Clinical trial NCT02180217
Conditions: Cushings Disease
Keywords: LCI699 osilodrostat Cushings Disease open-label dose titration randomized withdrawal
Sponsor: Novartis Pharmaceuticals
Start date: 2014-10-06; Completion date: 2019-12-04
Enrollment: 137 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The study aimed to confirm long-term efficacy and safety of LCI699 for the treatment of patients with Cushing's disease. It was a pivotal trial which supported the registration of LCI699 for the treatment of patients with Cushing's disease in the US and the EU.

This is a phase lll, multi-center, double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period which evaluated the safety and efficacy of LCI699 for the treatment of patients with Cushing's disease.

Detailed description:
The primary objective compared the complete response rate at the end of the 8-week period of randomized withdrawal (Week 34) between patients randomized to continued osilodrostat therapy vs.

placebo. The key secondary objective assessed the complete response rate at the end of individual dose titration and treatment with osilodrostat in the initial single-arm, open label period (Week 24).

Eligible patients were randomized in a double-blinded fashion at Week 26 at a 1:1 ratio either to continue treatment with osilodrostat at the same dose or to matching placebo. Randomization was stratified by osilodrostat dose at Week 24 (≤ 5mg bid vs. \>5mg bid); and history of pituitary irradiation (yes/no).

The study had four periods combined in the Core Period (Study Period 1 to 4) and an optional Extension Period. The optional Extension Period starting at Week 48.

Study Period 1 consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients (Week 1 to Week 12). Dose adjustments were based on the mean of three 24-hour UFC (mUFC) values as measured by the central laboratory.

During study Period 2 (Week 13 to Week 24), osilodrostat efficacy and safety were assessed at the therapeutic dose determined during study Period 1. Patients whose mUFC became elevated during this period had their osilodrostat dose increased further, if it was tolerated, up to 30 mg bid. Such patients were followed for long-term safety and efficacy and were not considered responders for the key secondary endpoint, hence were not randomized in Study Period 3.

Study Period 3 was a double-blind, placebo-controlled randomized withdrawal (RW) Period (Week 26 to Week 34). In order to be eligible for randomization in study Period 3, patients had to have completed dose titration during study Period 1, and had to be classified as complete responders at Week 24 of study Period 2. Patients not eligible for randomization received open-label osilodrostat until the end of the Core Period (Week 48), unless there was a reason to discontinue from the study prematurely.

During study Period 3, mUFC was measured at scheduled visits every 2 weeks. However, patients were also allowed to have unscheduled visits at any time during the RW if they reported symptoms of hypercortisolism or hypocortisolism.

The dose of study drug remained unchanged for patients who maintained a normal mUFC and did not develop adverse events (AEs) related to study drug during RW. The Investigator could reduce or temporally withhold a dose of study drug for safety reasons at any time during the study, including the RW Period.

During this study period, a patient was discontinued from the RW Period and declared a nonresponder, if the mUFC increased to \>1.5×ULN. After discontinuation from RW treatment, or at the end of the RW Period (Week 34), whichever came first, the patient resumed open-label osilodrostat at a dose selected by the Investigator.

Patients who discontinued from the study during the RW Period were no longer in the study, and consequently were not permitted to receive open-label osilodrostat and could not move to study Period 4.

Patients who discontinued from RW treatment due to lack of efficacy resumed open-label osilodrostat at the time of discontinuation, which could occur before Week 34. Patients who were not discontinued during RW resumed open-label osilodrostat at the end of RW (Week 34) and continued osilodrostat thereafter (study Period 4).

The Novartis study team, the patient, the Investigator, and all other site staff remained blinded to treatment assignment from the time of randomization to the time of database lock at the end of the Core Period. Novartis Drug Supply Management department members were unblinded in order to prepare the study drug supplies.

Study Period 4 was a single-arm, open-label therapy (end of Week 34 to Week 48). At the end of Week 34, all patients received open-label osilodrostat treatment. The Investigator had the discretion to select the dose during this period.

Patients continued open-label therapy until Week 48. At Week 48, patients had the option to enter an Extension Period, or discontinue osilodrostat at Week 48 to conclude with an end of Core Period visit 4 weeks off study drug (at Week 52).

Patients who continued to receive clinical benefit, as assessed by the study Investigator, and who wished to enter the Extension Period were re-consented at Week 48. Patients entered the Extension period without interruption of study drug or assessments. At the end of the study, patients who continued to benefit from treatment were offered to participate in a separate long-term safety follow-up study. The optional Extension Period ended after all patients completed Week 72 or discontinued early.

Arms: arm 1: Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period. arm 2: Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.
Interventions: intervention 1: osilodrostat intervention 2: LCI699 matching placebo
Intervention descriptions: intervention 1: Osilodrostat comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat was 30 mg bid. intervention 2: Osilodrostat placebo comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat placebo was 30 mg bid.

Protocol documents:
SAP_002.pdf: 
LCI699 (osilodrostat) 
CLCI699C2301 / NCT02180217
A Phase III, multi-center, double-blind, randomized withdrawal 
study of LCI699 following a 24 week, single-arm, open-label dose 
titration and treatment period to evaluate the safety and efficacy of 
LCI699 for the treatment of patients with Cushing’s disease 
Statistical Analysis Plan (SAP) for Final CSR 
Author: 
 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
02-Dec-2019
Number of pages: 
42 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title impacted (Current) 
02-Dec-
2019 
Prior to 
Final 
DBL 
Creation of SAP 
for Final DBL 
Creation of SAP for Final 
DBL 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Protocol amendments ............................................................................................... 7 
1.2 
Study design........................................................................................................... 11 
1.2.1 
Study Period 1 ....................................................................................... 12 
1.2.2 
Study Period 2 ....................................................................................... 12 
1.2.3 
Study Period 3 ....................................................................................... 13 
1.2.4 
Study Period 4 ....................................................................................... 14 
1.2.5 
Optional extension period ..................................................................... 14 
1.3 
Study objectives and endpoints ............................................................................. 15 
2 
Statistical methods ............................................................................................................. 17 
2.1 
Data analysis general information ......................................................................... 17 
2.1.1 
General definitions ................................................................................ 18 
2.2 
Analysis sets .......................................................................................................... 21 
2.2.1 
Subgroup of interest .............................................................................. 23 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 23 
2.3.1 
Patient disposition ................................................................................. 23 
2.3.2 
Demographic and baseline disease characteristics ................................ 25 
2.3.3 
Medical history ...................................................................................... 25 
2.3.4 
Protocol deviations ................................................................................ 25 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 25 
2.4.1 
Study treatment / compliance ................................................................ 25 
2.4.2 
Prior, concomitant and post therapies ................................................... 26 
2.5 
Analysis of the primary objective .......................................................................... 26 
2.6 
Analysis of the key secondary objective ............................................................... 27 
2.7 
Analysis of secondary efficacy objectives ............................................................. 28 
2.7.1 
Compare the time-to-last control of mUFC during the randomized 
withdrawal period between patients randomized to continued 
LCI699 and placebo .............................................................................. 28 
2.7.2 
Assess the complete, partial, and overall response rate at Week 12, 
Week 24, Week 48, and during the extension period ........................... 28 
2.7.3 
Assess the change in mUFC during the core and extension period 
of study .................................................................................................. 28 


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2.7.4 
Assess the change in cardiovascular-related metabolic parameters 
associated with Cushing’s disease during the core and extension 
period of the study ................................................................................. 28 
2.7.5 
Assess the change from baseline in physical features of Cushing’s 
disease by photography ......................................................................... 29 
2.7.6 
Assess the change from baseline in bone mineral density by DXA 
scan at Week 48 and the last available assessment ............................... 29 
2.7.7 
Assess the time-to-escape under treatment of LCI699 ......................... 29 
2.8 
Safety analyses ....................................................................................................... 30 
2.8.1 
Adverse events (AEs) ............................................................................ 30 
2.8.2 
Deaths .................................................................................................... 32 
2.8.3 
Laboratory data ..................................................................................... 33 
2.8.4 
Other safety data ................................................................................... 33 
2.9 
Pharmacokinetic endpoints .................................................................................... 36 
2.10 
PD and PK/PD analyses......................................................................................... 36 
2.11 
Patient-reported outcomes ..................................................................................... 36 
2.11.1 
CushingQoL .......................................................................................... 36 
2.11.2 
BDI-II .................................................................................................... 37 
2.11.3 
EQ-5D-5L ............................................................................................. 38 
2.11.4 
Secondary objective - Assess the change in Patient-Reported 
Outcomes (Health-Related Quality of Life) during the core and 
extension period of the study ................................................................ 39 
2.12 
Biomarkers ............................................................................................................. 39 
2.13 
Other Exploratory analyses .................................................................................... 39 
2.14 
Interim analysis ...................................................................................................... 40 
3 
Sample size calculation ..................................................................................................... 40 
3.1 
Sample size justification ........................................................................................ 40 
3.2 
Power consideration for analysis of key secondary objective ............................... 40 
4 
Change to protocol specified analyses .............................................................................. 41 
5 
Reference ........................................................................................................................... 41 


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List of abbreviations 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Chemical 
BDI-II 
Beck Depression Inventory-II 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTC 
Common Terminology Criteria 
DBL 
Database lock 
DBP 
Diastolic Blood Pressure 
DRL 
Drug Reference Listing 
DXA 
Dual-energy X-ray absorptiometry 
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 
LLOQ 
The limit of quantitation 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MID 
Minimal Important Difference 
MRI 
Magnetic Resonance Imaging 
PoC 
Proof of Concept 
PPFAS 
Per-Protocol Set for Full Analysis Set 
PPRAS 
Per-Protocol Set for Randomized Analysis Set 
PRO 
Patient-reported Outcomes 
QoL 
Quality of Life 
QTcF 
QT corrected (Fridericia QT formula) 
RAS 
Randomized Analysis Set 
RMP 
Risk Management Plans 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SBP 
Systolic Blood Pressure 
SCS 
Summary of Clinical Safety 


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CLCI699C2301 
 
SOC 
System Organ Class 
TBIL 
Total bilirubin 
UFC 
Urinary Free Cortisol 
ULN 
Upper limit of normal range 
WHO 
World Health Organization 
 


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1 
Introduction 
The SAP document describes the planned statistical analyses for the Final CSR of study 
LCI699C2301 in the treatment of Cushing’s disease. It incorporates analysis of the long-term 
safety and efficacy of the study, including data collected during both the core phase (up to Week 
48) and the optional extension period. The optional extension period will end 16 months after 
all patients have completed Week 72 or discontinued early (prior to Week 72). 
The analysis will be performed after all patients have completed the extension period or 
discontinued earlier. 
The analysis of the core phase, including the results of the primary and key secondary outcomes 
was detailed in the CSR written following the DBL which occurred once all patients had 
completed the core phase or discontinued earlier. These details of these analyses can be found 
in the corresponding SAP, with cover date 06-Jul-2018. 
After the interim CSR was published, additional protocol deviations were reported which affect 
the per-protocol populations used to perform the per-protocol analyses of the primary and key-
secondary endpoints, therefore the Final CSR will report the updated results of these per-
protocol analyses. 
1.1 
Protocol amendments 
At the time of finalization of this document the original study protocol had undergone five 
amendments, as summarized below.  
Amendment 1, 15-JUL-2014 
The purpose of this protocol amendment is to address requests from the Voluntary 
Harmonization Procedure (VHP) review. Changes made to the protocol during this 
amendment were summarized below: 
 The definition of the optional extension period was revised to specify the length of study 
treatment.  
 The definition of time-to-escape (one of the secondary objectives) was clarified. 
 To ensure that pregnancy was identified as an absolute withdrawal criterion, it was moved 
from the list of general study withdrawal criteria to the list of study specific criteria that 
require study treatment discontinuation. 
 To harmonize with ICH guidelines, treatment discontinuation criteria was revised to include 
an increase in QTcF > 60 msec from pre-first dose baseline measurement. 
 To improve monitoring for potential QT prolongation, 24-hour Holter recordings were 
added during the extension at Weeks 72 and 96. As a result of this addition, both the Visit 
Evaluation Schedule and the ECG Collection Table were also revised.  
Amendment 2, 11-Mar-2015 
The primary reason for this amendment is to add a local, country-specific intensive PK 
sampling for China in order to investigate potential ethnic differences in LCI699 
pharmacokinetics at steady-state and at doses used in the treatment of patients with Cushing’s 
disease. 


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Additional changes applicable to all countries include: 
 Inclusion of recent LCI699 clinical trial results information (longer-term safety and efficacy 
data (LCI699C2201) and results of the clinical drug-drug interaction study (LCI699C2102). 
 Relaxation of the protocol guidance on narrow therapeutic index/sensitive substrates of 
CYP1A2, CYP2C19, CYP2D6 and CYP3A4/5 as concomitant medication (based on the 
results of the clinical drug-drug interaction study (LCI699C2102)). 
 Blinding: The pharmacist, the bioanalyst and the pharmacokineticist are also blinded. 
 Inclusion criteria: 
o Minimum period since last stereotactic radiosurgery decreased from 3 to 2 years. 
o Rescreening is introduced, some therapies needed washouts are removed and the 
screening period is extended to accommodate for the need for long washout 
periods. 
 Exclusion criteria: 
o QTcF exclusion limits tightened from >470 ms to >450 ms (males) and >460 ms 
(females). 
o Definition of post-menopausal status and woman not of childbearing potential is 
added. 
o Male contraception is no longer required in patients treated with LCI699 based 
on a thorough review of the mechanism of action of LCI699 and re-evaluation 
of pre-clinical and clinical data. 
o The criterion on optic chiasm compression is updated and broaden. 
o Euthyroid status is based on investigator’s judgment (rather than biochemically).  
 
 
 
  
 Changes to safety monitoring schedule (removal of non-required assessments timepoints, 
additional sex hormone assessments, assessment of waist circumference) 
 Collection of additional baseline information (such as information on most recent prior 
medical therapy). 
 Permitted concomitant medications now includes spironolactone, eplerenone, cyproterone 
acetate or finasteride under certain conditions. 
 Discontinuation criteria revised to distinguish “confirmed” laboratory abnormalities and 
“confirmed and persistent laboratory abnormalities”; with the hypokalemia parameter 
relaxed. 
 Central reading of photographs removed, as it is not essential for the study. 
 Additional sex hormone assessments (Androstenedione, DHEA and Estrone) are introduced 
to better characterize the effects on hormone balance. 
 The CTCAE version is updated from 4.0 to 4.03. 


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 The “potential risk” for QT prolongation is changed to “risk”, based on one reported SAE 
with QTcF prolongation in a clinical study evaluating the longer-term efficacy and safety 
of LCI699 (LCI699C2201). 
 The QT monitoring section is clarified and the trigger for doing a triplicate ECG is 
updated from > 500 msec to > 480 msec. 
 Novartis Discontinuation of Clinical Trial Protocol Elements language has been 
implemented throughout the protocol.  
In addition, editorial changes and clarifications were made throughout the protocol. 
As of 02 March 2015, 16 patients have provided written informed consent for the study and 10 
patients have received LCI699. 
Amendment 3, 29-Mar-2016 
The purpose of this amendment is to include the following changes to reduce the risk of dosing 
errors. 
 Expand the description of the dose dispensation process; in particular to emphasize that 
more than one tablet strength of study drug may be dispensed at the same visit.  
 Elaborate on dose adjustments and communication of dosing instructions 
 Recommend the use of patient dose instruction card and phone contacts between 
scheduled visits. 
This amendment also includes changes 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.  
Other protocol changes are:  
 To provide more information regarding the study drug: 
 A summary of the benefit-risk assessment of LCI699 for this trial has been added  
 The results of the thorough QT/QTc study (LCI699C2105)  of LCI699 in healthy 
volunteers has been added 
 Additional measurements of serum cortisol and plasma ACTH have been added for 
patients in China undergoing extensive PK, 
 
. 
  Exclusion criterion # 16 is modified to exclude patients with serum total bilirubin > 1.5 x 
ULN; this is one of the criteria needed for effective screening of patients for potential 
DILI 
The duration of the optional extension period is increased in order to collect additional long-
term safety data as well as to provide continued access to the study drug for those patients 
benefitting from the treatment. Patients can continue on extension period until the last patient 
completes the core phase or discontinued early from core phase. Patients who continue to 
benefit from treatment will be offered participation in a separate long-term safety follow-up 
study. Study CLCI699C2301 ends when seamless transition to the long-term safety follow-up 


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study is possible or alternative treatment options are available; this period will not exceed 4 
months.  
Amendment 4, 06Jul-2017 
The main purpose of this amendment is to further increase the duration of the optional extension 
period in order to collect additional long-term safety and efficacy data as well as to provide 
continued access to the study drug for those patients benefitting from the treatment until a 
separate long-term safety follow-up study is set up at participating sites. Based on this extension, 
the end of study definition has been updated. In addition, the long-term safety follow-up study 
modalities have been detailed. 
As a result of the change in the duration of the optional extension period, the study objectives 
and associated statistical sections have been revised to include extension period time points.  
Other protocol changes include: 
 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®).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. 
Amendment 5, 29-Jun-2018 
The main purpose of this amendment is to increase the maximum duration of the optional 
extension period by one additional year in order to provide continued access to the study drug 
for those patients benefitting from the treatment until a separate long-term follow-up study is 
available at participating sites. 
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. 
 Glossary of terms, Section 7.1.6: the definition of the Personal Data and Withdrawal of 
Consent has been updated in line with the latest Novartis protocol template updated 
following the release of the General Data Protection Requirements (GDPR) in the 
European Economic Area (EEA). 
 List of abbreviations, Section 4.1.3.1, Section 6.5.2 and Section 6.5.3: Drug Supply 
Management replaced with Global Clinical Supply as per name change at Novartis. 
 Protocol Summary, Section 6.1, Section 6.6.1, Table 6-3 and Table 6-4: clarified as 20 mg 
tablets supplied depending on availability. 


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 Section 4.1.5, Section 6.1.5: revised to extend the duration of the optional extension 
period and study and to include the transition timeframe to the long-term safety follow-up 
study or local alternative treatment option. 
 Section 4.3: revised to extend the duration of the optional extension period and study. 
 Section 6.5.3: corrected that the bioanalyst and the bioanalytical study monitor will also be 
unblinded in line with Novartis standards. 
 Section 7.1.1 and Table 7-1: reference added to the Inclusion/Exclusion criteria for the 
eligibility assessment at screening. 
 Section 7.2.1.3: revised as there was an incorrect reference to the BMI matching for the 
BMD T-score. 
 Section 7.2.2.5, Section 10.5.3: added the central Pituitary MRI/CT assessment for tumor 
re-occurrence and tumor invasiveness. 
 Section 7.2.3.2: corrected as placebo samples will be analyzed for this trial. 
 Section 10: clarified that in this section SAS stands for Statistical Analysis System. 
1.2 
Study design 
This is a Phase III, multi-center, double-blind, randomized withdrawal study following a 24 
week, single-arm, open-label dose titration and treatment period to evaluate the safety and 
efficacy of LCI699 for the treatment of patients with Cushing’s disease. The study has a core 
phase (consists of four study periods 1-4, see schematic diagram below) and an optional 
extension period, which are described below. 
Figure 1-1 
Schematic of core study design 
 


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1.2.1 
Study Period 1 
This single-arm, open-label  LCI699 period (Week 1 to Week 12) is the individual patient 
dose titration period. 
Figure 1-2 
Schematic of study period 1 
 
Dose adjustments are based on the mean of three 24-hour UFC (mUFC) values as measured by 
the central lab. The triplicate urine samples are collected every two weeks during individual 
dose titration with the last urine sample preferably collected the day prior to the visit at site. 
The dose is increased if mUFC is above normal (> ULN). The dose is reduced if mUFC < LLN, 
or if the patient is symptomatic and mUFC is in the lower part of the normal range. The dose 
should be maintained if mUFC is within the normal range and the patient does not have signs 
or symptoms of adrenal insufficiency. At Week 0 and Week 2, dose increase is not permitted. 
1.2.2 
 Study Period 2 
This period (Week 13 to Week 26) aims to assess the efficacy and safety of  LCI699 at the 
therapeutic dose determined during the dose titration period. Patients whose mUFC becomes 
elevated during this period can have their LCI699 dose increased further, if it is tolerated and 
the maximum dose of 30 mg b.i.d. has not been reached. Such patients will be followed for 
long-term safety but will not be considered complete responders, and cannot be randomized. 
Dose reductions and temporary dose interruptions for safety reasons are permitted during this 
period without affecting eligibility for randomization. 
In order for a patient to be classified as a complete responder at Week 24, the following two 
conditions must be met: 1) mUFC ≤ ULN based on urine samples collected at Week 24; 2) 
LCI699 dose during Study Period 2 (Weeks 13-24) was not increased above the level 
established at the end of Study Period 1 (Week 12; end of individual dose titration period). Dose 
reductions and temporary dose interruptions for reasons of safety do not preclude the possibility 
of complete response assessment at Week 24.  
The key secondary endpoint, the proportion of patients with a complete response (mUFC ≤ 
ULN), is assessed at Week 24. 
Patients remain on open-label  LCI699 during the period between week 24 and week 26, in 
order to ensure that sufficient time is allowed for central laboratory results (Week 24 mUFC) 
to become available for all patients at all sites, and to standardize the time of randomization 
across sites. 
 
 


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1.2.3 
Study Period 3 
Study Period 3 is a double-blind, placebo-controlled randomized withdrawal period (Week 26 
to Week 34).  
 
Double blinding 
The Novartis study team, the patient, the investigator, and all other site staff remain blinded to 
treatment assignment from the time of randomization to the time of DBL for the core phase of 
the study. 
The study was unblinded at the time of the core phase DBL, which occurred on 10-May-2018. 
 
Eligibility for randomization 
In order to be eligible for randomization, patients must have completed dose titration during the 
first 12 weeks, continued on LCI699 treatment with no further dose increase during Weeks 13-
24, and have normal UFC (mUFC ≤ ULN) from urine samples collected at Week 24. 
Randomization is implemented at the Week 26 visit. 
Patients that are not eligible for randomization are followed on open-label LCI699 until the end 
of the core treatment (Week 48), unless there is a reason to discontinue from the study 
prematurely.  
 
Randomization 
Eligible patients are randomized in a double-blinded fashion at Week 26 at a 1:1 ratio either to 
continue treatment with LCI699 at the same dose or to matching placebo. Patients are stratified 
at randomization according to: LCI699 dose at Week 24 (≤ 5mg b.i.d. vs.  > 5 mg b.i.d.),  and 
history of pituitary irradiation (yes/no). 
 
UFC monitoring during randomized withdrawal 
During the 8-week randomized withdrawal study period, mUFC is measured at scheduled visits 
every 2 weeks. However, patients are also allowed to have unscheduled visits at any time during 
the randomized withdrawal period if they report symptoms of hypercortisolism or 
hypocortisolism. The investigator decides the dose of study drug (LCI699 or placebo) during 
this period, although is blinded to treatment assignment. All laboratory tests during the 
randomized withdrawal period must be sent to the central laboratory for analysis, and all 
treatment decisions must be based on central laboratory results. 
 
Dose adjustments during randomized withdrawal 
The dose of study drug (LCI699 or placebo) should remain unchanged for patients that maintain 
a normal mUFC and do not develop AE’s related to study drug during randomized withdrawal. 
The investigator may reduce or withhold a dose of study drug for safety reasons at any time 
during the study, including the randomized withdrawal period. Dose reductions or interruptions 


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for safety reasons during the randomized withdrawal period do not preclude the possibility of a 
complete response at Week 34. Dose increases are not permitted during the randomized 
withdrawal period. 
 
Discontinuation from randomized withdrawal 
During the randomized withdrawal study period, the patient must be discontinued from the 
randomized withdrawal period, declared a non-responder, if the mUFC increases to > 1.5 x 
ULN, and at least 2 individual urine samples show UFC > 1.5 x ULN at a single visit (scheduled 
or unscheduled).  
After discontinuation from randomized withdrawal, or at the end of the randomized withdrawal 
period (Week 34), whichever comes first, the patient resumes open-label LCI699 at a dose 
selected by the investigator.  
Patients who are discontinued from the study during the randomized withdrawal period are no 
longer in the study, and consequently they are not permitted to receive open-label LCI699 and 
cannot move forward to Study Period 4. 
1.2.4 
Study Period 4 
Study Period 4 is a single-arm, open-label therapy (Week 35 to Week 48). After Week 34 visit, 
all patients receive open-label LCI699 treatment until Week 48. Dose changes are permitted. 
At Week 48, patients have the option to enter an extension period or discontinue LCI699 at 
week 48 to conclude with an end of core study visit 4 weeks off study drug (at Week 52). 
1.2.5 
Optional extension period 
Patients who continue to receive clinical benefit, as assessed by the study investigator and who 
wish to enter the extension period must be re-consented at week 48. Patients who enter the 
extension period will do so without interruption of study drug or assessments. The optional 
extension period will end after all patients have completed Week 72 or have discontinued early 
(prior to Week 72).  
Study CLCI699C2301 ends when all ongoing patients have transitioned to the long-term safety 
follow-up study or have been offered local alternative treatment options; this period will not 
exceed 4 months after all ongoing patients have completed Week 72. Patients who continue to 
benefit from treatment and have completed Week 72 will be offered participation in a separate 
long-term safety follow-up study after the database lock of the core phase is completed.  
If the long-term safety follow-up study is opened at site, patients should transition to the long-
term safety follow-up study. If this option is not available, the patient can either be offered a 
local alternative treatment option or stay in the study until the study end (i.e. 4 months after the 
last patient completes Week 72) Patients entering the long-term safety follow-up study will 
complete an EOT visit. For these patients, the EOS visit is not applicable, as treatment on 
LCI699 will not be interrupted. Patients not entering the long-term safety follow-up study will 
complete an EOT visit, and an EOS visit 30 days after the last dose administration. 
 


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1.3 
Study objectives and endpoints 
The following table displays the study objectives/endpoints and the sections of this SAP 
document that describe the corresponding analyses. 
For the Final CSR, not all study objectives will be reported. This is documented in the 
corresponding SAP section for each objective. 
Table 1-1 
Study Objectives and endpoints 
Objective 
Endpoint 
Analysis 
Section 
Primary 
 
To compare the complete response rate at 
the end of the 8-week period of 
randomized withdrawal (Week 34) 
between patients randomized to 
continued LCI699 therapy vs. placebo. 
Proportion of randomized patients in each arm with: 
mUFC ≤ ULN at the end of 8 weeks of randomized 
withdrawal (Week 34), and were neither 
discontinued, nor had LCI699 dose increase above 
the level at week 26 during the randomized 
withdrawal period.  
2.5 
Key secondary 
To assess the complete response rate at 
the end of individual dose-titration and 
treatment with LCI699 in the initial 
single-arm, open label period (Week 24). 
Proportion of enrolled patients with mUFC ≤ ULN at 
Week 24 and had no dose increase above the level 
established at Week 12 between Week 13 and Week 
24. 
2.6 
Other secondary 
 
 
 To compare the time-to-last control of 
mUFC during the randomized withdrawal 
period between patients randomized to 
continued LCI699 therapy and placebo. 
Time-to-last control of mUFC, which is defined as 
the time (in days) from randomization to the last 
mUFC collection that was ≤ ULN before early 
discontinuation or completion of randomized 
withdrawal period, whichever is earlier. 
2.7.1 
To assess the complete, partial, and 
overall response rate at Week 12, Week 
24, Week 48, and at scheduled time 
points during the extension period and 
the last available assessment.  
Complete response rate: proportion of enrolled 
patients with mUFC ≤ ULN at Week 12, Week 24,  
Week 48, and at scheduled time points during the 
extension period (provided adequate follow-up), and 
the last available assessment 
 
Partial response rate: proportion of enrolled patients 
with ≥ 50% reduction from baseline in mUFC, but 
mUFC > ULN) at Week 12, Week 24, and Week 48, 
and at scheduled time points during the extension 
period (provided adequate follow-up), and the last 
available assessment   
Overall response rate: proportion of enrolled patients 
with mUFC ≤ ULN or at least 50% reduction from 
baseline at Week 12, Week 24,  Week 48,  and at 
scheduled time points during the extension period 
(provided adequate follow-up), and the last available 
assessment 
2.7.2 
To assess the change in mUFC during the 
core and extension periods of the study. 
 Actual and percentage change in mUFC from 
baseline to each post-baseline visit during the core 
and extension (provided adequate follow-up) at 
which UFC is collected 
2.7.3 


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Objective 
Endpoint 
Analysis 
Section 
 Actual and percentage change in mUFC from the 
time of randomization (Week 26) to the end of the 
randomized withdrawal period (Week 34), or the 
last mUFC measurement prior to early 
discontinuation, whichever occurs earlier. 
To assess the change in cardiovascular-
related parameters associated with 
Cushing’s disease during the core and 
extension periods of the study. 
 Actual and percentage change from baseline 
during the core and extension periods (provided 
adequate follow-up) of the study in: fasting 
glucose, HbA1c, fasting lipid profile, blood 
pressure, body weight, BMI and waist 
circumference  
 Actual and percentage change from the 
randomization (Week 26) to the end of 
randomized withdrawal period (Week 34), or the 
last measurement available prior to early 
discontinuation, whichever occurs earlier (see 
bullet above for individual parameters). 
2.7.4 
To assess the change from baseline in the 
physical features of Cushing’s disease by 
photography at Week 12, 24, 34,  48, and 
during the extension period. 
Categorical change from baseline to Week 12, 24, 34, 
48, during the extension at week 72 and EOT 
extension  in each of the following clinical signs of 
Cushing’s disease by photography: facial rubor, 
hirsutism, striae, supraclavicular fat pad, dorsal fat 
pad, proximal muscle wasting (atrophy), central 
(abdominal) obesity, and ecchymoses (bruises). 
2.7.5 
To assess the change from baseline in 
bone mineral density by DXA scan at the 
lumbar spine and total hip at Week 48 
and the last available assessment. 
Actual and percent change from baseline to Week 48 
and the last available assessment in bone mineral 
density as measured by DXA scan at the lumbar 
spine and total hip 
2.7.6 
To assess the time-to-escape. 
Time-to-escape is defined as the time (in days) from 
the first mUFC ≤ ULN to the first mUFC results > 
1.5 x ULN with at least 2 individual UFC results > 
1.5 x ULN. 
2.7.7 
To assess general safety and AEs of 
special interest 
Adverse events and laboratory abnormalities will be 
assessed using the National Cancer Institute-
Common Toxicology Criteria (NCI-CTC) grading 
scale (version 4.03). 
AEs of special interest, as reported by the 
investigator, or by laboratory evaluation, ECG, 
Holter recording, and pituitary MRI. 
2.8 
To evaluate exposures of LCI699 in 
patients with Cushing’s disease 
Plasma concentrations (predose, 0.5 h, 1.5 h, and 3.5 
h post-dose) of LCI699 
2.9 
To assess the change in Patient-Reported 
Outcomes (Health-Related Quality of 
Life) during the core and extension 
periods of the study. 
 Change in standardized score of CushingQoL (to 
include 2 subscale and total scores), Beck 
Depression Inventory-II, and EQ-5D-5L (utility 
index and VAS), from baseline to Week 24 and 
Week 48. 
2.11 


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Objective 
Endpoint 
Analysis 
Section 
 Change in standardized score of CushingQoL (to 
include 2 subscale and total scores), Beck 
Depression Inventory-II, and EQ-5D-5L (utility 
index and VAS), from the randomization (Week 
26) to the end of randomized withdrawal period 
(Week 34), or the last measurement prior to early 
discontinuation, whichever occurs earlier. 
 
Change from baseline in standardized score of 
CushingQoL (to include 2 subscale and total 
scores), Beck Depression Inventory-II, and EQ-
5D-5L (utility index and VAS), from baseline to 
Week 72, 96 and the EOT extension 
 
2 
Statistical methods 
2.1 
Data analysis general information 
Patients who discontinue study drug will be considered withdrawn from the study after the final 
visit assessments and the final safety follow-up visit are performed or when it is clear that the 
patient will not return for final visit assessments and/or final safety follow-up visit. 
The analysis of the core phase, including the primary and key secondary analyses was 
performed based on cumulative data collected up to the date when all enrolled patients had 
either completed or prematurely withdrawn from the core phase of study. The results and 
outcomes of this analysis were presented in an interim CSR. 
The study was powered based on the primary and key secondary analyses. All effiacy analyses 
presented in the Final CSR are considered as supportive, and no formal statistical testing will 
be performed. 
Analysis for the Final CSR will be performed once all patients have either completed the 
extension period or discontinued earlier.  
Data will be analyzed using the SAS System for data analysis V9.4 or higher.  


