 
safety risk?
Cardiologist confirms
Mean QTcF > 500 msec?
Cardiologist confirms (≥ 1 ECG
with) QTcF > 480 msec?
YES
NO
YES
YES
NO
NO
NO
NO
NO
YES
Patient can continue/
resume study 
treatment
YES
YES
Interrupt study treatment and obtain 
cardiology consultation on ECG
Clinical cardiology consultation as 
needed


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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 and baseline, the result of this test must be received before the 
patient may be dosed.
6.6.8
Meal record
Not applicable.
6.7
Pharmacokinetics
6.7.1
Pharmacokinetics
The PK parameters of LCI699 to be assessed are listed in Table 6-1. Visit schedules for 
LCI699 PK blood collection are shown in Table 6-2.
If data allows, Ctrough,ss will be utilized as concentration at 12 h post-dose for the 
calculation of AUC0-12,ss and T1/2,ss. This is based on the PK principle that at steady state, 
Ctrough is assumed to be the same at the beginning and end of the dose interval, in this case 
12 h.
Table 6-1
Non-compartmental pharmacokinetic parameters for LCI699
Cmax,ss
The maximum plasma concentration at steady state. The unit is ng/mL.
Tmax,ss
The time to reach the maximum plasma concentration at steady state. The unit is hr.
AUC0-6hr,ss
The AUC from time zero to 6 hours post dose at steady state. The unit is hr*ng/mL.
AUC0-12hr,ss
The AUC from time zero to 12 hours post dose at steady state, calculated by using the pre-dose 
concentration (Ctrough,ss) as the 12 hr concentration, assuming steady-state has been reached. 
The unit is hr*ng/mL
T1/2,ss
The elimination terminal half-life at steady-state. The unit is hr.
Ctrough,ss
The pre-dose concentration at steady-state. The unit is ng/mL.
6.7.1.1
LCI699 PK blood collection and processing
For new patients enrolled after Amendment 4 (expansion cohort), pharmacokinetic (PK) 
blood samples will be collected during visits on Study Day 14 (Visit 5), 28 (Visit 6), 42 (Visit 
7), 56 (Visit 8) and70 (Visit 9) in the dose escalation period. Briefly, PK samples will be 
collected at pre-dose (0 hour), and 1, 1.5, 2, 4, 6 hour post AM dose during Visit 5 on Day 14 
for the first dose level. If a patient is required to escalate to the next dose level (UFC>ULN) 
during the dose escalation phase of the study, then the above PK sample collection will be 
required again at the next visit (2 weeks after starting the next dose level). For patients who 
have normalized UFC, only pre-dose (trough) PK samples will be collected during the visits 
in the dose escalation phase of the study. (Table 6-2, PK collection No. of 2, 3, 4 or 5).
For patients re-entering the study (core PoC follow-up cohort), the 6-hr PK profile blood 
samples (pre-dose, 1, 1.5, 2, 4, and 6 hr post-dose) will only be collected from these patients 
at day 14 (Visit 5), and only pre-dose PK blood samples will be collected in the following 
visits 6, 7, 8 and 9.


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From Day 70 through Day 154, only pre-dose (trough) PK samples will be collected from all 
patients during visits on Study Day 98 (Visit 10), 126 (Visit 11), and 154 (Visit 777).
PK parameters of LCI699 will be determined (if feasible) by Phoenix WinNonlin using 
noncompartmental analysis (Table 6-1).
Table 6-2
PK blood sampling for LCI699
PK Sample No
PK Collection No
Treatment 
Period
Visit
No
Study Day
Time (hrs post 
dose)b
Volume 
(mL)
7
1
1
5
14
0(pre-dose)a
2
8
1
1
5
14
1
2
9
1
1
5
14
1.5
2
10
1
1
5
14
2
2
11
1
1
5
14
4
2
12
1
1
5
14
6
2
13
2
1
6
28
0(pre-dose)a
2
14
2
1
6
28
1
2
15
2
1
6
28
1.5
2
16
2
1
6
28
2
2
17
2
1
6
28
4
2
18
2
1
6
28
6
2
19
3
1
7
42
0(pre-dose)a
2
20
3
1
7
42
1
2
21
3
1
7
42
1.5
2
22
3
1
7
42
2
2
23
3
1
7
42
4
2
24
3
1
7
42
6
2
25
4
1
8
56
0(pre-dose)a
2
26
4
1
8
56
1
2
27
4
1
8
56
1.5
2
28
4
1
8
56
2
2
29
4
1
8
56
4
2
30
4
1
8
56
6
2
31
5
1
9
70
0(pre-dose)a
2
32
5
1
9
70
1
2
33
5
1
9
70
1.5
2
34
5
1
9
70
2
2
35
5
1
9
70
4
2
36
5
1
9
70
6
2
37
6
2
10
98
0(pre-dose)a
2
38
7
2
11
126
0(pre-dose)a
2
39
8
2
777
154
0(pre-dose)a
2
a Samples will be collected prior to the AM dose of LCI699
b Deviations for the following PK assessment times are acceptable based on logistical and operational 
considerations: ± 5 min for time-points up to and including 2 hours; ± 10 min for time-points up to and including 6 
hours.


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All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. A total of 2 mL of venous blood will be collected at each time 
point into K2-EDTA-containing polyethylene tubes.
Immediately after blood is drawn, the tube should be inverted gently several times to ensure 
the mixing of contents (e.g., anticoagulant). Avoid prolonged sample contact with the rubber 
stopper. Tubes should be stored on wet ice until centrifuged. Within 60 minutes, centrifuge 
the sample between 3 and 5°C for 10 minutes at approximately 1500 g. Immediately after 
centrifugation, transfer a minimum of 0.7 ml plasma into 2 ml conical polypropylene screw-
cap tubes (Sarstedt, part# 72.693) followed by proper mixing and put on dry ice. The labels 
will be provided by the site. The tubes will be kept frozen at approximately -60°C pending on 
shipment on dry ice for analysis. Note: the specified tubes are required for automation 
compatibility. No substitutions are permissible. The samples should be shipped to the central 
laboratory of the study as indicated in the laboratory manual.
The exact clock time of dosing, as well as actual sample collection date and time will be 
entered on the PK blood collection summary page of the CRF. Sampling problems will be 
noted in the relevant field of the CRF.
The plasma samples for the pharmacokinetic profile must be labeled according to the central 
laboratory requirements:
Labels will be provided by the central laboratory. The exact clock time of dosing will be 
entered on the dose administration page of the CRF, and the actual sample collection date and 
time will be entered on the PK blood collection summary page of the CRFs. Sampling 
problems will be noted in the relevant field of the CRF.
6.7.2
Urine collection and processing
Not applicable.
6.7.3
Pharmacokinetic analytical method(s)
The plasma samples from all patients will be assayed for LCI699 concentrations using a 
validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The limit 
of quantitation will be 0.05 ng/mL for plasma. Copies of the first 5% of the standard curves 
and sample chromatograms or instrument printouts will be included along with a summary of 
the analytical method. Data will be provided to demonstrate that the assay method has the 
required specificity, accuracy, precision, limits of quantification, linearity, recovery, and 
stability for LCI699 in plasma.
 


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7
Safety monitoring
7.1
Adverse events
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after obtaining informed consent even if the event is not 
considered to be related to study drug. Study drug includes the investigational drug under 
evaluation and the comparator drug or placebo that is given during any phase of the study. 
Medical conditions/diseases present before obtaining informed consent are only considered 
adverse events if they worsen. Abnormal laboratory values or test results constitute adverse 
events only if they induce clinical signs or symptoms, or are considered clinically significant, 
or require therapy.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 


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by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. All adverse events must be recorded on the Adverse Events e(CRF) with 
the following information:
1. the severity grade CTC grade 1 – 4.
2. its relationship to the study drug(s) (suspected/not suspected).
3. its duration (start and end dates or if continuing at final exam).
4. whether it constitutes a serious adverse event (SAE).
An SAE is defined as an event which:

is fatal or life-threatening.

results in persistent or significant disability/incapacity.

constitutes a congenital anomaly/birth defect.

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

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 the start of study drug.

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission.

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition.

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.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s 
hospitalization prolonged. The action taken to treat the adverse event should be recorded on 
the Adverse Event e(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 drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates 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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7.2
Serious adverse event reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 28 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) 
must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 28 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is 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. The investigator must assess the relationship of any SAE to study drug, complete the 
SAE Report Form in English, and send the completed, signed form by fax within 24 hours to 
the local Novartis Drug Safety and Epidemiology Department. The telephone and telecopy 
number of the contact persons in the local department of Clinical Safety and Epidemiology, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site.
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, 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 drug, a Drug Safety and 
Epidemiology 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.
7.3
Pregnancies
To ensure patient safety, each pregnancy in a patient on study drug 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.


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Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must 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
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and (e)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 (e)CRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.
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 on (e)CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (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 (e)CRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the (e)CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. After
database lock, the investigator will receive a CD-ROM or paper copies of the patient data for 
archiving at the investigational site.


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8.3
Database management and quality control
Novartis staff or CRO working on behalf of Novartis review the data entered into the eCRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data.
Concomitant 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.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be made available for data analysis.
9
Data analysis
9.1
Analysis sets
The 12 Cushing’s disease patients who were enrolled in the study prior to Amendment 4 are 
considered as core PoC cohort. Patients who re-enter the study after Amendment 4 are 
considered as core PoC follow-up cohort. The 15 new patients enrolled after Amendment 4
are considered as expansion cohort.
Core PoC cohort:
Safety analysis set (SAS): all patients that received at least one dose of study drug prior to 
Amendment 4.
The SAS will be applied for both efficacy and safety analyses for Core PoC.


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PK analysis set: all patients with at least one dose of study drug and at least one post-dose PK 
assessment prior to Amendment 4.
Core PoC follow-up cohort:
Full analysis set (FAS): all patients who are re-entering the study after Amendment 4.
Safety analysis set (SAS): all patients that received at least one dose of study drug after re-
entering the study.
PK analysis set: all patients with at least one dose of study drug and at least one post-dose PK 
assessment after re-entering the study.
Expansion cohort:
Full analysis set (FAS): all patients who were enrolled in the study after Amendment 4. Safety 
analysis set (SAS): all patients who received at least one dose of study drug.
The SAS will be applied for both efficacy and safety analyses for the expansion cohort. The 
FAS will be applied for the listing purpose.
PK analysis set: all enrolled patients with at least one dose of study drug and at least one post-
dose PK assessment.
9.2
Demographics and other baseline characteristics
Summary statistics will be provided for demographics and baseline characteristics. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum and maximum will be provided. All data for 
background and demographic variables will be listed.
Relevant medical history, current medical conditions, results of laboratory screens and any 
other relevant information will be listed.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Descriptive statistics will be used to summarize the total dose of study medication. 
Concomitant medications will be summarized by ATC class, preferred term by both primary 
and secondary safety analysis sets, by means of frequency and percentages. Study drug 
administration, concomitant medication will also be listed.
9.4
Analysis of the primary variable(s)
The primary objective of the study is to assess the effects of 10 weeks treatment of LCI699 on 
UFC in patients with Cushing’s disease for the core PoC cohort. The primary analysis will be 
based on the Week 10 mean UFC level treating response as a binary outcome for the patients 
included in the core PoC cohort.