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2.1.1 
General definitions  
2.1.1.1 
Study day 
Study Day 1 is the date of first administration of study drug.  
The study day for an event that occurred 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 occurred after study day 1 will be calculated as (date of event – 
date of first administration of study drug) +1. 
Study day will be displayed in the data listings.  
2.1.1.2 
Baseline 
For efficacy and safety evaluations (e.g. laboratory assessments and vital signs): the last 
available pre-dose assessment within 35 days prior to or on Study Day 1 (before the first dose 
of LCI699) is taken as the “baseline” assessment; the last available assessment within 21 days 
prior to the first dose of randomized treatment (LCI699 or Placebo) is taken as the 
“randomization” assessment; If patients have no value as defined above, the 
baseline/randomization result will be considered missing. 
2.1.1.3 
Visit number 
The time point (Day/Month) associated with an assessment will be determined by the visit 
number assigned to the assessment in the database. The mapping of visit numbers to time points 
in the core study and the extension study are provided in the table below.  
Table 2-1 Scheduled visits in core phase  
Core study Visit  
Day/Week 
Clarifying Notes 
Visit 1 
Day -35 to Day -8 
Screening 
Visit 2 
Day -7 to Day -1 
Baseline 
Visit 3 
Day 1/Week 0 
Dose escalation period 
Visit 4 
Day 15/Week 2 
Dose escalation period 
Visit 5 
Day 29/Week 4 
Dose escalation period 
Visit 6 
Day 43/Week 6 
Dose escalation period 
Visit 7 
Day 57/Week 8 
Dose escalation period 
Visit 8 
Day 71/Week 10 
Dose escalation period 
Visit 9 
Day 85/Week 12 
Dose escalation period 
Visit 10 
Day 113/Week 16 
Treatment period 
Visit 11 
Day 141/Week 20 
Treatment period 
Visit 12 
Day 169/Week 24 
Treatment period 
Visit 13 
Day 183/Week 26 
Randomized Withdrawal period 
Visit 14 
Day 197/Week 28 
Randomized withdrawal period 
Visit 15 
Day 211/Week 30 
Randomized withdrawal period 
Visit 16 
Day 225/Week 32 
Randomized withdrawal period 
Visit 17 
Day 239/Week 34 
Randomized withdrawal period 


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Core study Visit  
Day/Week 
Clarifying Notes 
Visit 1 
Day -35 to Day -8 
Screening 
Visit 18 
Day 253/Week 36 
Open Label period 
Visit 19 
Day 281/Week 40 
Open Label period 
Visit 20 
Day 309/Week 44 
Open Label period 
Table 2-2 
Scheduled visits in extension period 
Extension study Visit  
Day/Week 
Clarifying Notes 
Visit 21 
Day 337/Week 48 
Extension 
Visit 22 
Day 365/Week 52 
Extension 
Visit 23 
Day 393/Week 56 
Extension 
Visit 24 
Day 421/Week 60 
Extension 
Visit 25 
Day 449/Week 64 
Extension 
Visit 26 
Day 477/Week 68 
Extension 
Visit 27 
Day 505/Week 72 
Extension 
Visit 28 
Day 589/Week 84 
Extension 
Visit 29 
Day 673/Week 96 
Extension 
Visit 30 
 Day 757/Week 108 
Extension 
Visit 31 
 Day 841/Week 120 
Extension 
…………. 
Every 84 days/12 weeks 
Extension 
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 778 (End-of-Treatment in 
extension period) are scheduled when the patient either completes the respective study period 
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 
(LASTVIS) prior to the 777/778 visit, then it will be mapped to the next scheduled visit 
(LASTVIS+1) in the visit schedule (from the tables above).   
The 777/778 visit will be considered to have occurred neither too soon nor too late after the 
actual last scheduled visit if the number of days between the two visits is 
(i) at least half of the planned gap between the patient’s actual last scheduled visit (LASTVIS) 
and the next scheduled visit and 
(ii) at most the total of (a) the planned gap between the patient’s actual last scheduled visit 
(LASTVIS) and the next scheduled visit and (b) half of the planned gap between the patient’s 
next two scheduled visits. 
If the number of days between the 777/778 visit and LASTVIS is less than the range specified 
above then the 777/778 visit will be mapped to an unscheduled visit of LASTVIS; if it is more 
then it will be mapped to an unscheduled visit of LASTVIS + 1. 
2.1.1.4 
Calculating mean UFC 
To compute the mean UFC for a patient at any particular visit, at least two individual 24hr UFC 
specimens are required at that visit. If there are less than two samples available then mean UFC 


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will be considered missing for that assessment. The derived mUFC value, calculated by 
Novartis, will be used for all analyses. 
2.1.1.5 
Study day associated with a mUFC assessment 
The study day associated with a mUFC assessment at any particular visit is defined as the study 
day of the last UFC sample collection for that visit. 
2.1.1.6 
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 
2.1.1.7 
Calculation of proportions of responders 
All enrolled patients will be included in the analysis for calculating the proportion of responders 
at time points up to Week 48. 
For calculation of proportion of responders beyond Week 48 (e.g. a time point in extension 
period), the following rules will be applied to determine whether patients are included in the 
analysis. 
1) patients who declined to enter optional extension period after completion of the core phase  
will always be excluded.  
2) patients who discontinued prior to the data cutoff date for the Final DBL will be included up 
to the furthest scheduled visit they could have completed if they had not discontinued early 
based on data cut off and last completed based on the date of last completed schedule visit and 
analyses cut-off date. For example, if the last completed scheduled visit for an early 
discontinued patient is Week 52, and the time between data cutoff and last completed scheduled 
visit is 8 weeks, he/she will be included in the analyses up to Week 60.  
If included in the analysis for calculating the proportion of responders at a given timepoint, 
patients who discontinued before this timepoint will be counted as non-responders. 
Patients randomized to placebo during the RW period, will not be included in the denominator 
for visits at which they received placebo. 
2.1.1.8 
Method for calculating Confidence Intervals 
95% confidence intervals for proportions will be calculated using the exact (Clopper-Pearson) 
method, unless stated otherwise. 
95% confidence intervals for change and percentage change from baseline will assume normally 
distributed data and will be calculated using the t-distribution.  
2.1.1.9 
AE summary cutoff 
All data up to data cut-off date will be at least listed. All safety data prior to the data cut-off will 
be summarized with the exception of AEs and deaths, which will follow the cut-off rule 
specified below.   


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AE/death summary cut-off date = min { data cut-off date, max(last dosing date + 30 , safety 
follow-up visit date) }   
AEs/deaths that occur after the AE/death summary cut-off date but prior to the data cut-off date 
will be listed and flagged. 
2.1.1.10 Criteria of adequate follow-up for time points in the extension 
period 
For a given time point in the extension period, it will be considered to have adequate follow-up 
to be included in the reporting activities if there are at least 15 patients available for the analysis 
at that time point. 
2.2 
Analysis sets 
Full analysis set (FAS): comprises all enrolled patients who receive at least one dose of LCI699. 
FAS is used in efficacy analysis for study period other than RW period including key secondary 
endpoint. 
Safety set (SAS): comprises all enrolled patients who received at least one dose of LCI699 and 
had at least one valid post-baseline safety assessment. Please note: the statement that a patient 
had no adverse events (on the Adverse Event CRF) constitutes a safety assessment. 
Per-Protocol set: There are two per-protocol sets defined in this study. 
 The Per-Protocol Set for Randomized Analysis Set (PPRAS) consists of a subset of the 
patients in the RAS who had no selected protocol deviations. 
 The Per-Protocol Set for Full Analysis Set (PPFAS) consists of a subset of the patients 
in the FAS who had no selected protocol deviations. 
PPFAS will only be used in supportive analyses for key secondary efficacy endpoint, while 
PPRAS will only be used in supportive analyses for primary efficacy endpoint. Details of 
protocol deviations that lead to exclusion from PPS and/or PPRAS can be found in table below. 
Table 2-3 
Protocol deviations leading to exclusion from PPFAS and/or PPRAS 
Protocol Deviation description 
Protocol deviation 
Code(s) in VAP3 
(Amendment 4, July2017) 
Excluded 
from 
PPFAS? 
Excluded 
from 
PPRAS? 
Informed consent for core phase not documented  
I01 
Yes 
Yes 
mUFC related inclusion criteria not met 
I06/I07 
Yes 
Yes 
ACTH related inclusion criteria not met 
I09 
Yes 
Yes 
Cushing's disease confirmation is missing 
I10 
Yes 
Yes 
Pituitary surgery related inclusion criteria not met 
 
I11/I12 
Yes 
Yes 
Pituitary irradiation related inclusion criteria not 
met 
I14 
Yes 
Yes 
Washout period related inclusion criteria not met 
I13/I15/I16/I17/I18/I19/I20 
Yes 
Yes 


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Subject did not meet the eligibility criteria for 
randomization but was randomized at Week 26. 
I21 
No 
Yes 
Participation in another trial with an investigational 
drug does  meet the exclusion criteria 
E01 
Yes 
Yes 
Subject pregnant or lactating at study entry 
E04/E05 
Yes 
Yes 
Subject's history of hormone over secretion does 
meet the exclusion criteria 
E10 
Yes 
Yes 
Subject's medical history of Cushing's syndrome 
does meet the exclusion criteria 
E11 
Yes 
Yes 
Subject compliance history does meet the 
exclusion criteria 
E23 
Yes 
Yes 
Subject met the discontinuation criteria, but was 
not discontinued from study treatment 
D01/D02 
Yes* 
Yes** 
Subject took a prohibited concomitant medication 
M01 
Yes* 
Yes** 
*If protocol deviation happens before Week 24, when the key secondary endpoint is assessed 
**If protocol deviation happens before end of randomized withdrawal period, when the primary   
    endpoint is assessed 
The analysis sets used for various analyses in the Final CSR are summarized below 
Table 2-4 
Analysis sets used for specific analyses 
 
FAS 
SAS 
PPFAS/ 
PPRAS 
Patient Disposition 
X 
 
 
Demography and baseline disease characteristics 
X 
 
 
Medical History 
X 
 
 
Prior Medication 
X 
 
 
Protocol Deviation 
X 
 
 
Concomitant Medications 
 
X 
 
Exposure to study medication 
 
X 
 
Efficacy analyses 
X 
 
X* 
Safety analyses 
 
X 
 
Patient-reported outcomes 
X 
 
 
* PPFAS will only be used in supportive analyses for key secondary efficacy endpoint. 
* PPRAS will only be used in supportive analyses for primary efficacy endpoint. 
 
 
When  appropriate, patients in a given analysis set could be classified into mutually exclusive 
treatment groups as described below: 


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For patients in PPRAS 
 LCI699 group: patients randomized to continued treatment of LCI699 for the randomized 
withdrawal period of the study  
 Placebo group: patients randomized to placebo for the randomized withdrawal period of 
the study 
For patients in FAS/PPFAS  
 LCI699 group: patients randomized to continued treatment of LCI699 for the randomized 
withdrawal period of the study 
 Placebo group: patients randomized to placebo for the randomized withdrawal period of 
the study 
 Non-randomized patients: patients who do not enter randomized withdrawal period of the 
study (either discontinued study before the randomization or not eligible to be 
randomized) 
For patients in SAS 
 LCI699 group: patients receiving study treatment of LCI699 for the randomized 
withdrawal period of the study 
 Placebo group: patients receiving study treatment of placebo for the randomized 
withdrawal period of the study 
 Non-randomized patients: patients who do not enter randomized withdrawal period of 
the study (either discontinued study before the randomization or not eligible to be 
randomized) 
2.2.1 
Subgroup of interest 
Subgroups of interest for this study include the two stratification factors for randomization 
History of pituitary irradiation: Yes and No 
LCI699 dose at Week24: ≤ 5mg b.i.d. and  > 5mg b.i.d. 
For the Final CSR, the per-protocol analysis of the primary effiacy endpoint will be 
performed including adjustment for the two stratification factors. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Summary statistics of data pertaining to subject disposition, demographics, baseline 
characteristics, medical history, prior medications and protocol deviations will be tabulated and 
displayed using grouping described in Section 2.2.   
2.3.1 
Patient disposition 
For overall study period, counts of patients for the following items will be summarized by 
treatment group using FAS: 
 discontinued at any time* 
 Primary reason for discontinuation at any time  


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 discontinued at or prior to Week 12 
 Primary reason for discontinuation at or prior to Week 12 
 discontinued at or prior to Week 24 but after Week 12  
 Primary reason for discontinuation at or prior to Week 24 but after Week 12 
 discontinued prior to Week 48 but after Week 24 
 Primary reason for discontinuation prior to Week 48 but after Week 24 
 Completed Week 48 
 Completed Week 48 and did not enter Extension period 
 Completed Week 48 and enter Extension period 
 Ongoing in Extension  
 Discontinuation in the Extension 
 Primary reason for discontinuation in the Extension 
 Discontinued at or prior to Week 72 but after Week 48 
 Discontinued prior to Week 96 but after Week 72 
 Discontinued after Week 96 
 Completed extension  
* Patients who completed Week 48 and declined to enter optional extension period are not 
counted as discontinuations. 
For randomized withdrawal period, counts of patients for the following items will be provided 
in a separate disposition summaries presented by treatment group using RAS: 
 discontinued from randomized treatment before completing RW period 
 primary reason for discontinuation before completing RW period  
 discontinued from randomized treatment at or prior to Week 28 
 primary reason for discontinuation at or prior to Week 28  
 discontinued from randomized treatment at or prior to Week 30 but after Week 28 
 primary reason for discontinuation at or prior to Week 30 but after Week 28 
 discontinued from randomized treatment at or prior to Week 32 but after Week 30 
 primary reason for discontinuation at or prior to Week 32 but after Week 30 
 discontinued from randomized treatment at or prior to Week 34 but after Week 32 
 primary reason for discontinuation at or prior to Week 34 but after Week 32 
 Completed the RW period (Week 34) 
 


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2.3.2 
Demographic and baseline disease characteristics 
All demographic and baseline disease characteristics were summarized in the interim CSR. 
They will not be reported in the Final CSR. 
2.3.3 
Medical history 
Relevant medical history and ongoing medical conditions were summarized in the interim CSR. 
They will not be reported in the Final CSR. 
2.3.4 
Protocol deviations 
The number and percentage of patients with any PDs up to data cutoff will be tabulated by 
treatment group using FAS. 
PDs leading to exclusion from the PPFAS and PPRAS will be tabulated by treatment group 
using FAS and RAS respectively. 
All PDs up to data cutoff will be listed. 
The criteria for protocol deviation are specified in Validation and Planning (VAP) Module 3 
and will be finalized prior to database lock. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
In the Final CSR the exposure to the study drug will be summarized  for the overall study period 
only, using the SAS. 
Duration of exposure 
• For overall study period, duration of exposure to LCI699 for patients in the SAS is calculated 
as below:   
•for Placebo group: 
Duration of exposure (weeks) = (min (date of last administration of study 
medication, date of data cut-off, date of death) – date of first administration of 
LCI699 + 1)/7 – Duration of exposure to Placebo  
•for LCI group and non-randomized patients 
Duration of exposure (weeks) = (min (date of last administration of LCI699, date 
of data cut-off, date of death) – date of first administration of LCI699 + 1)/7   
The above duration calculation includes the periods of temporary interruption. 
Dose reduction/interruption   
The number of patient who has at least one dose reductions or interruptions, and the 
corresponding reasons will be summarized by study period. Although patients may have 
multiple dose reduction or interruption with the same reason, patient will be counted only once 
for each distinct reason. 


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The actual and planned doses administered and reason for dose change will be listed with UFC 
information. 
Dose of LCI699 
The LCI699 average total daily dose by visit during the overall study period will be summarized 
using descriptive statistics and displayed graphically. Dose levels whilst on placebo, for patients 
randomized to placebo during the RW period, will not be included in the calculations. 
2.4.2 
Prior, concomitant and post therapies 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system. Surgical and medical procedures will be coded 
using MedDRA and summarized by SOC and preferred term.  
Concomitant medications and significant non-drug therapies will be listed and summarized 
using frequency counts and percentages by ATC class, preferred term and treatment group 
within each of three study periods: first 26 weeks (FAS), randomized withdrawal period (RAS), 
and overall study period (FAS). 
Therapies for Cushing’s Disease taken prior to first dose of LCI699 will be summarized using 
frequency counts and percentages by ATC class, preferred term and treatment group. 
 
If the start date of a concomitant medication is missing or partially missing, then it will be 
imputed following Novartis standard rule for table and listing. 
2.5 
Analysis of the primary objective 
The primary objective was to compare the complete response rates at the end of the 8 weeks 
period of randomized withdrawal (Week 34) between patients randomized to continued LCI699 
therapy vs. placebo. 
The primary efficacy variable is the proportion of randomized patients in each treatment arm 
that are complete responders at the end of the 8 weeks of the randomized withdrawal period 
(Week 34). A complete responder is defined as a patient who has mUFC ≤ ULN (based on 
central laboratory result) at Week 34 and who was neither discontinued nor had LCI699 dose 
increase above the level at week 26 during the randomized withdrawal period of the study. 
Patients who discontinued during the randomized withdrawal period will be counted as non-
responders for the primary endpoint. Dose reductions and temporary dose interruptions for 
safety reason during randomized withdrawal period do not preclude patients from being 
complete responder for primary endpoint. 


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For the primary objective, the statistical null hypothesis states that the complete response rates 
at the end of 8-week randomized withdrawal period (i.e., at Week 34) are the same between the 
two randomized arms. To test this hypothesis, a Cochran–Mantel–Haenszel exact test stratified 
by the two stratification factors considered for randomization will be performed using the RAS 
following the intent-to-treat principle. 
If the 2-sided p-value is ≤ 0.05 and the odds ratio (LCI699 vs. Placebo) is > 1, the null 
hypothesis will be rejected and the complete response rate in the LCI699 arm will be considered 
higher than that in the placebo arm. 
As a supportive analysis to this analysis, 1) an un-stratified Fisher’s exact test of the primary 
endpoint will also be performed using RAS; 2) both stratified CMH exact test and un-stratified 
Fisher’s exact test of the primary endpoint will be performed using PPRAS. 
After the interim CSR was published, additional protocol deviations were reported which affect 
the per-protocol population used to perform the per-protocol analyses of the primary endpoint, 
therefore the Final CSR will report the updated result of the supportive analyses using the 
PPRAS. 
The analyses of the primary endpoint using the RAS are not impacted by these additional 
protocol deviations, and therefore will not be reported in the Final CSR. 
2.6 
Analysis of the key secondary objective 
The key secondary objective was to assess the complete response rate at the end of 24 weeks of 
dose-titration and treatment with LCI699 in the initial single-arm, open label part of this trial. 
The key secondary efficacy variable is the proportion of complete responders at Week 24. A 
complete responder is defined as an enrolled patient who has mUFC ≤ ULN at Week 24 and 
the dose of LCI699 during Study Period 2 (Weeks 13-24) was not increased above the level 
established at the end of Study Period 1 (Week 12). Dose reductions and temporary dose 
interruptions for safety reasons do not preclude patients from being complete responder for the 
key secondary endpoint. Enrolled patients who had missing mUFC assessment at Week 24 will 
be counted as non-responders for the key secondary endpoint. 
For the key secondary objective, the statistical null hypothesis states that the complete response 
rate at week 24 LCI699 is ≤ 30%. The analysis of the key secondary objective will be based on 
the 2-sided 95% exact confidence interval (Clopper-Pearson method). If the lower bound of this 
95% confidence interval is ≥ 30%, the null hypothesis will be rejected and the complete 
response rate will be considered at least 30% after 24 weeks of treatment with LCI699. 
The above testing on the key secondary objective will only be carried out if the null hypothesis 
for the primary objective is rejected. This sequential procedure will ensure preservation of the 
overall 2-sided type 1 error at 5%. 
The above analysis of the key secondary endpoint will be performed using FAS. As supportive 
analysis, same analysis will be performed using PPFAS. 
After the interim CSR was published, additional protocol deviations were reported which affect 
the per-protocol population used to perform the per-protocol analyses of the key secondary 


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endpoint, therefore the Final CSR will report the updated result of the supportive analyses using 
the PPFAS. 
The analyses of the key secondary endpoint using the FAS are not impacted by these additional 
protocol deviations, and therefore will not be reported in the Final CSR. 
2.7 
Analysis of secondary efficacy objectives 
For the objectives identified below, the definition of Baseline/Randomization assessment and 
the method of computing confidence intervals are specified in Section 2.1.1.2 and Section 
2.1.1.8 respectively. Last observation carried forward (LOCF) method will not be used in any 
of these analyses. For analysis using FAS, results will be presented by LCI699 group, Placebo 
group, Non-randomized patients, and All patients. 
2.7.1 
Compare the time-to-last control of mUFC during the randomized 
withdrawal period between patients randomized to continued LCI699 
and placebo 
The results of this objective were reported in the interim CSR, and will not be repeated for the 
Final CSR. 
2.7.2 
Assess the complete, partial, and overall response rate at Week 12, 
Week 24, Week 48, and during the extension period 
The proportion of complete responders (enrolled patients with mUFC ≤ ULN), partial 
responders (enrolled patients with mUFC > ULN and at least 50% reduction from baseline), 
and overall responders (enrolled patients with mUFC ≤ ULN or have at least 50% reduction 
from baseline) will be summarized using point estimates for every scheduled visit in the core 
and extension (provided adequate follow-up) at which UFC is collected. 95% 2-sided CIs for 
response rates will be provided for Week 48, Week 60, Week 72 and the last available 
assessment of the study. The FAS will be used for the analyses. 
2.7.3 
Assess the change in mUFC during the core and extension period of 
study  
For the actual value and change in mUFC from baseline during the overall study period, 
descriptive summaries will be provided for every scheduled visit in the core and extension 
(provided adequate follow-up) at which UFC is collected. The FAS will be used for the 
analysis. 
Patients randomized to placebo during the RW period, will not have their mUFC values 
included in the analysis for visits at which they received placebo. 
2.7.4 
Assess the change in cardiovascular-related metabolic parameters 
associated with Cushing’s disease during the core and extension 
period of the study  
The following parameters will be analyzed: glucose, HbA1c, fasting lipid profile, SBP, DBP, 
weight, waist circumference and BMI). 


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For the actual value and change from baseline during the overall study period, descriptive 
summaries will be provided for every scheduled visit in the core and extension (provided 
adequate follow-up). The FAS will be used for the analysis. 
Patients randomized to placebo during the RW period, will not have their values included in 
the analysis for visits at which they received placebo. 
2.7.5 
Assess the change from baseline in physical features of Cushing’s 
disease by photography 
For physical features of Cushing’s disease, such as facial rubor, hirsutism, striae, 
supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) 
obesity, and ecchymoses (bruises), the change from baseline (captured by a semi-quantitative 
Likert scale) at visits where photography is scheduled (Week 12, 24, 34 and 48 as well as Week 
72 and EOT extension) will be assessed by shift tables. In addition, the proportion of patients 
having a favorable shift from baseline at post-baseline time points will also be tabulated. The 
FAS will be used for the analyses. 
2.7.6 
Assess the change from baseline in bone mineral density by DXA 
scan at Week 48 and the last available assessment 
For bone mineral density measured by DXA scan at the lumbar spine and total hip, descriptive 
summaries of actual and percentage change from baseline at Week 48 and the last available 
assessment will be provided. The FAS will be used for the analysis. 
2.7.7 
Assess the time-to-escape under treatment of LCI699  
Escape is defined as the first loss of control of UFC that meets all of the following criteria: 
 prior normalization of UFC has occurred (mUFC≤ ULN) 
 both the mUFC and at least 2 individual values contributing to that mUFC have to be 
>1.5 x ULN  
 the loss of control of UFC is not related to a dose interruption or dose reduction due to 
safety reasons 
 happens beyond 12-week dose titration period (Study Period 1). 
Time-to-escape is defined as the time (in days) between the first UFC assessment with mUFC 
≤ ULN and either the UFC assessment of escape (event) or last UFC assessment before 
permanent discontinuation of LCI699 treatment (censored), whichever occurs earlier.  
For patients who attained normalization of UFC (mUFC ≤ ULN), time-to-escape will be 
analyzed using K-M plot. The quartiles of time to escape and corresponding two-sided 95% 
confidence interval will be calculated using Kaplan-Meier methodology. In addition, time-to-
escape will be summarized using descriptive statistics for patients who escape. FAS will be 
used for the analysis. 
Patients randomized to placebo are not included in this analysis.  


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2.8 
Safety analyses 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside the pre-determined ranges.  Other safety data (e.g. 
electrocardiogram, vital signs, and special tests) will also be presented.  
In the Final CSR results for the overall study period will be analyzed, using the SAS. Results 
will be presented by Randomized patients, Non-randomized patients and All patients. 
The safety results for the Final CSR will focus solely on the safety of LCI699. Therefore 
scheduled safety assessments performed whilst on placebo, for patients randomized to placebo 
during the RW period, will not be included. Similarly, adverse events with a start date which 
corresponds to when a patient was receiving placebo will not be included in adverse event 
summaries. 
2.8.1 
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. 
2.8.1.1 
Coding of AEs  
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. The latest version available at the time of database lock will be used. 
2.8.1.2 
Grading of AEs  
AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  
The CTCAE represents a comprehensive grading system for reporting acute and late effects of 
cancer treatments. CTCAE v4.03 is graded by definition a 5-point scale generally 
corresponding to clinical severity (mild, moderate, severe, life-threatening, and death). This 
grading system inherently places a value on the importance of an event although there is not 
necessarily proportionality among grades (a Grade 2 is not necessarily twice as bad as a Grade 
1).  
For adverse events for which CTCAE grades are not available, grades 1 – 4 corresponding to 
the severity of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) 
is not used in this study; rather, this information will be collected on the “End of Treatment” or 
“Study evaluation completion” eCRF pages 
2.8.1.3 
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) but no later than AE summary cutoff defined in Section 
2.1.1.9.  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.  


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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”. 
The frequency of CTC grades 3 and 4 AEs will be summarized separately. 
Any information collected (e.g. CTC grades, relationship to study drug, action taken etc.) will 
be listed as appropriate. 
Adverse events with a start date which corresponds to when a patient was receiving placebo 
will not be included in adverse event summaries. 
2.8.1.4 
AE summaries 
The following adverse event summaries will be produced: 
 Adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and maximum CTC grade 
 Adverse events, suspected to be study drug related, by primary system organ class, preferred 
term and maximum CTC grade 
 Adverse events, regardless of study drug relationship, by preferred term 
 Adverse events, suspected to be study drug related, by preferred term 
 All deaths, by primary system organ class and preferred term 
 Serious adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and maximum CTC grade 
 Serious adverse events,suspected to be study drug related, by primary system organ class, 
preferred term and maximum CTC grade 
 Serious adverse events, regardless of study drug relationship, by preferred term and 
treatment 
 Adverse events leading to study drug discontinuation, regardless of study drug relationship, 
by primary system organ class and preferred term  
 Adverse events requiring dose adjustment or study-drug interruption, regardless of study 
drug relationship, by primary system organ class and preferred term  
 Adverse events requiring additional therapy, regardless of study drug relationship, by 
primary system organ class and preferred term 
 Serious adverse events leading to study drug discontinuation, regardless of study drug 
relationship, by primary system organ class and preferred term  


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 Adverse events of Special Interest, regardless of study drug relationship, by category and 
preferred term 
 Adverse events of Special Interest with suspected study drug relationship, by category and 
preferred term 
 Adverse events of special interest leading to study drug discontinuation, regardless of study 
drug relationship, by category, and preferred term 
 Adverse events of special interest requiring dose adjustment or interruption, regardless of 
study drug relationship, by category, and preferred term 
 On-treatment deaths and serious adverse events by system organ class and preferred term 
 Non-serious adverse events (threshold = 5%) by system organ class and preferred term 
2.8.1.5 
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 LCI699 treatment (i.e. where LCI699 may influence a 
common mechanism of action responsible for triggering them) or adverse events which are 
similar in nature (although not identical). The list of AESIs is updated periodically after 
MedDRA update and/or review of accumulating trial data, and stored on the eCRS platform. 
The results for the Final CSR will use the list in place at the time of DBL. 
2.8.1.6 
Adverse events by time of onset 
AEs will also be categorized by the time of onset, and seperate summaries shown for defined 
time periods of the study. 
The time periods used will be 
 Baseline to Week 26 
 Week 26 to Week 48  
 Week 48 to Week 72 
 Week 72 onwards 
The denominator for each time period will be the number of patients still on the study at the 
start of that period.These summaries will be reported for 
 Adverse events of Special Interest, regardless of study drug relationship, by category and 
preferred term 
 Adverse events of Special Interest with suspected study drug relationship, by category and 
preferred term 
2.8.2 
Deaths 
Deaths will be reported, by primary system organ class and preferred term. Patients will not be 
followed-up for survival in this study, with patients considered to be off-treatment 30 days after 
treatment discontinuation. 


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2.8.3 
Laboratory data 
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 Periods through the last study visit. 
Eligible laboratory data will be classified into CTC grades according to NCI CTCAE v4.03. In 
the unlikely case a local laboratory normal range overlaps into the higher (i.e. non-zero) CTC 
grade, if the laboratory value is within local normal limits it will be assigned a CTC grade of 
zero.  
The following summaries will be produced for the laboratory data (by laboratory parameter) 
for the overall study period: 
• 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 from baseline to the worst post-baseline value and from baseline to the last 
post-baseline values using CTC grades will be produced for hematology, biochemistry, and 
urine laboratory parameters with CTC grades 
• For laboratory parameters in which CTC grades are not defined, shift tables from baseline 
to the worst post-baseline value and from baseline to the last post-baseline values will be 
produced using the low/normal/high classifications based on laboratory reference ranges  
• Shift tables of fasting blood glucose and HbA1c from baseline to the highest post-baseline 
value and from baseline to the last post-baseline values using the ADA (2010) classification. 
• Selected laboratory data will be also be displayed by presenting summary statistics of 
change from baseline value. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Fridericia’s formula (QTcF) will be used to calculate the heart rate-corrected QT interval (ms) 
based on the heart rate (HR bpm) and QT (ms) for centrally-read data. These calculated QTc 
values will be used in ECG summary tables and listings. The formula is as follows: 
QTcF (in ms) =QT/(RR)1/3 
The following analyses will be performed for variables PR, QRS, QT interval, heart rate, and 
QTcF (Fridericia’s) for the overall study period: 
 summary statistics at baseline, all post-baseline time points as well as corresponding 
change from baseline.  


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 For randomized withdrawal period:  summary statistics at randomization, all time 
points within randomized withdrawal period as well as corresponding changes from 
randomization  
 Listing of ECG data including all scheduled and unscheduled time points 
No imputation of missing data will be performed.  
The number and percentage of patients with notable ECG interval values will be summarized.  
A newly occurring ECG finding is defined as an notable finding at post-baseline that is not 
present at baseline.  
The notable criteria for PR are 
• > 200 ms post-baseline and ≤ 200 ms at baseline 
• Increase > 25% compared to baseline to a post-baseline value > 200 ms 
 
The notable criteria for QRS are 
• > 110 ms post-baseline and ≤ 110 ms at baseline 
• Increase > 25% compared to baseline to a post-baseline value > 110 ms 
 
The notable criteria for QT and QTcF are 
• > 450 ms at any post-baseline and ≤ 450 ms at baseline 
• > 480 ms at any post-baseline and ≤ 480 ms at baseline 
• > 500 ms at any post-baseline and ≤ 500 ms at baseline 
• an increase from baseline > 30 ms at any post-baseline 
• an increase from baseline > 60 ms at any post-baseline 
The percentage of patients having notable ECG interval values is based on the total number of 
patients who are at risk for a specific category. For new abnormality post-baseline values, this 
is the number of patients with both baseline and post-baseline evaluations who are normal at 
baseline. For abnormal change from baseline, this is the number of patients with both baseline 
and post baseline evaluations. A subject with multiple occurrences of a newly occurring 
abnormality is counted only once per abnormality. 
All ECG data will be listed. If corrected QTcF are provided (providing them is optional), they 
will be listed in addition to the values derived using the formulae above. (In the summaries only 
the derived values will be used.) The patients with notable ECG interval values will be listed 
and the corresponding notable values will be flagged in the listings. 
For 24hr Holter assessment, summaries of the key parameters will be provided. The worst 
observed post-baseline value for each patient, for each parameter will be presented. 
The following parameters will be presented using shift tables 
 % of patients with maximum HR >100 bpm 
 % of patients with minimum HR <40 bpm 
 % of patients with average HR >90 bpm 


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 % of patients with total SVEs >200 
 % of patients with total VEs >200 
The following parameters will be presented as change from baseline 
 Total number of pauses >2 seconds 
 Total SVE run events 
 Total VE run events 
To ensure accurate reporting of results, only Holter assessments which were performed for at 
least 20 hours will be used in any analysis. 
All 24hr summary results will also be listed for the reported assessments. 
2.8.4.2 
Vital signs 
All vital signs data (weight (kg), body temperature (0C), pulse rate (beats per minute), and 
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, triplicate measurements are planned when assessed, and the 
mean of available values will be taken for analysis purposes. Change over time from baseline  
will be summarized. 
The criteria for clinically notable abnormalities are defined as follows: 
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. 
• Pulse:  120 bpm with increase from baseline 15 bpm 
• Weight: Increase from baseline of  10% 
• Temperature: Increase from baseline of  39.10C 
 
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 
• Pulse:  50 bpm with decrease from baseline  15 bpm 
• Weight: Decrease from baseline of  5% 
2.8.4.3 
Tumor volume 
For tumor volume evaluated by MRI (or CT) scanning in patients with detectable tumor volume 
at baseline, descriptive summary of actual tumor volumes as well as its change from baseline 
will be provided at visits where evaluation is scheduled (Week 24, 48, 72 and any further visits 


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occurring every 24 weeks). For MRI (or CT) images that are not interpretable for tumor volume, 
the longest dimension (in mm) will be listed instead. 
Tumor invasiveness at each scheduled visit, and the change in status from baseline will be 
reported. 
The proportion of patients with measurable tumors at each visit, and the change in status from 
baseline will be reported. 
2.9 
Pharmacokinetic endpoints   
No PK analysis will be performed for the Final CSR. 
2.10 
PD and PK/PD analyses 
No PK/PD analysis will be performed for the Final CSR. 
2.11 
Patient-reported outcomes 
The Cushing’s QoL score (both the total score and two subscale scores) is identified as the 
primary PRO variable of interest. EQ-5D-5L utility index and visual analogue scale (VAS) 
scores, and Beck Depression Inventory-II (BDI-II) total score, are identified as secondary PRO 
variables of interest.  
2.11.1 
CushingQoL 
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses 
health-related quality of life (HRQoL) in patients with Cushing’s syndrome and has been 
validated in patients with Cushing’s disease (Webb SM, 2008; Nelson L., 2013). The 
CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects 
(e.g. ‘I bruise easily’), psychological aspects (e.g. ‘I am more irritable, I have sudden mood 
swings and angry outbursts’), and social aspects (e.g. ‘I have had to give up my social or leisure 
activities due to my illness’). 
The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how 
often (‘always’ to ‘never’) or how much (‘very much’ to ‘not at all’) each item has been related 
to the patient’s Cushing’s disease in the previous 4 weeks. Scoring of each item ranges from 1 
(‘Always’ or ‘Very much’) to 5 (‘Never’ or ‘not at all’). For the purpose of the clinical trial, the 
recall period has been modified to ‘within the past week’ in order to be more sensitive to the 
changes in patient HRQoL, specifically during the randomized withdrawal period, where it is 
believed that changes in Cushing’s disease symptoms will occur rapidly once patients 
withdrawal from LCI699 treatment  
Patients who complete 9 or more items at an assessment are considered evaluable for that visit. 
Standardized scores can be calculated as follows: 
 
The raw score is calculated by summing the individual item scores prior to being standardized 
so that the total score ranges from 0 to 100, with a lower score indicating a greater impact on 
HRQoL. The following formula can be used to calculate the total score: 
 
[(X – L) / (H – L)] * 100 


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Where X is the total score of the subscale of interest, L is the lowest possible score of the 
subscale, and H is the highest possible score for the subscale.  
 