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9.4.1
Variable
The primary variable is defined as the proportion of responders to LCI699 at week 10. A 
patient is considered to be a responder if the mean UFC level (at least two 24 hour 
measurements) from the Week 10 is ≤ ULN or represents a ≥50% decrease from baseline. 
Patients who discontinue for a disease or treatment related reason (e.g. death, adverse event, 
clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels are higher than 
the normal limit and experience <50% decrease in UFC are classified as non-responders. 
Patients who have <2 baseline or post-baseline 24-hour UFC measurement will not be 
included in the primary analyses.
In addition, responders will be classified further into controlled and partially controlled. 
Controlled UFC responder is defined as the patient whose mean UFC ≤ 1.0 x ULN. Partially 
Controlled UFC responder is defined as the patient whose mean UFC > 1.0 x ULN but 
declined by at least 50% from baseline.
9.4.2
Statistical model, hypothesis, and method of analysis
The proportion of responders and the associated 95% confidence interval will be estimated 
using the exact method.
9.4.3
Handling of missing values/censoring/discontinuations
Missing values will not be imputed.
9.4.4
Supportive analyses
The urine creatinine will be checked to ensure that the 24 hour urine collection is complete.
The proportion of responders among patients with one or more 24 hour measurements for 
both baseline and Week 10 will be estimated and the 95% confidence interval will be 
provided. If a patient has no UFC collections at the Week 10 visit, the UFC evaluation for that 
patient at the preceding visit will be used.
Summary statistics of UFC levels at each visit will be presented. A paired t-test will be 
performed to compare Week 10 and baseline mean 24 hour UFC. Mean 24 hour UFC will be 
log-transformed prior to the analysis. Point estimate and the associated 95% confidence 
interval for the ratio of geometric means (Week 10/baseline) will be obtained from the paired 
t-test. Salivary cortisol at midnight and other times of the day will be analyzed similarly.A 
second responders analysis will be performed to determine the proportion of patients who 
normalize their UFC in response to LCI699 (achieve a mean week 10 UFC ≤ ULN).
Additionally, the proportion of patients with at-least one (Week 2 to Week 8) or mean (Week
10) UFC measurement that is ≤ULN or represents a greater than 50% reduction from baseline 
will be determined.


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9.5
Analysis of secondary variables
9.5.1
Pharmacodynamics
Core PoC cohort
Plasma ACTH, aldosterone, renin, glucose, insulin, HOMA, and serum cortisol, sodium and 
potassium measurements will be summarized by visit. A paired t-test will be performed to 
compare Week 10 and baseline for each endpoint. Measurements will be log-transformed 
prior to the analysis. Point estimate and the associated 95% confidence interval for the ratio of 
geometric means (Week 10/baseline) will be obtained from the paired t-test.
Core PoC follow-up cohort & Expansion cohort
The following analyses will be conducted separately for each of the two cohorts (Core PoC 
follow-up and Expansion).
The proportion of responders at Weeks 10 and 22 will be summarized using point estimates 
and 95% CIs (Exact Method). Analyses will be based on the SAS. If mUFC is missing a 
particular time point, then the value will not be imputed but the patient will be considered a 
non-responder at that time point.
In addition, responders will be further classified as controlled and partially controlled.
Descriptive summaries will be generated for the change from the respective baselines to 
different time points in mUFC, plasma ACTH, serum cortisol, steroid hormones, tumor 
volume, SBP, DBP, weight, BMI, lipids, HbA1c and FPG. 95% CIs will also be provided for 
the changes from baseline.
9.5.2
Escape analysis
Only patients who attained UFC normalization during the study will be included in the escape 
analysis, where escape is defined as the loss of UFC control (i.e. UFC > ULN) on at least 2 
consecutive visits at the highest tolerated dose after previously attaining UFC normalization. 
“First-time escape” is used to describe the first occurrence of 2 consecutive visits with 
uncontrolled UFC at the patient’s highest tolerated dose after attaining UFC normalization. 
Time to escape is defined as the number of weeks from the visit of first UFC normalization 
(mUFC <= 1x ULN) to the first visit of first-time escape. For patients who have no safety 
issue, 30 mg bid is the highest tolerated dose. For patients who have dose reduction due to 
safety reasons, the resulting reduced dose will be the highest tolerated dose. For patients who 
discontinue the study due to AEs, the dosage at discontinuation will be considered the highest 
tolerated dose. For all other situations, patients will be considered as not reaching their highest 
tolerated dose.
The median time to escape and corresponding 95% confidence interval will be calculated 
using Kaplan-Meier methodology for each cohort. The Kaplan-Meier curves will be presented. 
In this analysis, a patient who never had two consecutive visits with uncontrolled UFC at 
his/her highest tolerated dose will be censored at his/her last visit with mUFC assessment.


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In addition, time to escape will be summarized using descriptive statistics by cohort for 
patients who meet escape criteria.
9.5.3
Safety
Safety analyses will be done separately for core PoC cohort, expansion cohort and core PoC 
follow-up cohort.
Vital signs
All vital signs data will be listed by patient and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by visit/time.
ECG evaluations
All ECG data will be listed by patient and visit/time, abnormalities will be flagged. Summary 
statistics will be provided by visit/time.
Standard clinical laboratory evaluations
All laboratory data will be listed by patient and visit/time. Abnormalities will be flagged. 
Summary statistics will be provided by visit/time.
Special clinical laboratory evaluations
All laboratory data will be listed by patient and visit/time and if ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time.
Adverse events
All information obtained on adverse events will be displayed by patient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term. A patient with multiple adverse events within a body system is only 
counted once towards the total of this body system.
Concomitant medications / significant non-drug therapies
All concomitant therapies will be listed by patient.
9.5.4
Health-related quality of life
Not applicable.
9.5.5
Pharmacokinetics
All completed patients with plasma concentration will be included in the pharmacokinetic 
data analysis. Pharmacokinetic analysis of this unblinded study may be performed at any time 
during the study, including prior to database lock. The steady-state PK parameters including 


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Cmax, Tmax, AUC0-6hr, AUC0-12hr, T1/2 and Ctrough levels will be summarized using 
descriptive statistics.
Plasma concentrations will be expressed in ng/mL. All concentrations below the limit of 
quantification or missing data will be labeled as such in the concentration data listings. 
Concentrations below the limit of quantification will be treated as zero in summary statistics.
9.5.7
Other biomarkers
Not applicable.
9.5.8
PK/PD
Relationship between LCI699 exposure and PD variables (including QTcF) will be explored 
by graphical approach and descriptive statistics will be provided. Additional statistical 
analysis such as ANOVA or linear or nonlinear regression analysis will be performed, if 
necessary. PK/PD analyses may be reported separately, if appropriate.
9.6
Sample size calculation
Assuming that response rates of less than or equal to 15% are not acceptable, and that 
response rates greater than or equal to 50% are good indication of a beneficial effect, data 
from 12 to 15 patients will provide 70% to 84% power to reject the null hypothesis of 15% 
response rate when the alternative hypothesis of a 50% response rate is true based on an exact 
(binomial) test for single proportion at a significance level of 0.05. The expected drop out rate 
is <20% and drop outs may be replaced to ensure a minimum of 12 completers. The estimated 
response rate (%) along with the 95% confidence interval based on the Exact Bionmial Test 
for each possible outcome in the study are provided in the table below.


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Table 9-1
Precision level (95% confidence interval for each response rate) in the 
study
Number of 
Responders
N=12
N=13
N=14
N=15
0
0 (0, 26)
0 (0, 25)
0 (0, 23)
0 (0, 22)
1
8 (0.2, 38)
8 (0.2, 36)
7 (0.2, 34)
7 (0.2, 32)
2
17 (2, 48)
15 (2, 45)
14 (0.2, 43)
13 (2, 40)
3
25 (5, 57)
23 (5, 54)
21 (5, 51)
20 (4, 48)
4
33 (10, 65)
31 (9, 61)
29 (8, 58)
27 (8, 55)
5
42 (15, 72)
38 (14, 68)
36 (13, 65)
33 (12, 62)
6
50 (21, 79)
46 (19, 75)
43 (18, 71)
40 (16, 68)
7
58 (28, 85)
54 (25, 81)
50 (23, 77)
47 (21, 73)
8
67 (35, 90)
62 (32, 86)
57 (29, 82)
53 (27, 79)
9
75 (43, 95)
69 (39, 91)
64 (35, 87)
60 (32, 84)
10
83 (52, 98)
77 (46, 95)
71 (42, 92)
67 (38, 88)
11
92 (62, 100)
85 (55, 98)
79 (49, 95)
73 (45, 92)
12
100 (74, 100)
92 (64, 100)
86 (57, 98)
80 (52, 96)
13
100 (75, 100)
93 (66, 100)
87 (60, 98)
14
100 (77, 100)
93 (68, 100)
15
100 (78, 100)
The 15 patients in the expansion cohort will also afford the same level of precision around the 
estimate of the responder rate at Month 6, as shown in Table 9-1.
9.7
Power for analysis of key secondary variables
Not applicable.
9.8
Interim analyses
Because this is an open label study, response to the therapy will be monitored as the study 
proceeds. In addition, an interim analysis will be performed after the first12 patients complete 
10 weeks of treatment (core PoC cohort) and a CSR will be generated from this data. 
Additional interim analyses may be conducted for the expansion cohort and the core-PoC 
follow-up cohort. Additional database locks may be conducted to provide data to support the 
market authorization applications for LCI699.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and 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, US Code of Federal Regulations Title
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.


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10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. 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.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study drug 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.
 
 
 
 
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or ethics committee approval will be 
obtained.
10.3
Responsibilities of the investigator and IRB/IEC
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) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. 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 


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Protocol No. CLCI699C2201
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
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 
trial 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 it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
11.1
Protocol Amendments
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. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
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 within 10 working days.


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Protocol No. CLCI699C2201
12
References (available upon request)
Bochicchio D, Losa M, Buchfelder M, et al (1995); Factors influencing the immediate and 
late outcome of Cushing's disease treated by transsphenoidal surgery: a retrospective study by 
the European Cushing's Disease Survey Group. Journal of Clinical Endocrinology and 
Metabolism; 80, 3114-3120.
Estrada J, Boronat M, Mielgo M, et al. (1997). The Long-Term Outcome Of Pituitary 
Irradiation After Unsuccessful Transsphenoidal Surgery In Cushing’s Disease. N Engl J Med 
1997; 336:172-7.
Fridericia L (1920). The duration of systole in the electrocardiogram of normal subjects and 
of patients with heart disease. Acta Medica Scandinavica (53): 469–486.
Losa M, Picozzi P, Redaelli G, et al. Pituitary Radiotherapy for Cushing’s Disease. 
Neuroendocrinology 2010;92 v(suppl 1):107–110.
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.
Minniti G, Osti M, Jaffrain-Rea M, et al. Long-term follow-up results of postoperative 
radiation therapy for Cushing’s disease.ffJ Neurooncol (2007) 84:79–84.
Sonino N, Zielezny M, Fava G, et al (1996); Risk factors and long-term outcome in pituitary-
dependent Cushing’s disease. Journal of Clinical Endocrinology and Metabolism; 81, 2647-
2652.