Recent research recommends that a 2 sub-scale scoring (namely, a psychosocial issues scale 
and a physical problems scale) provides the optimal interpretation, rather than the total score.  
(Tiemensma J. 2016).  The CushingQoL 2 sub-scale scoring of each subscale is exactly the 
same as the total score. The items which comprise each subscale are shown in the table below: 
 
Table 2-4 Items for the two subscales of CushingQoL 
Psychosocial issues subscale 
 
Physical problems subscale 
2 
I have pain that keeps me from leading a 
normal life 
 
1 
I have trouble sleeping 
5 
I am more irritable, I have sudden mood 
swings and angry outbursts 
 
3 
My wounds take a long time to heal 
6 
I have less self-confidence, I feel more 
insecure 
 
4 
I bruise easily 
7 
I am worried about the changes in my 
physical appearance due to my illness 
 
 
 
8 
I feel less like going out or seeing relatives 
or friends 
 
 
 
9 
I had to give up my social or leisure 
activities due to my illness 
 
 
 
10 
My illness affects my everyday activities 
such as working or studying 
 
 
 
11 
It is difficult for me to remember things 
 
 
 
12 
I am worried about my health in the future 
 
 
 
 
Currently a minimal important difference (MID) of 10.1 is defined in the literature based on the 
distribution method of a 0.5 SD unit change using baseline data, with the original 4 week recall 
period (Nelson, 2013, Norman, 2003). However, anchor-based methods for calculating MIDs 
have been referenced as more reliable estimates for interpreting change in PRO scores over time 
(based on an individual’s level of change rather than a group level of change) in PRO guidelines 
(FDA, 2009).  Given the importance of anchor-based MIDs and that the recall period has been 
modified to 1 week, the MID will be derived by Novartis from data collected in previous clinical 
trial(s) using the CushingQoL, as possible, and analyses of the present clinical trial data will 
then be performed for confirmatory purposes for this anchor-based MID (as possible). The 
proportion of patients whose CushingQoL standardized score change from baseline by at least 
the newly derived MID and the associated 95% CI will be summarized by study period and 
group (specifically for study period 3 analyses). 
2.11.2 
BDI-II 
The BDI-II is a patient-reported instrument developed to measure the severity of depression in 
adults and adolescents aged 13 years and older.  The BDI-II is designed to be completed by the 
patient on paper and takes approximately five minutes to complete.  The BDI-II comprises 21-
items assessing the common cognitive symptoms of depression over the previous two weeks  
Items are rated on a four-point severity scale of 0 (‘not at all’) to 3 (‘extreme’ form of each 
symptom) with differing response options for each item.  A global score ranging from 0 to 63 
is calculated with a higher score representing a greater level of depression.   


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The following scoring guidelines for interpretation of the BDI-II have been suggested (Smarr, 
2011):  
Minimal range = 0-13 
Mild depression = 14-19 
Moderate depression = 20-28 
Severe depression = 29-63 
A minimal clinically important difference for improvement in BDI-II scores has been reported 
as a 17.5% reduction in scores from baseline; however, this is dependent on baseline severity 
(Button Ks, 2015) 
2.11.3 
EQ-5D-5L  
Health status will be assessed using the EQ-5D-5L. The EQ-5D-5L has two components, the 
EQ-5D-5L descriptive system and the EQ-5D-5L visual analog scale (VAS) (Herdman, M., 
2011, The EuroQoL Group, 2013).  The EQ-5D-5L descriptive system comprises the following 
five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  
Each dimension has five levels: ‘no problems’, ‘slight problems’, ‘moderate problems’, ‘severe 
problems’ and ‘unable to do activity or extreme problems’.  A utility index can be computed 
from the EQ-5D-5L descriptive system with utility scores ranging from -0.281 (worst 
imaginable health state) to 1 (best imaginable health state), with -0.281 representing an 
“unconscious” health state.  The EQ-5D-5L VAS records the subject’s self-rated health state on 
a 100-point vertical VAS (0=worst imaginable health state; 100=best imaginable health state) 
(The EuroQoL Group, 1990)  A score difference of 0.037-0.069 for the EQ-5D-5L utility score 
will be used as MID (McClure, 2017). A score difference of 7 for the EQ-5D-5L VAS will be 
used as MID estimates for the EQ-5D-5L (Pickard, 2007). 
The relevant scoring algorithm will be applied to patient-level data in order to derive EQ-5D -
5L index-based scores.  The United Kingdom Measurement and Valuation of Health study value 
set is generally considered the base case scoring function for the purposes of publication (Dolan 
1997). Therefore, the EQ-5D-5L utility scores will be based on United Kingdom values for 
reporting in the CSR. An example of calculating the utility index from raw scores on the EQ-
5D-5L are shown below: 


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Table 2-5 
Illustration of calculating the utility index from raw score on the EQ-
5D-5L  
 
2.11.4 
Secondary objective - Assess the change in Patient-Reported 
Outcomes (Health-Related Quality of Life) during the core and 
extension period of the study  
Changes in PRO that are either statistically significant (based on two-sided 95% confidence 
interval with no adjustment for multiplicity) or  exceeding the MID will be flagged. 
For each of four PRO variables (CushingQoL score (2 subscale and total score), BDI total score, 
EQ-5D-5L utility index, and EQ-5D-5L VAS score), descriptive summaries of the actual value 
and change from baseline during the overall study period will be provided. The FAS will be 
used for this analysis. 
2.12 
Biomarkers 
No biomarker analyses will be performed for the Final CSR. 
2.13 
Other Exploratory analyses 
No exploratory analyses will be performed for the Final CSR. 


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2.14 
Interim analysis 
The study has no planned interim analysis for efficacy. 
3 
Sample size calculation 
The sample size calculation relates to the primary and key secondary efficacy analyses, which 
will not be reported in the Final CSR. 
3.1 
Sample size justification 
Eligible patients will be stratified at randomization according to: LCI699 dose at Week 24 (≤ 
5mg bid vs. > 5mg bid); and history of pituitary irradiation (yes/no). It is estimated that 10 %, 
40%, 10% and 40 % of randomized patients respectively will be in the 4 strata defined by two 
randomization stratification factors (≤ 5mg b.i.d and Yes; ≤ 5mg b.i.d and No; > 5mg b.i.d. and 
Yes; and > 5mg b.i.d. and No) based on the following considerations: 
 LCI699 dose at week 24 (≤ 5mg b.i.d. vs. > 5mg b.i.d.): Based on the data from the PoC 
study, 5mg b.i.d. is estimated to be the median LCI dose at week 24 for this phase 3 trial. 
 History of pituitary irradiation (Yes/No): Although supportive data is not available, it is 
assumed that approximately 20% of randomized patients will have a history of pituitary 
radiation. 
 In the absence of data to expect otherwise, it is assumed that these two stratification 
factors are independent of each other. 
To detect a difference of 40% in complete response rate between 70% in LCI699 arm and 30% 
in placebo arm (equivalent odds ratio equals 5.444), a sample size of 33 patients per arm will 
be considered adequate based on a two-sided Cochran-Mantel-Haenszel (CMH) test at the 0.05 
level with 87% power. Assuming that 50% of enrolled patients will be eligible for 
randomization (mUFC ≤ ULN at the end of the 24 week open-label LCI699 study period), 132 
patients need to be enrolled into the study. 
3.2 
Power consideration for analysis of key secondary objective 
The analysis of the key secondary objective will be based on the 2-sided 95% confidence 
interval constructed using the Clopper-Pearson exact method. If the lower bound of this 95% 
confidence interval is ≥ 30%, the null hypothesis will be rejected and the complete response 
rate will be considered at least 30% after 24 weeks of treatment with LCI699. 
The above testing on the key secondary objective will only be carried out if the null hypothesis 
for the primary objective is rejected. This sequential procedure will ensure preservation of the 
overall 2-sided type 1 error at 5%. 
Assuming a 50% complete response rate (mUFC ≤ ULN) at end of 24 weeks of LCI699 
treatment, for 132 enrolled patients, there is 99.7% chance that the lower bound of 95% 2-sided 
CI of observed response rate (based on Clopper-Pearson Exact method) is larger than 30.0%. 


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4 
Change to protocol specified analyses 
5 
Reference 
American Diabetes Association, (2010), ‘Diagnosis and Classification of Diabetes Mellitus’, 
Diabetes Care, 33, Supplement 1, S62-S69. 
Button KS, Kounali1 D, Thomas N, Wiles NJ,  Peters TJ, Welton NJ, Ades AE, and Lewis G 
(2015), Minimal clinically important difference on the Beck Depression Inventory – II 
according to the patient’s Perspective,  Psychological Medicine, 45: 3269–3279. 
 
Dolan P (1997), Modeling valuations for EuroQol health states,  Med Care, 35:1095-108. 
 
FDA PRO Guidance (2009) https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf 
retreived 27/07/2017 
 
Herdman, M., Gudex, C., Lloyd, A., Janssen, M. F., Kind, P., Parkin, D., ... & Badia, X. 
(2011), Development and preliminary testing of the new five-level version of EQ-5D (EQ-
5D-5L),  Quality of life research, 20(10): 1727-1736. 
 
McClure, Nathan S., et al. (2017), "Instrument-defined estimates of the minimally important 
difference for EQ-5D-5L index scores", Value in Health, 20.4: 644-650. 
 
Nelson LM, Forsythe A, McLeod L et al (2013), ‘Psychometric evaluation of the Cushing’s 
Quality of Life Questionnaire’, The Patient: 6, No. 1: 1-14. 
Norman GR, Sloan JA, Wyrwich KW (2003), Interpretation of changes in health-related 
quality-of-life: the remarkable universality of half a standard deviation, Med Care, 41:582-92. 
 
Pickard AS, Neary MP, Cella D (2007), Estimation of minimally important differences in EQ-
5D utility and VAS scores in cancer,  Health Qual Life Outcomes, 5:70. 
 
Smarr, K.L. & Keefer, A.L. (2011), Measures of Depression and Depressive Symptoms, 
Arthritis Care and Research Vol. 63, No. S11: pp S454–S466 
 
Smith B, Vandenhende F, DeSante K, et al (2000),  ‘Confidence interval criteria for 
assessment of dose proportionality’, Pharmaceutical research, 17, No 10: 1278-83. 
 
The EuroQol Group. EQ-5D-3L User Guide. 2013. Available at: URL: 
https://www.euroqol.org/about-eq-5d/publications/use-guide.html  Accessed Jul 26, 2017. 
 
The EuroQol Group. EuroQol-5D: a new facility for the measurement of health-related 
quality of life. Health Policy 1990;16:199-208 


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Tiemensma, J., Depaoli, S., & Felt, J. M. (2016), Using subscales when scoring the Cushing's 
quality of life questionnaire, European journal of endocrinology, 174(1): 33-40 
 
Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, 
Pivonello R, Stalla G, Lamberts SWJ et al (2008), Evaluation of health-related quality of life 
in patients with Cushing’s syndrome with a new questionnaire,  European Journal of 
Endocrinology, 158: 623–630. (doi:10.1530/EJE-07-0762) 
 
 

Prot_003.pdf: 
Clinical Development 
LCI699 (osilodrostat) 
Protocol CLCI699C2301 / NCT02180217
A Phase III, multi-center, double-blind, randomized 
withdrawal study of LCI699 following a 24 week, single-
arm, open-label dose titration and treatment period to 
evaluate the safety and efficacy of LCI699 for the treatment 
of patients with Cushing’s disease 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2013-004766-34 
Version number 
v05 (Clean) 
Development phase 
III 
Document status 
Final 
Release date 
29-Jun-2018
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 19-Nov-2015 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 7 
List of appendices ................................................................................................................ 8 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 11 
Amendment 5 (29-Jun-2018) ............................................................................................ 13 
Amendment 4 (06-Jul-2017) ............................................................................................. 15 
Amendment 3 (29-Mar-2016) ........................................................................................... 16 
Amendment 2 (11-Mar-2015) ........................................................................................... 19 
Amendment 1 (15-Jul-2014) ............................................................................................. 23 
Protocol summary: ............................................................................................................. 25 
1 
Background ........................................................................................................................ 30 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 30 
1.1.1 
Epidemiology and pathogenesis of Cushing’s syndrome and 
Cushing’s disease .................................................................................. 30 
1.1.2 
Current treatment modalities ................................................................. 31 
1.1.3 
Unmet medical need .............................................................................. 32 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 33 
1.2.1 
Overview of LCI699 ............................................................................. 33 
2 
Rationale ............................................................................................................................ 42 
2.1 
Study rationale and purpose ................................................................................... 42 
2.2 
Rationale for the study design ............................................................................... 42 
2.3 
Rationale for dose and regimen selection .............................................................. 45 
2.4 
Rationale for choice of combination drugs ............................................................ 46 
2.5 
Rationale for choice of comparators drugs ............................................................ 46 
2.6 
Rationale for inclusion of patients post pituitary irradiation ................................. 46 
2.7 
Benefit-risk assessment of LCI699 in study population ........................................ 46 
 
 48 
 
 48 
3 
Objectives and endpoints ................................................................................................... 49 
4 
Study design ...................................................................................................................... 53 
4.1 
Description of study design ................................................................................... 53 
4.1.1 
Study Period 1 ....................................................................................... 53 
4.1.2 
Study Period 2 ....................................................................................... 54 
4.1.3 
Study Period 3 ....................................................................................... 55 


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4.1.4 
Study Period 4 ....................................................................................... 57 
4.1.5 
Optional Extension Period .................................................................... 58 
4.1.6 
Escape ................................................................................................... 58 
4.1.7 
Schematic diagram of core study design ............................................... 59 
4.2 
Timing of interim analyses and design adaptations ............................................... 59 
4.3 
Definition of end of the study ................................................................................ 59 
4.4 
Early study termination .......................................................................................... 59 
5 
Population .......................................................................................................................... 60 
5.1 
Patient population .................................................................................................. 60 
5.2 
Inclusion criteria .................................................................................................... 60 
5.3 
Exclusion criteria ................................................................................................... 61 
6 
Treatment ........................................................................................................................... 63 
6.1 
Study treatment ...................................................................................................... 63 
6.1.1 
Dosing regimen ..................................................................................... 64 
6.1.2 
Ancillary treatments .............................................................................. 66 
6.1.3 
Rescue medication ................................................................................ 66 
6.1.4 
Guidelines for continuation of treatment .............................................. 66 
6.1.5 
Treatment duration ................................................................................ 66 
6.2 
Dose escalation guidelines ..................................................................................... 67 
6.3 
Dose modifications ................................................................................................ 67 
6.3.1 
Dose modification and dose delay ........................................................ 67 
6.3.2 
Follow-up for toxicities ......................................................................... 70 
6.3.3 
Follow up on potential drug-induced liver injury (DILI) cases ............ 70 
6.3.4 
Anticipated risks and safety concerns of the study drug ....................... 71 
6.4 
Concomitant medications ...................................................................................... 72 
6.4.1 
Permitted concomitant therapy ............................................................. 72 
6.4.2 
Prohibited concomitant therapy ............................................................ 73 
6.5 
Patient numbering, treatment assignment or randomization ................................. 74 
6.5.1 
Patient numbering ................................................................................. 74 
6.5.2 
Treatment assignment or randomization ............................................... 74 
6.5.3 
Treatment blinding ................................................................................ 75 
6.6 
Study drug preparation and dispensation ............................................................... 75 
6.6.1 
Study drug packaging and labeling ....................................................... 75 
6.6.2 
Drug supply and storage ........................................................................ 76 
6.6.3 
Study drug compliance and accountability ........................................... 76 
6.6.4 
Disposal and destruction ....................................................................... 77 


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7 
Visit schedule and assessments ......................................................................................... 77 
7.1 
Study flow and visit schedule ................................................................................ 77 
7.1.1 
Screening ............................................................................................... 92 
7.1.2 
Run-in period ........................................................................................ 94 
7.1.3 
Treatment period ................................................................................... 94 
7.1.4 
End of treatment visit including study completion and premature 
withdrawal ............................................................................................. 94 
7.1.5 
Discontinuation of study treatment ....................................................... 95 
7.1.6 
Withdrawal of informed consent ........................................................... 96 
7.1.7 
Follow up for safety evaluations ........................................................... 97 
7.1.8 
Lost to follow-up ................................................................................... 97 
7.2 
Assessment types. .................................................................................................. 97 
7.2.1 
Efficacy assessments ............................................................................. 97 
7.2.2 
Safety and tolerability assessments ....................................................... 99 
7.2.3 
Pharmacokinetics ................................................................................ 107 
 
 114 
7.2.5 
Resource utilization ............................................................................. 116 
7.2.6 
Patient reported outcomes ................................................................... 116 
8 
Safety monitoring and reporting ...................................................................................... 118 
8.1 
Adverse events ..................................................................................................... 118 
8.1.1 
Definitions and reporting .................................................................... 118 
8.1.2 
Laboratory test abnormalities .............................................................. 119 
8.1.3 
Adverse events of special interest ....................................................... 119 
8.2 
Serious adverse events ......................................................................................... 120 
8.2.1 
Definitions ........................................................................................... 120 
8.2.2 
Reporting ............................................................................................. 121 
8.3 
Emergency unblinding of treatment assignment ................................................. 122 
8.4 
Pregnancies .......................................................................................................... 122 
8.5 
Warnings and precautions .................................................................................... 122 
8.6 
Data Monitoring Committee ................................................................................ 123 
8.7 
Steering Committee ............................................................................................. 123 
9 
Data collection and management ..................................................................................... 123 
9.1 
Data confidentiality ............................................................................................. 123 
9.2 
Site monitoring .................................................................................................... 124 
9.3 
Data collection ..................................................................................................... 124 
9.4 
Database management and quality control .......................................................... 125 


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10 Statistical methods and data analysis .............................................................................. 125 
10.1 
Analysis sets ........................................................................................................ 126 
10.1.1 
Randomized Analysis Set ................................................................... 126 
10.1.2 
Full Analysis Set ................................................................................. 126 
10.1.3 
Safety set ............................................................................................. 126 
10.1.4 
Per-Protocol set ................................................................................... 126 
10.1.5 
Pharmacokinetic analysis set ............................................................... 127 
10.1.6 
Other analysis sets ............................................................................... 127 
10.2 
Patient demographics/other baseline characteristics ........................................... 127 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ..................... 127 
10.4 
Primary objective ................................................................................................. 128 
10.4.1 
Variable ............................................................................................... 128 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 129 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 129 
10.4.4 
Supportive and sensitivity analyses .................................................... 129 
10.5 
Secondary objectives ........................................................................................... 129 
10.5.1 
Key secondary objective(s) ................................................................. 129 
10.5.2 
Other secondary efficacy objectives ................................................... 130 
10.5.3 
Safety objectives ................................................................................. 132 
10.5.4 
Pharmacokinetics ................................................................................ 134 
 
 135 
10.5.6 
Resource utilization ............................................................................. 135 
10.5.7 
Patient-reported outcomes ................................................................... 135 
 
 135 
 
 
 135 
 
 136 
 
 136 
 
 136 
 
 136 
10.7 
Interim analysis .................................................................................................... 137 
10.8 
Sample size calculation ........................................................................................ 138 
10.9 
Power for analysis of key secondary variables .................................................... 138 
11 Ethical considerations and administrative procedures .................................................... 138 
11.1 
Regulatory and ethical compliance ...................................................................... 138 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 139 


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11.3 
Informed consent procedures ............................................................................... 139 
11.4 
Discontinuation of the study ................................................................................ 139 
11.5 
Publication of study protocol and results............................................................. 140 
11.5.1 
Communication and publication of clinical trial results ..................... 140 
11.6 
Study documentation, record keeping and retention of documents ..................... 140 
11.7 
Confidentiality of study documents and patient records ..................................... 141 
11.8 
Audits and inspections ......................................................................................... 141 
11.9 
Financial disclosures ............................................................................................ 141 
12 Protocol adherence .......................................................................................................... 141 
12.1 
Amendments to the protocol ................................................................................ 142 
13 References (available upon request) ................................................................................ 143 
14 Appendices ...................................................................................................................... 145 
14.1 
Appendix 1: Summary of Common Toxicity Criteria for Adverse Events 
v4.03 (CTCAE) .................................................................................................... 145 
14.2 
Appendix 2: List of drugs to be used with caution with LCI699 ........................ 146 
14.3 
Appendix 3: Medications with a “Known risk to cause TdP” and with a 
“Possible risk to cause TdP” ................................................................................ 149 
14.4 
Appendix 4: Patient Quality of Life questionnaires ............................................ 150 
 
List of figures 
Figure 1-1 
Structural formula of LCI699 ................................................................ 33 
Figure 1-2 
Mechanism of action of LCI699 in Cushing’s Disease ........................ 34 
 
 
 
 38 
Figure 1-4 
Arithmetic mean and SE plots for fold ULN of mUFC (PD analysis 
set) ......................................................................................................... 39 
Figure 1-5 
Mean (+/-SE) mUFC (nmol/24h) over time by cohort ......................... 40 
Figure 4-1 
Schematic of study period 1 .................................................................. 53 
Figure 4-2 
Example: Timing of study visits, UFC collection, and dose 
adjustments during Period 1 in a patient with dose up-titration ............ 54 
Figure 4-3 
Schematic of core study design ............................................................. 59 
Figure 6-1 
Appearance of LCI699 tablets by strength ............................................ 63 
Figure 7-1 
Sequence of cardiovascular data collection ........................................ 105 
Figure 7-2 
QT Monitoring Flow Chart (except for Day 1) ................................... 107 
 


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List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 50 
Table 6-1 
Dose Modification Guidelines1 for LCI699-suspected toxicities ......... 68 
Table 6-2 
Criteria for interruption and re-initiation of LCI699 for abnormal 
liver function ......................................................................................... 69 
Table 6-3 
Preparation and dispensing ................................................................... 75 
Table 6-4 
Packaging and labeling ......................................................................... 76 
Table 6-5 
Supply and storage of study treatment .................................................. 76 
Table 7-1 
Visit evaluation schedule – Dose escalation and treatment periods ..... 78 
Table 7-2 
Visit evaluation schedule – Randomized withdrawal and open label 
period for randomized patients.............................................................. 81 
Table 7-3 
Visit evaluation schedule – Randomized withdrawal and open label 
period for non randomized patients ....................................................... 84 
Table 7-4 
Visit evaluation schedule – Optional Extension period (Year 1) .......... 87 
Table 7-5 
Visit evaluation schedule – Optional Extension period (After Year 
1) ........................................................................................................... 89 
Table 7-6 
Imaging and disease assessment collection plan ................................... 97 
Table 7-7 
Central clinical laboratory parameters collection plan ........................ 100 
Table 7-8 
Imaging assessment collection plan .................................................... 102 
Table 7-9 
ECG collection plan ............................................................................ 103 
Table 7-10 
Pharmacokinetic blood collection for sparse PK assessment ............. 109 
Table 7-11 
Pharmacokinetic blood collection for extensive PK assessment 
(subset of approximately 20 patients) ................................................. 110 
Table 7-12 
[(China only) Pharmacokinetic blood collection for Chinese 
patients] ............................................................................................... 112 
Table 7-13 
[(China only) Non-compartmental pharmacokinetic parameters] ...... 114 
 
 
 
 116 
Table 7-16 
Patient reported outcomes (PROs) collection plan ............................. 117 
Table 14-1 
List of summary of Common Toxicity Criteria for Adverse Events 
v4.03 (CTCAE) ................................................................................... 145 
Table 14-2 
List of medications with potential drug-drug interactions with 
LCI699 – to be used with caution ....................................................... 146 
 


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List of appendices 
Appendix 1: Summary of Common Toxicity Criteria for Adverse Events (CTCAE) 
Appendix 2: List of drugs to be used with caution with LCI699 
Appendix 3: Medications with a “Known risk to cause TdP” and with a “Possible risk to cause 
TdP” 
Appendix 4: Patient-reported outcomes: EQ-5D-5L, CushingQoL, Beck Depression Inventory 
BDI-II 


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List of abbreviations 
AE 
Adverse Event 
ACTH 
Adrenocorticotropic Hormone 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
b.i.d. 
bis in diem/twice a day 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BIPSS 
Bilateral Inferior Petrosal Sinus Sampling 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRH 
Corticotropin-Releasing Hormone 
CRO 
Contract Research Organization 
CSP 
Clinical Study Protocol 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDAVP 
Desmopressin acetate 
DILI 
Drug Induced Liver Injury 
DS&E 
Drug Safety and Epidemiology 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
GCS 
Global Clinical Supply 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
ITT 
Intention To Treat 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit Of Quantification 
o.d. 
omnia die/once a day 
MRI 
Magnetic Resonance Imaging 
PAS 
Pharmacokinetic Analysis Set 
PoC 
Proof of Concept 
PPFAS 
Per-Protocol Set for Full Analysis Set 
PPRAS 
Per-Protocol Set for Randomized Analysis Set 
PHI 
Protected Health Information 
PT 
Preferred Term 
q.d. 
quaque die/ once a day 
q.o.d. 
quaque otra die/ every other day 
RAS 
Randomized Analysis Set 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 


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SASR 
Safety Analysis Set for Randomized withdrawal period 
SMR 
Standardized Mortality Ratio 
SRS 
Stereotactic RadioSurgery 
TBIL 
Total Bilirubin 
TdP 
Torsades de Pointes 
(m)UFC 
(mean) Urine Free Cortisol 
ULN 
Upper Limit of Normal 
ULOQ 
Upper Limit Of Quantification 
VAS 
Visual Analog Scale 


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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 treatment 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 treatment 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.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not 
include other study treatments administered as concomitant background therapy 
required or allowed by the protocol when used in within approved 
indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is linked 
to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment 
Patient Number (Patient No.) 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Personal Data 
Patient information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial. This data includes patient identifier information, 
study information and biological samples. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned completion 
of all study treatment administration and/or assessments; at this time all study 
treatment administration is discontinued and no further assessments are 
planned, unless the patient will be followed for progression and/or survival 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stage related to study 
timeline 
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 
treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins. 
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this 
case refers to the investigational and non-investigational treatments in 
combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason. 
Treatment group 
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points. 


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Withdrawal of Consent 
Withdrawal of consent from the study occurs only when a patient does not want 
to participate in the study any longer, and does not allow any further collection of 
personal data. 


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Amendment 5 (29-Jun-2018) 
Amendment rationale 
As of 25 June 2018, 91 patients are ongoing on the study. The study enrollment was completed 
on 22-Mar-2017. 
The main purpose of this amendment is to increase the maximum duration of the optional 
extension period by one additional year in order to provide continued access to the study drug 
for those patients benefitting from the treatment until a separate long-term follow-up study is 
available at participating sites. 
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. 
 Glossary of terms, Section 7.1.6: the definition of the Personal Data and Withdrawal of 
Consent has been updated in line with the latest Novartis protocol template updated 
following the release of the General Data Protection Requirements (GDPR) in the 
European Economic Area (EEA). 
 List of abbreviations, Section 4.1.3.1, Section 6.5.2 and Section 6.5.3: Drug Supply 
Management replaced with Global Clinical Supply as per name change at Novartis. 
 Protocol Summary, Section 6.1, Section 6.6.1, Table 6-3 and Table 6-4: clarified as 20 mg 
tablets supplied depending on availability. 
 Section 4.1.5, Section 6.1.5: revised to extend the duration of the optional extension 
period and study and to include the transition timeframe to the long-term safety follow-up 
study or local alternative treatment option. 
 Section 4.3: revised to extend the duration of the optional extension period and study. 
 Section 6.5.3: corrected that the bioanalyst and the bioanalytical study monitor will also be 
unblinded in line with Novartis standards. 
 Section 7.1.1 and Table 7-1: reference added to the Inclusion/Exclusion criteria for the 
eligibility assessment at screening. 
 Section 7.2.1.3: revised as there was an incorrect reference to the BMI matching for the 
BMD T-score. 
 Section 7.2.2.5, Section 10.5.3: added the central Pituitary MRI/CT assessment for tumor 
re-occurrence and tumor invasiveness. 
 Section 7.2.3.2: corrected as placebo samples will be analyzed for this trial. 
 Section 10: clarified that in this section SAS stands for Statistical Analysis System. 
IRBs/IECs 
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. 


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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 4 (06-Jul-2017) 
Amendment rationale 
As of 22 March 2017, 137 patients have been enrolled (treated). The study enrollment has been 
completed. 
The main purpose of this amendment is to further increase the duration of the optional extension 
period in order to collect additional long-term safety and efficacy data as well as to provide 
continued access to the study drug for those patients benefitting from the treatment until a 
separate long-term safety follow-up study is set up at participating sites. Based on this 
extension, the end of study definition has been updated. In addition, the long-term safety follow-
up study modalities have been detailed. 
As a result of the change in the duration of the optional extension phase, the study objectives 
and associated statistical sections have been revised to include extension phase time points. 
Other protocol changes include: 
 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®). 
 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. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
 Protocol synopsis: edited to be consistent with the changes made throughout the protocol. 
 Editorial change has been made based on new Novartis terminology (Reporting Analysis 
Plan changed by Statistical Analysis Plan, SAP). 
 Section 1.1.2, Section 2.1, Table 3-1, definition of the partial responder has been updated 
to be consistent throughout the protocol. 
 Section 2.2, Table 3-1, Section 10.5.2.2, Section 10.5.2.4, Section 10.5.2.5, Section 
10.5.2.6, Section10.5.7: updated to add the data collected during the optional extension 
phase into the objectives assessments. 
 Section 2.7 : updated to include the possibility of neutropenia based on observed cases 
with LCI699. 
 Section 4.1.5, Section 6.1.5: revised to update the duration of the optional extension 
period and end of study definition and to include the long term safety follow-up study 
modalities. 


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 Section 6.4.2, Section 6.4.2.1, Appendix 3: revised to update the QT-specific concomitant 
medication guidance for LCI699 limiting the list of prohibited drugs to medications with a 
“Known risk to cause TdP” and “Possible risk to cause TdP” instead of all drugs known to 
prolong QT. 
 Section 7.2.2.4.6, Section 7.2.3: revised to clarify the serial sampling (PK and associated 
lab parameters) if LCI699 administration was interrupted prior to a planned visit. 
 Figure 7-2: Clarification added. 
 Table 7-8: Corrected to be in line with the visit evaluation schedule. 
 Section 10: Clarification added on data collected for the primary analysis. 
 Section 10.5.3.1: Clarification on analysis set and treatments groups for the overall study 
period. 
 Section 13: Reference added. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Amendment 3 (29-Mar-2016) 
Amendment rationale 
Study status: As of 01 March 2016, 75 patients have been enrolled (treated). 
The purpose of this amendment is to include the following changes to reduce the risk of dosing 
errors. 
 Expand the description of the dose dispensation process; in particular to emphasize that 
more than one tablet strength of study drug may be dispensed at the same visit. 
 Elaborate on dose adjustments and communication of dosing instructions 
 Recommend the use of patient dose instruction card and phone contacts between 
scheduled visits. 
This amendment also includes changes 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. 
Other protocol changes are: 
 To provide more information regarding the study drug: 
 A summary of the benefit-risk assessment of LCI699 for this trial has been added 
 The results of the thorough QT/QTc study (LCI699C2105) of LCI699 in healthy 
volunteers has been added 


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 Additional measurements of serum cortisol and plasma ACTH have been added for 
patients in China undergoing extensive PK, 
 
. 
 Exclusion criterion # 16 is modified to exclude patients with serum total bilirubin > 1.5 x 
ULN; this is one of the criteria needed for effective screening of patients for potential 
DILI 
The duration of the optional extension period is increased in order to collect additional long-
term safety data as well as to provide continued access to the study drug for those patients 
benefitting from the treatment. Patients can continue on extension phase until the last patient 
completes the core period or discontinued early from core period. Patients who continue to 
benefit from treatment will be offered participation in a separate long-term safety follow-up 
study. Study CLCI699C2301 ends when seamless transition to the long-term safety follow-up 
study is possible or alternative treatment options are available; this period will not exceed 4 
months. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
 Section 1.1.2 : clarification to current treatment modalities included 
 Section 1.2.1: additional details added to the overview of LCI699 
 Section 1.2.1.2.4: added the cardiac repolarization (QT/QTc) data of LCI699 in healthy 
volunteers. 
 Section 2.2, Section 4.3, Table 7-4, Table 7-7, Table 7-8 and Table 7-16 updated to 
include the changes due to the increase in duration of the optional extension period. 
 Section 2.7: added a summary of the benefit-risk assessment of LCI699 specific to this 
study. 
 Section 4.1.1, Section 4.1.2, Section 4.1.3.5, Section 4.1.3.6, Section 4.1.3.7, Section 
4.1.4, Section 6.1, Section 6.1.1, Section 6.6, and Table 6-3: Added a description of the 
dose dispensation process, guidance on dose adjustments, recommendation for a patient 
dose instruction card and site communication with the patient between scheduled visits. 
 Section 5.3: exclusion criteria # 16 updated to exclude patients with serum total 
bilirubin > 1.5 x ULN 
 Section 6.1.5: updated to include the change in duration of the optional extension period 
and the study. 
 Table 6-1: explained when emergency un-blinding may be considered 
 Table 6-2: added to provide guidance for monitoring liver function and criteria for 
interruption and re-initiation of LCI699 for abnormal liver function. 
 Section 6.5.3: added to provide guidance for follow-up on potential drug-induced liver 
injury cases. 
 Section 6.5.3: added that Novartis DSM are unblinded in the study 
 Table 7-1: explained EOT titration visit is Visit number 775, updated to specify samples to 
be collected in patients in China undergoing extensive PK. 