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Protocol No. CLCI699C2201
13
Appendices
13.1
Appendix 1: Sample Log table - all matrices
Sample Log:
Time schedule for sampling for safety bloods, pharmacokinetic (PK), pharmacodynamic (PD), 
 
Visit no.
Time
Safety 10mL
Plasma LCI699
PK 2mL
LCI699 PK
Collection No
Sample No
Plasma ACTH
4mL
Sample No
Plasma cortisol
3mL
Sample No
Plasma renin
3mL
Sample No
Plasma
Aldosterone
3mL
Sample No
Plasma 
Deoxycorticosterone,
11-deoxycortisol 7mL
Sample No
1
Screening
x
2
Baseline
x
x1
301
x
308
x
315
x
401
x
408
3
Day 1
x
5
Day 14
x
x 6
1
7 
to 
12
x
302
x
309
x
316
x
402
x
409
6
Day 28
x
x 6*
2
13 
to 
18
x
303
x
310
x
317
x
403
x
410
7
Day 42
x
x 6*
3
14 
to 
24
x
304
x
311
x
318
x
404
x
411
8
Day 56
x
x 6*
4
25 
to 
30
x
305
x
312
x
319
x
405
x
412


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Amended Protocol Version 09 (Clean)
Protocol No. CLCI699C2201
Visit no.
Time
Safety 10mL
Plasma LCI699
PK 2mL
LCI699 PK
Collection No
Sample No
Plasma ACTH
4mL
Sample No
Plasma cortisol
3mL
Sample No
Plasma renin
3mL
Sample No
Plasma
Aldosterone
3mL
Sample No
Plasma 
Deoxycorticosterone,
11-deoxycortisol 7mL
Sample No
9
Day 70
x
x 6*
5
31 
to 
36
x
306
x
313
x
320
x
406
x
413
10
Day 98
x
x
6
37
x
350
x
361
x
372
x
450
x
461
11
Day 126
x
x
6
38
x
351
x
362
x
373
x
451
x
462
V777
Day 154
x
x
6
39
x
352
x
363
x
374
x
452
x
463
13
Day 182
x
x
353
x
364
x
375
x
453
x
464
14
Day 210
x
x
354
x
365
x
376
x
454
x
465
15
Day 238
x
x
355
x
366
x
377
x
455
x
466
16
Day 266
x
x
356
x
367
x
378
x
456
x
467
17
Day 294
x
x
357
x
368
x
379
x
457
x
468
18
Day 322
x
x
358
x
369
x
380
x
458
x
469
19
Day 406
x
x
359
x
370
x
381
x
459
x
470
V777
Day 490
x
x
360
x
371
x
382
x
460
x
471
21-26 
Every 3 
monthsX
x
x
2383-2388,
x
2389-2394
x
2395-2400
x
2472,-2477
x
2478-2483
27,28,2
9,..
Every 6 
months
x
x
2501, 
2502,2503,...
x
2601,2602,2
603,...
x
2701,2702,2
703,...
x
2801,2802,28
03, ...
x
2901, 
2902,2903,...
V777
(EOT-2)
x
x
1100
x
1102
x
1103
x
1104
x
1105
V778
EOS
x
x
307
x
314
x
321
x
407
x
414


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Amended Protocol Version 09 (Clean)
Protocol No. CLCI699C2201
Visit no.
Time
Safety 10mL
Plasma LCI699
PK 2mL
LCI699 PK
Collection No
Sample No
Plasma ACTH
4mL
Sample No
Plasma cortisol
3mL
Sample No
Plasma renin
3mL
Sample No
Plasma
Aldosterone
3mL
Sample No
Plasma 
Deoxycorticosterone,
11-deoxycortisol 7mL
Sample No
999
Unschedule
d
20
01
3001
4001
5001
6001
7001
* PK samples to be collected at (1) pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or (2) pre-dose (trough) for maintained dose
1 to be collected between day-14 and day-7
X to be collected every 3 months for the first 18 months and then every 6 months until EOT extension-2
Visit no.
Time
free T4, TSH, LH,
FSH, 7.5mL
Sample No
HbA1C, 2mL
Sample No
Insulin, 3.5mL
Sample No
Testosterone
2mL
Sample No
Estradiol 2mL
Sample No
IGF-1 6mL
Sample No
1
Screening
x
426
x
433
2
Baseline
x1
415
x1
417
x
419
x
427
x
434
x
440
3
Day 1
5
Day 14
x
420
x
428
x
435
6
Day 28
x
421
x
429
x
436
7
Day 42
x
422
x
430
x
437
8
Day 56
x
423
x
431
x
438
9
Day 70
x
416
x
418
x
424
x
502
x
514
x
441
10
Day 98
x
472
x
491
x
503
x
515
x
526


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Amended Protocol Version 09 (Clean)
Protocol No. CLCI699C2201
Visit no.
Time
free T4, TSH, LH,
FSH, 7.5mL
Sample No
HbA1C, 2mL
Sample No
Insulin, 3.5mL
Sample No
Testosterone
2mL
Sample No
Estradiol 2mL
Sample No
IGF-1 6mL
Sample No
11
Day 126
x
473
x
492
x
504
x
516
x
527
V777
Day 154
x
474
x
484
x
493
x
505
x
517
x
528
13
Day 182
x
475
x
494
x
506
x
518
x
529
14
Day 210
x
476
x
495
x
507
x
519
x
530
15
Day 238
x
477
x
485
x
496
x
508
x
520
x
531
16
Day 266
x
478
x
497
x
509
x
521
x
532
17
Day 294
x
479
x
486
x
498
x
510
x
522
x
533
18
Day 322
x
480
x
487
x
499
x
511
x
523
x
534
19
Day 406
x
481
x
488
x
500
x
512
x
524
x
535
V777
Day 490
x
482
x
489
x
501
x
513
x
525
x
536
21-26
Every 3 
months
x
2538-2543
x
2544-2549
x
2550-2555
x
2556-2561
x
2562-2567
x
2568-2573
27,28,29
…
Every 6 
months
x
2574,2575,257
6…
x
2577,2578,257
9…
x
2580,2581,258
2…
x
2583,2584,258
5…
x
2586,2587,258
8…
x
2589,2590,259
1…
EOT-
EXT-2
EOT
x
1110
x
1111
1114
1115
1116
V778
EOS
x
483
x
425
x
432
x
439
x
537
1 to be collected between day-14 and day-7
X to be collected every 3 months for the first 18 months and every 6 months until EOT for extension-2


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Amended Protocol Version 09 (Clean)
Protocol No. CLCI699C2201
Urine Log:
Time schedule for urine sampling pharmacodynamic (PD)
Study Phase
Urine 
Aldosterone
(5ml)
Sample
Number
Urine 
Sodium/
Potassium 
(20ml)
Sample
Number
Urine 
deoxycorticosterone 
(5ml)
Sample
Number
Treatment
Day
Time
Baseline
Day -14 to 0
n/a
x
101
x
108
x
116
Treatment
Day 1
0-24 hr pre 
am dose D1
x
109
Treatment
Day 14
Pre-dose1
x
102
x
110
x
117
Treatment
Day 28
Pre-dose1
x
103
x
111
x
118
Treatment
Day 42
Pre-dose1
x
104
x
112
x
119
Treatment
Day 56
Pre-dose1
x
105
x
113
x
120
Treatment
Day 70
Pre-dose1
x
106
x
114
x
121
Treatment
Day 98
Pre-dose1
x
150
x
161
x
172
Treatment
Day 126
Pre-dose1
x
151
x
162
x
173
Treatment
Day 154
Pre-dose1
x
152
x
163
x
174
Extension-
Day 182
Pre-dose1
x
153
x
164
x
175
Extension-1
Day 210
Pre-dose1
x
154
x
165
x
176
Extension-1
Day 238
Pre-dose1
x
155
x
166
x
177
Extension-1
Day 266
Pre-dose1
x
156
x
167
x
178
Extension-1
Day 294
Pre-dose1
x
157
x
168
x
179
Extension-1
Day 322
Pre-dose1
x
158
x
169
x
180
Extension-1
Day 406
Pre-dose1
x
159
x
170
x
181


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Amended Protocol Version 09 (Clean)
Protocol No. CLCI699C2201
Study Phase
Urine 
Aldosterone
(5ml)
Sample
Number
Urine 
Sodium/
Potassium 
(20ml)
Sample
Number
Urine 
deoxycorticosterone 
(5ml)
Sample
Number
Treatment
Day
Time
Baseline
Day -14 to 0
n/a
x
101
x
108
x
116
Extension-1
Day 490
n/a
x
160
x
171
x
182
Extension-2x
Every 3 months
Pre-dose1
2186-2191
x
2192-2197
x
2198-2203
Extension-2x
Every 6 months 
Pre-dose1
2204,2205,2206…
x
2207,2208,2209…
x
2210,2211,2212…
Ext-2 EoT
EOT
Pre-dose1
1201
x
1202
x
1203
EOS
EOS
n/a
107
x
115
x
122
1= urine sample collected for the 24 hours prior to am dose of clinic visit
X= to be collected every 3 months for the first 18 months and every 6 months until EOT for extension-2


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Protocol No. CLCI699C2201
Saliva Log: Time schedule for saliva sampling pharmacodynamic (PD)
Study Phase
Saliva Sample
Treatment
Day
Time
Sample No
Time
Sample No
Baseline
-14
06-08:00
601
23-24:00
602
Baseline
-7
06-08:00
615
23-24:00
616
Baseline
-1
06-08:00
627
23-24:00
628
Treatment
6
06-08:00
639
23-24:00
640
Treatment
13
06-08:00
653
23-24:00
654
Treatment
20
06-08:00
667
23-24:00
668
Treatment
27
06-08:00
681
23-24:00
682
Treatment
34
06-08:00
695
23-24:00
696
Treatment
41
06-08:00
709
23-24:00
710
Treatment
48
06-08:00
723
23-24:00
724
Treatment
55
06-08:00
737
23-24:00
738
Treatment
62
06-08:00
751
23-24:00
752
Treatment
69
06-08:00
765
23-24:00
766
Treatment
76
06-08:00
779
23-24:00
780
Treatment
83
06-08:00
793
23-24:00
794
Treatment
90
06-08:00
797
23-24:00
798
Treatment
97
06-08:00
799
23-24:00
800
Treatment
104
06-08:00
801
23-24:00
802
Treatment
111
06-08:00
803
23-24:00
804
Treatment
118
06-08:00
805
23-24:00
806
Treatment
125
06-08:00
807
23-24:00
808
Treatment
132
06-08:00
809
23-24:00
810
Treatment
139
06-08:00
811
23-24:00
812
Treatment
146
06-08:00
813
23-24:00
814
Treatment
153
06-08:00
815
23-24:00
816
Ext-1
181
06-08:00
817
23-24:00
818
Ext-1
209
06-08:00
819
23-24:00
820
Ext-1
237
06-08:00
821
23-24:00
822
Ext-1
265
06-08:00
823
23-24:00
824
Ext-1
293
06-08:00
825
23-24:00
826
Ext-1
321
06-08:00
827
23-24:00
828
Ext-1
405
06-08:00
829
23-24:00
830
Ext-1
489
06-08:00
831
23-24:00
832
Ext-2
Every 3 months
06-08:00
2835-2840
23-24:00
2841-2846
Ext-2
Every 6 months
06-08:00
2847,2848,2849…
23-24:00
2850,2851,2852…
EOT- Ext-2
n/a
06-08:00
1301
23-24:00
1302
EOS
n/a
06-08:00
833
23-24:00
834