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 Table 7-2, Table 7-3, Table 7-4, Section 7.1.4, Section 7.1.7, Table 7-9, Section 8.1.1 and 
Section 8.2.2: Safety follow-up updated to 30 days after the last dose of study treatment. 
 Table 7-2: updated to specify samples to be collected in patients in China undergoing 
extensive PK. 
 Table 7-3: updated to specify samples to be collected in patients in China undergoing 
extensive PK and to correct inconsistency. 
 Table 7-5: added to include visit schedule for year 2 and 3 of the optional extension 
period. 
 Section 7.1.1: Clarified that consideration can be given to switching to medications with 
shorter washout during screening. 
 Section 7.1.3: Clarified that dose is usually stable during study period 2 and dose 
adjustments may be needed based on mUFC and for safety. 
 Section 7.1.4: Added exceptions when EOT pituitary MRI (or CT) and DXA scans are not 
needed. 
 Section 7.1.5: added hepatic safety related discontinuation criteria, modified pituitary 
tumor growth related criteria. 
 Section 7.2.2.4.6: updated to specify additional samples being collected and explain the 
samples and collection times for the samples to be collected in patients in China 
undergoing extensive PK. 
 Section 8.1.1: additional instructions regarding AE reporting provided. 
 Section 8.1.3: added definition of adverse events of special interest 
 Section 8.1.3.1: added results of the thorough QT/QTc study (LCI699C2105) data of 
LCI699 in healthy volunteers and removed preliminary clinical data 
 Section 10.1.3: provided more details about the safety analysis 
 Section 10.1.4: provided more details about the Per-Protocol Set for Randomized Analysis 
Set and Per-Protocol Set for Full Analysis Set. 
 Section 10.2, Section 10.3, Section 10.5.3.2 and Section 10.5.3.3: provided more details 
about the data that will be summarized. 
 Section 10.5.3.1: provided more details about the treatment groups in the study 
 Appendix 2: was updated to remove the corticosteroids (budesonide, fluticasone) as use of 
glucocorticoids is prohibited except under certain conditions as specified in Section 6.4.2. 
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 2 (11-Mar-2015) 
Amendment rationale 
The primary reason for this amendment is to add a local, country-specific intensive PK sampling 
for China in order to investigate potential ethnic differences in LCI699 pharmacokinetics at 
steady-state and at doses used in the treatment of patients with Cushing’s disease. 
Additional changes applicable to all countries include: 
 Inclusion of recent LCI699 clinical trial results information (longer-term safety and 
efficacy data (LCI699C2201; 22-week interim analysis) and results of a clinical drug-drug 
interaction study (LCI699C2102). 
 Relaxation of the protocol guidance on narrow therapeutic index/sensitive substrates of 
CYP1A2, CYP2C19, CYP2D6 and CYP3A4/5 as concomitant medication (based on the 
results of the clinical drug-drug interaction study (LCI699C2102)). 
 Blinding: Corrected in the protocol, randomization is managed via an IRT system and the 
pharmacist, the bioanalyst and the pharmacokineticist will be blinded in the study. 
 Inclusion criteria: 
 Based on the more rapid action of stereotactic radiosurgery compared to conventional 
radiation, the minimum period of elapsed time since the last stereotactic radiosurgery 
was decreased from 3 years to 2 years. 
 Rescreening is introduced in order to accommodate the long washout periods required 
for some cortisol-lowering medical therapies at the time of enrollment. 
 Exclusion criteria: 
 QTcF exclusion limits are tightened from >470 ms to >450 ms for males, and >460 
ms for females in accordance with Novartis Clinical Safety Standard Guideline. 
 Definitions for post-menopausal status and woman not of childbearing potential are 
added for clarity. 
 Male contraception is no longer required in patients treated with LCI699 based on a 
thorough review of the mechanism of action of LCI699 and re-evaluation of pre-
clinical and clinical data. 
 The criterion on optic chiasm compression is broadened to include patients at high 
risk from macroadenomas within 2 mm of the optic chiasm. 
 Euthyroid status is based on investigator’s judgment in addition to biochemical data. 
 
 
 
 
 Based on a re-evaluation of the safety monitoring schedule, certain hormone 
assessments have been reduced in frequency (serum 11-deoxycortisol, serum 
aldosterone, 
, and serum 11-deoxycorticosterone) or 
removed (urine aldosterone and urine 11-deoxycorticosterone), while other hormone 
assessments have been added (adrenal sex steroids: androstenedione, DHEAS, and 
estrone). 


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 The collection of specific information on the most recent medical therapy for 
hypercortisolism has been added to the screening assessment. 
 Additional concomitant medications are now permitted, under certain conditions, 
including: spironolactone, eplerenone, cyproterone acetate or finasteride. 
 Discontinuation criteria clarified to distinguish “confirmed” laboratory abnormalities 
from “confirmed and persistent laboratory abnormalities”; with the hypokalemia 
parameter relaxed. 
 Central reading of photographs has been removed, as it is not essential for the study. 
 The CTCAE version is updated from 4.0 to 4.03. 
 The “potential risk” for QT prolongation is changed to “risk”, based on one reported 
SAE with QTcF prolongation in a clinical study evaluating the longer-term efficacy 
and safety of LCI699 in patients with Cushing’s disease (LCI699C2201, 22-week 
interim analysis). 
 The QT monitoring section is clarified and the threshold for collecting triplicate ECG 
tracings is modified to include both > 500 msec and > 480 msec. 
 Updated standard Novartis Discontinuation of Clinical Trial Protocol Elements 
language has been implemented in relevant parts of the protocol. 
In addition, editorial changes and clarifications were made at various places in the protocol. 
As of 02 March 2015, 16 patients have provided written informed consent for the study and 12 
patients have received LCI699. 
Changes to the protocol 
Protocol synopsis: Edited to be consistent with the changes made throughout the protocol. 
Section 1.1.2: Additional information provided on the radiation modalities for the treatment 
options in Cushing’s disease. In addition, text was added in line with the reference (Assie et al 
2007). 
Sections 1.2.1.1, 1.2.1.2, 6.4.1, 6.4.2.2, Appendices 2 and 3: Revised in line with the availability 
of results from a clinical drug-drug interaction study [LCI699C2102]. Appendix 2 and 3 were 
merged. 
Sections 1.2.1.2.2 and 1.2.1.2.3.3: Safety data moved from Section 1.2.1.2.2 to 1.2.1.2.3.3 and 
revised in line with available recent LCI699 clinical trial results information (longer-term safety 
and efficacy data [LCI699C2201, 22-week interim analysis]. 
Section 2.2: Additional information was added to explain how 24-hour UFC results reliability 
is ensured. In addition, the following example “following accumulation of precursors and/or 
ACTH” was removed since it was misleading. 
Section 2.6: In line with the information added in Section 1.1.2. on the radiation modalities, the 
language has been updated. 
 
 


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Sections 4.1.1, 4.1.2 and 7.2.1.1.: Revised to provide clarity on the study conduct. 
Sections 4.1.3.1, 6.1.1.1 and 6.5.3.: Corrected since patients, investigators, site personnel and 
the Novartis team will remain blinded until the time of treatment unblinding. 
Sections 4.4, 6.1.5., 7.1.4, 7.1.5., 7.1.6, 7.1.7., 7.1.8 and the List of Abbreviations: Revised to 
implement the Novartis Discontinuation of Clinical Trial Protocol Elements language. 
Section 5.2: The following inclusion criteria have been updated: 
 3a. Revised for clarity. 
 7: Revised in line with the added information in Section 1.1.2. on the radiation modalities. 
 8: Revised to add clarity, make updates and add information on rescreening, information 
also added in Section 7.1.1. 
Section 5.3: The following exclusion criteria have been updated: 
 4. Updated in line with Novartis Clinical Safety Standard Guideline and for clarity. 
 6. Updated in line with Novartis Guideline on the Prevention of Pregnancies in 
Participants in Clinical Trials and for clarity since due to the disease a patient might 
qualify, patient who has had bilateral oophorectomy (making pregnancy impossible) but 
does not have a high FSH due to the hypercortisolemia. 
 7. Criterion no longer applicable since male contraception is no longer required in patients 
treated with LCI699, decision made by Novartis Medical Safety Review Board based on a 
thorough review of the mechanism of action of LCI699 and re-evaluation of pre-clinical 
and clinical data. 
 8. Updated to include not only patients with ongoing compression of the optic chiasm, but 
also patients at high risk from this complication, which may require emergency surgery. 
High risk patients are those with a macroadenoma within 2 mm of the optic chiasm. The 
rationale is that LCI699 therapy may increase the risk of corticotroph tumor progression 
and thereby increase the risk of optic chiasm compression. 
 14. Updated since euthyroid status should be assessed not only on the basis of laboratory 
results but also on clinical judgment. 
Section 6.1.1.: Revised to provide clarity on the dosing regimen and add information on adrenal 
insufficiency for guidance. 
Section 6.3: Revised to provide clarity on dose modifications, add information on adrenal 
insufficiency and on medications to treat suspected toxicities for guidance. 
Section 6.4.: Corrected since there is no patient replacement policy in the study. 
Section 6.4.1: Revised to provide additional information. 
Sections 6.4.2.1.: As a result of one reported suspected serious adverse reaction in the clinical 
study LCI699C2201 of Electrocardiogram QT prolongation; the term “potential risk” has been 
replaced with the term “risk”. The link to the list of medications that have a known risk for 
causing QT prolongation has also been updated. 


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Section 7.1.: Revised to add rescreening information. 
Section 7.1.1.3: Revised to add an assessment currently being captured in the CRF and for the 
most recent prior medical therapy for Cushing Disease to be captured. 
Section 7.1.5: Discontinuation criteria revised to distinguish confirmed laboratory 
abnormalities and confirmed and persistent laboratory abnormalities. 
Section 7.2.1.2: Central readings of the photographic assessments have been removed for 
operational reasons. 
Section 7.2.1.3: Editorial changes made. 
Section 7.2.1.4: Revised for clarity and to be in line with what is currently being captured in the 
CRF. 
Section 7.1.1.4: Revised to add an assessment currently being captured in the CRF. 
Section 7.2.2.4.: The following changes were made: 
 Revised for clarity. 
 Assessments removed for operational reasons. 
 LH and FSH information moved from the thyroid panel to additional hormones sections. 
 Serum Androstenedione, DHEAS, Estrone added to better characterize the change in 
adrenal sex steroids. 
 
 
 
 For the subset of patients participating in extensive PK assessment as well as Chinese 
patients, additional serum cortisol and salivary cortisol samples in correspondence to PK 
assessment times will be collected to allow for robust exposure-response analysis for 
LCI699. 
Section 7.2.2.5: Revised to add clarity. 
Section 7.2.2.5.6: Revised to add clarity. 
Section 7.2.2.7: Revised in line with Novartis Clinical Safety Standard Guideline. 
Tables 7-1, 7-2 and 7-3: Revised Visit Evaluation Schedule in line with the changes made in 
Sections 7.1.1.3, 7.1.1.4 and 7.2.2.4. 
Section 7.2.3 and 10.5.4.: Revised to add local, country-specific intensive PK sampling for 
China to investigate potential ethnic differences in LCI699 pharmacokinetics at steady-state 
and at doses used in the treatment of patients with Cushing’s disease. 
Section 8.1.1.: Text removed since added incorrectly. 
Section 8.1.3: Updated for clarity and remove the list of Adverse Events of Special Interest 
since it is not exhaustive. 
Sections 3.0, 7.2.2.4, 8.1.1., 10.5.3.2, 10.5.3 and Appendix 1: Latest version of the Common 
Terminology Criteria for Adverse Events updated. 


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Section 8.1.3.1.: As a result of one reported suspected serious adverse reaction in the clinical 
study LCI699C2201 of Electrocardiogram QT prolongation; the term “potential risk” has been 
replaced with the term “risk”. Additional data added to the preliminary clinical data for clarity. 
Section 8.3.: Text removed since added incorrectly. 
Section 8.7.and 10.7.: Revised to clarify the Steering Committee role as to ensure transparent 
management of the study and not also data review. 
Sections 9.3 and 9.4: Revised to be in line with changes made in Sections 7.2.1.2 and 7.2.2.4. 
Section 10.1.4: Updated to clarify the definition. 
Section 10.5.1.: Editorial change made. 
Section 10.5.2.1, 10.5.2.3, 10.5.2.4., 10.5.2.5 and 10.6.1.: Revised to clarify how the analysis 
will be performed. 
Section 10.5.4.: Revised to clarify how the tumor volume will be evaluated. 
Section 13: References added. 
Appendix 3: The link to the list of QT drugs that prolong QT has been updated. 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. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Amendment 1 (15-Jul-2014) 
Amendment rationale 
The purpose of this protocol amendment is to address requests from the Voluntary 
Harmonization Procedure (VHP) review. The VHP review required that changes to the protocol 
be implemented to address the findings. 
 In order to study efficacy and long term safety in this trial, a specified length of treatment 
must be defined. As a result of this finding, the definition of the optional extension period 
was revised. 
 One of the secondary objectives is to address escape. The time-to-escape definition was 
not clear and required clarification. 
 The premature patient withdrawal criteria required revision to ensure that pregnancy was 
identified as an absolute withdrawal criterion. Therefore, pregnancy will be moved from 
the list of general study withdrawal criteria to the list of study specific criteria that require 
study treatment discontinuation. 


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 To harmonize with ICH guidelines, treatment discontinuation criteria was revised to 
include an increase in QTcF > 60 msec from baseline before the first dose. 
 To improve monitoring for potential QT prolongation, 24-hour Holter recordings were 
added during the extension at Weeks 72 and 96. As a result of this addition, both the Visit 
Evaluation Schedule and the ECG Collection Table were also revised. 
Changes to the protocol 
Section 4.1.4: Revised to define the extension period. 
Section 4.1.6: Revised to clarify the assessment of Escape. 
Section 7.1.4.1: Revised premature patient withdrawal criteria. 
Section 7.2.2.7: Revised QTcF based withdrawal criteria. 
Table 7-4: Revised Visit Evaluation Schedule. 
Table 7-8: Revised ECG Collection Table. 
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. 
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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Protocol summary: 
Protocol number 
CLCI699C2301 
Title 
A Phase III, multi-center, double-blind, randomized withdrawal study of LCI699 
following a 24 week, single-arm, open-label dose titration and treatment period to 
evaluate the safety and efficacy of LCI699 for the treatment of patients with 
Cushing’s disease 
Brief title 
Safety and efficacy of LCI699 for the treatment of patients with Cushing’s disease 
Sponsor and Clinical 
Phase 
Novartis 
Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The study aims to confirm long-term efficacy and safety of LCI699 for the treatment 
of patients with Cushing’s disease. It is a pivotal trial intended to support the 
registration of LCI699 for the treatment of patients with Cushing’s disease in the EU, 
Japan, and other countries. 
Promising results of a 10-week analysis proof of concept showed that all patients 
reached the primary endpoint (24-hour urine free cortisol [UFC] ≤ upper limit of 
normal [ULN] or ≥ 50% reduction in mUFC from baseline). In addition, all 12 patients 
had normalization of mUFC at least once during the study, and LCI699 was 
generally well tolerated. 
Primary Objective(s) and 
Key Secondary 
Objective 
Primary objective: 
 
To compare the complete response rate at the end of the 8 weeks period of 
randomized withdrawal (Week 34) between patients randomized to continued 
LCI699 therapy vs. placebo by comparing the proportion of randomized patients 
in each arm with: mUFC ≤ ULN at the end of 8 weeks of randomized withdrawal 
(Week 34), and were neither discontinued nor had LCI699 dose increase above 
the level at week 26 during the randomized withdrawal period. 
Key secondary: 
 
To assess the complete response rate at the end of individual dose-titration and 
treatment with LCI699 in the initial single-arm, open label period (Week 24) by 
assessing the proportion of enrolled patients with mUFC ≤ ULN at Week 24 and 
had no dose increase above the level established at Week 12 between Week 
13 and Week 24. 
Secondary Objectives 
 
To compare the time-to-last control of mUFC during the randomized withdrawal 
period between patients randomized to continued LCI699 therapy and placebo 
by assessing time-to-last control of mUFC, which is defined as the time (in 
days) from randomization to the last mUFC collection that was ≤ ULN before 
discontinuation or completion of randomized withdrawal period, whichever is 
earlier. 
 
To assess the complete (mUFC ≤ULN), partial (mUFC ≥ 50% reduction from 
baseline, but mUFC > ULN), and overall response (proportion of enrolled 
patients with mUFC ≤ ULN or at least 50% reduction from baseline) rate at 
Week 12, Week 24, Week 48 and at scheduled time points during the extension 
phase (provided adequate follow-up as specified in the SAP) and the last 
available assessment. 
 
To assess the change in mUFC during the core and extension periods of the 
study by assessing: the actual and percentage change in mUFC from baseline 
to each post-baseline visit during the core and extension (provided adequate 
follow-up as specified in the SAP) at which UFC is collected; and the actual and 
percentage change in mUFC from the time of randomization (Week 26) to the 
end of the randomized withdrawal period (Week 34), or the last mUFC 
measurement prior to discontinuation from randomized withdrawal, whichever 
occurs earlier. 
 
To assess the change in cardiovascular-related parameters associated with 
Cushing’s disease during the core and extension period (provided adequate 
follow-up as specified in the SAP) of the study by assessing: the actual and 


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percentage change from baseline in: fasting glucose, HbA1c, fasting lipid 
profile, blood pressure, body weight, BMI and waist circumference; and the 
actual and percentage change from the randomization (Week 26) to the end of 
randomized withdrawal period (Week 34), or the last measurement (same 
individual parameters as before) available prior to discontinuation from 
randomized withdrawal, whichever occurs earlier. 
 
To assess the change in Patient-Reported Outcomes (Health-Related Quality of 
Life) during the core and extension periods of the study by assessing: the 
change in standardized score of CushingQoL, Beck Depression Inventory-II, 
and EQ-5D-5L, from baseline to Week 24 and Week 48; the change in 
standardized score of CushingQoL, Beck Depression Inventory-II, and EQ-5D-
5L, from the beginning of randomization (Week 26) to the end of the 
randomized withdrawal period (Week 34), or the last measurement prior to 
discontinuation from randomized withdrawal, whichever occurs earlier; and the 
change from baseline in standardized score of CushingQoL, Beck Depression 
Inventory-II, and EQ-5D-5L, from baseline to Week 72, 96 and the EOT 
extension 
 
To assess the change from baseline in the physical features of Cushing’s 
disease by photography at Week 12, 24, 34, 48, and during the extension 
phase by assessing the mean change from baseline to Week 12, 24, 34, 48, 
during the extension at week 72 and EOT extension in each of the following 
clinical signs of Cushing’s disease by photography: facial rubor, hirsutism, 
striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting 
(atrophy), central (abdominal) obesity, and ecchymoses (bruises). 
 
To assess the change from baseline in bone mineral density by DXA scan at 
the lumbar spine and total hip at Week 48 and the last available assessment by 
assessing the actual and percent change from baseline to Week 48 and the last 
available assessment in bone mineral density as measured by DXA scan at the 
lumbar spine and total hip. 
 
To assess the time-to-escape by assessing the time (in days) from the first 
mUFC ≤ ULN to the first mUFC results > 1.5 x ULN with at least 2 individual 
UFC results > 1.5 x ULN. 
 
To assess general safety and AEs of special interest by assessing adverse 
events and laboratory abnormalities (using the National Cancer Institute-
Common Toxicology Criteria (NCI-CTC) grading scale (version 4.03). AEs of 
special interest, as reported by the investigator, or by laboratory evaluation, 
ECG, Holter recording, and pituitary MRI. 
 
To evaluate exposures of LCI699 in patients with Cushing’s disease by 
measuring plasma concentrations of LCI699. 
Study design 
This is a phase III, multi-center, double-blind, randomized withdrawal study of 
LCI699 following a 24 week, single-arm, open-label dose titration and treatment 
period to evaluate the safety and efficacy of LCI699 for the treatment of patients 
with Cushing’s disease. Once eligibility (screening criteria met) has been confirmed, 
patients will enter the study. The study has four periods plus an optional extension 
period: 
Period 1: Single-arm, open-label (Week 1 to Week 12), is the individual patient 
dose titration period. Dose adjustments are based on the mean of three 24-hour 
UFC (mUFC) values as measured by the central lab. 
Period 2: (Week 13 to Week 24) is the period to assess the efficacy and safety of 
LCI699 at the therapeutic dose determined during dose titration period. 
Period 3: Double-blind, placebo-controlled randomized withdrawal (Week 26 to 
Week 34). Randomization is implemented at the Week 26 visit based on urine 
samples collected at Week 24. Eligible patients are randomized in a double-blinded 
fashion at Week 26 at a 1:1 ratio either to continue treatment with LCI699 at the 
same dose or to placebo. Patients are stratified at randomization according to: 
LCI699 dose at Week 24 (≤ 5mg b.i.d. vs. > 5mg b.i.d.); and history of pituitary 
irradiation (yes/no). 


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Period 4: Single-arm, open-label therapy (Week 35 to Week 48). At Week 35, 
patients continue open-label treatment until Week 48 based on mUFC result. 
Optional Extension Period: Patients who wish to enter the extension period must be 
re-consented at week 48. Patients who enter the extension period will do so without 
interruption of study drug or assessments. 
After discontinuing the study treatment, the patient will be followed for 30-day safety 
follow-up visit. 
Population 
The study population will be comprised of adult male and female patients with 
Cushing’s disease who have persistent or recurrent hypercortisolism after primary 
pituitary surgery and/or irradiation, and patients with de novo Cushing’s disease who 
are not surgical candidates for medical reasons, or refuse to undergo surgery. 
Inclusion criteria 
 
Patients must have confirmed Cushing’s disease that is persistent or recurrent 
as evidenced by: 
A. mUFC > 1.5 x ULN at screening (the mean of three 24-hour urine samples 
collected during screening, after completion of the washout period (if 
applicable), confirmed by the central laboratory and available at Day 1). 
B. Morning plasma ACTH above lower limit of normal. 
C. Confirmation of pituitary source of excess ACTH is defined by any of the 
following three criteria: 
(1) MRI confirmation of pituitary adenoma > 6 mm; OR 
(2) bilateral inferior petrosal sinus sampling (BIPSS) with either 
Corticotropin-Releasing Hormone (CRH) or Desmopressin acetate 
(DDAVP) stimulation for patients with a tumor ≤ 6mm. The criteria for a 
confirmatory BIPSS test are any of the following: 
 
Pre-dose central to peripheral ACTH gradient > 2; 
 
Post-dose central to peripheral ACTH gradient > 3 after either 
CRH or DDAVP stimulation; 
(3) histopathologic confirmation of an ACTH-staining adenoma in patients 
who have had prior pituitary surgery. 
 
Patients with a history of prior pituitary surgery must be at least 30 days post-
surgery to be eligible for inclusion in this study. 
 
Patients that received glucocorticoid replacement therapy post-operatively must 
have discontinued such therapy for at least one week, or (5 half-lives), 
whichever is longer, prior to screening. 
 
Patients with de novo Cushing’s disease can be included only if they are not 
considered candidates for surgery (e.g., poor surgical candidates, surgically 
unapproachable tumors, patients who refuse to have surgical treatment, or 
surgical treatment is not available) 
 
Patients with a history of pituitary irradiation can be included, provided that at 
least 2 years (stereotactic radiosurgery) have elapsed or 3 years (conventional 
radiation) have elapsed from the time of last radiation treatment to the time of 
enrollment into this study. 
 
Patients are permitted to washout current drug therapy to meet these entry 
criteria if they have a known diagnosis of Cushing’s disease. Rescreening can 
be used as needed to ensure washout is complete. The following washout 
periods must be completed before baseline efficacy assessments are 
performed: 
A. Steroidogenesis inhibitors (ketoconazole, metyrapone): 1 week 
B. Pasireotide s.c. (immediate release formulation): 1 week 
C. Dopamine agonists (e.g., cabergoline), or PPAR-gamma agonists (e.g., 
rosiglitazone, pioglitazone): 4 weeks 
D. Mifepristone: 4 weeks 
E. Pasireotide LAR: 8 weeks 
F. 
Mitotane: 6 months 


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Key Exclusion criteria 
 
Patients with risk factors for QTc prolongation or Torsades de Pointes, 
including: 
 
patients with a baseline QTcF > 450ms for males and QTcF > 460ms for 
females, 
 
personal or family history of long QT syndrome, or concomitant 
medications known to prolong the QT interval, 
 
hypokalemia, hypocalcaemia, or hypomagnesemia if not corrected before 
pre-dose Day 1. 
 
Patients with compression of the optic chiasm due to a macroadenoma or 
patients at high risk of compression of the optic chiasm (tumor within 2 mm of 
optic chiasm). 
 
Patients who have a known inherited syndrome as the cause for hormone over 
secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP). 
 
Patients with Cushing’s syndrome due to ectopic ACTH secretion or ACTH-
independent (adrenal) Cushing’s syndrome. 
 
Patients who have undergone major surgery within 1 month prior to screening. 
 
Hypertensive patients with uncontrolled blood pressure defined as SBP > 180 
and/or DBP > 100. 
 
Diabetic patients with poorly controlled diabetes as evidenced by HbA1c > 9 %. 
 
Patients who are not euthyroid as judged by the investigator. 
Investigational and 
reference therapy 
LCI699 or matching placebo in the form of film-coated tablets of 1 mg, 5 mg, 10 mg 
and (depending on availability) 20 mg for continuous b.i.d. oral administration 
Efficacy assessments 
 
24-hour urine to test for Urine Free Cortisol and creatinine. 24-hour UFC are 
mandated at screening, baseline, every 2 or 4 weeks depending on study 
period in core phase and every 12 weeks in extension phase. Three 24-hour 
samples at each time point. 
Safety assessments 
 
Adverse events 
 
Laboratory Evaluations (biochemistry, hematology, coagulation, Thyroid Panel, 
fasting plasma glucose, urinalysis and pregnancy test), 
 
ECG, vital signs, physical exam and Cardiac Imaging 
Other assessments 
 
Patient’s health-related quality of life questionnaires 
Data analysis 
The primary efficacy variable is the proportion of randomized patients in each 
treatment arm that are complete responders at the end of the 8 weeks of the 
randomized withdrawal period (Week 34). A complete responder is defined as a 
patient who has mUFC ≤ ULN (based on central laboratory result) at Week 34 and 
was not discontinued during the randomized withdrawal period of the study. 
For the primary objective, the statistical null hypothesis states that the complete 
response rates at the end of 8-week randomized withdrawal period (i.e., at Week 
34) are the same between the two randomized arms. To test this hypothesis, a 
Cochran–Mantel–Haenszel exact test stratified by the two stratification factors 
considered for randomization will be performed using the RAS following the intent-
to-treat principle. If the 2-sided p-value is ≤ 0.05, the null hypothesis will be rejected 
and the complete response rate in the LCI699 arm will be considered higher than 
that in the placebo arm. 
The key secondary objective is to assess the complete response rate (proportion of 
enrolled patients with mUFC ≤ ULN) at the end of 24 weeks of dose-titration and 
treatment with LCI699 in the initial single-arm, open label part of this trial. 
The key secondary efficacy variable is the proportion of complete responders at 
Week 24. A complete responder is defined as an enrolled patient who has mUFC ≤ 
ULN (based on central laboratory result) at Week 24 and had no dose up-titration 
between Week 12 and Week 24. 
Enrolled patients who had missing mUFC assessment at Week 24 will be counted 
as non-responders for the key secondary endpoint. 


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For the key secondary objective, the statistical null hypothesis states that the 
complete response rate at the end of 24 weeks open label period of LCI699 
treatment is ≤ 30%. The analysis of the key secondary objective will be based on 
the 2-sided 95% exact confidence interval (Clopper-Pearson method). If the lower 
bound of this 95% confidence interval is ≥ 30%, the null hypothesis will be rejected 
and the complete response rate will be considered at least 30% after 24 weeks of 
treatment with LCI699. 
The above testing on the key secondary objective will only be carried out if the null 
hypothesis for the primary objective is rejected. This sequential procedure will 
ensure preservation of the overall 2-sided type 1 error at 5%. 
The primary analysis of the key secondary endpoint will be performed using FAS. 
An additional analysis will be performed using PPFAS. 
Key words 
Cushing disease, LCI699, Pituitary Gland, Adrenocorticotropic Hormone 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1 
Epidemiology and pathogenesis of Cushing’s syndrome and 
Cushing’s disease 
Cushing’s syndrome is rare: the reported incidence of either endogenous Cushing’s syndrome 
or Cushing’s disease in the U.S., European countries (Spain, Denmark, Belgium, and Iceland) 
and New Zealand has been estimated to be 1.2 to 2.4 cases per million persons per year (Etxabe 
et al 1994; Lindholm et al 2001; Daly et al 2006; Arnardottir and Sigurjonsdottir 2011; and 
Bolland et al 2011). In the U.S., a recent abstract (Broder et al 2013) reported an estimated 
incidence of approximately 7.6 cases per million persons per year. Among the studies listed 
above, the prevalence rates have been reported to range from 19 to 79 cases per million 
inhabitants, with the highest prevalence (79 cases per million) reported from New Zealand 
(Bolland et al 2011). In the US, the prevalence is less than 20,000. Cushing’s disease most 
commonly affects adults aged 20-50 years, with a marked female preponderance. 
The causes of endogenous Cushing’s syndrome are classified into ACTH-dependent and 
ACTH-independent etiologies. The most common cause of Cushing’s syndrome is Cushing’s 
disease, which occurs in about 70% of cases, and is due to an ACTH-secreting pituitary 
corticotroph adenoma. The other main cause of ACTH-dependent Cushing’s syndrome is 
ectopic ACTH secretion from non-pituitary tumors (e.g., small cell lung cancer). The ACTH-
independent etiologies of Cushing’s syndrome are adrenal diseases such as adrenal tumors 
(adenomas or carcinomas) or bilateral adrenal hyperplasia. 
Endogenous Cushing’s syndrome is characterized by chronic hypercortisolism, which results 
in a variety of metabolic abnormalities and co-morbidities that collectively lead to an overall 4-
fold higher mortality rate than age- and gender-matched subjects in the general population 
(Etxabe et al 1994; Arnaldi et al 2003). The increased cardiovascular risk is related to the 
following clinical manifestations of Cushing’s syndrome: metabolic syndrome, insulin 
resistance, visceral 
obesity, 
glucose intolerance, hypertension, 
dyslipidemia, 
and 
hypercoagulation. Other clinical signs and symptoms of Cushing’s Syndrome include: 
supraclavicular and dorsal fat pads; proximal muscle weakness; osteoporosis with increased 
risk of fractures; skin changes (wide purple striae, hirsutism, acne); impaired immune function 
with increased risk of infection; neuropsychiatric disorders (depression, mood changes, and 
cognitive impairment), hypogonadism, and menstrual disorders in women (Newell-Price et al 
2006). 
At the time of diagnosis of Cushing’s disease, the prevalence of co-morbidities has been 
reported as follows: 58–85% of patients have hypertension, 32–41% have obesity, 20–47% 
have diabetes mellitus, 50–81% have major depression, 31–50% have osteoporosis, and 38–
71% have dyslipidemia (Feelders et al 2012). 
Correction of hypercortisolism in patients with Cushing’s disease is expected to improve or 
reverse the increased morbidity and mortality associated with untreated disease. Recently 
published data have suggested that recovery from the co-morbidities does occur, but may be 


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delayed or incomplete (Valassi et al 2012; Arnaldi et al 2012). The duration and severity of 
chronic hypercortisolism may impact the reversibility of the co-morbidities associated with 
Cushing’s disease (Feelders et al 2012). 
However, mortality studies have consistently shown that the mortality rate is significantly 
impacted by the biochemical status of the disease, i.e., persistent/recurrent hypercortisolism 
compared to biochemical remission of the disease. A recent meta-analysis of published 
mortality studies (Clayton et al 2011) showed that the standardized mortality ratio (SMR) is 
much higher in Cushing’s disease patients with persistent hypercortisolism (SMR=5.5) than 
those in remission (SMR=1.2). 
1.1.2 
Current treatment modalities 
In the International Consensus Statement on the treatment of ACTH-dependent Cushing’s 
syndrome (Biller et al 2008), the goals of treatment are stated as: reversal of clinical features; 
normalization of biochemical changes with minimum morbidity; and long-term control without 
recurrence. 
The treatment options for Cushing’s disease include pituitary surgery, pituitary irradiation, 
medical therapy and bilateral adrenalectomy. The primary treatment is surgical removal of the 
pituitary tumor via transsphenoidal resection with the intention of cure. Second-line treatments 
include: more radical pituitary surgery (re-operation), radiation therapy, medical therapy, and 
bilateral adrenalectomy. This categorization of primary and secondary therapies reflects the 
International Consensus Statement prepared by 32 academic experts from 9 countries (Biller et 
al 2008). 
Post-surgical remission rates of 70-80% have been reported. However, a 25% incidence of 
recurrent hypercortisolism has been reported at 10 years of follow up (Bochicchio et al 1995; 
Sonino et al 1996). With second pituitary surgery (re-operation), success rates are lower and 
complications are higher than with primary pituitary surgery; therefore patients should be 
carefully selected (Fleseriu et al 2007; Friedman et al 1989). 
Pituitary irradiation is an option for patients who are not surgical candidates or have persistent 
or recurrent hypercortisolism following primary pituitary surgery. However, the response to 
pituitary irradiation is slow and is related to the type of radiation administered. The two most 
commonly used radiation modalities are stereotactic radiosurgery (SRS), which consists of a 
single high-dose treatment (e.g. proton beam, gamma knife or cyber knife), and conventional, 
fractionated radiation (linear accelerator; Loeffler and Shih 2011). SRS is not only more 
convenient to the patient; it also has a faster onset of biochemical remission median of 17 
months (Sheehan et al 2013), than with conventional fractionated radiation, with an onset of 2-
3 years (Loeffler and Shih 2011). In some cases of conventional fractionated radiation, 
remission may be delayed until 10 years or longer (Losa et al 2010; Minniti et al 2007). The 
long term complications include hypopituitarism (Newell-Price et al 2006), secondary 
malignant tumors (Sedney et al 2012), and possibly an increased risk of death from 
cerebrovascular disease post-radiation (Ayuk 2012). 
Medical therapy is an attractive option for patients with Cushing’s disease who have persistent 
or recurrent hypercortisolism after prior surgery and/or pituitary irradiation, and for patients 


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with de novo Cushing’s disease who are not candidates for pituitary surgery because of medical 
reasons, or because of refusal to undergo surgery. 
Pasireotide (Signifor®), a second generation somatostatin analogue, is the only drug currently 
approved in the US and in EU for the treatment of Cushing’s disease per se. In the pivotal phase 
3 trial, pasireotide was effective in normalizing or reducing by ≥ 50% urinary free cortisol in 
34% to 41% of patients, in study groups randomized to 0.6mg s.c. bid and 0.9mg s.c. bid, 
respectively. 
Mifepristone, a glucocorticoid receptor antagonist, was recently approved in the US for the 
treatment of hyperglycemia secondary to hypercortisolism in adult patients with endogenous 
Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance. 
Several other drugs have been used with or without regulatory approval for the treatment of 
Cushing’s disease, including: ketoconazole and metyrapone (steroidogenesis inhibitors), 
mitotane (adrenolytic agent), and cabergoline (dopamine agonist). Use of these drugs is based 
on limited data. None of these drugs have been prospectively studied in multicenter randomized 
trials. Thus, neither the efficacy nor the safety profiles of these medications can be considered 
established in the Cushing's disease population. 
Bilateral adrenalectomy is generally deferred until all other options have been exhausted (Biller 
et al 2008). The benefit of bilateral adrenalectomy is immediate and permanent control of the 
hypercortisolism in all patients. Yet the inescapable consequence of bilateral adrenalectomy is 
immediate and permanent primary adrenal insufficiency, which requires life-long 
glucocorticoid and mineralocorticoid replacement therapy and monitoring. Part of the 
management of primary adrenal insufficiency includes emergency treatment for situations of 
acute stress such as sepsis or trauma. These events can be life-threatening if not treated with 
high “stress doses” of these hormones intravenously. Additionally, Nelson’s syndrome is a 
potential complication of bilateral adrenalectomy that is marked by progressive pituitary 
corticotroph growth and rising ACTH levels. This can be a serious complication because it may 
result in compression of structures adjacent to the pituitary gland within or above the sella 
turcica, and pituitary apoplexy, although this ultimate complication should not occur in the 
modern era when close follow-up with pituitary MRI allows early detection of corticotroph 
tumor growth (Assie et al 2007). 
1.1.3 
Unmet medical need 
Cushing’s disease is rare and associated with multiple co-morbidities that increase the risk of 
cardiovascular disease and mortality. Currently available modalities of therapy include pituitary 
surgery, pituitary irradiation, medical therapy and bilateral adrenalectomy. Although currently 
available therapies address the needs of most patients, there remain patients that have persistent 
or recurrent hypercortisolism and/or unacceptable toxicities. 
With regard to medical therapies, the recent approvals of pasireotide and mifepristone represent 
major advancements. However, there is still much room for improvement beyond the existing 
medical therapies, because substantial subsets of patients in the target population either do not 
achieve normalization of mUFC or do not have the co-morbidity profile in the approved 
indication that would make them eligible for treatment. 