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Protocol No. CLCI699C2201
13.2
Appendix 2: Sample labeling and shipping information
Labels will need to be provided by the central laboratory. No added label should cover the 
original label.
The Sample Numbers are reported in the Blood / Urine Log table in Appendix 1.
Detailed instructions for collection, handling, storage and shipment of samples are outlined in 
the [CLCI699C2201 Central Laboratory Manual].
PK blood samples will be shipped to the central laboratory where they will be stored and 
finally forwarded to the following address for bioanalysis:
,
Novartis Pharmaceuticals Corporation
One Health Plaza
East Hanover, NJ 07936, USA


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Protocol No. CLCI699C2201
13.3
Appendix 3: Possible drug-drug interactions with LCI699
CYP2E1
CYP1A2
CYP2D6
enflurane
amitriptyline
tamoxifen
halothane
caffeine
carvedilol
isoflurane
clomipramine
S-metoprolol
methoxyflurane
clozapine
propafenone
sevoflurane
cyclobenzaprine
timolol
acetaminophen
estradiol
amitriptyline
chlorzoxazone
fluvoxamine
clomipramine
ethanol
haloperidol
desipramine
N,N-dimethylformamide
imipramine
fluoxetine
theophylline
mexiletine
imipramine
naproxen
paroxetine
olanzapine
haloperidol
ondansetron
perphenazine
phenacetin
risperidone
acetaminophen
thioridazine
propranolol
zuclopenthixol
riluzole
alprenolol
ropivacaine
amphetamine
tacrine
aripiprazole
theophylline
atomoxetine
tizanidine
bufuralol
verapamil
chlorpheniramine
(R)warfarin
chlorpromazine
zileuton
codeine
zolmitriptan
debrisoquine
dexfenfluramine
dextromethorphan
donepezil
duloxetine
encainide
flecainide
fluvoxamine
lidocaine
metoclopramide
methoxyamphetamine
mexiletine
minaprine
nebivolol
nortriptyline
ondansetron
oxycodone
perhexiline
phenacetin
phenformin


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Protocol No. CLCI699C2201
CYP2E1
CYP1A2
CYP2D6
promethazine
propranolol
sparteine
tramadol
venlafaxine


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Protocol No. CLCI699C2201
13.4
Appendix 4: Determination of body mass index (weight[kg] / height[m]2)
Height 
(m)
Weight (kg)
46
48
50
52
54
56
58
60
62
64
66
68
70
72
74
76
78
80
82
84
86
88
90
92
1.4
4
22.
2
23.
1
24.
1
25.
1
26.
0
27.
0
28.
0
28.
9
29.
9
30.
9
31.
8
32.
8
33.
8
34.
7
35.
7
36.
7
37.
6
38.
6
39.
5
1.4
6
21.
6
22.
5
23.
5
24.
4
25.
3
26.
3
27.
2
28.
1
29.
1
30.
0
31.
0
31.
9
32.
8
33.
8
34.
7
35.
7
36.
6
37.
5
38.
5
39.
4
1.4
8
21.
0
21.
9
22.
8
23.
7
24.
7
25.
6
26.
5
27.
4
28.
3
29.
2
30.
1
31.
0
32.
0
32.
9
33.
8
34.
7
35.
6
36.
5
37.
4
38.
3
39.
3
1.5
0
20.
4
21.
3
22.
2
23.
1
24.
0
24.
9
25.
8
26.
7
27.
6
28.
4
29.
3
30.
2
31.
1
32.
0
32.
9
33.
8
34.
7
35.
6
36.
4
37.
3
38.
2
39.
1
1.5
2
19.
9
20.
8
21.
6
22.
5
23.
4
24.
2
25.
1
26.
0
26.
8
27.
7
28.
6
29.
4
30.
3
31.
2
32.
0
32.
9
33.
8
34.
6
35.
5
36.
4
37.
2
38.
1
39.
0
1.5
4
19.
4
20.
2
21.
1
21.
9
22.
8
23.
6
24.
5
25.
3
26.
1
27.
0
27.
8
28.
7
29.
5
30.
4
31.
2
32.
0
32.
9
33.
7
34.
6
35.
4
36.
3
37.
1
37.
9
38.
8
1.5
6
18.
9
19.
7
20.
5
21.
4
22.
2
23.
0
23.
8
24.
7
25.
5
26.
3
27.
1
27.
9
28.
8
29.
6
30.
4
31.
2
32.
1
32.
9
33.
7
34.
5
35.
3
36.
2
37.
0
37.
8
1.5
8
18.
4
19.
2
20.
0
20.
8
21.
6
22.
4
23.
2
24.
0
24.
8
25.
6
26.
4
27.
2
28.
0
28.
8
29.
6
30.
4
31.
2
32.
0
32.
8
33.
6
34.
4
35.
3
36.
1
36.
9
1.6
0
18.
0
18.
8
19.
5
20.
3
21.
1
21.
9
22.
7
23.
4
24.
2
25.
0
25.
8
26.
6
27.
3
28.
1
28.
9
29.
7
30.
5
31.
3
32.
0
32.
8
33.
6
34.
4
35.
2
35.
9
1.6
2
18.
3
19.
1
19.
8
20.
6
21.
3
22.
1
22.
9
23.
6
24.
4
25.
1
25.
9
26.
7
27.
4
28.
2
29.
0
29.
7
30.
5
31.
2
32.
0
32.
8
33.
5
34.
3
35.
1
1.6
4
17.
8
18.
6
19.
3
20.
1
20.
8
21.
6
22.
3
23.
1
23.
8
24.
5
25.
3
26.
0
26.
8
27.
5
28.
3
29.
0
29.
7
30.
5
31.
2
32.
0
32.
7
33.
5
34.
2
1.6
6
18.
1
18.
9
19.
6
20.
3
21.
0
21.
8
22.
5
23.
2
24.
0
24.
7
25.
4
26.
1
26.
9
27.
6
28.
3
29.
0
29.
8
30.
5
31.
2
31.
9
32.
7
33.
4
1.6
8
17.
7
18.
4
19.
1
19.
8
20.
5
21.
3
22.
0
22.
7
23.
4
24.
1
24.
8
25.
5
26.
2
26.
9
27.
6
28.
3
29.
1
29.
8
30.
5
31.
2
31.
9
32.
6
1.7
0
18.
0
18.
7
19.
4
20.
1
20.
8
21.
5
22.
1
22.
8
23.
5
24.
2
24.
9
25.
6
26.
3
27.
0
27.
7
28.
4
29.
1
29.
8
30.
4
31.
1
31.
8


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Protocol No. CLCI699C2201
Height 
(m)
Weight (kg)
46
48
50
52
54
56
58
60
62
64
66
68
70
72
74
76
78
80
82
84
86
88
90
92
1.7
2
17.
6
18.
3
18.
9
19.
6
20.
3
21.
0
21.
6
22.
3
23.
0
23.
7
24.
3
25.
0
25.
7
26.
4
27.
0
27.
7
28.
4
29.
1
29.
7
30.
4
31.
1
1.7
4
17.
8
18.
5
19.
2
19.
8
20.
5
21.
1
21.
8
22.
5
23.
1
23.
8
24.
4
25.
1
25.
8
26.
4
27.
1
27.
7
28.
4
29.
1
29.
7
30.
4
1.7
6
18.
1
18.
7
19.
4
20.
0
20.
7
21.
3
22.
0
22.
6
23.
2
23.
9
24.
5
25.
2
25.
8
26.
5
27.
1
27.
8
28.
4
29.
1
29.
7
1.7
8
17.
7
18.
3
18.
9
19.
6
20.
2
20.
8
21.
5
22.
1
22.
7
23.
4
24.
0
24.
6
25.
2
25.
9
26.
5
27.
1
27.
8
28.
4
29.
0
1.8
0
17.
9
18.
5
19.
1
19.
8
20.
4
21.
0
21.
6
22.
2
22.
8
23.
5
24.
1
24.
7
25.
3
25.
9
26.
5
27.
2
27.
8
28.
4
Appendix 4: Determination of body mass index (cont. from previous page)
1.82
17.5
18.1
18.7
19.3
19.9
20.5
21.1
21.7
22.3
22.9
23.5
24.2
24.8
25.4
26.0
26.6
27.2
27.8
1.84
17.7
18.3
18.9
19.5
20.1
20.7
21.3
21.9
22.4
23.0
23.6
24.2
24.8
25.4
26.0
26.6
27.2
1.86
17.9
18.5
19.1
19.7
20.2
20.8
21.4
22.0
22.5
23.1
23.7
24.3
24.9
25.4
26.0
26.6
1.88
18.1
18.7
19.2
19.8
20.4
20.9
21.5
22.1
22.6
23.2
23.8
24.3
24.9
25.5
26.0
1.9
18.3
18.8
19.4
19.9
20.5
21.1
21.6
22.2
22.7
23.3
23.8
24.4
24.9
25.5
1.92
18.4
19.0
19.5
20.1
20.6
21.2
21.7
22.2
22.8
23.3
23.9
24.4
25.0
1.94
18.6
19.1
19.7
20.2
20.7
21.3
21.8
22.3
22.9
23.4
23.9
24.4


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Protocol No. CLCI699C2201
Appendix 4: Determination of body mass index (cont. from previous page)
Height 
(m)
Weight (kg)
92
94
96
98
100
102
104
106
108
110
112
114
116
118
120
122
124
126
128
130
132
1.44
1.46
1.48
1.50
1.52
1.54
38.8
39.6
1.56
37.8
38.6
39.4
1.58
36.9
37.7
38.5
39.3
1.60
35.9
36.7
37.5
38.3
39.1
1.62
35.1
35.8
36.6
37.3
38.1
38.9
1.64
34.2
34.9
35.7
36.4
37.2
37.9
38.7
39.4
1.66
33.4
34.1
34.8
35.6
36.3
37.0
37.7
38.5
39.2
1.68
32.6
33.3
34.0
34.7
35.4
36.1
36.8
37.6
38.3
39.0
39.7
1.70
31.8
32.5
33.2
33.9
34.6
35.3
36.0
36.7
37.4
38.1
38.8
1.72
31.1
31.8
32.4
33.1
33.8
34.5
35.2
35.8
36.5
37.2
37.9
38.5
39.2
1.74
30.4
31.0
31.7
32.4
33.0
33.7
34.4
35.0
35.7
36.3
37.0
37.7
38.3
1.76
29.7
30.3
31.0
31.6
32.3
32.9
33.6
34.2
34.9
35.5
36.2
36.8
37.4
38.1
1.78
29.0
29.7
30.3
30.9
31.6
32.2
32.8
33.5
34.1
34.7
35.3
36.0
36.6
37.2
37.9
1.80
28.4
29.0
29.6
30.2
30.9
31.5
32.1
32.7
33.3
34.0
34.6
35.2
35.8
36.4
37.0
37.7


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Protocol No. CLCI699C2201
Appendix 4: Determination of body mass index (cont. from previous page)
1.82
27.8
28.4
29.0
29.6
30.2
30.8
31.4
32.0
32.6
33.2
33.8
34.4
35.0
35.6
36.2
36.8
37.4
1.84
27.2
27.8
28.4
28.9
29.5
30.1
30.7
31.3
31.9
32.5
33.1
33.7
34.3
34.9
35.4
36.0
36.6
37.2
1.86
26.6
27.2
27.7
28.3
28.9
29.5
30.1
30.6
31.2
31.8
32.4
33.0
33.5
34.1
34.7
35.3
35.8
36.4
37.0
37.6
1.88
26.0
26.6
27.2
27.7
28.3
28.9
29.4
30.0
30.6
31.1
31.7
32.3
32.8
33.4
34.0
34.5
35.1
35.6
36.2
36.8
37.3
1.90
25.5
26.0
26.6
27.1
27.7
28.3
28.8
29.4
29.9
30.5
31.0
31.6
32.1
32.7
33.2
33.8
34.3
34.9
35.5
36.0
36.6
1.92
25.0
25.5
26.0
26.6
27.1
27.7
28.2
28.8
29.3
29.8
30.4
30.9
31.5
32.0
32.6
33.1
33.6
34.2
34.7
35.3
35.8
1.94
24.4
25.0
25.5
26.0
26.6
27.1
27.6
28.2
28.7
29.2
29.8
30.3
30.8
31.4
31.9
32.4
32.9
33.5
34.0
34.5
35.1
1.96
23.9
24.5
25.0
25.5
26.0
26.6
27.1
27.6
28.1
28.6
29.2
29.7
30.2
30.7
31.2
31.8
32.3
32.8
33.3
33.8
34.4


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Protocol No. CLCI699C2201
13.5
Appendix 5: Summary of Common Toxicity Criteria for Adverse 
Events v4.0 (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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Protocol No. CLCI699C2201
13.6
Appendix 6: 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 
LCI699.
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.


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Protocol No. CLCI699C2201
13.7
Appendix 7: List of drugs to be used with caution with LCI699
Drugs in the following list have the potential to alter LCI699 drug exposure, and should be 
used with caution when co-administered with LCI699.
Table 13-1
List of strong CYP3A4/5 and CYP2D6 inhibitors and inducers
Strong inhibitors of CYP3A4/5
Generic Name
Brand Name
Class
clarithromycin
Biaxin®
Antibiotic
telithromycin
Ketek®
Antibiotic
troleandomycin
Tao®
Antibiotic
indinavir
Crixivan®
Protease inhibitor
lopinavir
Kaletra®
Protease inhibitor
nelfinavir
Viracept®
Protease inhibitor
ritonavir
Norvir®
Protease inhibitor
saquinavir
Fortovase®; Invirase®
Protease inhibitor
tipranavir
Aptivus®
Protease inhibitor
itraconazole
Onmel®; Sporanox®
Anti-fungal
ketoconazole
Nizoral®
Anti-fungal
posaconazole
Noxafil®
Anti-fungal
voriconazole
Vfend®
Anti-fungal
boceprevir
Victrelis®
Anti-viral
telaprevir
Incivek®
Anti-viral
cobicistat
Stribild®
Enzyme inhibitor
conivaptan
Vaprisol®
Diuretic
elvitegravir
Stribild®
Integrase inhibitor
nefazodone
Serzone®
Antidepressant
Strong inducers of CYP3A4/5
Generic Name
Brand Name
Class
carbamazepine
Carbatrol®; Epitol®; Equetro®; Tegretol®; Teril®
Antiepileptic
mitotane
Lysodren®
Anti-neoplastic
phenobarbital
Luminal®; Solfoton®
Anticonvulsant
phenytoin
Dilantin®
Antiepileptic
rifabutin
Mycobutin®
Antibiotic
rifampin (rifampicin)
Rifadin®; Rifamate®; Rifater®; Rimactane®
Antibiotic
St. John's wort 
(hypericum perforatum)
N/A
Herbal supplement


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Protocol No. CLCI699C2201
Strong inhibitors of CYP2D6 
Generic Name
Brand Name
Class
bupropion
Aplenzin®; Forfivo XL®; Wellbutrin®; Zyban®
Antidepressant; smoking cessation
fluoxetine
Prozac®; Sarafem®; Symbyax®
Antidepressant
paroxetine
Paxil®; Pexeva®
Antidepressant
quinidine
Nuedexta®
Anti-arrhythmic

SAP_001.pdf: 
Clinical Development 
LCI699 
CLCI699C2201 / NCT01331239
A proof of concept, open-label, forced titration, multi-center 
study to access the safety/tolerability and efficacy of 10-
weeks treatment of LCI699 followed by a 12-week treatment 
period in patients with Cushing’s disease  
RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Final 1.0 Amendment 2 
Release date: 
13-Mar-2019
Number of pages: 
27 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Page 13 
RAP Module 3 
 
CLCI699C2201 
 
Document history 
 
Version 
Date 
Changes 
Final 1.0 
16-Oct-2013 
NA 
Amendment 2 
13-Mar-2019 
Updated for the Final CSR analysis 
The main changes are: 
Section 1: Addition of further protocol amendment details 
Section 3: Update of study objectives to align them with the Final 
CSR 
Section 5: Update to cutoff date used for Final CSR analyses 
Section 7.3.2: Secondary efficacy analyses updated 
Section 7.4: PK evaluations removed for Final CSR 
Section 7.5.1.3: Addition of text for the AE disclosure outputs 
Section 7.5.1.4: Removed specific AE summaries to be performed 
Table 8-2: Addition of extension 2 visits to the visit summary table. 
 


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RAP Module 3 
 
CLCI699C2201 
 
Table of contents 
Table of contents ............................................................................................................. 3 
1 
Introduction .................................................................................................................... 6 
2 
Study description ............................................................................................................ 7 
3 
Objectives ..................................................................................................................... 10 
3.1 
Primary objective ............................................................................................... 10 
3.2 
Secondary objectives ......................................................................................... 10 
 
 11 
4 
Sample size and power considerations ........................................................................... 11 
5 
Data Cutoff for Analyses ............................................................................................... 12 
6 
Analysis Populations ..................................................................................................... 12 
6.1 
Core PoC follow-up cohort: ............................................................................... 12 
6.2 
Expansion cohort: .............................................................................................. 13 
6.3 
Imputation rules of partial or missing dates ........................................................ 14 
7 
Statistical analyses ........................................................................................................ 14 
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 ............................... 15 
7.1.4 
Medical history .................................................................................. 15 
7.1.5 
Prior therapy ...................................................................................... 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 .................................................................... 16 
7.3 
Efficacy evaluation ............................................................................................ 16 
7.3.1 
Primary efficacy analysis ................................................................... 16 
7.3.2 
Secondary efficacy analysis ............................................................... 16 
7.4 
Pharmacokinetic evaluation ............................................................................... 18 
7.4.3 
Other biomarkers ............................................................................... 18 
7.5 
Safety evaluation ............................................................................................... 18 
7.5.1 
Adverse events (AEs) ........................................................................ 18 
7.5.2 
Laboratory abnormalities ................................................................... 20 
7.5.3 
Vital signs .......................................................................................... 21 
7.5.4 
ECG................................................................................................... 21 
 
 22 
8 
Definitions .................................................................................................................... 22 


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RAP Module 3 
 
CLCI699C2201 
 
8.1 
Study day ........................................................................................................... 22 
8.2 
Baseline ............................................................................................................. 22 
8.3 
Visit number ...................................................................................................... 22 
8.4 
Calculating mean UFC ....................................................................................... 26 
8.5 
Study day associated with a UFC assessment ..................................................... 26 
8.6 
Conversion of duration in days to duration in months/years ............................... 26 
8.7 
Method for calculating confidence interval ........................................................ 26 
9 
References .................................................................................................................... 26 
10 Appendix: ..................................................................................................................... 27 


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RAP Module 3 
 
CLCI699C2201 
 
List of abbreviations 
 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Chemical (Classification) 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTC 
Common Terminology Criteria 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiograms 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FPG 
Fasting Plasma Glucose 
HbA1C 
Glycosylated Hemoglobin 
HPA (-Axis) 
Hypothalamic Pituitary Adrenal 
MRI 
Magnetic Resonance Imaging 
PD 
Pharmacodynamics 
PoC 
Proof of Concept 
RAP 
Report Analysis Plan 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
UFC 
Urinary Free Cortisol 
ULN 
Upper limit of normal range 
 


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Page 13 
RAP Module 3 
 
CLCI699C2201 
 
1 
Introduction 
This document describes the detailed statistical methodology to be used in analyzing the data 
for the Final database lock collected consequent to Amendment 9 to study CLCI699C2201 in 
patients with Cushing’s disease.  
The analyses described are predominantly for the core PoC follow-up cohort (defined in Section 
6.2) and the expansion cohort (defined in Section 6.3). These analyses will be conducted after 
all enrolled patients have completed the extension phase or discontinued earlier. Analyses will 
be  reported in the Final CSR. 
A history of the protocol amendments is provided below: 
Amendment 1, 17-DEC-2010 
Amendment 1 amended the inclusion criteria to ensure that only Cushing’s Disease patients are 
enrolled. The definition of a positive response to LCI699 has been revised to include ≥50% 
decrease in urine free cortisol (UFC) in addition to normalization of UFC. The study stopping 
rules for the study have also been amended to minimize premature termination of a subject from 
the study for AEs that are expected in this population or are efficacy related. In addition, the 
interim analysis for lack of efficacy has been removed to allow collection of more data for 
adequate evaluation of LCI699 in this small study. To maximize the utilization of all available 
data, the Last Observation Carried Forward (LOCF) method has been added to impute missing 
data for the primary endpoint. The opportunity has also been taken to remove minor 
inconsistencies between the protocol text and Schedule of Assessments as well as the addition 
of a Saliva log. 
Amendment 2, 31-JAN-2011 
Amendment 2 updated the blood log with regards to the amount of blood taken. The original 
optimal testing blood volume estimates received from the central labs were plasma/serum 
volumes instead of whole blood estimates. Due to the expected yield of plasma/serum from the 
collected blood, the amount of blood taken has increased from 244 ml to 454 ml per subject. 
This blood will be collected over a period of approximately 3 months.   
Amendment 3, 16-MAR-2011 
Amendment 3 revised and clarified the statistical analysis that would occur at the end of the 
study. In addition, the need for a UFC assessment at screening has also been removed to reduce 
undue burden to the patients. 
Amendment 4, 26-MAR-2012 
Amendment 4 amended this proof of concept (PoC) study by enrolling a new cohort (Expansion 
cohort) of patients and evaluating the long-term efficacy and safety of LCI699 treatment for a 
total duration of 22 weeks. This longer treatment period will help address questions on the 
sustainability of the cortisol reductions and longer term safety. At the end of the 22 weeks, 
patients will have the option to enter into the long term extension for duration up to 12 months. 