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Therefore there is an unmet medical need to develop new drugs with improved safety and 
efficacy. Based on the preliminary data from a proof-of-concept (PoC) study in patients with 
Cushing’s disease, LCI699 shows promise in fulfilling this unmet medical need. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
LCI699 is a potent, oral inhibitor of 11β-hydroxylase (CYP11B1), the enzyme that catalyzes 
the last step in the biosynthesis of cortisol. This provides the rationale for investigating the use 
of LCI699 in endogenous causes of Cushing’s syndrome. The current development activity of 
LCI699 is focused on the treatment of patients with Cushing’s disease (hypercortisolism due to 
a pituitary corticotroph adenoma), because it is the most common cause and it is relatively 
homogeneous. This drug also inhibits aldosterone synthase (CYP11B2), and therefore is a dual 
inhibitor of both cortisol and aldosterone synthesis. 
1.2.1 
Overview of LCI699 
LCI699 is a new chemical entity with the chemical structure 4-[(5R)-6,7-Dihydro-5H-
pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile phosphate. The structural formula is shown 
below in Figure 1-1: 
Figure 1-1 
Structural formula of LCI699 
 
LCI699 is a potent, orally-administered dual inhibitor of 11 β-hydroxylase (CYP11B1) and 
aldosterone synthase (CYP11B2) in the adrenal cortex. It is manufactured as a phosphate salt 
and available in film-coated tablets of 1 mg, 5 mg, 10 mg and 20 mg, with matching placebo 
tablets, for this phase 3 study. This compound was initially developed for hypertension and 
primary hyperaldosteronism. At doses >3mg daily, dose-dependent impairment in the cortisol 
response to ACTH, and a marked decrease in the circadian rhythm of cortisol was observed. 
These findings raised concern of the potential for clinically significant hypocortisolism or 
adrenal insufficiency, and therefore the development in these indications was halted. Phase 2 
studies were completed in more than 500 hypertension patients. Given the mechanism of action 
to inhibit cortisol synthesis at the adrenal glands, LCI699 has therapeutic potential in all forms 
of endogenous Cushing’s syndrome (e.g., ACTH-dependent causes such as Cushing’s disease 
due to a pituitary adenoma, and ectopic ACTH syndrome, which is associated with a benign or 
N
H
+
N
F
C
N
O
H
P
O
OH
O


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malignant tumor. ACTH-independent causes include adrenal tumors (benign and malignant), 
and bilateral adrenal hyperplasias of various causes. 
The compound is currently being developed for the treatment of patients with Cushing’s 
disease. Higher doses of LCI699 (currently up to 30 mg b.i.d.) are being investigated for the 
endocrine indication relative to those used for the cardiovascular indication (up to 1 mg b.i.d). 
The mechanism of action of LCI699 is depicted in Figure 1-2 below. 
Figure 1-2 
Mechanism of action of LCI699 in Cushing’s Disease 
 
1.2.1.1 
Non-clinical experience 
For detailed non-clinical pharmacokinetics and toxicity findings, please refer to the 
[Investigator Brochure]. 
1.2.1.1.1 Non-clinical pharmacokinetics and metabolism 
LCI699 has been tested pre-clinically in a number of in vitro and in vivo mechanistic models. 
LCI699 inhibited human recombinant CYP11B1 (11 β-hydroxylase, the last enzyme in the 
glucocorticoid synthesis pathway) in vitro with an IC50 = 2.5 nM. Other effects of LCI699 
include dose dependent inhibition of recombinant human aldosterone synthase CYP11B2 (IC50 
= 0.7 ± 0.03 nM) and human aromatase in vitro, albeit at a much higher concentration with IC50 
= 1.7 μM. 
In vivo pharmacokinetics (PK) and toxicokinetics have been evaluated in rat and dog. LCI699 
displayed high permeability in Caco-2 cells and was not a substrate for efflux mechanisms. In 
rats, absorption was rapid and complete with complete bioavailability indicating a minimal first-
pass effect. The plasma half-life of LCI699 in rat and dog was short (~ 2 h). Exposure was dose-


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proportional within the dose range investigated in the rat but over-proportional in dogs and 
mice. No accumulation or gender differences were observed in either species. 
Protein binding was low (26.6–36.4%) with no significant species differences. Regardless of 
the dosing route (i.v. or p.o.), the rat and dog ADME studies indicated that elimination is mainly 
through metabolism and excretion in urine (~79% in rats and ~90% in dogs; unchanged LCI699 
~ 5-10% in urine and < 3% in feces). Based on in vitro CYP P450 inhibition profile and 
predicted steady state maximum concentration of 1.26 µM at 30 mg twice daily in humans, 
there is potential of drug-drug interaction for LCI699 with CYP1A2, CYP2C19, CYP2D6, 
CYP3A4/5, and CYP2E1. Results from a clinical drug-drug interaction study [LCI699C2102] 
are summarized in Section 1.2.1.2.1. It is unlikely for LCI699 to increase in the systemic 
exposure of co-medications whose clearance is mediated by P-gp, BCRP, OAT1, OAT3, OCT1, 
and OCT2 transport activity. 
1.2.1.1.2 Preclinical safety 
Safety pharmacology: 
In safety pharmacology studies, proarrhythmic indices and QTc interval prolongation were 
observed in in vitro study in isolated rabbit heart and in vivo studies in dog and monkey with 
LCI699. Proarrhythmic indices were observed at 10 µM in isolated rabbit heart assay. QTc 
interval prolongation was noted at 50 mg/kg after 2 weeks of intravenous dosing in dogs, at 30 
mg/kg oral (gavage) after single dose, and at 10 mg/kg/day in a two week study in monkeys. 
The preclinical data show consistency across in vitro and in vivo studies, including a monkey 
telemetry study. Based on the monkey telemetry data, it appears that the observed QTc effects 
occurred at or above 16 times the exposure of the planned maximum clinical dose of 30mg b.i.d. 
in healthy volunteers. 
Toxicology: 
In single dose toxicity study in mice, no acute toxicity was observed in mice following 
administration of oral doses up to 125 mg/kg, and mortality was observed at the dose of 150 
mg/kg. 
In repeated dose general toxicity studies up to 26-weeks in duration in the rat, and up to 39 –
weeks in the dog, the main target organs were central nervous system (CNS), liver, female 
reproductive organs, and adrenal gland. Reversible CNS effects were seen at very high doses 
in dogs (≥10 mg/kg) and mice (doses ≥ 30 mg/kg). Hepatocellular hypertrophy and vacuolation 
were seen in 13-week and 26-week rat studies at doses ≥ 5 mg/kg and in a 13-week study in 
mice at doses ≥ 10 mg/kg (partially reversible). In female dogs, transient increases in ALT and 
AST were observed at week 5 during the 13-week study at 0.1 and 10 mg/kg. Effects on female 
reproductive organs (ovary, uterus and vagina) were seen in rats at doses ≥ 5 mg/kg (reversible) 
and in mice at doses ≥ 30 mg/kg. Male reproductive organ changes were limited to a decrease 
in prostate weights (no microscopic correlate) in the 26-week rat study at 20 mg/kg. No effects 
on female or male reproductive organs were found in dogs. In the adrenal cortex, morphological 
alterations were observed in dogs (zona glomerulosa) and at much higher exposure in rats (zona 
fasciculata/glomerulosa). They may be a result of the inhibition of adrenocortical steroid 
biosynthesis leading to an adaptive induction of the aldosterone/cortisol synthase pathway. In 


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the chronic toxicity studies, the NOAEL was 2 mg/kg in the rat (26-week), and was 10 mg/kg 
in the dog (39-week). 
In genetic toxicology studies, no evidence of mutagenic activity was observed in the Ames test, 
and no evidence of chromosomal damage in the in vitro micronucleus test. Clastogenic effects 
at high concentrations with and without metabolic activation were reported in cultured human 
peripheral blood lymphocytes. In vivo genotoxicity tests in rats (micronucleus test and comet 
assay) were clearly negative and it is therefore concluded that LCI699 has no relevant genotoxic 
potential in humans. 
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 and the rabbit, and increased 
incidence of fetal malformation was observed in rats (only occurred at the maternally toxic 
dose). 
1.2.1.2 
Clinical experience 
1.2.1.2.1 Summary of clinical pharmacokinetics 
The pharmacokinetics of LCI699 has been studied in healthy volunteers, patients with 
hypertension, and patients with hyperaldosteronism, as well as in an ongoing proof-of-concept 
study in Cushing’s disease patients. For detailed information, please refer to the [Investigator’s 
Brochure]. 
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, consistent at all doses 
studied. The elimination half-life of LCI699 was 3-5 hours across all doses examined. About 
6% of the dose is excreted unchanged in the urine. The pharmacokinetics of LCI699 were over-
dose proportional in the dose range of 0.5 to 200 mg (single dose); for a 2-fold increase in dose, 
the AUC increase would be about 2.4-fold, and Cmax increase would be 2.1-to 2.4-fold 
[LCI699A2101]. 
Due to its short elimination half-life, LCI699 does not accumulate in plasma following twice-
daily multiple dosing up to 3 mg b.i.d., and there is no change in the kinetics on repeated dosing. 
Accumulation ratio based on AUC (Day 1 vs. Day 14) is 0.8 - 1.3 in subjects dosed with ≤3 mg 
b.i.d. Typically, the coefficient of variation for plasma LCI699 AUC is in the region of 11 – 
40% in healthy subjects after an oral dose [LCI699A2101]. 
For exploratory assessment of food effect, pharmacokinetics of a single oral dose of 100 mg 
LCI699 under fasting conditions was compared with that following a high fat meal in the first-
in-human study (n=3 – 5). Administration of 100 mg LCI699 with a high fat meal resulted in a 
reduction in AUC and Cmax by 14% and 25%, respectively, and the median Tmax was delayed 
from 1 h to 2.5 h after high fat meal. The impact is not considered clinically significant; the 
delay in Tmax and impact on Cmax is expected as food delays gastric emptying and prolongs 
intestinal transit time. 
Impact of ethnic origin on LCI699 pharmacokinetics was investigated in Caucasian and 
Japanese healthy male subjects following single and multiple doses of LCI699 (0.25, 0.5, 1, 2 
mg). LCI699 exposure (AUC) was 18%, 44%, and 66% higher in Japanese healthy volunteers 
in comparison to Caucasians after single dose of 0.5 mg, 1 mg and 2 mg LCI699, respectively, 


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and a larger difference is observed at higher doses. Body weight difference (mean body weight: 
64.6 to 68.6 kg for Japanese vs. 70.7 to 77.6 kg for Caucasians) was not shown to be a major 
determinant of the race effect on exposure [LCI699A2102]. 
Results from the human ADME study indicate that the majority of the [14C]-LCI699 
radioactivity 50 mg dose was eliminated in the urine (mean: 90.6%) with only a minor amount 
eliminated in the feces (mean: 1.58%). The percentage of the dose eliminated in the urine as 
unchanged LCI699 was also minor (mean: 5.19%). Thus, metabolism was found to be the major 
clearance pathway for LCI699 in humans with renal clearance making only a minor 
contribution. Metabolism of LCI699 was extensive in humans via multiple pathways (and 
combination of pathways). The primary metabolic reactions observed in this study included 
direct glucuronidation, hydroxylation of the pyrrolidine-ring system, oxidation and degradation 
of the imidazole ring, N-methylation, and ribose conjugation. The most abundant circulating 
metabolite was M34.5, which was formed via di-oxygenation of the imidazole ring of LCI699. 
There is no single metabolic pathway that contributes significantly to the overall elimination of 
LCI699 [LCI699C2101]. 
Results from a cocktail drug-drug interaction study [LCI699C2102] showed that LCI699 is a 
weak inhibitor for CYP3A4/5 and CYP2D6 (increased AUCs of midazolam and 
dextromethorphan ~1.5-fold), and a moderate inhibitor for CYP1A2 and CYP2C19 (increased 
AUC of caffeine and omeprazole ~2.5- and ~1.9-fold, respectively). 
Assessment of LCI699 PK is ongoing in Cushing’s disease patients. Trough concentrations 
were available for 10 patients from the interim analysis after 10 weeks of LCI699 treatment, 
and ranged from 0.336 ng/mL (after 2 mg b.i.d) to 204 ng/mL (after 50 mg b.i.d). The median 
(range) of trough plasma LCI699 concentrations at the time when mUFC was normalized, or 
reduced by at least 50%, was 5.0 (0.3 – 49.3) ng/mL (n=10). [LCI699C2201 Interim CSR]. 
1.2.1.2.2 Results of LCI699C2201study in Cushing’s disease 
The purpose of the LCI699C2201 study was to determine whether the ability of LCI699 to 
inhibit 11β-hydroxylase could safely reduce urinary free cortisol (UFC) in patients with 
Cushing’s disease. This was initially studied over a 10-week treatment duration Proof-of 
Concept (Part I). Part II of the study aimed to further evaluate the observations from the Part I 
by enrolling a cohort of patients who participated in Part I (Follow-up cohort) and a new cohort 
(Expansion cohort) of patients and to evaluate the longer-term efficacy and safety of LCI699 
treatment for a total duration of 22 weeks; results of the longer-term efficacy and safety of 
LCI699 are also available. 
In Part I, LCI699 was effective in controlling cortisol production in all 12 patients studied. At 
daily LCI699 doses between 2 mg b.i.d. and 50 mg bid, 24-hour mUFC decreased rapidly and 
normalized at least once in all patients studied. Individual patient mUFC reduction over time 
and dose-response is depicted in 
. In general at 5 mg b.i.d. patients showed mUFC 
reduction after 2 weeks (at first mUFC measurement after dose titration). 
The primary endpoint, defined as mUFC ≤ ULN or ≥ 50% decrease from baseline at day 70, 
was achieved by all patients. Overall, the mean time to response (UFC normalization or ≥ 50% 
reduction from baseline) was 34.3±14.1 days. The mean daily dose (± SD) of LCI699 required 
to reach the primary endpoint was 13.5±13.9 mg b.i.d. with 75% of patients normalizing mUFC 


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on ≤ 10mg b.i.d. At Day 84, two weeks after LCI699 was withdrawn, mUFC levels increased 
to a mean of 4-fold above upper limit of normal (ULN) (Figure 1-4). 
 


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Figure 1-4 
Arithmetic mean and SE plots for fold ULN of mUFC (PD analysis set) 
 
Source: In-text Figure 11-2, 10-week interim CSR study [LCI699C2201]. 
Significant decreases in mean plasma cortisol and aldosterone from baseline (-60% and -70%, 
respectively), and marked increases in their precursors from baseline (11-deoxycortisol [13-
fold] and 11-deoxycorticosterone [42-fold], respectively), and ACTH [2.4-fold] were observed 
at Day 70. These biochemical changes were as expected based on the mechanism of action of 
the drug, i.e., primarily related to hypocortisolism, hypoaldosteronism, accumulation of their 
precursors, and increase in ACTH from baseline. 
In Part II, 17 out of 19 patients completed the 22 weeks treatment period and 15 of 19 (79%) 
had normal mUFC levels at week 22. During treatment with LCI699, the mean mUFC levels 
decreased quickly and stabilized to a normal level (11 to 138 nmol/24h) at Week 4 (Figure 1-
5). After Week 4, normal mean mUFC levels were observed through the study up to Week 22. 
All patients attained UFC normalization at least once during the study, and no patient “escaped” 
UFC control. 
LCI699 dose escalation
Washout


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Figure 1-5 
Mean (+/-SE) mUFC (nmol/24h) over time by cohort 
 
1.2.1.2.3 Overview of LCI699 clinical safety 
Clinical safety data with LCI699 has been obtained from seven completed studies and one 
ongoing study. A total of approximately 954 subjects participated in these studies. Of these, a 
total of 683 were treated with LCI699: 131 healthy male volunteers, 516 patients with 
hypertension, and 27 patients with Cushing’s disease. 
In the clinical trials for the treatment of hypertension or primary hyperaldosteronism, LCI699 
was tolerated with the overall incidence of adverse events being similar to placebo. AEs were 
generally of mild to moderate intensity. Both SAEs and discontinuations due to AE were 
infrequent, and were reported at a rate similar to placebo in the hypertension studies. The most 
common AEs across these studies were: headache, dizziness (including postural dizziness), 
nausea, diarrhea and fatigue. There were also AEs of hyperkalemia and impaired ACTH-
stimulated cortisol response in these trials, which are consistent with the potential for 
hypocortisolism and hypoaldosteronism. 
In Part I of the study [LCI699C2201], all 12 patients (100%) experienced adverse events but 
these were generally mild to moderate in severity (NCI CTC grade 1 or grade 2). Fatigue, 
muscle cramps, dizziness and gastrointestinal events were the most common events suspected 
to be drug related. Four patients reported AEs consistent with cortisol and/or aldosterone 
withdrawal; dose reductions or temporary dose interruption in these patients improved the 
symptoms. There were no discontinuations related to study drug and no serious adverse events 
of suspected drug relationship. 
In Part II of study LCI699C2201, LCI699 was generally well tolerated. Except for one patient 
in the Expansion cohort, all patients experienced AEs, grade 1/2 in most of the cases. Adrenal 
insufficiency, nausea, fatigue and increased levels of oxycorticosteroids, blood corticotrophin, 
blood testosterone in females were the most common AEs suspected to be drug related (by PT). 
Two patients experienced a total of 3 SAEs. 


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One patient experienced grade 3 pituitary-dependent Cushing's syndrome (PT). The SAE 
resulted in hospitalization/prolonged hospitalization and was not suspected to be related to the 
study drug. This SAE was continuing at the time of the data cut-off date. 
Another patient experienced 2 SAEs concurrently: grade 3 gastroenteritis (PT) and grade 1 
Electrocardiogram 
QT 
prolongation 
(PT). 
The 
gastroenteritis 
resulted 
in 
hospitalization/prolonged hospitalization, was not suspected to be related to the study drug and 
resolved with concomitant medication. The Electrocardiogram QT prolongation was suspected 
to be related to the study drug by the investigator, but causality is not clear. There were no 
cardiac symptoms or arrhythmia reported. The SAE “electrocardiogram QT prolongation” was 
ongoing at the time of the data cut-off date. 
One patient discontinued the study drug due to AEs. This patient reported (by PT) grade 3 
papule, and grade 1 diarrhea, malaise, muscular weakness and nausea. All the AEs were 
suspected to be related to study drug and the patient discontinued the study drug after two weeks 
treatment. 
In reviewing the clinical trial experience with LCI699 to date, AEs have been identified that are 
consistent with the mechanism of action of the drug as an inhibitor of both cortisol and 
aldosterone synthesis. These can be summarized as follows: 
 Changes in adrenal hormones: cortisol decreased, aldosterone decreased, and their 
precursors (11-deoxycortisol, 11-deoxycorticosterone) increased 
 Change in pituitary hormone: ACTH increased 
 Changes in electrolytes: potassium increased or decreased 
 Changes in body weight and blood pressure: potentially increased by mineralocorticoid 
effect of the aldosterone precursor 11-deoxycorticosterone 
 Changes in sex hormones: testosterone and estradiol increased (testosterone more than 
estradiol, and more pronounced in women than in men) 
A more detailed list of potential AEs related to the mechanism of action of LCI699 can be found 
in Section 8.1.3, “AEs of Special Interest”. For a comprehensive review of clinical safety data 
with LCI699, see the [Investigator’s Brochure]. 
1.2.1.2.4 Study CLCI699C2105: QT/QTc data in healthy volunteers 
The cardiac repolarization liability of LCI699 was assessed in the definitive ICH E14 compliant 
thorough QT/ QTc Study (TQT) study [CLCI699C2105] in 86 healthy male and female 
subjects. A maximum mean ∆∆QTcF of 25.4 ms was observed on the supratherapeutic LCI699 
dose of 150 mg (5-fold higher than the maximum clinical dose of 30 mg), with absence of a 
relevant QT effect on the therapeutic LCI699 dose of 10 mg (∆∆QTcF 0.3 ms; 90% CI −1.50, 
2.16).). No subject experienced QTcF values >500 ms, nor increases from baseline >60 ms. The 
maximum effect was observed at Tmax (1 hour post-dose). No dose-related effects were 
observed for the cardiac intervals (QRS, PR, or HR), or on blood pressure on LCI699 10 mg or 
150 mg. No new safety concerns were identified in this study. 
A population-PK analysis was performed to estimate the peak exposure (Cmax) of the highest 
planned clinical doses of LCI699 (20 mg and 30 mg), based on the pooled PK data from the 
LCI699 studies A2101, C2105, and C2201 (total N=178). The predicted arithmetic mean and 


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geometric mean Cmax,ss of LCI699 20 mg was 174 and 168 ng/mL, and on LCI699 30 mg was 
284 and 275 ng/mL, respectively. The concentration-QTcF effect model from study 
[LCI699C2105] was then applied to the predicted Cmax values for LCI699 20 mg and 30 mg 
from the Population-PK analysis. Based on the predicted exposure levels, the predicted 
maximum mean QTcF on LCI699 20 mg is 4.1 ms (CI 2.98, 5.28), and the predicted maximum 
mean QTcF on LCI699 30 mg is 6.3 ms (CI 5.13, 7.42). 
The results remained below the QTcF effect of regulatory concern (i.e., an upper boundary of 
the 90% CI < 10 ms) and fully support the use of LCI699 doses up to 30 mg. 
2 
Rationale 
2.1 
Study rationale and purpose 
LCI699 is a potent inhibitor of 11β-hydroxylase, the enzyme that catalyzes the last step in the 
biosynthesis of cortisol. This provides the rationale for investigating the use of LCI699 in 
endogenous causes of Cushing’s syndrome. This drug also inhibits aldosterone synthase. 
The most common cause of Cushing’s syndrome is an ACTH-secreting pituitary adenoma 
(Cushing’s disease). The effect of LCI699 in patients with recurrent or persistent 
hypercortisolism from Cushing’s disease was investigated in the Proof-of-Concept (PoC) study 
[CLCI699C2201]. The results of the10-week analysis showed that all 12 patients reached the 
primary endpoint (24-hour urine free cortisol [UFC] ≤ upper limit of normal [ULN] or ≥ 50% 
reduction in mUFC from baseline). In addition, all 12 patients had normalization of mUFC at 
least once during the study, and LCI699 was generally well tolerated. 
These promising results are now being further evaluated in an amendment to protocol 
[CLCI699C2201] that plans to study patients for a longer period of time (22 weeks with an 
optional one year extension). A total of 19 patients have been enrolled in the amended study, 
including 15 new patients and 4 patients that were previously enrolled. 
The present Phase 3 study [CLCI699C2301] is intended to support the registration of LCI699 
for the treatment of patients with Cushing’s disease who have persistent or recurrent 
hypercortisolism after primary pituitary surgery, and patients with de novo Cushing’s disease 
who are not surgical candidates for medical reasons, or refuse to undergo surgery. 
2.2 
Rationale for the study design 
The study aims to confirm long-term efficacy and safety of LCI699. A period of individual-
patient dose titration during the first 12 weeks (see Section 4.1 for details of the study design) 
is followed by monitoring for sustained efficacy and safety of this therapeutic dose for the 
second 12 weeks of the study. At week 24, the proportion of patients with normal UFC 
(complete responders, mUFC ≤ ULN) is assessed as the key secondary endpoint. 
Patients with normal mUFC (≤ ULN) at week 24 and that meet the criteria specified in Section 
4.1.3.2 are eligible to enter a double-blind, placebo-controlled, randomized withdrawal period 
that is designed to confirm the efficacy of LCI699 in controlling UFC relative to placebo for up 
to 8 weeks. At the end of randomized withdrawal, the randomized patients enter a second open-


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label period of LCI699 therapy to week 48 (in the core study). Patients that were not randomized 
continue to be monitored for efficacy and safety on LCI699 to week 48. 
Patients that plan to participate only in the core part of the study stop study drug at Week 48, 
and return for an end of study visit 4 weeks later, at week 52. Patients that wish to continue on 
to the extension part of this study are re-consented at Week 48, and continue study drug and 
assessments without interruption. The extension part of the study is intended to collect long-
term safety and efficacy data. The optional extension period will end after the last patient 
completes the core period or discontinued early from core period. Patients who continue to 
benefit from treatment will be offered participation in a separate long-term safety follow-up 
study. This study design was selected for the pivotal trial of LCI699 in patients with Cushing’s 
disease for several reasons: 
 Individual dose titration is required based on the available data due to high inter-subject 
variability in effective dose and narrow therapeutic window (potential risk of 
hypocortisolism or acute adrenal insufficiency) 
 Follow-up at steady dose during weeks 12-24, as well as during the second open-label 
period (from the end of randomized withdrawal to Week 48) aim to demonstrate long-term 
safety and efficacy without the need for further dose escalation due to therapeutic escape. 
 The design permits dose reductions and temporary dose interruptions for safety reasons at 
any time during the study, but the investigator is blinded to randomized treatment 
assignment only if this occurs during the randomized withdrawal period 
 The randomized withdrawal period provides an efficient way to demonstrate the efficacy 
of LCI699 vs. placebo. Efficiency of design is relevant in a rare disease, because of the 
difficulty in finding eligible patients. Randomized withdrawal, in this case with a rescue 
treatment available (see below) minimizes the duration of placebo treatment, while 
allowing efficacy to be demonstrated. 
 It is not ethical to use a long-term placebo control, because chronic uncontrolled 
hypercortisolism results in increased morbidity and mortality (Clayton et al 2011). 
 Randomized withdrawal provides the design elements of double-blinding, placebo control 
therapy for comparison, and randomized allocation to continue study drug or change to 
placebo. 
FDA (Draft Guidance for Industry on Enrichment Strategies for Clinical Trials to Support 
Approval of Human Drugs and Biological Products, December 2012) recommends a 
randomized withdrawal design for target populations with the above listed characteristics. 
Some of the advantages of the proposed study design are: 
 The population that undergoes randomized withdrawal is enriched by including only those 
patients that have responded to treatment during an open-label run-in period. This design 
is an efficient way to demonstrate the efficacy of a drug without requiring long-term 
exposure of patients to a placebo control. 
 Patients who do not have a complete response may receive benefit from a partial response. 
Such patients are not randomized but continue to be monitored for long-term efficacy and 
safety until the end of the trial. 


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 In the case of this study, there is a procedure for managing patients with uncontrolled 
hypercortisolism during the 8-week randomized withdrawal. Patients with mUFC > 1.5 x 
ULN (with at least 2 individual UFC results > 1.5 x ULN) at any study visit during 
randomized withdrawal will be discontinued from this period of the study, and will 
resume treatment with open-label LCI699 at a dose selected by the investigator. This 
minimizes the duration of exposure to ineffective treatment. 
Primary and secondary endpoints 
One of the key treatment goals in patients with Cushing’s disease is normalization of the 
biochemical abnormalities (Biller et al 2008). The results of the 10-week analysis in 12 patients 
with Cushing’s disease in the proof of concept (PoC) study [CLCI699C2201] demonstrated that 
LCI699 is highly effective in normalizing urinary free cortisol in this population. 
The clinical importance of normalizing UFC in patients with Cushing’s disease is emphasized 
by the results of a recent meta-analysis of published mortality (Clayton et al 2011). This meta-
analysis showed that the standardized mortality ratio (SMR) is much higher in Cushing’s 
disease patients with persistent hypercortisolism (SMR=5.5) than those in remission 
(SMR=1.2). 
The 24-hour UFC test is considered the best diagnostic test for hypercortisolism. The primary 
efficacy assessment in Study [CLCI699C2301] is based on the mean of three 24-hour urinary 
free cortisol (mUFC) collections, within a period of two weeks, at the end of 8 weeks (at Week 
34) of randomized withdrawal. The primary objective is to compare the complete response rate 
(proportion of patients with mUFC ≤ ULN) at the end of 8 weeks of randomized withdrawal (at 
Week 34) between patients randomized to continued LCI699 therapy or placebo. 
As 24-hour UFC is the primary efficacy assessment, special care is taken to ensure that the 
results are reliable. The 24-hour urine collection must be within defined upper and lower limits 
for urine volume and urine creatinine. These limits are intended to avoid the reporting of 
misleading results because of incomplete urine collections or extremes of urine concentration 
from undertreatment or overtreatment of central diabetes insipidus if present. In addition, 
patients with eGFR < 60 mL/min are excluded because reduced urine free cortisol excretion has 
been reported in patients with moderate or severe renal impairment (Allen Chan et al 2004; Issa 
et al 1999; and Sharp et al 1986). The method used for measurement of UFC at the central 
laboratory is liquid chromatography-tandem mass spectrometry (LC-MS/MS). In contrast to 
immunoassays, LC-MS/MS has the advantage of measuring cortisol accurately and exclusively, 
without concern of interference by cross-reactivity of accumulating cortisol precursors (e.g., 
11-DOC) with LCI699 therapy (Monaghan et al 2014). 
In addition to the primary endpoint, the key secondary endpoint is the complete response rate 
(proportion of patients with mUFC ≤ ULN) at the end of 24 weeks of dose-titration and 
treatment with LCI699 in the initial single-arm, open label part of this trial. This is a clinically 
meaningful endpoint in that it assesses the proportion of patients that have achieved fully 
controlled mUFC at that time point. In addition, the requirement for a normal mUFC (mUFC ≤ 
ULN) presents a hurdle for eligibility to enter the randomized withdrawal part of the study. 
Other secondary endpoints 
 endpoints correspond to the secondary 
 
 objectives, respectively. Several relevant clinical endpoints are captured: the 


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change from baseline in fasting glucose, HbA1c, fasting lipids, blood pressure, weight, BMI, 
and waist circumference; the change from baseline in BMD by DXA scan at the lumbar spine 
and total hip; and the change from baseline, in Health Related Quality of Life, as measured by 
the Cushing’s disease-specific QoL questionnaire (CushingQoL), the Beck Depression 
Inventory (BDI-II), and the general HRQoL instrument EQ-5D-5L at time points indicated in 
Section 3. 
2.3 
Rationale for dose and regimen selection 
The rationale for b.i.d. dosing of LCI699 is based on its half-life of 3-5 h. This regimen was 
used in the PoC study [CLCI699C2201] as well. Originally modeling of PK exposure estimated 
that a dose of 4-5 mg b.i.d. is expected to achieve a plasma concentration above the in vitro 
IC50 for CYP11B1 (2.5 nM) for a full 24 hours for efficacy consideration; however, 2 mg b.i.d 
was chosen to be the starting dose in the PoC study based on safety considerations, i.e., to reduce 
the risks associated with potential hypocortisolism or adrenal insufficiency: 
 Glucocorticoid withdrawal due to rapid correction of elevated serum cortisol, 
 Biochemical hypocortisolism (UFC < LLN), 
 Symptomatic hypocortisolism or adrenal insufficiency (potentially life-threatening). 
There were four events of suspected hypocortisolism (glucocorticoid withdrawal) that improved 
with dose reduction or dose interruption during the 10-week PoC study [CLCI699C2201]. Since 
these events occurred during the 10-week dose titration period, they support a conservative 
approach to the starting dose of LCI699. In addition, since the 10-week analysis, one patient in 
the ongoing study [CLCI699C2201] had biochemical evidence of hypocortisolism on 2mg 
b.i.d., and their LCI699 dose was reduced to 1 mg b.i.d. 
The 10-week analysis of the PoC study [CLCI699C2201] showed that the dose of LCI699 
required for normalization of mUFC ranged from 2 mg b.i.d to 50 mg b.i.d after individual dose 
titration, with nearly all patients (11/12) achieving UFC normalization at > 2 mg b.i.d. Trough 
concentrations at mUFC normalization also varied widely, ranging from 0.3-49 ng/mL. This 
indicates that there is a broad range (up to 25-fold in LCI699 dose) of between-patient 
sensitivity to LCI699 with respect to normalization of mUFC, and there was no apparent 
relation between the therapeutic dose or exposure (trough concentrations) and the baseline 
mUFC. 
Thus, it appears that individual dose titration starting at 2 mg b.i.d. is an appropriate method to 
assess the efficacy and safety of LCI699. Fixed-dose comparisons of LCI699 doses would carry 
the risk of hypocortisolism if a relatively high dose is administered to a patient that is very 
sensitive to LCI699; in extreme cases, such a complication could present as a potentially life-
threatening adrenal crisis. 
This pivotal study will therefore start with a single-arm, open-label, individual patient dose 
titration period during the first 12 weeks. The following dose escalation sequence will be 
followed: 2 mg b.i.d., 5 mg b.i.d., 10 mg b.i.d., 20 mg b.i.d., and 30 mg b.i.d. The dose of 
LCI699 is titrated on the basis of the mean of three 24-hour urine free cortisol (mUFC) levels 
that are collected every two weeks during the dose titration period. Since at least one patient 
(see above) in the ongoing study [CLCI699C2201] had biochemical evidence of 


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hypocortisolism on 2mg b.i.d., the dose can be lowered to 1mg b.i.d. if this occurs in the present 
study. 
Please refer to Section 6.1.1 for more detailed information regarding dose adjustment. 
2.4 
Rationale for choice of combination drugs 
Not applicable. 
2.5 
Rationale for choice of comparators drugs 
Not applicable. 
2.6 
Rationale for inclusion of patients post pituitary irradiation 
In this protocol, patients with a history of pituitary irradiation are eligible for enrollment, 
provided that at least 2 years (stereotactic radiosurgery (SRS)) have elapsed or 3 years 
(conventional radiation) have elapsed from the time of last radiation to the time of enrollment 
into this study. Such patients must have uncontrolled hypercortisolism post-radiation at the time 
of screening. The justification for including such patients is that the therapeutic effect of 
radiation is delayed, but with SRS the median onset of biochemical remission is 17 months 
(Sheehan et al 2013), while with conventional radiation the onset is typically within 2-3 years 
after treatment (Minniti et al 2007). With conventional radiation, there is a plateau with a small 
incremental benefit up to 10 years or longer after treatment (Losa et al 2010). 
Published data show that biochemical remission is observed in 28% of patients at 1 year, 73% 
at 3 years, 78% at 5 years, and 84% at 10 years (Minniti et al 2007). Since the rate of decline in 
UFC is expected to be much slower as a result of radiation than as a result of LCI699 treatment, 
the potential for a confounding effect of radiation on efficacy is low. 
2.7 
Benefit-risk assessment of LCI699 in study population 
Potential patient benefits 
There is an unmet medical need in patients with Cushing’s disease which is a rare and serious 
disease with limited options for medical therapy. A proof-of-concept study ([LCI699C2201] 
Part 1) in 12 patients with uncontrolled Cushing’s disease showed that 11/12 patients had a 
normal mean UFC at the end of 10 weeks of LCI699 therapy. Continuation of the amended 
study ([LCI699C2201], Part II core) showed that 15/19 (79%) patients had normal mean UFC 
levels at the end of 22 weeks of LCI699 therapy; there was a trend toward improved fasting 
glucose and HbA1c in patients with diabetes at baseline, and an improved fasting lipid profile 
in patients with dyslipidemia at baseline. Based on these results LCI699 is a promising potential 
new therapy in patients with uncontrolled Cushing’s disease who have failed or are unable to 
receive primary surgical therapy 
Study-specific risks 
Study-specific risks in study [LCI699C2301] include: the potential for prolonged periods of 
uncontrolled hypercortisolism during the screening period while prior cortisol-lowering therapy 
is washed out. The duration of washout ranges from 1-8 weeks for nearly all drugs, and 6 months 
for mitotane. For patients who begin the study on a medication that requires a washout periods 


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of ≥ 4 weeks, it is possible to switch to a medication with a short washout period (e.g., 1 week) 
until the last part of the washout. Patients randomized to the placebo arm during the randomized 
withdrawal period may also experience uncontrolled hypercortisolism for up to 8 weeks 
duration (Week 26 to Week 34); this risk is mitigated by the “rescue” procedure, in which 
patients with mean UFC > 1.5 x ULN (with at least 2 of the 3 individual UFC levels > 1.5 x 
ULN) during the randomized withdrawal period are discontinued from randomized withdrawal 
and changed to open-label treatment with LCI699. 
Risks of LCI699 treatment in study population 
Known risks of treatment with LCI699 in patients with Cushing’s disease include: QT 
prolongation, adrenal insufficiency, AEs related to the accumulation of precursor molecules, 
including: increased or decreased blood pressure, hypokalemia or hyperkalemia, hyponatremia, 
weight gain, edema, and increase in the synthesis of sex steroids (primarily adrenal androgens 
in women) that may lead to menstrual changes and hirsutism in women and acne in either men 
or women. Skin rash has been observed. Corticotroph tumor progression, with or without 
compressive symptoms, is a potential risk. 
In addition, 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. 
Mitigation of the potential risks related to LCI699 treatment include: frequent study visits with 
careful monitoring for adverse events and toxicities including those that have been observed in 
previous studies with LCI699: vital signs, blood chemistry including urine, serum, 
 
cortisol levels, plasma ACTH, electrolytes, renal and liver function, fasting lipid profiles, 
HbA1c, sex steroid levels (testosterone, estradiol, adrenal androgens), immediate precursor 
levels to cortisol and aldosterone, safety ECGs at the time of Cmax, and pituitary MRI scans. 
In addition, the protocol provides specific guidance for safety follow-up of possible liver 
toxicity (increased transaminases, increased total bilirubin) and an algorithm for monitoring and 
management of QT prolongation. PK sampling will be conducted in all patients to measure 
LCI699 plasma concentrations and assess for any correlation with adverse events or for 
potential drug-drug interaction. 
A Steering Committee has been established; see Section 8.7 for additional detail. A Novartis 
Safety Management Team (SMT) exists to review and evaluate all emerging safety data for 
potential new safety signals on a regular basis and to evaluate safety management across the 
program. 


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Conclusion 
Based on current data, and the planned risk mitigation processes, the overall benefit-risk of trial 
participation is expected to be positive for all trial subjects, including those randomized to 
placebo during the randomized withdrawal period. 


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


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
Refer to 
Section 10.4. 
To compare the complete response rate at the end of the 8-week 
period of randomized withdrawal (Week 34) between patients 
randomized to continued LCI699 therapy vs. placebo. 
Proportion of randomized patients in each arm with: mUFC ≤ ULN at the end of 8 
weeks of randomized withdrawal (Week 34), and were neither discontinued, nor 
had LCI699 dose increase above the level at week 26 during the randomized 
withdrawal period. 
 
Key secondary 
Refer to 
Section 10.5.1. 
To assess the complete response rate at the end of individual 
dose-titration and treatment with LCI699 in the initial single-arm, 
open label period (Week 24). 
Proportion of enrolled patients with mUFC ≤ ULN at Week 24 and had no dose 
increase above the level established at Week 12 between Week 13 and Week 
24. 
 
Other secondary 
Refer to 
Section 10.5.2. 
To compare the time-to-last control of mUFC during the 
randomized withdrawal period between patients randomized to 
continued LCI699 therapy and placebo. 
Time-to-last control of mUFC, which is defined as the time (in days) from 
randomization to the last mUFC collection that was ≤ ULN before early 
discontinuation or completion of randomized withdrawal period, whichever is 
earlier. 
 
To assess the complete, partial, and overall response rate at 
Week 12, Week 24, Week 48, and at scheduled time points 
during the extension phase and the last available assessment. 
Complete response rate: proportion of enrolled patients with mUFC ≤ ULN at 
Week 12, Week 24, Week 48, and at scheduled time points during the extension 
phase (provided adequate follow-up as specified in the SAP), and the last 
available assessment 
Partial response rate: proportion of enrolled patients with ≥ 50% reduction from 
baseline in mUFC, but mUFC > ULN) at Week 12, Week 24, Week 48, and at 
scheduled time points during the extension phase (provided adequate follow-up 
as specified in the SAP), and the last available assessment. 
Overall response rate: proportion of enrolled patients with mUFC ≤ ULN or at 
least 50% reduction from baseline at Week 12, Week 24, Week 48, and at 
scheduled time points during the extension phase (provided adequate follow-up 
as specified in the SAP), and the last available assessment. 
 


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Objective 
Endpoint 
Analysis 
To assess the change in mUFC during the core and extension 
periods of the study. 
 
Actual and percentage change in mUFC from baseline to each post-
baseline visit during the core and extension (provided adequate follow-up as 
specified in the SAP) at which UFC is collected 
 
Actual and percentage change in mUFC from the time of randomization 
(Week 26) to the end of the randomized withdrawal period (Week 34), or the 
last mUFC measurement prior to early discontinuation, whichever occurs 
earlier. 
 
To assess the change in cardiovascular-related parameters 
associated with Cushing’s disease during the core and extension 
periods of the study. 
 
Actual and percentage change from baseline during the core and extension 
periods (provided adequate follow-up as specified in the SAP) of the study 
in: fasting glucose, HbA1c, fasting lipid profile, blood pressure, body weight, 
BMI and waist circumference 
 
Actual and percentage change from the randomization (Week 26) to the end 
of randomized withdrawal period (Week 34), or the last measurement 
available prior to early discontinuation, whichever occurs earlier (see bullet 
above for individual parameters). 
Refer to 
Section 10.5.2.4. 
To assess the change in Patient-Reported Outcomes (Health-
Related Quality of Life) during the core and extension periods of 
the study. 
 
Change in standardized score of CushingQoL, Beck Depression Inventory-
II, and EQ-5D-5L, from baseline to Week 24 and Week 48. 
 
Change in standardized score of CushingQoL, Beck Depression Inventory-
II, and EQ-5D-5L, from the randomization (Week 26) to the end of 
randomized withdrawal period (Week 34), or the last measurement prior to 
early discontinuation, whichever occurs earlier. 
 
Change from baseline in standardized score of CushingQoL, Beck 
Depression Inventory-II, and EQ-5D-5L, from baseline to Week 72, 96 and 
the EOT extension 
 
To assess the change from baseline in the physical features of 
Cushing’s disease by photography at Week 12, 24, 34, 48, and 
during the extension phase. 
Categorical change from baseline to Week 12, 24, 34, 48, during the extension 
at week 72 and EOT extension in each of the following clinical signs of Cushing’s 
disease by photography: facial rubor, hirsutism, striae, supraclavicular fat pad, 
dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, 
and ecchymoses (bruises). 
 
To assess the change from baseline in bone mineral density by 
DXA scan at the lumbar spine and total hip at Week 48 and the 
last available assessment. 
Actual and percent change from baseline to Week 48 and the last available 
assessment in bone mineral density as measured by DXA scan at the lumbar 
spine and total hip 
 
To assess the time-to-escape. 
Time-to-escape is defined as the time (in days) from the first mUFC ≤ ULN to the 
first mUFC results > 1.5 x ULN with at least 2 individual UFC results > 1.5 x 
ULN. 
 


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Objective 
Endpoint 
Analysis 
To assess general safety and AEs of special interest 
Adverse events and laboratory abnormalities will be assessed using the National 
Cancer Institute-Common Toxicology Criteria (NCI-CTC) grading scale (version 
4.03). 
AEs of special interest, as reported by the investigator, or by laboratory 
evaluation, ECG, Holter recording, and pituitary MRI. 
 
To evaluate exposures of LCI699 in patients with Cushing’s 
disease 
Plasma concentrations (predose, 0.5 h, 1.5 h, and 3.5 h post-dose) of LCI699 
 


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4 
Study design 
4.1 
Description of study design 
This is a Phase III, multi-center, double-blind, randomized withdrawal study of LCI699 
following a 24 week, single-arm, open-label dose titration and treatment period to evaluate the 
safety and efficacy of LCI699 for the treatment of patients with Cushing’s disease. The study 
has four periods plus an optional extension period, which are described below. 
4.1.1 
Study Period 1 
This single-arm, open-label LCI699 period (Week 1 to Week 12), is the individual patient dose 
titration period. 
Figure 4-1 
Schematic of study period 1 
 
Dose adjustments are based on the mean of three 24-hour UFC (mUFC) values as measured by 
the central lab. The triplicate urine samples are collected every two weeks during individual 
dose titration with the last urine sample preferably collected the day prior to the visit at site. 
The dose is increased if mUFC is above normal (> ULN). The dose is maintained if mUFC is 
within the normal range and the patient does not have signs or symptoms of hypocortisolism or 
adrenal insufficiency. The dose is reduced if mUFC < LLN, or if the patient is symptomatic and 
mUFC is in the lower part of the normal range. At Week 0 and Week 2, dose increase is not 
permitted. 
If a dose adjustment is required, sites should inform patients of the dose change by phone, as 
soon as possible once the mUFC results are available (e.g. ideally within 24 hours), which is 
expected to occur in between study visits. Please refer to Section 6.1.1 for details on 
communication and implementation of dose changes. 
To minimize the risk of dosing errors, it is very important that the patient receive written 
instructions that are clear and detailed but easy to follow at every visit. Please refer to Section 
6.1.1 for details on dosing instructions at visits. 


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Figure 4-2 
Example: Timing of study visits, UFC collection, and dose 
adjustments during Period 1 in a patient with dose up-titration 
 
Study visits are at Week 0 (Day1) and Weeks 2, 4, 6, 8, 10 and 12. Once mUFC results are available 
and a dose adjustment is required, sites should inform patients of the dose change by phone or under 
direct supervision by the site during an unscheduled visit prior to the next scheduled visit. 
Note: 
 
LCI699 dose is increased if the mean of 3 urine samples (mUFC) is above normal (> ULN). 
 
LCI699 dose is maintained if the mUFC value is in the normal range and the patient does not 
have signs or symptoms of hypocortisolism or adrenal insufficiency. 
 
LCI699 dose is reduced if the mUFC value is < LLN OR the patient has signs and symptoms of 
hypocortisolism or adrenal insufficiency and the mUFC value is in the lower part of the 
normal range. 
 
Dose reductions and temporary dose interruptions for safety reasons are permitted at any 
time during the study. 
Refer to Section 6.1.1 for additional details. 
4.1.2 
Study Period 2 
This period (Week 13 to Week 24) aims to assess the efficacy and safety of LCI699 at the 
therapeutic dose determined during the dose titration period. 
Patients whose mUFC becomes elevated during this period can have their LCI699 dose 
increased further, if it is tolerated and the maximum dose of 30 mg b.i.d. has not been reached. 
Such patients will be followed for long-term safety but will not be considered complete 
responders, and cannot be randomized. Decreases or temporary interruptions in the dose of 
LCI699 for safety reasons are permitted during this period without affecting eligibility for 
randomization. 
Dose adjustments may be managed via a phone call between visits or via an unscheduled visit 
at the site. Please refer to Section 6.1.1 for details. 
In order for a patient to be assessed as a complete responder at Week 24, the following two 
conditions must be met: 
 mUFC ≤ ULN based on urine samples collected at Week 24 
 The dose of LCI699 during Study Period 2 (Weeks 13-24) was not increased above the 
level established at the end of Study Period 1 (Week 12; end of individual dose titration 
period) 
Dose reductions and temporary dose interruptions for reasons of safety do not preclude the 
possibility of complete response assessment at Week 24. 


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The key secondary endpoint, the proportion of patients with a complete response (mUFC ≤ 
ULN), is assessed at Week 24. 
Patients remain on open-label LCI699 during the period between week 24 and week 26, in order 
to ensure that sufficient time is allowed for central laboratory results (Week 24 mUFC) to 
become available for all patients at all sites, and to standardize the time of randomization across 
sites. 
4.1.3 
Study Period 3 
Study Period 3 is a double-blind, placebo-controlled randomized withdrawal period (Week 26 
to Week 34). 
4.1.3.1 
Double-blinding 
The Novartis study team (except Global Clinical Supply (GCS))the patient, the investigator, 
and all other site staff remain blinded to treatment assignment from the time of randomization 
to the time of database lock for the core period of the study. 
4.1.3.2 
Eligibility for randomization 
In order to be eligible for randomization, patients must have completed dose titration during the 
first 12 weeks, continued on LCI699 treatment with no further dose increase during Weeks 13-
24, and have normal UFC (mUFC ≤ ULN) from urine samples collected at Week 24. Decreases 
or temporary interruptions in the dose of LCI699 for safety reasons are permitted and does not 
affect eligibility for randomization. Randomization is implemented at the Week 26 visit. 
Patients that are not eligible for randomization include: partial responders (mUFC reduced by 
≥ 50% from baseline, but above ULN) at Week 24, non-responders (mUFC reduced by < 50% 
from baseline and > ULN) at Week 24, and any patient whose dose was increased above the 
level established at the end of Week 12 (dose titration) between Week 13 and Week 24. These 
patients are followed on open-label LCI699 until the end of the core treatment (Week 48), unless 
there is a reason to discontinue from the study prematurely. 
4.1.3.3 
Randomization 
Eligible patients are randomized in a double-blinded fashion at Week 26 at a 1:1 ratio either to 
continue treatment with LCI699 at the same dose or to matching placebo. Patients are stratified 
at randomization according to: LCI699 dose at Week 24 (≤ 5mg b.i.d. vs. > 5mg-b.i.d.); and 
history of pituitary irradiation (yes/no). 
4.1.3.4 
UFC monitoring during randomized withdrawal 
During the 8-week randomized withdrawal study period, mUFC is measured at scheduled visits 
every 2 weeks. However, patients are also allowed to have unscheduled visits at any time during 
the randomized withdrawal period if they report symptoms of hypercortisolism or 
hypocortisolism. The investigator decides the dose of study drug (LCI699 or placebo) during 
this period, although is blinded to treatment assignment. All laboratory tests during the 
randomized withdrawal period must be sent to the central laboratory for analysis, and all 
treatment decisions must be based on central laboratory results. 


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4.1.3.5 
Dose adjustments during randomized withdrawal 
The dose of study drug (LCI699 or placebo) should remain unchanged for patients that maintain 
a normal mUFC and do not develop AE’s related to study drug during randomized withdrawal. 
The investigator may reduce or withhold a dose of study drug for safety reasons at any time 
during the study, including the randomized withdrawal period. Dose reductions or interruptions 
for safety reasons during the randomized withdrawal period do not preclude the possibility of a 
complete response at Week 34. Dose increases are not permitted during the randomized 
withdrawal period. 
Dose adjustments may be managed via a phone call between visits or via an unscheduled visit 
at the site. Please refer to Section 6.1.1 for details. 
4.1.3.6 
Discontinuation from randomized withdrawal 
During the randomized withdrawal study period, the patient must be discontinued from the 
randomized withdrawal period, declared a non-responder, if the mUFC increases to > 1.5 x 
ULN, and at least 2 individual urine samples show UFC > 1.5 x ULN at a single visit (scheduled 
or unscheduled). 
After discontinuation from randomized withdrawal, or at the end of the randomized withdrawal 
period (Week 34), whichever comes first, the patient resumes open-label LCI699 at a dose 
selected by the investigator. 
Patients who are discontinued from the study for reasons other than those described above 
during the randomized withdrawal period are no longer in the study, and consequently they are 
not permitted to receive open-label LCI699 and cannot move forward to Study Period 4. 
4.1.3.7 
Monitoring and dosing guidelines on resuming open-label LCI699 
Patients that are discontinued from randomized withdrawal due to lack of efficacy as described 
in Section 4.1.3.6, will resume open-label LCI699 at the time of discontinuation, which will 
typically occur before Week 34. Patients that are not discontinued during randomized 
withdrawal will resume open-label LCI699 at the end of randomized withdrawal (Week 34) and 
thereafter (Study Period 4). 
Precaution 
The investigator is advised to monitor patients closely upon resuming open-label LCI699, 
which may occur either during the randomized withdrawal period (if the patient is discontinued 
from randomized withdrawal), or at Week 34 (if the patent was not discontinued from 
randomized withdrawal). Week 34 is the time of entry into Study Period 4. Some patients may 
experience a period of instability with respect to UFC levels and symptoms. In particular, 
patients with uncontrolled UFC may experience glucocorticoid withdrawal syndrome if UFC is 
reduced (corrected) too rapidly. Unscheduled visits are permitted as often as needed until UFC 
stabilizes. In addition, local laboratory results may be used to guide treatment decisions, but all 
UFC tests must be sent to the central laboratory for later confirmation. This is the only time 
during the study in which local laboratory results can be used for LCI699 dose decisions. 


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Upon resuming open-label LCI699, the investigator has the discretion to select the dose, and is 
advised to consider the following guidelines: 
 Patients with a normal UFC during randomized withdrawal should resume the same dose 
of study drug on re-starting open-label LCI699. 
 Patients with uncontrolled UFC that were discontinued from randomized withdrawal are at 
increased risk of developing glucocorticoid withdrawal syndrome. 
 LCI699 could be prescribed at the same dose that was used at Week 26 
 Alternatively, LCI699 could be prescribed at a lower dose than the one used at Week 
26, to reduce the risk of glucocorticoid withdrawal syndrome. With this strategy, it is 
expected that the dose will need to be titrated upward. 
 It is not recommended to prescribe a dose higher than was used at Week 26, because 
there may be an excess risk of glucocorticoid withdrawal syndrome, hypocortisolism 
or adrenal insufficiency. 
 Patients whose dose was reduced for safety reasons during the randomized withdrawal 
period should resume the reduced dose of study drug on re-starting LCI699. 
 Patients with temporary interruption of study drug for safety reasons during randomized 
withdrawal that has resolved by Week 34 are advised to continue the same dose they were 
receiving at week 34. 
 Patients with dose interruption for safety that remains ongoing at week 34 may resume 
open-label LCI699 at the investigator’s discretion, if the patient is expected to remain on 
study. 
At the time of discontinuation from randomized withdrawal due to uncontrolled UFC, or at the 
end of the randomized withdrawal period (Week 34), whichever occurs first, patients that were 
randomized to placebo will automatically be crossed-over to open-label LCI699, while patients 
randomized to LCI699 will remain on LCI699, but in an open-label fashion. 
4.1.3.8 
Complete response and primary endpoint assessment 
In order for a patient to be assessed as a complete responder at Week 34, all of the following 
conditions must be met: 
 mUFC ≤ ULN at Week 34 
 Patient was not discontinued during the randomized withdrawal period 
The primary endpoint is assessed on the basis of mUFC results at the end of the randomized 
withdrawal period (Week 34) for all randomized patients. The endpoint compares the complete 
response rate (proportion of patients with mUFC ≤ ULN) at the end of 8 weeks of randomized 
withdrawal (at Week 34) between patients randomized to continued LCI699 therapy vs. 
placebo. Patients who are discontinued during the randomized withdrawal period are not 
considered complete responders. 
4.1.4 
Study Period 4 
Study Period 4 is a single-arm, open-label therapy (Week 35 to Week 48). At the end of Week 
34, all patients receive open-label LCI699 treatment. The investigator has the discretion to 
select the dose during this period and is advised to consider the guidelines mentioned in Section 


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4.1.3.7. Once the patient is on open-label LCI699, the dose may remain unchanged, increased, 
decreased or withheld, depending on the mUFC level, and whether or not there is an AE 
requiring temporary interruption of study drug. Particularly during the first few weeks of open-
label LCI699 treatment (after randomized withdrawal), patients may have unscheduled visits if 
they report symptoms of continuing hypercortisolism, glucocorticoid withdrawal, 
hypocortisolism, or any adverse event. 
Dose adjustments may be managed via a phone call or via an unscheduled visit at the site. Please 
refer to Section 6.1.1 for details. 
Patients continue open-label therapy until Week 48. At Week 48, patients have the option to 
enter an extension period or discontinue LCI699 at week 48 to conclude with an end of core 
study visit 4 weeks off study drug (at Week 52). 
4.1.5 
Optional Extension Period 
Patients who continue to receive clinical benefit, as assessed by the study investigator and who 
wish to enter the extension period must be re-consented at week 48. Patients who enter the 
extension period will do so without interruption of study drug or assessments. The optional 
extension period will end 16 months after all patients have completed Week 72 or have 
discontinued early (prior to Week 72). 
Study CLCI699C2301 ends when all ongoing patients have transitioned to the long-term safety 
follow-up study or have been offered local alternative treatment options; this period will not 
exceed 16 months after all ongoing patients have completed Week 72. Patients who continue to 
benefit from treatment and have completed Week 72 will be offered participation in a separate 
long-term safety follow-up study after the database lock of the core period is completed.  
If the long-term safety follow-up study is opened at site, patients should transition to the long-
term safety follow-up study within 2 months from the initiation visit of the study. If this option 
is not available, the patient can be offered a local alternative treatment option and should 
transition within 2 months of the option being available at site; if no local alternative treatment 
option is available, the patient can stay in the study until the study end (i.e. 16 months after the 
last patient completes Week 72). Patients entering the long-term safety follow-up study will 
complete an EOT visit. For these patients, the EOS visit is not applicable, as treatment on 
LCI699 will not be interrupted. Patients not entering the long-term safety follow-up study will 
complete an EOT visit, and an EOS visit 30 days after the last dose administration. 
Dose adjustments if needed after Week 72 during extension period will have to be managed via 
a scheduled or an unscheduled visit at the site. 
4.1.6 
Escape 
Escape is defined as loss of control of UFC after prior UFC normalization in patients who have 
completed the dose titration period (Period 1). The following criteria have to be met: 
 prior normalization of mUFC has occurred (mUFC≤ULN) 
 both the mean UFC and at least 2 individual values contributing to that mUFC have to be 
>1.5 x ULN 
 the escape is not related to a dose interruption or dose reduction due to safety reasons 


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Patients that are randomized to placebo will not be assessed for escape. 
4.1.7 
Schematic diagram of core study design 
A schematic diagram of the core study design is shown below in Figure 4-3; the optional 
extension part of the study starting at Week 48 is not represented: 
Figure 4-3 
Schematic of core study design 
 
4.2 
Timing of interim analyses and design adaptations 
The study will have no interim efficacy analysis. The Steering Committee (SC) will conduct 
interim safety analyses as detailed in Section 8.7, the SC Charter and SC Report and Analysis 
Plan. 
4.3 
Definition of end of the study 
Completion of the study as a whole (last patient last visit) will occur after all patients have 
completed all assessments as per Table 7-1 to Table 7-3 (core phase), Table 7-4 and Table 7-5 
(extension phase) or have discontinued early. Study CLCI699C2301 ends when seamless 
transition to the long-term safety follow-up study is possible or alternative treatment options 
are available; this period will not exceed 16 months after all patients have completed Week 72 
or have discontinued early (prior to Week 72). Refer to Section 6.1.5 for details. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient will be contacted by the investigator or his/her designee. The patient should be seen 
as soon as possible and the same assessments should be performed as described in Section 7 for 


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a discontinued or prematurely withdrawn patient. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the patient’s interests. The investigator will be responsible for informing IRBs 
and/or ECs of the early termination of the trial. 
5 
Population 
5.1 
Patient population 
The study population will be comprised of approximately 132 adult male and female patients 
with Cushing’s disease who have persistent or recurrent hypercortisolism after primary pituitary 
surgery and/or irradiation, and patients with de novo Cushing’s disease who are not surgical 
candidates for medical reasons, or refuse to undergo surgery. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
Eligibility criteria for entering the randomized withdrawal period are described in Section 4.1. 
5.2 
Inclusion criteria 
Patients must fulfill all of the following criteria to be eligible for inclusion in this study: 
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: 
a. mUFC > 1.5 x ULN at screening (the mean of three 24-hour urine samples collected 
during screening, after completion of the washout period (if applicable), confirmed by 
the central laboratory and available at Day 1) 
b. Morning plasma ACTH above lower limit of normal 
c. Confirmation of pituitary source of excess ACTH is defined by any of the following 
three criteria: 
1. MRI confirmation of pituitary adenoma > 6 mm; OR 
2. bilateral inferior petrosal sinus sampling (BIPSS) with either CRH or DDAVP 
stimulation for patients with a tumor ≤ 6mm. The criteria for a confirmatory 
BIPSS test are any of the following: 
 Pre-dose central to peripheral ACTH gradient > 2; 
 Post-dose central to peripheral ACTH gradient > 3 after either CRH or DDAVP 
stimulation 
3. histopathologic confirmation of an ACTH-staining adenoma in patients who have 
had prior pituitary surgery. 
4. Patients with a history of prior pituitary surgery must be at least 30 days post-surgery to be 
eligible for inclusion in this study. 


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5. Patients that received glucocorticoid replacement therapy post-operatively must have 
discontinued such therapy for at least one week, or (5 half-lives), whichever is longer, 
prior to screening. 
6. Patients with de novo Cushing’s disease can be included only if they are not considered 
candidates for surgery (e.g., poor surgical candidates, surgically unapproachable tumors, 
patients who refuse to have surgical treatment, or surgical treatment is not available) 
7. Patients with a history of pituitary irradiation can be included, provided that at least 2 
years (stereotactic radiosurgery) or 3 years (conventional radiation) have elapsed from the 
time of last radiation treatment to the time of enrollment into this study. 
8. Patients are permitted to washout current drug therapy to meet these entry criteria if they 
have a known diagnosis of Cushing’s disease. Rescreening can be used as needed to 
ensure washout is complete. The following washout periods must be completed before 
baseline efficacy assessments are performed: 
a. Steroidogenesis inhibitors (ketoconazole, metyrapone): 1 week 
b. Pasireotide s.c. (immediate release formulation): 1 week 
c. Dopamine agonists (e.g., cabergoline), or PPAR-gamma agonists (e.g., rosiglitazone, 
pioglitazone): 4 weeks 
d. Mifepristone : 4 weeks 
e. Pasireotide LAR: 8 weeks 
f. Mitotane: 6 months 
5.3 
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 at the time 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 LCI699 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. Patients with risk factors for QTc prolongation or Torsade de Pointes, including: 
 patients with a baseline QTcF > 450ms for males and QTcF > 460ms for females, 
 personal or family history of long QT syndrome, or concomitant medications known 
to prolong the QT interval, 
 hypokalemia, hypocalcaemia, or hypomagnesemia, if not corrected before pre-dose 
Day 1. 
5. Pregnant or nursing (lactating) women. 
6. 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: 


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a. 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. 
b. 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 bilateral oophorectomy, documentation is required (e.g. operative report, 
pelvic ultrasound or other reliable imaging method). 
c. 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. 
d. Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral*, injected, or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
 
*In the case of use of oral contraception, women should have been stable on the same 
pill for a minimum of 3 months before taking study treatment. 
 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
case of bilateral oophorectomy, documentation is required (e.g. operative report, pelvic 
ultrasound or other reliable imaging method). 
7. Patients with compression of the optic chiasm due to a macroadenoma or patients at high 
risk of compression of the optic chiasm (tumor within 2 mm of optic chiasm). 
8. Patients who have a known inherited syndrome as the cause for hormone over secretion 
(i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP). 
9. Patients with Cushing’s syndrome due to ectopic ACTH secretion or ACTH-independent 
(adrenal) Cushing’s syndrome. 
10. Patients who have undergone major surgery within 1 month prior to screening. 
11. Hypertensive patients with uncontrolled blood pressure defined as SBP > 180 and/or DBP 
> 100. 
12. Diabetic patients with poorly controlled diabetes as evidenced by HbA1c > 9 %. 
13. Patients who are not euthyroid as judged by the investigator. 
14. Patients who have a history of: congestive heart failure (NYHA Class III or IV), unstable 
angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced 
heart block, acute MI less than one year prior to study entry, or clinically significant 
impairment in cardiovascular function. 
15. Patients with moderate to severe renal impairment (estimated GFR < 60 mL/min by the 
MDRD formula, or serum creatinine > 2.0 x ULN. 


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16. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent 
hepatitis, or patients with serum ALT/AST > 3 x ULN, or serum total bilirubin > 1.5 x 
ULN. 
17. 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. 
18. Patients who have a history of alcohol or drug abuse in the 6 month period prior to study 
treatment. 
19. Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will be unable to complete the entire study. 
6 
Treatment 
6.1 
Study treatment 
The study treatment consists of LCI699 and matching placebo, in the form of film-coated tablets 
for oral administration, in the following tablet strengths: 1 mg, 5 mg, 10 mg, and (depending on 
availability) 20 mg. Each strength has a unique size, color and imprint (Y1, Y2, Y3 and Y4) on 
each tablet which can be used for specific identification. (Figure 6-1). 
Figure 6-1 
Appearance of LCI699 tablets by strength 
 
 
Each strength of LCI699 (and matching placebo) has a unique size, color and imprint to aid in recognition. The 
appearance of the actual tablets may vary slightly from the photograph. 
 