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RAP Module 3 
 
CLCI699C2201 
 
Amendment 5, 05-MAY-2013 
Amendment 5 added intensified ECG monitoring in the study to further enhance patient safety 
and collect additional safety information. The maximum LCI699 study dose was reduced from 
50 mg bid to 30 mg bid to avoid any QTcF prolongation effect. Inclusion and exclusion criteria 
are modified to exclude patients who have pituitary irradiation within 5 years prior to study 
entry. Escape analysis is added to summarize patients who lost UFC control after attained 
normalization on LCI699. 
Amendment 6, 14-Apr-2014 
The purpose of this protocol amendment is to continue the study to monitor patients for long - 
term safety and efficacy, and to provide continued access to LCI699 to patients who have 
completed long term extension-1. 
In addition, the protocol has been updated to indicate that the formulation of LCI699 will be 
changed from capsules to tablets during long term extension-2. 
Amendment 7, 17-Feb-2016 
The primary purpose of this protocol amendment is to ensure patient safety by adding specific 
criteria for the identification and management of patients with potential drug induced liver 
injury (DILI). 
Update to the requirement for contraception by male study participants. 
Clarification of protocol language regarding withdrawal of consent, study drug 
discontinuation, and discontinuation procedures 
Amendment 8, 11-Jul-2017 
The main purpose of this amendment is to provide continued access to the study drug for those 
patients benefitting from the treatment into a separate long-term safety follow-up study (roll-
over study) is set up at participating sites. Based on this, the end of study definition has been 
updated. 
Amendment 9 (03-May-2018) 
The purpose of this amendment is to extend the study end date from 31 December 2018 to 31 
December 2019 to allow continued access to the study drug for those patients benefitting from 
the treatment until a separate long-term safety follow-up study (roll-over study) is set up at 
participating sites.  
Additional updates were made to the Protocol glossary and withdrawal of informed consent 
section to align with the new Personal Data and Withdrawal of Consent language requirement. 
2 
Study description 
This is a proof of concept, open-label, single arm, sequential dose-escalation, multi-center study 
to assess the safety/tolerability and efficacy of LCI699 in patients with Cushing’s disease. 
The study will consist of a screening period of up to 60 days (to allow adequate washout period 
for any medications that modify cortisol levels), a 10-14-day baseline period, a 10-week 
sequential dose escalation treatment period, a 12-week treatment period at the last efficacious 


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dose, an End-of-Treatment (EOT)-Core evaluation at the end of 22 weeks, and an optional 12-
month extension. Patients are to have an end-of-study (EOS) visit 28 days after the last drug 
administration. 
Following protocol amendment 6, the study was extended (Extension-2) to provide continued 
access to LCI699 to patients who have completed long term extension-1. 
Patients who enrolled into the study prior to Amendment 4 and completed the trial treatment 
will be allowed to re-enter the study as the core PoC follow-up cohort if their Urinary Free 
Cortisol (UFC) is > upper limit of normal range (ULN) and all other eligibility criteria have 
been met. In addition, approximately 15 new patients with Cushing’s disease who did not 
previously participate the study will be enrolled and comprise the expansion cohort. Patients 
from both the core POC follow up cohort and the expansion cohort will be screened and follow 
similar visit schedule for this 22-week treatment period except certain differences described in 
the protocol.  
Every 7 days during the baseline period, patients will collect a morning and evening saliva 
sample, and will also perform at least three 24 hour urine collections. Patients will bring urine 
bottle on Day -3, at which time the baseline safety and Pharmacodynamics (PD) samples will 
be collected. All baseline evaluation result will be reviewed, and confirmation of 
inclusion/exclusion criteria determined prior to the patient dosing with LCI699. 
Newly enrolled patients (the expansion cohort) with a baseline 1.5xULN< UFC ≤ 3xULN will 
start at 2 mg bid on Day 1. Patients with baseline UFC > 3xULN will start LCI699 at 5 mg bid 
on Day 1. Every 7 days during the dose escalation period, patients will collect a morning and 
evening saliva sample. Patients will perform three 24 hour urine collections within 7 days of 
Day 7±1 and 14±1 day. A pre-dose PK sample and post-dose PK samples at 1, 1.5, 2, 4, and 6 
hours post morning dose will be collected. The schedule of events will continue every 2 weeks 
for the dose escalation period, with the dose of LCI699 increasing as represented in Figure 2-1. 
If at any time the patient’s UFC is < ULN, dose escalation will be halted and the patient will 
remain on the current efficacious dose through Week 10, with continued monitoring of UFC 
response every 2 weeks to allow for continued dose adjustments. If at any time the patient 
experiences side effects which are either intolerable or meet dose adjustment criteria, the 
prescribed dose will be adjusted as outlined in Section 6.7.3 in study protocol. 
Patients in the core PoC follow-up cohort will be started at the penultimate LCI699 dose that 
was efficacious and well tolerated during the core PoC study with the possibility to up-titrate 
the dose within one week based on the tolerability. 
Safety assessments will include physical examinations, electrocardiograms (ECGs), vital signs, 
standard clinical laboratory evaluations (hematology, blood chemistry, urinalysis,) adverse 
events (AEs), and serious adverse events (SAEs) monitoring. 
At Day 70 ± 2 days (Week 10), all patients will enter the 12 week assessment period. Three 
visits will be performed at Day 98, Day 126, and Day 154. Patients will continue the home 
saliva collections every 7 days twice daily, and perform three 24 hour urine collections over 7 
days prior to the next scheduled visit. From Day 70 through Day 154, patients can have their 
LCI699 dose adjusted based on the criteria in Section 5.5.4 in the study protocol. At Day 154, 
patients will complete the End-of-Treatment-Core visit. They have the option to enter the 12-
month extension phase at the investigators discretion provided they do not meet any 
discontinuation criteria. During the optional long term extension, patients will visit monthly for 


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the first 6 months and every 3 months from month 6 through month 12. Patients not continuing 
into the optional long term extension will also complete an End-of-Study visit 28 days after the 
last dose administration. 
The study design for newly enrolled patients (the expansion cohort) is depicted in Figure 2-1 
below.  Patients that were in the core POC study and re-enrolled (core POC follow up cohort) 
will have LCI699 dosing as described in the text above.   
      Figure 2-1 
 
Study Design  
 
Note: patients with baseline UFC > 3×ULN will start at 5 mg bid (in lieu of 2 mg bid) at Day 
1. 
 
 


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3 
Objectives 
The primary objective of this study as well as several other objectives related to the safety and 
efficacy of 10-week and 22-week treatment of LCI699 have already been analyzed for the PoC 
cohort and described previous CSRs. For the sake of completeness, the objectives of the 
protocol (up to and including Amendment 9) are listed below. 
The Final CSR will concentrate on reporting long-term safety and efficacy of osilodrostat in 
patients with Cushing’s disease, 
. For the 
assessment of efficacy, the analyses given for the secondary objectives will form the basis of 
the assessments. For each objective listed below it is indicated if this will be included in the 
Final CSR analyses. 
3.1 
Primary objective 
• To assess the effect of 10-week treatment of LCI699 on 24 hour urine free cortisol (UFC) 
in patients with Cushing’s disease; not included in Final CSR 
3.2 
Secondary objectives 
• To assess the 10-week safety and tolerability of multiple doses of LCI699 in patients with 
Cushing’s disease; not specifically included in the Final CSR 
• To assess the 22-week safety and tolerability of multiple doses of LCI699 in patients with 
Cushing’s disease; extended to cover entire study duration, and included in the Final CSR 
• To assess the effect of 22-week treatment with LCI699 monotherapy on 24 hour urine free 
cortisol (UFC) in patients with Cushing’s disease; extended to cover entire study duration, 
and included in the Final CSR 
At each scheduled assessment, the proportion of responders (mUFC ≤ ULN or ≥ 50% 
decrease from baseline) will be presented. 
In addition, the proportion of patients classified as either controlled or partially controlled 
will be determined as follows: 
• Controlled UFC: defined as a mean of UFC level ≤ ULN 
• Partially controlled UFC: defined as a mean of UFC level > ULN but with ≥ 50% 
reduction from baseline 
• To assess the effect of LCI699 on steroid hormones of Hypothalamic Pituitary Adrenal 
(HPA)-axis in plasma, urine and saliva; included in the Final CSR 
• To assess the effects of LCI699 on improving the metabolic abnormalities (hypertension, 
dyslipidaemia, obesity, insulin sensitivity, glycosylated hemoglobin (HbA1c) and fasting 
plasma glucose (FPG)) of Cushing’s disease; included in the Final CSR 
• To assess the steady state pharmacokinetics of LCI699 in patients with Cushing’s disease; 
not included in the Final CSR 
• To assess escape. Escape is defined as loss of UFC control (i.e. UFC > ULN) on at least 2 
consecutive visits at the highest tolerated dose after previously attaining UFC 
normalization; included in the Final CSR 


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4 
Sample size and power considerations 
The 15 patients in the expansion cohort will afford the level of precision around the estimate of 
the responder rate (controlled or partially controlled as defined in the secondary objective) at 
Week 22, as shown in Table 4-1. 
 
Table 4-1 
Precision level (two-sided 95% confidence interval for each 
response rate) in the study 
 


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            # Patients 
#Responders 
Response rate and two-sided 95% CI in (%) 
N=12 
N=13 
N=14 
N=15 
0 
0 (0, 26) 
0 (0, 25) 
0 (0, 23) 
0 (0, 22) 
1 
8 (0.2, 38) 
8 (0.2, 36) 
7 (0.2, 34) 
7 (0.2, 32) 
2 
17 (2, 48) 
15 (2, 45) 
14 (0.2, 43) 
13 (2, 40) 
3 
25 (5, 57) 
23 (5, 54) 
21 (5, 51) 
20 (4, 48) 
4 
33 (10, 65) 
31 (9, 61) 
29 (8, 58) 
27 (8, 55) 
5 
42 (15, 72) 
38 (14, 68) 
36 (13, 65) 
33 (12, 62) 
6 
50 (21, 79) 
46 (19, 75) 
43 (18, 71) 
40 (16, 68) 
7 
58 (28, 85) 
54 (25, 81) 
50 (23, 77) 
47 (21, 73) 
8 
67 (35, 90) 
62 (32, 86) 
57 (29, 82) 
53 (27, 79) 
9 
75 (43, 95) 
69 (39, 91) 
64 (35, 87) 
60 (32, 84) 
10 
83 (52, 98) 
77 (46, 95) 
71 (42, 92) 
67 (38, 88) 
11 
92 (62, 100) 
85 (55, 98) 
79 (49, 95) 
73 (45, 92) 
12 
100 (74, 100) 
92 (64, 100) 
86 (57, 98) 
80 (52, 96) 
13 
 
100 (75, 100) 
93 (66, 100) 
87 (60, 98) 
14 
 
 
100 (77, 100) 
93 (68, 100) 
15 
 
 
 
100 (78, 100) 
5 
Data Cutoff for Analyses 
The data cutoff for the Final CSR will be the date on which the last patient either completes 
extension-2, or discontinues from the study. 
6 
Analysis Populations  
The 12 Cushing’s disease patients who were enrolled in the study prior to protocol Amendment 
4 comprise the core PoC cohort. Patients who are re-enrolled into the study after protocol 
Amendment 4 comprise the core PoC follow-up cohort. The 15 new patients enrolled after 
protocol Amendment 4 comprise the expansion cohort. In the Final CSR, the two cohorts will 
be presented separately for efficacy and safety analysis, alongside an All Patients column which 
will combine the patients from the two cohorts. 
6.1 
Core PoC follow-up cohort: 
Full analysis set (FAS): all patients in Core PoC follow-up cohort.  
Safety analysis set (SAS): all patients in the Core PoC follow-up cohort who received at least 
one dose of study drug after reentering the study. 