1 mg: tablets are approximately 6 mm in diameter, with a pale yellow color and Y1 imprint 
 
5 mg tablets are approximately 7 mm diameter, with a yellow color and Y2 imprint 
 
10 mg tablets are approximately 9 mm in diameter, with a pale orange brown color and Y3 imprint and 
 
20 mg tablets are approximately 11 mm in diameter, with a light brown color and Y4 imprint 


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6.1.1 
Dosing regimen 
The dosing regimen of LCI699 in the planned pivotal study will be up-titrated according to the 
following escalation sequence: LCI699 2 mg b.i.d., 5 mg b.i.d., 10 mg b.i.d., 20 mg b.i.d., and 
30 mg b.i.d. The up-titration continues till the mUFC ≤ ULN. The maximum dose of LCI699 
in this study is 30 mg b.i.d. 
Study treatment should be taken twice daily (b.i.d.). For example, a patient on the starting dose 
of 2 mg b.i.d. dose will take two tablets of 1 mg strength in the morning and two tablets of 1 
mg strength in the evening, providing a total daily dose of 4 mg. Study drug should be taken at 
approximately the same time each day, with about 12 hours between each dose administration. 
LCI699 can be dosed without regard to food. If vomiting occurs during the course of treatment, 
patients should not take the study drug again before the next scheduled dose. Patients should be 
instructed not to make up missed doses. 
On study visit days, patients should be reminded to not take the study treatment prior to the site 
visit to ensure compliance with the pre-dose PK sampling procedure. The morning dose on the 
visit days should be taken at the site after the pre-dose PK sampling. 
Triplicate urine samples are collected every two weeks during individual dose titration with the 
last urine sample preferably collected the day prior to the visit at site. 
 The LCI699 dose is increased if the mean of three urine samples (mUFC) is above normal 
(> ULN). 
 The LCI699 dose is maintained if the mUFC value is in the normal range and the patient 
does not have signs or symptoms of hypocortisolism or adrenal insufficiency. 
 The LCI699 dose is reduced if the mUFC value is < LLN or the patient has signs and 
symptoms of hypocortisolism or adrenal insufficiency and the mUFC value is in the lower 
part of the normal range. 
Hypocortisolism or adrenal insufficiency is suspected on the basis of clinical signs/symptoms, 
which may include gastrointestinal symptoms (nausea, vomiting), fatigue, weakness, failure to 
thrive, morning headache, symptoms consistent with hypoglycemia, or dizziness. 
Dose reductions and temporary dose interruptions for safety reasons are permitted at any time 
during the study. For patients that enter the randomized withdrawal period, both the investigator 
and the patient are blinded to the randomized treatment assignment from the time of 
randomization until the time of database lock for the core period of the study. 
If hypocortisolism occurs at 2 mg b.i.d., the dose can be lowered to 1 mg b.i.d. or lower, e.g., 1 
mg q.d. (once a day) or 1mg q.o.d. (every other day), if needed. Any lower dose other than 1 
mg bid is not a standard dose and as mentioned below must be discussed with the sponsor on a 
case-by-case basis before implementation. 
Once the patient’s mUFC is controlled (mUFC ≤ ULN) during the dose titration period, 
intermediate doses (doses other than the standard doses specified in the escalation sequence – 
LCI699 2 mg b.i.d., 5 mg b.i.d., 10 mg b.i.d., 20 mg b.i.d., and 30 mg b.i.d) can be given. In 
such cases the same dose should be used in the a.m. and the p.m., as a b.i.d. regimen, if possible, 
to ensure consistent drug exposure. 
Permitted intermediate dose levels are: 3, 7 and 15 mg b.i.d. 


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Any doses other than one of the standard planned doses for the dose escalation sequence or the 
permitted intermediate doses must be discussed with the sponsor on a case-by-case basis before 
implementation. 
The investigators and other site staff should be aware that the use of non-standard doses 
increases the complexity of dispensing drug to the patient, and self-administration of drug by 
the patient. Increased complexity of self-administration by the patient may increase the risk of 
dosing errors. 
Communication and implementation of dose changes: 
If a dose change is needed, this will typically occur between scheduled visits. The dose change 
should be done as soon as possible after receipt of mUFC results (e.g. ideally within 24 hours). 
Sites should inform patients of the dose change via phone contact or an unscheduled visit prior 
to the next scheduled visit, as noted in Section 4.1.1. 
If the dose adjustment is communicated by telephone: 
 the site must confirm the current dose the patient is taking 
 Instruct the patient on how to administer the new dose, and ensure that the patient has 
adequate supplies at the new dose to last until the next scheduled visit. The dose 
instructions must include the tablet strength(s), number of tablets, and time of day 
administered (morning or evening); this should be done individually for morning and 
evening doses. The patient should repeat back all dosing instructions. 
 The patient should also be questioned on the signs and symptoms of glucocorticoid 
withdrawal/hypocortisolism/adrenal insufficiency and other abnormal signs and symptoms 
with any positive symptom(s) graded for severity and reported as an AE and this should be 
taken into account when making the dose adjustment. 
 All phone communications should be included in the source documents at the site. Also, 
refer to Section 6.3.1 for details on dose modification and dose delay. 
If, in the investigator’s judgment, the patient is not reliable or cannot safely make the dose 
adjustment at home, the patient could return to the site for an unscheduled visit prior to the next 
scheduled visit to receive instructions regarding the dose change under the direct supervision 
of the site staff. 
If the dose is maintained without change, the patient does not need to return to the site until the 
next scheduled study visit. However, it is still recommended that the site contact the patient to: 
confirm the current dose; ask about potential signs and symptoms of hypocortisolism or adrenal 
insufficiency; remind the patient to continue to take the same dose of LCI699. 
At the time of the next study visit, the patient must: 
 Return all unused tablets to the site for drug accountability 
 Receive medication supplies for the new dose as specified by the IRT system if there is no 
dose change needed for safety, together with the next higher and lower standard dose(s). 
The IRT system specifies which study drug bottles (kits) are to be dispensed to the patient. 
It is very important for the site personnel and the patient to be aware that it is possible 
that more than one tablet strength may be dispensed at the same visit. 


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 Receive detailed written instructions on how to administer the new dose and dosing 
schedule. Dose instructions should include the tablet strength, number of tablets to take 
and the time of the day (morning or evening); the instructions should be given individually 
for the morning and evening dose, rather than “twice per day.” Patients should be asked to 
read back all documented instructions to ensure comprehension. Such explicit written 
instructions are particularly important in view of the possibility of cognitive impairment 
and/or mood disorder in the study population. A patient dosing instruction card is 
recommended as a tool to provide the written instructions to allow the patient a means of 
confirming the strength of any study drug tablet by visual inspection, if needed, by 
comparison to photographs of each tablet strength which are on the card. 
It is expected that patients will be seen urgently in an unscheduled visit at the site in the event 
of signs/symptoms of suspected hypocortisolism or adrenal insufficiency or any AE that 
requires study drug interruption with or without glucocorticoid therapy. However, there may be 
occasions in which the patient has been seen at another health care facility, or has called in to 
report symptoms; in these cases, patients should be advised to come to the site as soon as 
possible if it is safe, or go to the nearest hospital emergency room. 
For further details on dosing regimen for each study period, please refer to Section 4.1 
“Description of study design.” 
6.1.2 
Ancillary treatments 
Not applicable. 
6.1.3 
Rescue medication 
Not applicable. 
6.1.4 
Guidelines for continuation of treatment 
LCI699 therapy (or matching placebo) is continued unless it must be interrupted or discontinued 
for safety or other reasons. See Section 6.3 ‘Dose modifications’ for details. 
6.1.5 
Treatment duration 
The treatment duration is 48 weeks in the core phase of the study, and patients will have the 
option to continue treatment in the extension phase; patients who wish to enter the extension 
period must be re-consented at Week 48. The optional extension period will end 16 months 
after all patients have completed Week 72 or discontinued early (prior to Week 72). 
Study CLCI699C2301 ends when all ongoing patients have transitioned to the long-term safety 
follow-up study or have been offered local alternative treatment options; this period will not 
exceed 16 months after all ongoing patients have completed Week 72. Patients who continue to 
benefit from treatment and have completed Week 72 will be offered participation in a separate 
long-term safety follow-up study, after the database lock of the core period is completed. 
If the long-term safety follow-up study is opened at site, patients should transition to the long-
term safety follow-up study within 2 months from the initiation visit of the study. If this option 
is not available, the patient can be offered a local alternative treatment option and should 


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transition within 2 months of the option being available at site; if no local alternative treatment 
option is available, the patient can stay in the study until the study end (i.e. 16 months after the 
last ongoing patient completes Week 72). Patients entering the long-term safety follow-up study 
will complete an EOT visit. For these patients, the EOS visit is not applicable, as treatment on 
LCI699 will not be interrupted. Patients not entering the long-term safety follow-up study will 
complete an EOT visit and an EOS visit 30 days after the last dose administration. 
Patients may be discontinued from treatment with the study drug earlier if unacceptable toxicity 
has been experienced, and/or treatment is discontinued at the discretion of the investigator or 
the patient. 
6.2 
Dose escalation guidelines 
Not Applicable. This is not a dose escalation study. Please refer to Section 6.1.1 for dose 
titration procedure. 
6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
Dose reductions and temporary dose interruptions for safety reasons are permitted at any time 
during the study. Both the investigator and the patient are blinded to the randomized treatment 
assignment during randomized withdrawal from the time of randomization until the time of 
database lock for the core period of the study. Dose reductions may be required for AEs 
suspected to be related to LCI699. 
A unique feature of LCI699 treatment in patients with Cushing’s disease is that regardless of 
suspected drug causality, an AE may require not only interruption of study drug, but also stress 
doses of glucocorticoids until the AE has resolved. 
Please refer to Section 4.1 “Description of study design” and Section 6.1.1 “Dosing regimen” 
for further information about dose and dosing regimen during various periods during the trial. 
Patients with suspected acute, symptomatic hypocortisolism or adrenal insufficiency may 
require emergency unblinding (see Section 8.3) because such an AE is potentially life 
threatening. Unblinding does not apply during the open-label period throughout the trial (for 
patients that are not randomized), or the open-label period from the time of the first dose of 
LCI699 to until the time of randomization (for patients that are randomized). 
Hypocortisolism or adrenal insufficiency is suspected on the basis of clinical signs/symptoms, 
which may include gastrointestinal symptoms (nausea, vomiting), fatigue, weakness, failure to 
thrive, morning headache, symptoms consistent with hypoglycemia, dizziness. When 
hypocortisolism or adrenal insufficiency is suspected, the investigator may order urgent local 
laboratory testing, including serum cortisol to help differentiate glucocorticoid withdrawal 
symptoms from hypocortisolism or adrenal insufficiency. The turnaround time for central 
laboratory results in this circumstance is unacceptably long from a clinical safety viewpoint. 
For patients whose dose needs to be fine-tuned to provide the requested efficacy or are unable 
to tolerate the protocol-specified dosing schedule, dose adjustments to other than standard dose 
levels (2, 5, 10, 20 and 30 mg respectively b.i.d) are permitted in order to keep the patient on 


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study drug. The following guidelines should be followed. These changes must be recorded on 
the Dosage Administration Record CRF. 
Table 6-1 
Dose Modification Guidelines1 for LCI699-suspected toxicities 
Toxicity 
Suggested Actions 
Symptomatic hypocortisolism 
or adrenal insufficiency 
If the investigator at any time suspects hypocortisolism or adrenal insufficiency, 
they can immediately interrupt study drug and initiate replacement with 
glucocorticoids. Emergency un-blinding may be considered if this occurs during 
the double-blind randomized withdrawal period of the study. Upon recovery as 
assessed by the investigator*, glucocorticoid therapy can be tapered as 
tolerated, and study drug can be re-started. The decision to restart study drug 
will be made by the investigator. The AE and associated treatments with 
changes to study drug need to be appropriately documented in the eCRF. 
*Recovery is assessed clinically by the investigator. A general guideline is that 
glucocorticoid taper can begin when mUFC is in the upper part of the normal 
range or > ULN, and study drug can be re-started if the patient is clinically stable 
off glucocorticoid therapy for at least one week, and the mUFC is normal or > 
ULN. 
Persistent asymptomatic 
hypocortisolism (mUFC < 
LLN) at the lowest dose of 
LCI699 (1 mg every other 
day) 
The investigator can interrupt study drug and restart at the same dose as 
clinically indicated. 
Glucocorticoid withdrawal 
syndrome 
Reduce or withhold dose until improved 
*Hypotension (mild, 
reversible) 
Reduce or withhold dose until improved 
*Hypertension 
Reduce or withhold dose until improved; consider ACE inhibitors if appropriate 
for treatment of hypertension, or spironolactone as a second line treatment, 
particularly if hypokalemia is present. ACE inhibitors and spironolactone should 
not be used in combination. 
*Weight gain, edema 
Reduce or withhold dose until improved; consider spironolactone for treatment of 
edema. 
*Hypokalemia 
Consider reducing or withholding dose until improved; replace potassium; 
consider spironolactone or eplerenone for prevention and treatment of 
hypokalemia 
*Hyperkalemia 
Consider reducing or withholding dose until improved; if on spironolactone or 
eplerenone, reduce or withhold; treat with kayexalate and other potassium 
lowering therapies as needed. 
*Hirsutism (women only) 
Reduce or withhold dose until improved; review testosterone level; consider 
spironolactone, cyproterone acetate or finasteride per local guidelines. 
*Acne (women or men) 
Reduce or withhold dose until improved; review testosterone level; consider 
spironolactone, cyproterone acetate or finasteride per local guidelines. 
1The investigator must specify the reduced dose of study drug (LCI699/Placebo) during the randomized 
withdrawal period, and the reduced dose of LCI699 during the open-label periods of the study. 
* Abbreviations: UFC, 24-hour urine free cortisol; ULN, upper limit of the normal reference range; LLN, lower limit 
of the normal reference range. 
In addition, any AE, regardless of suspected drug causality, may require interruption of LCI699 
and replacement or stress doses of glucocorticoid therapy until resolution of the event. 
 Upon recovery from the AE, the investigator may consider re-starting LCI699 if the dose 
interruption has been ≤ 14 days. 


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 If the dose interruption has been > 14 days, then the patient should be observed. If mUFC 
rises to above the ULN, and has been off glucocorticoid therapy for at least one week, 
LCI699 may be re-started. 
If the patient has interruption of LCI699 for more than 4 weeks, the investigator should consider 
early discontinuation from the study. Patients that had interruption of LCI699 and mUFC 
remains ≤ ULN off LCI699 should remain on study for observation. 
These changes must be recorded on the Dosage Administration Record CRF. 
Instructions for monitoring liver function, and the criteria for interrupting, reducing, and re-
initiating study drug therapy, or discontinuation of study drug are provided in Table 6-2 below. 
Table 6-2 
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 
Withhold study drug. Monitor liver function tests (LFT)a 
weekly, or more frequently if clinically indicated, until 
resolved to ≤ 1.5 x ULN: 
If resolved in ≤ 14 days, then maintain dose level 
If resolved in > 14 days, then decrease by one dose level. 
> 3.0 - 10.0 x ULN* 
Withhold study drug. Monitor LFTsa weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x 
ULN: 
If resolved in ≤ 14 days, then 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 returned 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 returned 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 
Withhold 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 treatment 


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> 10.0 x ULN 
Discontinue study drug. Repeat LFTsa as soon as possible, 
preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsa weekly, or more frequently 
if clinically indicated, until resolved to ≤3 x ULN. 
Combined b, c elevations of AST or ALT and total bilirubin 
For patients with normal baseline ALT and AST 
and total bilirubin value: 
AST or ALT >3.0 x ULN combined with total 
bilirubin >2.0 x ULN without evidence of 
cholestasisc 
OR 
For patients with elevated baseline AST or ALT or 
total bilirubin value: 
[AST or ALT>2x baseline AND > 3.0 xULN] OR 
[AST or ALT > 8.0 xULN], combined with [total 
bilirubin >2x baseline AND >2.0 xULN 
 
Permanently discontinue patient from study drug treatment. 
 
Repeat as soon as possible, preferably within 48 hours 
from awareness of the abnormal results, then with weekly 
monitoring of LFTsa), or more frequently if clinically 
indicated, until AST, ALT, or bilirubin have returned to 
baseline or stabilized over 4 weeks. 
Refer to Section 6.3.3 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 (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 treatment at the situation when 
omit dose is needed for one parameter and discontinue treatment 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 (>2xULN and R value (ALT/ALP in x ULN) < 2). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. 
It denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), 
hepatocellular ( R ≥ 5), or mixed (R >2 and < 5) liver injury 
*Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin 
determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator. 
6.3.2 
Follow-up for toxicities 
Please refer to Section 6.3.1 and Section 8.1.3. 
6.3.3 
Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with Total Bilirubin (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] 


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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. 
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 evaluation for 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. 
 Obtain PK sample, as close as possible to last dose of study drug 
 Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented. 
6.3.4 
Anticipated risks and safety concerns of the study drug 
Anticipated drug-related risks are summarized in Section 2.7. Many of the safety concerns and 
recommendations for actions are reviewed in Section 6.3.1 “Dose modification and dose delay.” 
Additional anticipated risks are summarized in Section 8.1.3 “Adverse events of special 
interest.” Two of these AEs are described in greater detail: the potential for QT prolongation 
(Section 8.1.3.1), and glucocorticoid withdrawal, hypocortisolism or adrenal insufficiency 
(Section 8.1.3.2). Recommendations for QT prolongation monitoring and management are 
provided in Section 7.2.2.7. Other AEs of special interest for LCI699 (either reported or 
anticipated based on the mechanism of action of the drug) include: cardiac arrhythmia, 
corticotroph tumor progression (Nelson’s syndrome) and potential associated symptoms (visual 
field loss, cranial nerve palsy, diplopia, and hyperpigmentation); these particular AEs may 
require premature discontinuation from the study. 
For a comprehensive review of safety, see the [Investigator’s Brochure]. 


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6.4 
Concomitant medications 
Stable doses of concomitant medications (except those for hypercortisolism) are allowed during 
the study. All pre-existing concomitant medications should be recorded at study start. The 
investigator should instruct the patient to notify the study site about any new medications he/she 
takes after the start of the study. All medications and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the patient signs the informed 
consent must be listed on the Concomitant medications/Significant non-drug therapies after 
start of study CRF. 
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 CRF. Medication entries should be 
specific to trade name, the single dose and unit, the frequency and route of administration, the 
start and discontinuation dates and the reason for therapy. 
All concomitant medications received during the study should be reported on the CRF, and 
include the drug name (specific trade name), the single dose and unit, the frequency and route 
of administration, start and discontinuation dates and the reason for therapy. Medications used 
for the treatment of hypertension, diabetes or impaired glucose tolerance, and hyperlipidemia, 
in particular, require this detailed information as part of the efficacy assessment. 
6.4.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications 
CRF. Spironolactone and eplerenone are permitted for the treatment or prevention of study 
drug-related edema or hypokalemia. The use of these drugs should be done with close 
monitoring for the potential risk of severe hyperkalemia, which is further increased if renal 
insufficiency is present. 
Spironolactone, cyproterone acetate or finasteride for treatment of hirsutism are approved in 
some countries and are not prohibited. 
Medications that are metabolized by CYP450 enzymes 
In vitro drug metabolism studies show that LCI699 is a potential inhibitor of CYP1A2, 
CYP2C19, CYP2D6, CYP3A4/5 and CYP2E1, and may consequently increase exposure to 
drugs metabolized by this enzyme. 
In a clinical DDI study, LCI699 was found to be a moderate inhibitor of CYP1A2 (2.5-fold 
increase in substrate exposure), a weak to moderate inhibitor of CYP2C19 (1.9-fold increase in 
substrate exposure), and a weak inhibitor of CYP2D6 and CYP3A4/5 (1.5-fold increase in 
substrate exposure). Therefore concomitant medications that are known substrates of these 
enzymes (see Appendix 2) should be used with caution. 


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The patient and the Investigator should be aware of potential signs of overdose of the 
concomitant medication and in the event of suspected toxicities; administration of either the 
substrate or LCI699 should be discontinued according to Investigators’ judgment 
6.4.2 
Prohibited concomitant therapy 
Use of the following concomitant medication is prohibited during the study: 
 Other drug treatments for Cushing’s disease; 
 Medications with a “known risk to cause Torsades des Pointes (TdP)” and “possible risk 
to cause TdP”; 
 Eplerenone and glucocorticoids, except under certain conditions: 
 Eplerenone may be used if necessary in acute post-myocardial infarction 
management, and in the event of refractory hypokalemia in patients with hypertension 
or edema; glucocorticoids may be used as required for the short-term treatment of 
hypocortisolism or adrenal insufficiency. 
 Glucocorticoids (e.g., prednisone, prednisolone, and dexamethasone) may be used as 
required for the short-term treatment of hypocortisolism or adrenal insufficiency. If 
glucocorticoids are used in stress doses, or as replacement therapy, for > 4 weeks, 
then the investigator should consider temporary interruption of LCI699, weaning and 
discontinuation of glucocorticoid therapy, or early discontinuation from the study. 
6.4.2.1 
Concomitant medications with a “Known risk to cause TdP” and with 
a “Possible risk to cause TdP”. 
Preclinical and clinical data indicate that there is a risk of QTc prolongation in humans (see 
Section 8.1.3.1). Therefore, the use of medications with a “known risk to cause TdP” and with 
a “possible risk to cause TdP” concomitantly with LCI699 is prohibited. 
If a patient requires a long-term medication from the two categories mentioned above, and there 
is no appropriate alternative medication available, 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 treatment may be interrupted temporarily while this drug is 
administered after a thorough risk-benefit assessment. This does not require the patient to 
discontinue from the study prematurely. Washout periods for 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. 
Please refer to Appendix 3 for an e-link to a list of medications that have a “known risk to cause 
TdP” and “possible risk to cause TdP”. Investigators are advised to utilize this website when 
considering the addition of a new concomitant medication, as the lists are periodically updated. 
If necessary, a discussion can be held with the Novartis Medical Monitor when considering the 
use of medications with a “known risk to cause TdP” and with a “possible risk to cause TdP” 


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6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each 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. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient No. must 
not be reused for any other patient and the Patient No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized or start treatment for any 
reason, the reason will be entered into the Screening Log page. 
IRT must be notified within 2 days that the patient was not randomized. 
6.5.2 
Treatment assignment or randomization 
At week 26, and based upon the mUFC results from the Week 24 assessment, and the LCI699 
dose at week 26 compared to week 12, patients will either: 
 Not be randomized, and continue LCI699 treatment according to the schedule in Table 7-
3. 
 Be randomized to one of the two treatment assignments (LCI699 or placebo) in a 1:1 ratio 
(Section 4.1 and Section 6.1). 
Randomization will be stratified by LCI699 dose at Week 24 (≤ 5mg b.i.d. vs. > 5mg b.i.d.); 
and history of pituitary irradiation (yes/no). 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization list 
will be produced by or under the responsibility of Novartis Global Clinical Supply  using a 
validated system that automates the random assignment of medication numbers to medication 
packs containing each of the study treatments. 
Prior to dosing on Week 26, all patients who fulfill mUFC criteria will be randomized via IRT 
to one of the treatment arms. The investigator or his/her delegate will call or log on to the IRT 
and confirm that the patient fulfills mUFC criteria. The IRT will assign a randomization number 
to the patient, which will be used to link the patient to a treatment arm and will specify a unique 
medication number for the first package of study treatment to be dispensed to the patient. The 
randomization number will not be communicated to the caller. 


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The randomization scheme for patients will be reviewed and approved by a member of the 
Biostatistics Quality Assurance Group. Specific instructions for IRT will be provided separately 
to each study site. 
6.5.3 
Treatment blinding 
Patients, investigators, site personnel, and the Novartis Clinical Trial Team (except GCS, the 
bioanalyst and the bioanalytical study monitor) will remain blinded to the identity of the 
randomized treatment assignments from the time of randomization (Week 26) until database 
lock, using the following methods: (1) randomization data are kept strictly confidential until the 
time of treatment unblinding. (2) the identity of the randomized treatment assignments will be 
concealed by the use of matching placebo during the randomized withdrawal period. The 
matching placebo is identical in packaging, labeling, schedule of administration, and 
appearance (color, size, and weight). Novartis Global Clinical Supply department members will 
be unblinded in order to prepare the study drug supplies. 
Unblinding before database lock will only occur in the case of emergencies (Section 8.3 
“Emergency unblinding”). 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF. 
Patients may be dispensed bottles of more than one tablet strength at the same visit. For 
example, at Visit 2, when the patient is on 2 mg b.i.d dose level, the patient would be provided 
with bottles of 1 mg and 5 mg tablet strengths to cover for the current dose level, any dose 
decrease in case of safety concerns and any up-titration to 5 mg b.i.d. Consequently, to ensure 
patient safety, it is very important that site staff educate the patient on how to recognize the 
tablet strength dispensed at each visit, both on the bottle labels, and by the appearance of tablets 
by tablet strength. 
Also, refer to Section 6.1.1 for details on dosing regimen, communication and implementation 
of dose changes 
Table 6-3 
Preparation and dispensing 
Study treatments 
Dispensing 
Preparation 
LCI699 or placebo 
(1 mg, 5 mg, 10 mg 
and (depending on 
availability) 20 mg) 
Tablets including instructions for administration are dispensed by 
study personnel on an outpatient basis. 
Patients will be provided with adequate supply of study treatment for 
self-administration at home until at least their next scheduled study 
visit (including any dose increase required in between visits). More 
than one tablet strength may be dispensed to patients at the 
same visit. 
Not applicable 
6.6.1 
Study drug packaging and labeling 
LCI699/placebo will be supplied as 1 mg, 5 mg, 10 mg and (depending on availability) 20 mg 
film coated tablets, and will be given orally twice a day. 


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The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms and a [specific visit or 
dose/dose level]. Responsible site personnel will identify the study treatment package(s) to 
dispense to the patient by using the IRT and obtaining the medication number(s). Site personnel 
will add the patient number on the label. Immediately before dispensing the package to the 
patient, site personnel will detach the outer part of the label from the packaging and affix it to 
the source document (Drug Label Form) for that patient’s unique patient number. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the patient. 
Table 6-4 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
LCI699 or placebo 
(1 mg, 5 mg, 10 mg and (depending 
on availability) 20 mg) 
Tablets in bottles 
LCI699, LCI699/Placebo (b.i.d.) 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [Investigator’s Brochure]. 
Table 6-5 
Supply and storage of study treatment 
Study treatments 
Supply 
Storage 
LCI699 or placebo 
Centrally supplied by Novartis 
Refer to study treatment label 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
using tablets counts and information provided by the patient and/or caregiver will be captured 
in the Drug Accountability Form. This information must be captured in the source document at 
each patient visit. 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 


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accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.6.3.3 
Handling of other study treatment 
Not applicable. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1, Table 7-2, Table 7-3, Table 7-4, Table 7-5 list all of the assessments and indicates 
with an “X”, the visits when they are performed. All data obtained from these assessments must 
be supported in the patient’s source documentation. The table indicates which assessments 
produce data to be entered into the database (D) or remain in source documents only (S) 
(“Category” column). 
Table 7-6, Table 7-7, Table 7-8, Table 7-9, Table 7-10, Table 7-11, Table 7-12, Table 7-14 and 
Table 7-15 list all of the assessments required for the collection plan for Imaging and Disease 
Assessment, Clinical Laboratory parameters, ECG, PK samples, 
. 
Patients who discontinue study treatment before visit 777 (if patient is in the core phase of the 
study) or 778 (if patient is in any year of the extension phase of the study), should be scheduled 
for a visit as soon as possible, at which time all of the assessments listed for the EOT visit will 
be performed. 


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Table 7-1 
Visit evaluation schedule – Dose escalation and treatment periods 
 
Category 
Protocol 
Section 
Screening 
Baseline 
Dose escalation period 
EOT 
titration 
Treatment period 
Visit Number 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
775 
10 
11 
12 
Day 
 
 
-35 to -8 
-7 to -1 
1 
15 
29 
43 
57 
71 
85 
 
113 
141 
169 
week 
 
 
-5 to -2 
-1 
0 
2 
4 
6 
8 
10 
12 
 
16 
20 
24 
Obtain Informed consent 
D 
7.1.1. 
x 
 
 
 
 
 
 
 
 
 
 
 
 
IWRS/IRT 
S 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Patient history 
Demography 
D 
7.1.1.3. 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
D 
5.2, 5.3 & 
7.1.1 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history/Current 
medical conditions 
D 
7.1.1.3. 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Cushing's Disease history/prior therapy 
D 
7.1.1.3. 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medication 
D 
7.1.1.3. 
As required 
Physical examination 
S 
7.2.2.1. 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Body height 
D 
7.2.2.3. 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
D 
7.2.2.3. 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Waist circumference 
D 
7.2.2.3. 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Vital signs 
Body temperature 
D 
7.2.2.2. 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Blood pressure/Pulse rate 
D 
7.2.2.2. 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1. 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
Chemistry - full 
D 
7.2.2.4.2. 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
Chemistry - partial 
D 
7.2.2.4.2. 
 
 
 
x 
 
x 
 
x 
 
 
 
 
 
Thyroid Panel 
D 
7.2.2.4.5. 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 


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Category 
Protocol 
Section 
Screening 
Baseline 
Dose escalation period 
EOT 
titration 
Treatment period 
Visit Number 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
775 
10 
11 
12 
Day 
 
 
-35 to -8 
-7 to -1 
1 
15 
29 
43 
57 
71 
85 
 
113 
141 
169 
week 
 
 
-5 to -2 
-1 
0 
2 
4 
6 
8 
10 
12 
 
16 
20 
24 
Luteinizing Hormone (LH) and Follicle 
stimulating hormone (FSH) 
D 
7.2.2.4.6. 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
Coagulation 
D 
7.2.2.4.4. 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
Urinalysis 
D 
7.2.2.4.3. 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Pregnancy test (serum) 
D 
7.2.2.4.8. 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) 
D 
7.2.2.4.8. 
 
 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Efficacy Assessment 
24-hour Urinary Free Cortisol and 
creatinine 
D 
7.2.1.1. 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Serum testosterone and estradiol 
D 
7.2.2.4.6. 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
Serum Androstenedione, DHEAS, 
Estrone 
D 
7.2.2.4.6. 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
Plasma ACTH, serum cortisol 
D 
7.2.2.4.6. 
 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Serum 11-deoxycortisol 
D 
7.2.2.4.6. 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
Serum aldosterone 
D 
7.2.2.4.6. 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
Renin 
D 
7.2.2.4.6. 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
Serum11-Deoxycorticosterone 
D 
7.2.2.4.6. 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
Fasting serum Insulin and plasma 
glucose 
D 
7.2.2.4.7. 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
HbA1C 
D 
7.2.2.4.7. 
x 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Safety 
Adverse Events 
D 
8.1. 
As required 
12 Lead safety ECG assessment 
D 
7.2.2.6.2. 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
12-Lead 24-hour Holter ECG recording 
D 
7.2.2.6.1. 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 


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Category 
Protocol 
Section 
Screening 
Baseline 
Dose escalation period 
EOT 
titration 
Treatment period 
Visit Number 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
775 
10 
11 
12 
Day 
 
 
-35 to -8 
-7 to -1 
1 
15 
29 
43 
57 
71 
85 
 
113 
141 
169 
week 
 
 
-5 to -2 
-1 
0 
2 
4 
6 
8 
10 
12 
 
16 
20 
24 
Pituitary MRI (or CT) 
D 
7.2.2.5. 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Photography 
D 
7.2.1.2. 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
DXA scan 
D 
7.2.1.3. 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
HRQoL EQ-5D-5L, CushingQoL, Beck 
Depression Inventory 
D 
7.2.6. 
 
x 
 
 
x 
 
x 
 
x 
 
 
 
x 
Study Drug administration 
D 
6.1.1. 
 
 
continuous b.i.d. dosing 
PK sampling 
D 
7.2.3. 
 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Serum cortisol, salivary cortisol, plasma 
ACTH (China subset) 
D 
7.2.2.4.6. 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Serum cortisol (Extensive PK subset) 
D 
7.2.2.4.6. 
 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
End of treatment titration form 
D 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 


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Table 7-2 
Visit evaluation schedule – Randomized withdrawal and open label period for randomized patients 
 
Category 
Protocol 
Section 
Randomized Withdrawal 
period 
EOT 
randomized 
withdrawal 
period 
Open Label 
period 
EOT 
core 
Study 
completion 
Visit Number 
 
 
13 
14 
15 
16 
17 
776 
18 
19 
20 
777 
779 
Day 
 
 
183 
197 
211 
225 
239 
 
253 
281 
309 
337 
30 days from 
last dose 
week 
 
 
26 
28 
30 
32 
34 
 
36 
40 
44 
48 
IWRS/IRT 
S 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Prior/concomitant medication 
D 
7.1.1.3. 
As required 
IWRS/IRT Randomization 
S 
 
x 
 
 
 
 
 
 
 
 
 
 
Physical examination 
S 
7.2.2.1. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Body weight 
D 
7.2.2.3. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Waist circumference 
D 
7.2.2.3. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Vital signs 
Body temperature 
D 
7.2.2.2. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Blood pressure/Pulse rate 
D 
7.2.2.2. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Chemistry - full 
D 
7.2.2.4.2. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Chemistry - partial 
D 
7.2.2.4.2. 
 
x 
 
x 
 
 
 
 
 
 
 
Thyroid Panel 
D 
7.2.2.4.5. 
 
 
 
 
x 
 
 
 
 
x 
x 
Luteinizing Hormone (LH) and Follicle 
stimulating hormone (FSH) 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Coagulation 
D 
7.2.2.4.4. 
 
 
 
 
 
 
 
 
 
x 
x 
Urinalysis 
D 
7.2.2.4.3. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Pregnancy test (urine) 
D 
7.2.2.4.8. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Efficacy Assessment 
24-hour Urinary Free Cortisol and creatinine 
D 
7.2.1.1. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Serum testosterone and estradiol 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 


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Category 
Protocol 
Section 
Randomized Withdrawal 
period 
EOT 
randomized 
withdrawal 
period 
Open Label 
period 
EOT 
core 
Study 
completion 
Visit Number 
 
 
13 
14 
15 
16 
17 
776 
18 
19 
20 
777 
779 
Day 
 
 
183 
197 
211 
225 
239 
 
253 
281 
309 
337 
30 days from 
last dose 
week 
 
 
26 
28 
30 
32 
34 
 
36 
40 
44 
48 
Serum Androstenedione, DHEAS, Estrone 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Plasma ACTH, serum cortisol 
D 
7.2.2.4.6. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Serum 11-deoxycortisol 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Serum aldosterone 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Renin 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Serum 11-Deoxycorticosterone 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Fasting serum Insulin and plasma glucose 
D 
7.2.2.4.7. 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
HbA1C 
D 
7.2.2.4.7. 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
Safety 
Adverse Events 
D 
8.1. 
As required 
12 Lead safety ECG assessment 
D 
7.2.2.6.2. 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
x 
12-Lead 24-hour Holter ECG recording 
D 
7.2.2.6.1. 
 