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6.2 
Expansion cohort: 
Full analysis set (FAS): all patients in the Expansion cohort. 
Safety analysis set (SAS): consists of all patients in the Expansion cohort who received at least 
one dose of study drug after protocol Amendment 4. 
The analysis sets to be used for various analyses in each cohort are summarized in the following 
table: 
 
 


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Table 6-1 
Analysis sets 
 
FAS 
SAS 
Patient Disposition 
√ 
 
Protocol Deviation 
√ 
 
Demography and baseline 
disease characteristics 
 
√ 
Medical History 
 
√ 
Prior Medication 
 
√ 
Concomitant Medications 
 
√ 
Exposure to study 
medication 
 
√ 
Primary efficacy analyses 
 
√ 
Other efficacy analyses 
 
√ 
Safety analyses 
 
√ 
PK analyses 
 
 
PK/PD analyses 
 
 
6.3 
Imputation rules of partial or missing dates 
Partial dates will remain partial in the data listing. For the purpose of analysis, the following 
imputation rules will be used to impute the partial dates: if the day and month is missing, it will 
be replaced by 30th June (to be used only for prior events, e.g. medical history); if only the day 
is missing it will be replaced by the 15th of that month. For the dates known to be within the 
trial period, if this imputation make the date later then the trial completion date, use the trial 
completion date; if the imputed date is earlier then the first medication date, use the first 
medication date. 
The imputation of partial date for AE and concomitant medication will follow Novartis standard 
rules (See module 8 for details). 
7 
Statistical analyses 
7.1 
Patients studied 
7.1.1 Grouping for analyses 
For analyses of all endpoints, patients will be grouped into expansion cohort and core PoC 
follow-up cohort, respectively (defined in Section 6). Additionally, for the Final CSR, an All 
Patients column will be included for all relevant analyses. 
7.1.2 Patient Disposition 
Patient disposition will be summarized separately using the FAS. Counts of the following items 
will be included in disposition summaries.. 


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• Patients enrolled: 
o Not treated 
o Treated 
• Patients treated 
o Discontinued 
• Primary reason for end of treatment in the core phase (prior to Week 22) 
• Patients completed core phase  
 Patients did not enter extension phase 
 Entered extension phase  
o Completed extension phase 
o Discontinued in extension, with reasons for discontinuation 
7.1.3 Demography and baseline disease characteristics 
Summary statistics will be provided for demographics, and baseline characteristics using safety 
analysis set for each cohort. Categorical data will be presented by frequencies and percentages. 
Continuous data will be summarized by mean, standard deviation, minimum, median, and 
maximum. All data for background and demographic variables, as well as medical history, 
current medical conditions, results of lab screens, and any other relevant information will also 
be presented in listing. 
7.1.4 Medical history 
Relevant medical history and ongoing medical conditions will be summarized and listed. The 
summary will be presented for SAS by primary system organ class (SOC) and preferred term 
(PT). 
7.1.5 Prior therapy 
Medications taken prior to first dose of LCI699 will be listed and summarized for SAS by ATC 
class and preferred term by means of frequency counts and percentages. 
7.1.6 Protocol deviations (PDs) 
Protocol deviation criteria are specified in the Validation and Planning (VAP) document 
Module 3. The number and percentage of FAS patients with protocol deviations will be 
provided for PDs by Week 22, and by the end of extension phase. 
All protocol deviations up to data cutoff will be listed. 
7.2 
Study medication 
7.2.1 Exposure to Study Treatment 
The duration of exposure to the study drug will be summarized by descriptive statistics using 
the SAS.  


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Duration of exposure is calculated as    
Duration of exposure (weeks) = (min (date of last administration of LCI699, date of data cut-
off) – date of first administration of LCI699 + 1)/7 
7.2.2 Concomitant medication 
Concomitant medications will be summarized and listed by Anatomical Therapeutic Chemical 
(ATC) class and preferred term by means of frequency counts and percentages.  
7.3 
Efficacy evaluation 
7.3.1 Primary efficacy analysis 
7.3.1.1 Week 10 treatment effect 
As mentioned in Section 3, the primary efficacy analysis has already been reported in a CSR. 
It was based on the core PoC cohort.  The 10-week treatment effect of LCI699 in the core PoC 
follow-up cohort and expansion cohort will be analyzed as part of the secondary efficacy 
analyses (described below) and reported in a separate CSR.  
7.3.2 Secondary efficacy analysis 
7.3.2.1 Week 22 treatment effect 
As mentioned in Section 3, the Week 22 treatment effect of LCI699 has already been reported 
in a CSR.  
Similar analyses to those performed for the Week 22 treatment effect will be performed for 
scheduled assessment time points during the extension periods of the study. 
A patient is considered to be a responder at a particular time point if the mean UFC level (at 
least two 24-hour measurements) at that time point is ≤ ULN or represents a ≥ 50% decrease 
from baseline. Patients who discontinue for a disease or treatment related reason (e.g. death, 
adverse event, clinical disease progression etc.), or whose mean UFC levels are higher than the 
normal limit and experience < 50% decrease in UFC are classified as non-responders or 
uncontrolled. If mUFC is missing at a particular time point, then the value will not be imputed 
but the patient will be considered a non-responder at that time point. 
The denominator for the response rate calculation is the number of patients in the safety analysis 
set for weeks 10 and 22, which is the core phase. For time points after the core phase, the 
denominator will exclude patients who did not enter the extension phase. Patients who 
discontinued due to administrative reasons will also not be included in the denominator of any 
time points after the time of their discontinuation. In addition, patients who are ongoing without 
reaching the analysis time point will also be excluded. Early discontinued patients (including 
those discontinuing in the core phase) will be considered as non-responders for all time points 
after discontinuation. 
As a supportive analysis, the response rate will be calculated using only the number of observed 
mUFC samples at each time point. Patients who have discontinued prior to the assessment time 


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point, or who are ongoing but do not have a valid mUFC value, will not be counted in the 
denominator. 
The proportion of responders and the associated two-sided 95% confidence interval will be 
estimated using the exact method.  
In addition, responders will be classified further into controlled and partially controlled. 
Controlled UFC responder is defined as the patient whose mean UFC ≤ 1.0 × ULN. Partially 
controlled UFC responder is defined as the patient whose mean UFC > 1.0 × ULN but declined 
by at least 50% from baseline. The proportion of patients with controlled or partially controlled 
will be provided. 
7.3.2.2 Treatment effect on steroid hormones of HPA-axis 
Descriptive statistics will be generated for the change from the respective baselines to different 
time points in mUFC, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and steroid 
hormones, plasma 11-deoxycortisol, 11-deoxycorticosterone, salivary cortisol and aldosterone 
(morning and evening), urine creatinine, plasma and urine sodium, plasma and urine potassium, 
plasma renin, testosterone, estradiol, insulin, LH, FSH, IGF-1, free T4, TSH, two-sided 95% 
CIs using exact method will be provided for the changes from baseline. 
 
7.3.2.3 Treatment effect on metabolic abnormalities 
The treatment effect on improving the metabolic abnormalities including hypertension, 
dyslipidaemia, obesity, insulin sensitivity, HbA1c and FPG will be assessed by descriptive 
statistics on the change from baseline in systolic blood pressure (SBP), diastolic blood pressure 
(DBP), weight, body mass index (BMI), lipids which includes total cholesterol, triglycerides, 
HDL-cholesterol, and LDL-cholesterol, QUICKI, HbA1C, and FPG over time, as well as their 
two-sided 95% CIs using exact method, where QUICKI is the quantitative insulin sensitivity 
check index derived using the inverse of the sum of logarithms (base 10) of the fasting insulin 
and fasting glucose as in the following formula: 
1/(log(fasting insulin µU/mL)+log(fasting glucose mg/dL)) 
In addition, a listing of relevant concomitant medication(s), with total daily doses and the 
corresponding cardiovascular/metabolic variable (blood pressure, fasting glucose, HbA1c, 
fasting lipid profile) lab over time as well as figures and statistical modeling may be provided 
as an exploratory analysis. 
7.3.2.4 Escape analysis 
Only patient who attained UFC normalization during the study will be included in this analysis, 
where escape is defined as the loss of UFC control (i.e. UFC > ULN) on at least 2 consecutive 
visits at the highest tolerated dose after previously attaining UFC normalization. “First-time 
escape” is used to describe the first occurrence of 2 consecutive visits with uncontrolled UFC 
at the patient’s highest tolerated dose after attaining UFC normalization. Time to escape is 
defined as the number of weeks from the visit of first UFC normalization (mUFC <= 1x ULN) 
to the first visit of first-time escape. The definition for “highest tolerable dose” of LCI699 is 
provided in this paragraph.  For patients who have no safety issue, 30 mg bid is the highest 


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tolerated dose. For patients who have dose reduction(s) because of an intolerable adverse 
event, the highest tolerated dose is the highest dose at which no AE requiring dose reduction is 
reported. For patients who discontinue the study due to AE, the highest tolerated dose is the 
highest prior dose at which no intolerable AE was reported. For all other situations (i.e., LCI699 
dose is < 30mg bid, and there has been no AE leading to dose reduction or study drug 
discontinuation reported at the effective treatment dose), patients will be considered as not 
reaching their highest tolerated dose. 
The median time to escape and corresponding two-sided 95% confidence interval will be 
calculated using Kaplan-Meier methodology for each cohort. The Kaplan-Meier curves will be 
presented. In this analysis, a patient who never had two consecutive visits with uncontrolled 
UFC at his/her highest tolerated dose will be censored at his/her last visit with mUFC 
assessment. In addition, time to escape will be summarized using descriptive statistics by cohort 
for patients who meet escape criteria. 
7.4 
Pharmacokinetic evaluation 
No pharmacokinetic assessments were performed after Week 22, and the pharmacokinetic 
results have been reported in previous CSRS. No PK analyses will be included in the Final CSR. 
 
7.4.3 Other biomarkers 
Not applicable. 
7.5 
Safety evaluation 
The assessment of safety will be based on the frequency of adverse events, laboratory values 
that fall outside the pre-determined ranges, vital signs, as well as ECG data.  
7.5.1 Adverse events (AEs) 
All information obtained on adverse events will be displayed by patient. 
The number and percentage of subjects with adverse events will be tabulated by system organ 
class and preferred term. A subject with multiple adverse events within a body system is only 
counted once towards the total of this body system if no change in severity. 
7.5.1.1 Coding of AEs 
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. The latest version at the time of database lock will be used. 
7.5.1.2 Grading of AEs 
AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 (http://ctep.cancer.gov/forms/CTCAEv4.pdf).  
The CTCAE represents a comprehensive grading system for reporting acute and late effects of 
cancer treatments. CTCAE v4.0 is graded by definition a 5-point scale generally corresponding 
to clinical severity (mild, moderate, severe, life-threatening, and death). This grading system 


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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.  Information regarding death will be collected in the “Study Phase 
Completion Evaluation” CRF pages.  
7.5.1.3 
General rules 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) and ending no later than 28 days after last study treatment 
or the follow-up visit, whichever is later.  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.  
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. A 
subject with multiple occurrences of an AE will be counted only once in the AE category. 
Separate AE summaries will be presented by primary system organ class, preferred term, and 
maximum CTC grade. A patient with multiple CTC grades for an AE will be summarized 
under the maximum CTC grade recorded for the event. In the summaries presented by grade, 
all AEs will be pooled regardless of whether they are CTC gradable or not. 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. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 
5% and 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 set 
population. 
If for the 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 of study treatment relationship will be provided by SOC and PT. 


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7.5.1.4 
Adverse events of special interest / grouping of AEs 
Groupings of AEs of special interest consist of adverse events for which there is a specific 
clinical interest in connection with osilodrostat treatment (i.e. where osilodrostat 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 the 
CREDI folder “/CREDI Projects/L/LCI699C/Administrative files/CIS (Clinical Information 
Sciences)/Biostatistics” 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. Prior to database lock, the file will be copied to proper CREDI study 
specific folder such as RAP folder. 
7.5.2 Laboratory abnormalities 
For analyzing laboratory results, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments up to data cut-off date. All 
laboratory assessments will be listed. Results will be reported for each visit at which collected 
in the core, follow-up, and extension phases through the last study visit. 
Biochemistry, hematology, and urine laboratory data, will be presented using 
• shift tables using CTC grades (if available), otherwise by normal ranges: both standards 
from baseline to most extreme post-baseline value and baseline to last value   
• listings flagging values with elevated CTC grades (i.e. greater than 0), and outside of the 
normal ranges otherwise 
All laboratory values will be converted into SI units and the severity grade derived using NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Blood glucose will be 
presented as mg/dL and will be assessed using the ADA criteria 2010. Insulin and QUICKI may 
also be presented in US unit. 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.  
The following summaries will be produced for the laboratory data (by laboratory parameter): 
• Number and percentage of patients with worst post-baseline CTC grade (regardless of the 
baseline status). Each patient will be counted only for the worst grade observed post-
baseline 
• 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 
• Shift tables using CTC grades to compare baseline to the worst post-baseline values will be 
produced for hematology and biochemistry laboratory parameters with CTC grades 
• For laboratory parameters in which CTC grades are not defined, shift tables to the worst 
post-baseline values will be produced using the low/normal/high classifications based on 
laboratory reference ranges  
• Selected laboratory data will be also be displayed by presenting summary statistics of 
change from baseline values. 


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The following listings will be produced for the laboratory data: 
• Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and/or ADA classifications (normal/impaired/diabetic) and the classifications relative to the 
laboratory reference ranges   
• Listing of notable laboratory abnormalities (i.e. newly occurring CTC grade 3 or 4 
laboratory toxicities). 
7.5.3 Vital signs 
All vital signs data (height (cm), weight (kg), body temperature (0C), sitting pulse rate (bpm), 
systolic/diastolic blood pressure (mmHg)) will be listed by patient and visit/time, and 
abnormalities will be flagged on listing. Shift table based on notable value will be provided for 
vital signs. For blood pressure, we will provide the mean of the 3 measurements. 
The criteria for clinically notable abnormalities are defined as follows: 
7.5.3.1 Clinically notable elevated values 
• Systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline 
• Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline. 
• Supine pulse: ≥ 120 bpm with increase from baseline ≥15 bpm 
7.5.3.2 Clinically notable below normal values 
• Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline 
• Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline 
• Supine pulse: ≤ 50 bpm with decrease from baseline ≥ 15 bpm 
7.5.4 ECG 
Bazett’s formula (QTcB) and Fridericia’s formula (QTcF) will be used to calculate the heart 
rate-corrected QT interval (msec) on the heart rate (HR bpm) and QT (msec) as follows. 
QTcB (msec) = QT / (RR)1/2 and QTcF (msec) = QT / (RR)1/3All ECG data (heart rate (bpm), 
PR interval (msec), QT interval (msec), QRS duration (msec), QTcB interval (msec)) will be 
listed by patient and visit/time. Abnormalities will be flagged.  
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
provided by visit/time for the above parameters. Descriptive statistics will be provided for 
change from baseline to different time points in heart rate, PR interval, QT interval, QRS 
duration, and QTcB interval. Shift table based on notable values will be provided for ECGs. 
The notable criteria for PR is 
• Increase > 25% compared to baseline to a post-baseline value > 200 ms 
The notable criteria for QRS is 
• Increase > 25% compared to baseline to a post-baseline value > 110 ms 
The notable criteria for HR are  


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• Increase > 25% compared to baseline to a post-baseline value > 100 bpm 
• Decrease > 25% compared to baseline to a post-baseline value < 50 bpm 
The notable criteria for QT, QTcF, and QTcB are 
• an increase from baseline > 30 ms at any post-baseline 
• an increase from baseline > 60 ms at any post-baseline 
 
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 (date of event 
– 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 (date of 
event – date of first administration of study drug) + 1. 
8.2 
Baseline 
For efficacy and safety evaluations, the last available pre-dose assessment within 20 days prior 
to study Day 1 is taken as “baseline” assessment. For MRI and ECG, the last available pre-dose 
evaluation prior to study Day 1 will be taken as “baseline” assessment. If several measurements 
are taken on the same day, the last one prior dose is used as measurement of that day. 
8.3 
Visit number 
The time point (Day/Week) associated with an assessment, will be determined by the visit 
number assigned to the corresponding assessment in the database. The mappings of visit 
numbers to time points in the core study and the extension study are provided in the table below. 
Saliva samples as well as other ECG, lab and PK parameters collected not following protocol 
schedule may only be presented in listings and not included in any statistical analysis.  


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Table 8-1 
Visit number in core phase  
Core study Visit  
Day/Week 
Clarifying Notes 
Visit 1 
Day -74 to Day -15 
Screening 
Visit 2 
Day -14 to Day -1 
Baseline 
Visit 3 
Day 1 
Dose escalation / Treatment period 
Visit 4 
Day 7/Week 1 
Dose escalation / Treatment period 
Visit 5 
Day 14/Week 2 
Dose escalation / Treatment period 
Visit 6 
Day 28/Week 4 
Dose escalation / Treatment period 
Visit 7 
Day 42/Week 6 
Dose escalation / Treatment period 
Visit 8 
Day 56/Week 8 
Dose escalation / Treatment period 
Visit 9 
Day 70/Week 10 
Dose escalation / Treatment period 
Visit 10 
Day 98/Week 14 
12-week Treatment period 
Visit 11 
Day 126/Week 18 
12-week Treatment period 
Visit 775 
Day 154/Week 22 
End of treatment in core phase 
Visit 778 
28 days after last dose 
End of study 
 
 
Table 8-2 
Visit number in extension phase 
Extension study Visit  Day/Week 
Clarifying Notes 
Visit 12 
Day 154/Week 22 
Long term extension 1 
Visit 13 
Day 182/Week 26 
Long term extension 1 
Visit 14 
Day 210/Week 30 
Long term extension 1 
Visit 15 
Day 238/Week 34 
Long term extension 1 
Visit 16 
Day 266/Week 38 
Long term extension 1 
Visit 17 
Day 294/Week 42 
Long term extension 1 
Visit 18 
Day 322/Week 46 
Long term extension 1 
Visit 19 
Day 406/Week 58 
Long term extension 1 
Visit 776 
Day 490/Week 70/ End 
of Treatment Ext 1 
End of treatment in extension phase 1 
Visit 20 
Month 16 
Long term extension 2 
Visit 21 
Month 19 
Long term extension 2 


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Extension study Visit  Day/Week 
Clarifying Notes 
Visit 22 
Month 22 
Long term extension 2 
Visit 23 
Month 25 
Long term extension 2 
Visit 24 
Month 28 
Long term extension 2 
Visit 25 
Month 31 
Long term extension 2 
Visit 26 
Month 34 
Long term extension 2 
Visit 27 
Month 40 
Long term extension 2 
Visit ... 
Month ... 
Long term extension 2 
Visit 777 
End of Treatment Ext 2 End of treatment in extension phase 2 
Visit 778 
28 days after last dose 
End of study 
After Visit 27 / Month 40, visits occur every 6 months. The Visit Number increases by 1 each 
time, and the Month increases by 6. 
Unlike the above visits that are scheduled to occur after a fixed number of days have elapsed 
since Day 1, the Visits 777 (End-of-Treatment in core phase and extension phase) and 778 (End 
of study) are scheduled when the patient either completes the respective study phase or decides 
(or is mandated by the protocol) to prematurely discontinue from the study.  
If such a visit happens neither too soon nor too late after the actual last scheduled visit, then it 
will be mapped to the next scheduled visit that would have occurred had the patient continued 
in the study. Otherwise, the early discontinuation visit will be mapped to an unscheduled visit. 
The 777visit will be considered to have occurred neither too soon nor too late after the actual 
last scheduled visit if number of days between the two visits is 
i. 
at least half of the planned gap between the patient’s actual last scheduled visit and the 
next scheduled visit and 
ii. 
at most the total of 
a. the planned gap between the patient’s actual last scheduled visit and the next 
scheduled visit (that would have occurred if the patient had not discontinued)   
b. half of the planned gap between the patient’s next two scheduled visits (that would 
have occurred if the patient had not discontinued). 
If the number of days between the 777visit and last scheduled visit (last scheduled visit +1) is 
less than the range specified above, then the 777visit will be mapped to an unscheduled visit of 
the last scheduled visit (last scheduled visit +1); if it’s more than the range, then it will be 
mapped to an unscheduled visit of the last scheduled visit + 1 (last scheduled visit+2).  
For example, if a patient’s last scheduled visit is Visit 6, then his next two planned visits would 
have been Visit 7 and Visit 8 if he had not discontinued. Thus, the early discontinuation visit 
will be mapped to Visit 7 only if it occurs between 7 (Day 42 – Day 28)/2 and 21 (14 + (Day 
56 – Day 42)/2) days after Visit 6. 


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Further, if a patient continued into the extension phase, then we set Visit 777 in the core phase 
to Visit 12 without checking the days-in-between. Visit 778 will not be mapped. 
8.4 
Calculating mean UFC 
Three 24-hour urine specimens will be collected to calculate mean UFC for baseline record and 
throughout the core study phase. During the long term extension phase, patients will collect two 
24-hour urine specimens for calculation of the mean UFC level. 
To compute the mean UFC 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 mean UFC will be 
considered missing for that assessment. 
8.5 
Study day associated with a 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 for that visit. 
8.6 
Conversion of duration in days to duration in months/years  
Duration in months = 12 * (Duration in days)/365.25 
Duration in years = (Duration in days)/365.25 
8.7 
Method for calculating confidence interval  
Two-sided 95% confidence intervals for proportions will be calculated using the exact 
(Clopper-Pearson) method, unless stated otherwise. 
Two-sided 95% confidence intervals for change and percentage change from baseline will 
assume normally distributed data and will be calculated using the t-distribution. 
9 
References 
 
 
 
 
 
 
 
 
 
 


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10 
Appendix: 
Table 10-1 
Precision level (two-sided 95% confidence interval for each response 
rate) in the study 
 
            # Patients 
#Responders 
Response rate and two-sided 95% CI in (%) 
 
N=6 
N=8 
N=10 
N=12 
0 
0 (0, 45.9) 
0 (0, 36.9) 
0 (0, 30.9) 
0 (0, 26) 
1 
16.7 (0.4, 64.0) 
12.5 (0.3, 52.6) 
10 (0.2, 44.5) 
8 (0.2, 38) 
2 
33.3 (4.3, 77.8) 
25 (3.2, 65.1) 
20 (2.5, 55.6) 
17 (2, 48) 
3 
50.0 (11.8, 88.2) 
37.5 (8.5, 75.5) 
30 (6.7, 65.3) 
25 (5, 57) 
4 
66.7 (22.3, 95.7) 
50 (15.7, 84.3) 
40 (12.2, 73.8) 
33 (10, 65) 
5 
83.3 (35.9, 99.6) 
62.5 (24.5, 91.5) 
50 (18.7, 81.3) 
42 (15, 72) 
6 
100 (54.1, 100) 
75 (34.9, 96.8) 
60 (26.2, 87.8) 
50 (21, 79) 
7 
 
87.5 (47.4, 99.7) 
70 (34.8, 93.3) 
58 (28, 85) 
8 
 
100 (63.1, 100) 
80 (44.4, 97.5) 
67 (35, 90) 
9 
 
 
90 (55.5, 99.8) 
75 (43, 95) 
10 
 
 
100 (69.1, 100) 
83 (52, 98) 
11 
 
 
 
92 (62, 100) 
12 
 
 
 
100 (74, 100)