 
 
 
 
 
 
 
 
x 
 
Imaging 
Pituitary MRI (or CT) 
D 
7.2.2.5. 
 
 
 
 
 
 
 
 
 
x 
 
Photography 
D 
7.2.1.2. 
 
 
 
 
x 
 
 
 
 
x 
 
DXA scan 
D 
7.2.1.3. 
 
 
 
 
 
 
 
 
 
x 
 
Patient Reported Outcomes 
HRQoL EQ-5D-5L, CushingQoL, Beck 
Depression Inventory 
D 
7.2.6. 
x 
x 
x 
x 
x 
 
 
 
 
x 
 
Study Drug administration 
D 
6.1.1. 
continuous b.i.d. dosing 
 
 
PK sampling 
D 
7.2.3. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 


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Protocol No. CLCI699C2301 
 
 
 
Category 
Protocol 
Section 
Randomized Withdrawal 
period 
EOT 
randomized 
withdrawal 
period 
Open Label 
period 
EOT 
core 
Study 
completion 
Visit Number 
 
 
13 
14 
15 
16 
17 
776 
18 
19 
20 
777 
779 
Day 
 
 
183 
197 
211 
225 
239 
 
253 
281 
309 
337 
30 days from 
last dose 
week 
 
 
26 
28 
30 
32 
34 
 
36 
40 
44 
48 
Serum cortisol, salivary cortisol, plasma ACTH 
(China subset) 
D 
7.2.2.4.6. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
Serum cortisol (Extensive PK subset) 
D 
7.2.2.4.6. 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
End of randomized withdrawal period form 
D 
 
 
 
 
 
 
x 
 
 
 
 
 
End of treatment core form 
D 
 
 
 
 
 
 
 
 
 
 
x 
 
End of study form 
D 
 
 
 
 
 
 
 
 
 
 
 
x 


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Protocol No. CLCI699C2301 
 
 
Table 7-3 
Visit evaluation schedule – Randomized withdrawal and open label period for non randomized patients 
 
Category 
Protocol 
Section 
Randomized Withdrawal 
period 
EOT 
randomized 
withdrawal 
period 
Open Label 
period 
EOT 
core 
Study 
completion 
Visit Number 
 
 
13 
14 
15 
16 
17 
776 
18 
19 
20 
777 
779 
Day 
 
 
183 
197 
211 
225 
239 
 
253 
281 
309 
337 
30 days from 
last dose 
week 
 
 
26 
28 
30 
32 
34 
 
36 
40 
44 
48 
IWRS/IRT 
S 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Prior/concomitant medication 
D 
7.1.1.3. 
As required 
IWRS/IRT Randomization 
D 
 
x 
 
 
 
 
 
 
 
 
 
 
Physical examination 
S 
7.2.2.1. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Body weight 
D 
7.2.2.3. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Waist circumference 
D 
7.2.2.3. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Vital signs 
Body temperature 
D 
7.2.2.2. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Blood pressure/Pulse rate 
D 
7.2.2.2. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Chemistry - full 
D 
7.2.2.4.2. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Thyroid Panel 
D 
7.2.2.4.5. 
 
 
 
 
x 
 
 
 
 
x 
x 
Luteinizing Hormone (LH) and Follicle stimulating 
hormone (FSH) 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Coagulation 
D 
7.2.2.4.4. 
 
 
 
 
 
 
 
 
 
x 
x 
Urinalysis 
D 
7.2.2.4.3. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Pregnancy test (urine) 
D 
7.2.2.4.8. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Efficacy Assessment 
24-hour Urinary Free Cortisol and creatinine 
D 
7.2.1.1. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Serum testosterone and estradiol 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Serum Androstenedione, DHEAS, Estrone 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 


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Protocol No. CLCI699C2301 
 
 
 
Category 
Protocol 
Section 
Randomized Withdrawal 
period 
EOT 
randomized 
withdrawal 
period 
Open Label 
period 
EOT 
core 
Study 
completion 
Visit Number 
 
 
13 
14 
15 
16 
17 
776 
18 
19 
20 
777 
779 
Day 
 
 
183 
197 
211 
225 
239 
 
253 
281 
309 
337 
30 days from 
last dose 
week 
 
 
26 
28 
30 
32 
34 
 
36 
40 
44 
48 
Plasma ACTH, serum cortisol 
D 
7.2.2.4.6. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Serum 11-deoxycortisol 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Serum aldosterone 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Renin 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Serum 11-Deoxycorticosterone 
D 
7.2.2.4.6. 
 
 
 
 
x 
 
 
 
 
x 
x 
Fasting serum Insulin and plasma glucose 
D 
7.2.2.4.7. 
 
 
 
 
x 
 
 
 
 
x 
x 
HbA1C 
D 
7.2.2.4.7. 
 
 
 
 
x 
 
 
 
 
x 
x 
Safety 
Adverse Events 
D 
8.1. 
As required 
12 Lead safety ECG assessment 
D 
7.2.2.6.2. 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
12-Lead 24-hour Holter ECG recording 
D 
7.2.2.6.1. 
 
 
 
 
 
 
 
 
 
x 
 
Imaging 
Pituitary MRI (or CT) 
D 
7.2.2.5. 
 
 
 
 
 
 
 
 
 
x 
 
Photography 
D 
7.2.1.2. 
 
 
 
 
x 
 
 
 
 
x 
 
DXA scan 
D 
7.2.1.3. 
 
 
 
 
 
 
 
 
 
x 
 
Patient Reported Outcomes 
HRQoL EQ-5D-5L, CushingQoL, Beck 
Depression Inventory 
D 
7.2.6. 
x 
 
x 
 
x 
 
 
 
 
x 
 
Study Drug administration 
D 
6.1.1. 
continuous b.i.d. dosing 
 
 
PK sampling 
D 
7.2.3. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
 
Serum cortisol, salivary cortisol, plasma ACTH 
(China subset) 
D 
7.2.2.4.6. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
 


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Protocol No. CLCI699C2301 
 
 
 
Category 
Protocol 
Section 
Randomized Withdrawal 
period 
EOT 
randomized 
withdrawal 
period 
Open Label 
period 
EOT 
core 
Study 
completion 
Visit Number 
 
 
13 
14 
15 
16 
17 
776 
18 
19 
20 
777 
779 
Day 
 
 
183 
197 
211 
225 
239 
 
253 
281 
309 
337 
30 days from 
last dose 
week 
 
 
26 
28 
30 
32 
34 
 
36 
40 
44 
48 
Serum cortisol (Extensive PK subset) 
D 
7.2.2.4.6. 
x 
 
x 
 
x 
 
x 
x 
x 
x 
 
End of randomized withdrawal period form 
D 
 
 
 
 
 
 
x 
 
 
 
 
 
End of treatment core form 
D 
 
 
 
 
 
 
 
 
 
 
x 
 
End of study form 
D 
 
 
 
 
 
 
 
 
 
 
 
x 


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Protocol No. CLCI699C2301 
 
 
Table 7-4 
Visit evaluation schedule – Optional Extension period (Year 1) 
 
Category 
Protocol 
Section 
Extension 
Visit Number 
 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
Day 
 
 
337 
365 
393 
421 
449 
477 
505 
589 
673 
week 
 
 
48 
52 
56 
60 
64 
68 
72 
84 
96 
Obtain Informed consent 
S 
 
x 
 
 
 
 
 
 
 
 
IWRS/IRT 
S 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prior/concomitant medication 
D 
7.1.1.3. 
As required 
Physical examination 
S 
7.2.2.1. 
 
x 
x 
x 
x 
x 
x 
x 
x 
Body weight 
D 
7.2.2.3. 
 
x 
x 
x 
x 
x 
x 
x 
x 
Waist circumference 
D 
7.2.2.3. 
 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
Body temperature 
D 
7.2.2.2. 
 
x 
x 
x 
x 
x 
x 
x 
x 
Blood pressure/Pulse rate 
D 
7.2.2.2. 
 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1. 
 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry - full 
D 
7.2.2.4.2. 
 
x 
x 
x 
x 
x 
x 
x 
x 
Thyroid Panel 
D 
7.2.2.4.5. 
 
 
 
x 
 
 
x 
 
x 
Luteinizing Hormone (LH) and Follicle stimulating hormone (FSH) 
D 
7.2.2.4.6. 
 
 
 
x 
 
 
x 
 
x 
Coagulation 
D 
7.2.2.4.4. 
 
 
 
x 
 
 
x 
x 
x 
Urinalysis 
D 
7.2.2.4.3. 
 
 
 
x 
 
 
x 
x 
x 
Pregnancy test (urine) 
D 
7.2.2.4.8. 
 
x 
x 
x 
x 
x 
x 
x 
x 
Efficacy Assessment 
24-hour Urinary Free Cortisol and creatinine 
D 
7.2.1.1. 
 
 
 
x 
 
 
x 
x 
x 
Serum testosterone and estradiol 
D 
7.2.2.4.6. 
 
 
 
x 
 
 
x 
x 
x 
Plasma ACTH, serum cortisol 
D 
7.2.2.4.6. 
 
 
 
x 
 
 
x 
x 
x 
Serum 11-deoxycortisol 
D 
7.2.2.4.6. 
 
 
 
x 
 
 
x 
x 
x 
Serum Androstenedione, DHEAS, Estrone 
D 
7.2.2.4.6. 
 
 
 
x 
 
 
x 
x 
x 


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Protocol No. CLCI699C2301 
 
 
 
Category 
Protocol 
Section 
Extension 
Visit Number 
 
 
21 
22 
23 
24 
25 
26 
27 
28 
29 
Day 
 
 
337 
365 
393 
421 
449 
477 
505 
589 
673 
week 
 
 
48 
52 
56 
60 
64 
68 
72 
84 
96 
Serum aldosterone 
D 
7.2.2.4.6. 
 
 
 
x 
 
 
x 
x 
x 
Renin 
D 
7.2.2.4.6. 
 
 
 
x 
 
 
x 
x 
x 
Serum11-Deoxycorticosterone 
D 
7.2.2.4.6. 
 
 
 
x 
 
 
x 
x 
x 
Fasting serum Insulin and plasma glucose 
D 
7.2.2.4.7. 
 
 
 
x 
 
 
x 
x 
x 
HbA1C 
D 
7.2.2.4.7. 
 
 
 
x 
 
 
x 
x 
x 
Safety 
Adverse Events 
D 
8.1. 
As required 
12 Lead safety ECG assessment 
D 
7.2.2.6.2. 
x 
 
 
x 
 
 
x 
x 
x 
24-hour Holter ECG recording 
D 
7.2.2.6.1. 
 
 
 
 
 
 
x 
 
 
Imaging 
Pituitary MRI (or CT) 
D 
7.2.2.5. 
 
 
 
 
 
 
x 
 
 
Photography 
D 
7.2.1.2. 
 
 
 
 
 
 
x 
 
 
DXA scan 
D 
7.2.1.3. 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
HRQoL EQ-5D-5L, CushingQoL, Beck Depression Inventory 
D 
7.2.6. 
 
 
 
 
 
 
x 
 
x 
Study Drug administration 
D 
6.1.1. 
continuous b.i.d. dosing 


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Protocol No. CLCI699C2301 
 
 
Table 7-5 
Visit evaluation schedule – Optional Extension period (After Year 1) 
 
Category 
Protocol 
Section 
Extension 
EOT Extension 
Study 
completion 
 
Subsequent Visits 
Visit Number 
 
 
30 
31 
32 
33 
34, 35, 36, … 
778 
779 
Day 
 
 
757 
841 
925 
1009 
1093, 1177, 1261, … 
28 days since last visit 
30 days from 
last dose 
week 
 
 
108 
120 
132 
144 
156, 168, 180, … 
4 weeks since last visit 
Obtain Informed consent 
S 
 
 
 
 
 
 
 
 
IWRS/IRT 
S 
 
x 
x 
x 
x 
x 
x 
x 
Prior/concomitant medication 
D 
7.1.1.3. 
As required 
Physical examination 
S 
7.2.2.1. 
x 
x 
x 
x 
x 
x 
x 
Body weight 
D 
7.2.2.3. 
x 
x 
x 
x 
x 
x 
Waist circumference 
D 
7.2.2.3. 
x 
x 
x 
x 
x 
x 
Vital signs 
Body temperature 
D 
7.2.2.2. 
x 
x 
x 
x 
x 
x 
x 
Blood pressure/Pulse rate 
D 
7.2.2.2. 
x 
x 
x 
x 
x 
x 
Laboratory assessments 
Hematology 
D 
7.2.2.4.1. 
x 
x 
x 
x 
Same Extension 
assessments will be 
performed with 
same frequency. 
x 
x 
Chemistry - full 
D 
7.2.2.4.2. 
x 
x 
x 
x 
x 
x 
Thyroid Panel 
D 
7.2.2.4.5. 
 
x 
 
x 
 
x 
Luteinizing Hormone (LH) and Follicle 
stimulating hormone (FSH) 
D 
7.2.2.4.6. 
 
x 
 
x 
 
x 
Coagulation 
D 
7.2.2.4.4. 
x 
x 
x 
x 
x 
x 
Urinalysis 
D 
7.2.2.4.3. 
x 
x 
x 
x 
x 
x 
Pregnancy test (urine) 
D 
7.2.2.4.8. 
x 
x 
x 
x 
x 
x 


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Protocol No. CLCI699C2301 
 
 
 
Category 
Protocol 
Section 
Extension 
EOT Extension 
Study 
completion 
 
Subsequent Visits 
Visit Number 
 
 
30 
31 
32 
33 
34, 35, 36, … 
778 
779 
Day 
 
 
757 
841 
925 
1009 
1093, 1177, 1261, … 
28 days since last visit 
30 days from 
last dose 
week 
 
 
108 
120 
132 
144 
156, 168, 180, … 
4 weeks since last visit 
Efficacy Assessment 
24-hour Urinary Free Cortisol and creatinine 
D 
7.2.1.1. 
x 
x 
x 
x 
Same Extension 
assessments will be 
performed with 
same frequency. 
x 
x 
Serum testosterone and estradiol 
D 
7.2.2.4.6. 
 
x 
 
x 
x 
x 
Plasma ACTH, serum cortisol 
D 
7.2.2.4.6. 
x 
x 
x 
x 
x 
x 
Serum 11-deoxycortisol 
D 
7.2.2.4.6. 
 
x 
 
x 
 
x 
Serum Androstenedione, DHEAS, Estrone 
D 
7.2.2.4.6. 
 
x 
 
x 
 
x 
Serum aldosterone 
D 
7.2.2.4.6. 
 
x 
 
x 
 
x 
Renin 
D 
7.2.2.4.6. 
 
x 
 
x 
 
x 
Serum11-Deoxycorticosterone 
D 
7.2.2.4.6. 
x 
x 
x 
x 
 
x 
Fasting serum Insulin and plasma glucose 
D 
7.2.2.4.7. 
 
x 
 
x 
 
x 
HbA1C 
D 
7.2.2.4.7. 
 
x 
 
x 
 
x 
Safety 
Adverse Events 
D 
8.1. 
As required 
12 Lead safety ECG assessment 
D 
7.2.2.6.2. 
x 
x 
x 
x 
Same Extension 
assessments will be 
performed with 
same frequency. 
x 
x 
24-hour Holter ECG recording 
D 
7.2.2.6.1. 
 
x 
 
 
x 
 
Imaging 
Pituitary MRI (or CT) 
D 
7.2.2.5. 
 
x 
 
 
Same Extension 
assessments will be 
performed with 
same frequency. 
x 
 
Photography 
D 
7.2.1.2. 
 
 
 
 
x 
 
DXA scan 
D 
7.2.1.3. 
 
 
 
 
x 
 


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Protocol No. CLCI699C2301 
 
 
 
Category 
Protocol 
Section 
Extension 
EOT Extension 
Study 
completion 
 
Subsequent Visits 
Visit Number 
 
 
30 
31 
32 
33 
34, 35, 36, … 
778 
779 
Day 
 
 
757 
841 
925 
1009 
1093, 1177, 1261, … 
28 days since last visit 
30 days from 
last dose 
week 
 
 
108 
120 
132 
144 
156, 168, 180, … 
4 weeks since last visit 
Patient Reported Outcomes 
HRQoL EQ-5D-5L, CushingQoL, Beck 
Depression Inventory 
D 
7.2.6. 
 
 
 
 
 
x 
 
Study Drug administration 
D 
6.1.1. 
continuous b.i.d. dosing 
 
 
End of treatment extension form 
D 
 
 
 
x 
 
End of study form 
D 
 
 
 
 
x 


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Protocol No. CLCI699C2301 
 
 
7.1.1 
Screening 
Written main informed consent must be obtained before any study specific assessments are 
performed. 
The screening assessments must be performed within 35 days before planned patient’s 
eligibility confirmation and before the start of the first study drug dose of LCI699 at day 1. 
For patients who are on a medication requiring a >4 week washout, consideration can be given 
to switching them to a medication with a shorter washout (1 week) until the last part of the 
washout. 
Based on the central laboratory turnaround time, it is highly recommended to send the three 24-
hour Urinary Free Cortisol samples to the central Laboratory at least 14 days prior to day 1 in 
order to ensure that sufficient time is allowed for central laboratory results to become available. 
Eligibility is assessed based on the screening results only collected at the screening visit, unless 
specified otherwise as per the Inclusion/Exclusion criteria. For details, refer to Section 5.2 and 
Section 5.3. 
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. If the 
repeated laboratory result does not meet the criteria, the patient will be considered a screening 
failure. In this case, the patient will not be required to sign another ICF. 
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed. The rescreening should be documented in the source files and re-
registered in IRT using the same Patient Number. 
If the rescreening occurs within 60 days of the end of the original screening period, the 
following procedures do not have to be repeated: pituitary MRI, photography and DXA scan 
and all other assessments must be repeated. 
If the rescreening occurs more than 60 days after the end of the original screening period, all 
assessments must be repeated. 
An individual patient may only be rescreened once for the study. Once the number of patients 
screened and enrolled is likely to ensure target enrollment, the Sponsor may close the study to 
further screening. In this case the patients who screen failed will not be permitted to re-screen. 
For details of assessments, refer to Table 7-1. 
 
 
7.1.1.1 
Eligibility screening 
While the investigator is responsible to ensure that each patient meets all inclusion/exclusion 
criteria prior to randomization, a subset of those criteria have been identified as key eligibility 
criteria and will also be verified by the sponsor through IRT prior to permitting the patient to 
be randomization. Patient’s eligibility is checked in IRT. The eligibility checklist form must be 
completed in IRT by the investigator or designee at day 1 prior to starting the treatment phase 


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Protocol No. CLCI699C2301 
 
 
and receiving the first dose of study drug (LCI699). Verification of all eligibility criteria must 
be done prior to contacting IRT. After the eligibility has been checked in IRT and confirmed 
that the patient is eligible for the trial, then the patient can be enrolled into the treatment phase 
of the study. 
Please refer and comply with detailed guidelines in the IRT manual. 
7.1.1.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Failure Log, and each patient’s demographic information will be recorded on the 
Demography CRF page. 
No other data will be entered into the clinical database for patients who are screen failures, 
unless the patient experienced a Serious Adverse Event during the Screening Phase (see Section 
8.2 for SAE reporting details). 
If the patient fails to start the treatment, the IRT must be notified within 2 days of the screen 
fail that the patient was not enrolled. 
7.1.1.3 
Patient demographics and other baseline characteristics 
The following patient demographics and baseline characteristics will be collected on the CRF: 
 Demography including date of birth, sex, predominant race and ethnicity (where 
permitted), 
 Height, weight, waist circumference (see Section 7.2.2.3), 
 Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g., all relevant current medical conditions which are present at the 
time of signing informed consent). Ongoing medical conditions, symptoms and disease 
which are recorded on the Medical History CRF should include the toxicity grade, 
 Information on the most recent prior medical therapy for Cushing’s disease will be 
collected and will include information on drug, dose, duration of therapy and outcomes 
provided such data are available. 
 Where possible, diagnoses and not symptoms will be recorded. Cushing’s disease history 
together with the medication/treatment used will be collected. 
 Prior and concomitant medications, 
Furthermore the following assessments will be performed: 
 Physical Examination (see Section 7.2.2.1), 
 Vital signs including blood pressure and pulse (see Section 7.2.2.2), 
 Patient quality of life questionnaires (CushingQoL, Beck Depression Inventory, HRQoL 
EQ-5D-5L) (see Section 7.2.6), 
 ECG and 24-hour Holter (see Section 7.2.2.6), 
 MRI, photography and DXA Imaging (see Section 7.2.2.5, Section 7.2.1.2 and Section 
7.2.1.3), 


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Protocol No. CLCI699C2301 
 
 
 Laboratory evaluations (e.g., hematology, biochemistry, thyroid panel, coagulation, lipase, 
glycosylated hemoglobin (HbA1c), fasting insulin and plasma glucose, urinalysis, 24-hour 
Urinary Free Cortisol and creatinine, testosterone and estradiol, LH and FSH, plasma 
ACTH, cortisol, 11-deoxycortisol, renin, serum aldosterone, 
 
, serum 11-deoxycorticosterone, serum androstenedione, DHEAS, estrone) 
(see Section 7.2.2.4), 
 Serum pregnancy (see Section 7.2.2.4.8). 
7.1.2 
Run-in period 
Although there is no Run-in period, washout requirements as described in Inclusion criteria 
(Section 5.2) must be followed. 
7.1.3 
Treatment period 
Treatment period is divided in 4 study periods as described in Section 4.1. Patients should be 
seen for all visits on the designated day with a visit window of ± 3 days and in a fasting state. 
During study period 1 (Week 1 to 12), patients will come to the site every 2 weeks. Between 
visits, they may be contacted by the Investigator/designee in order to increase or decrease the 
study drug dose based on UFC results from previous visit. 
During study period 2 (Week 13 to 24), patients will come to site every 4 weeks. Although 
study drug dose usually remains stable during this period, adjustment may be needed based on 
mUFC results and for safety. 
Blood samples will be collected for all patients for sparse PK purpose throughout the core study 
(week 1 – 48). Pharmacokinetic blood collection for a subset of approximately 20 patients will 
be carried out for extensive PK assessment. 
During study period 3 (Week 26 to 34), patients will either continue LCI699 open label if they 
are not randomized and will have visits every 4 weeks; or will be randomized to one of the 2 
arms and will come to site every 2 weeks. 
During study period 4 (Week 35 to 48), patients will come to site every 4 weeks. 
During study periods 3 and 4, patients are also allowed to have unscheduled visits at any time 
if they report symptoms of hypercortisolism and have their dose adjusted accordingly. 
For details of assessments, please refer to Table 7-1 to Table 7-5 depending on study period. 
7.1.4 
End of treatment visit including study completion and premature 
withdrawal 
Patients who discontinue study treatment before visit 777 (if patient is in the core phase of the 
study) or 778 (if patient is in the extension phase of the study), should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the EOT visit will be 
performed (Table 7-1, Table 7-3 or Table 7-5) with the following exceptions: 
 Patients discontinuing treatment prior to the Week 36 visit do not need to have an EOT 
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 Patients discontinuing prior to the Week 12 visit or between the Week 24 and Week 36 
visits do not need to have an EOT core pituitary MRI (or CT) (i.e. scans are needed if 
patients discontinue within the 12 week period prior to the Week 24 and Week 48 visits). 
 Patients discontinuing or completing extension phase within 36 weeks since their last 
pituitary MRI (or CT) or DXA scan do not need to have an EOT extension pituitary MRI 
(or CT) or DXA scans. 
An End of Treatment Phase Disposition CRF page should be completed, giving the date and 
reason for stopping the study treatment. At a minimum, all patients who discontinue study 
treatment, including those who refuse to return for a final visit, will be contacted for safety 
evaluations during the 30 days following the last dose of study treatment (Visit 779). 
If a patient withdraws or discontinues from the study prematurely, an unscheduled PK sample 
should be taken, and the sample should be recorded in the “Unscheduled PK” CRF page. 
7.1.5 
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 must make every effort 
(e.g. telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information in the patient’s chart and on the appropriate CRF pages. They may be considered 
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to 
follow-up for any other reason. 
 The investigator should discontinue study treatment for a given patient if, on balance, 
he/she believes that continuation would be detrimental to the patient’s well-being. 
Study treatment must be discontinued under the following circumstances: 
 Emergence of the following adverse events: 
 hypertension defined as office mean sitting systolic BP > 180 mmHg or mean sitting 
diastolic BP > 110 mmHg (confirmed and persistent*). 
 Any of the following laboratory abnormalities (confirmed): 
 hyperkalemia (serum potassium > 6.0 mmol/L). 
 hypokalemia (serum potassium < 2.8 mmol/L). 
 Any of the following laboratory abnormalities (confirmed and persistent*): 
 hyperkalemia (serum potassium > 5.5 mmol/L). 
 hypokalemia (serum potassium < 3.0 mmol/L). 
 hyponatremia (serum sodium < 130 mmol/L). 
 AST or ALT >3.0 x ULN combined with total bilirubin >2.0 x ULN without evidence 
of cholestasis 
 QTcF > 500 msec, if confirmed by a cardiologist (see Section 7.2.2.7). 
QTcF > 480 msec, if the investigator determines it is no longer safe for the patient to continue 
in the study, based on ECGs, cardiac examination, and recommendation from a cardiologist 
(see Section 7.2.2.7). 
 QTcF increase > 60 msec from pre-first dose baseline measurement. 


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 Mean increase in QTcF > 30 ms from the mean baseline value at 1.5 hour post-first dose 
or mean QTcF > 480 ms at day 1 (see Section 7.2.2.7). 
 Pituitary tumor growth, if the tumor is < 2mm from the optic chiasm, or symptoms of 
actual compression of the optic chiasm emerge (visual field loss, cranial nerve palsies, 
diplopia) confirmed by MRI of the pituitary. 
* Persistent is defined as unresolved with LCI699 dose and/or other concomitant medication 
changes. 
 Pregnancy. 
 Use of prohibited concomitant medications (see Section 6.4.2). 
 Any other protocol deviation that results in a significant risk to the patient’s safety. 
The appropriate personnel from the site and Novartis will assess whether study treatment should 
be discontinued for any patient whose treatment code has been broken inadvertently for any 
reason. 
Patients who discontinue study treatment should NOT automatically be considered withdrawn 
from the study. They should return for the assessments indicated in Section 7.2. If they fail to 
return for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) 
should be made to contact them as specified in Section 7.1.8. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
7.1.5.1 
Replacement policy 
Not applicable. 
7.1.6 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient: 
 Does not want to participate in the study anymore, and 
 Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.  
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
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Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until their time of withdrawal) according to applicable 
law. 
For United States and Japan: All biological samples not yet analyzed at the time of withdrawal 
may still be used for further testing/analysis in accordance with the terms of this protocol and 
of the informed consent form.  
For European Union and RoW (Rest of World, i.e. all countries except the United States, Japan 
and the member states of the European Union): All biological samples not yet analyzed at the 
time of withdrawal will no longer be used, unless permitted by applicable law. They will be 
stored according to applicable legal requirements. 
7.1.7 
Follow up for safety evaluations 
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF. 
7.1.8 
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 
Study phase completion CRF. 
7.2 
Assessment types. 
7.2.1 
Efficacy assessments 
Table 7-6 
Imaging and disease assessment collection plan 
Procedure 
Screening/Baseline 
During Treatment/Extension 
24-hour urine to test for Urine 
Free Cortisol and creatinine 
Mandated at screening 
and baseline 
Mandated, every 2 or 4 weeks depending on study 
period in core phase and every 12 weeks in extension 
phase. Three 24-hour samples at each time point 
Photography 
Mandated at baseline 
Mandated at week 12, 24, 34 and 48 in core phase, 
week 72 and EOT in extension 
DXA scan 
Mandated at baseline 
Mandated at end of treatment core and end of 
treatment extension 
7.2.1.1 
Urinary Free Cortisol 
The primary efficacy parameter will be Urinary Free Cortisol (UFC) and will be assessed using 
a central laboratory. UFC will be measured in three 24-hour urine samples. The three samples 
will be averaged to obtain the mean UFC (mUFC) level. 


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Throughout the study, patients will collect three 24-hour UFC samples according to the Table 
7-1 to Table 7-5: 
Screening: three 24-hour UFC samples should be collected and sent to central laboratory at 
least 14 days prior to day 1 in order to ensure that sufficient time is allowed for central 
laboratory results to become available. These samples will be used to assess eligibility of the 
patient. A repeated evaluation within the screening window is permitted for screening results 
out of the defined range. If the repeated laboratory result meets the criteria, that result may be 
used to determine eligibility. If the repeated laboratory result does not meet the criteria, the 
patient will be considered a screening failure. 
Baseline: another three 24-hour UFC samples will be collected within 7 days prior to first day 
of treatment to serve as baseline value. 
Treatment period: patient will collect three 24-hour UFC samples within 7 days prior to the 
next visit and with the last urine sample preferably collected the day prior to the visit at site as 
defined in Table 7-1 during study periods 1 and 2; as defined in Table 7-2 (for randomized 
patients) or Table 7-3 (for non-randomized patients) during study periods 3 and 4; and as 
defined in Table 7-4 and Table 7-5 during extension period. Please refer to Section 4.1 for 
complete description of study design. 
During study periods 3 and 4, patients are also allowed to have unscheduled visits at any time 
if they report symptoms of hypercortisolism. 
7.2.1.2 
Photographic assessments of physical findings 
The following clinical signs (physical findings) of Cushing’s disease will be assessed at time 
points defined in Table 7-1 to Table 7-5 : facial rubor, hirsutism (females only), striae, 
supraclavicular and dorsal fat pads, proximal muscle wasting (atrophy), central (abdominal) 
obesity, and ecchymoses (bruising). These clinical signs are to be rated on a semi-quantitative 
scale as follows: 0=absent; 1=mild; 2=moderate; and 3=severe. The photographs will be 
reviewed locally by the investigator and used for analysis. Photographs will be centrally 
collected and checked for quality by an imaging vendor. The quality checks will be detailed in 
the vendor manual. 
Two photographs, one frontal and one lateral from the shoulders up will be taken to assess facial 
plethora (rubor), supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of 
the trunk with patient in standing position will be taken to assess hirsutism (females only), 
striae, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses 
(bruising). In order to maintain confidentiality, photographs will not be published without the 
explicit written consent of the patient. 
If for cultural reasons or usual lifestyle of the patient, photographic assessments cannot be 
performed, this must be discussed with the sponsor on a case-by-case basis and sponsor 
approval will be required. 
7.2.1.3 
Bone mineral density assessments 
Bone mineral density of the lumbar vertebrae (L1-L4 or L2-L4, depending upon manufacturer) 
and left total hip are to be measured using Lunar or Hologic DXA (dual-energy X-ray 


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absorptiometry) Instruments. A patient should be scanned on the same DXA instrument 
throughout the study. If a scan of the left femur is not possible, then the right femur can be used 
which is then to be used consistently throughout the study. Patients are to be positioned and 
scanning is to be performed according to the instructions from the manufacturer. Detailed 
instructions on scanning methods, calibration of individual DXA machines and across DXA 
machines at different sites will be provided in a DXA manual. The BMD results should be 
reported in actual density (gm/cm2) and standardized against the peak bone mass in a healthy 
young adult population (BMD T-score). BMD results will be reviewed centrally by the imaging 
vendor. This assessment will be done as defined in Table 7-1 to Table 7-5. 
Bone mineral density assessments will not be done in patients that are enrolled in Germany. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examination, vital signs, laboratory evaluations, 
radiological examinations, radiological assessments, cardiac assessments, as well as collecting 
of the adverse events at every visit. For details on AE collection and reporting, refer to Section 
8. 
7.2.2.1 
Physical examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
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 Table 7-1 to Table 7-5. 
Significant findings that were present prior to the signing of informed consent must be included 
in the Relevant Medical History/Current Medical Conditions page on the patient’s CRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
Adverse Event page of the patient’s CRF. 
7.2.2.2 
Vital signs 
Vital signs include body temperature, blood pressure and pulse measurements, and will be 
assessed according to Table 7-1 to Table 7-5. 
After the patient has been sitting for five minutes, with back supported and both feet placed on 
the floor, systolic and diastolic blood pressure will be measured three times using an automated 
validated device, with an appropriately sized cuff. The repeat sitting measurements will be made 
at 1 - 2 minute intervals and the three measurements will be reported. An appropriately sized 
cuff should be used. 
7.2.2.3 
Height, weight and waist circumference 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured. Body height will be measured at screening and body 
weight and waist circumference will be measured at visits according to Table 7-1 to Table 7-5. 
To measure the waist circumference, patients should remove clothing from around the waist to 
ensure the measuring tape is correctly positioned. Using e.g. a cosmetic pencil, make a mark at 


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the “natural waist” midway between the palpated iliac crest and the palpated lowest rib margin 
in the left and right mid-axillary lines. Place the non-stretchable tape evenly around the natural 
waist covering the left and right natural waist marks. The measurement scale should face 
outward, and there should be no twists in the tape. Ensure that the tape is just touching the skin 
but not compressing the soft tissue. Instruct patients to stand erect with abdomen relaxed, arms 
at sides, feet together, and weight divided equally over both legs. 
7.2.2.4 
Laboratory evaluations 
Clinical laboratory analyses (hematology, chemistry (full or partial), coagulation, urinalysis, 
thyroid panel and additional tests mentioned in Table 7-7 below) are to be performed by the 
central laboratory. Visit windows of +/- 3 days are allowed. 
At any time during the study, abnormal laboratory parameters which are clinically significant 
and require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
CRF page. Laboratory data will be summarized using the CTCAE version 4.03. Additional 
laboratory evaluations are left to the discretion of the investigator. 
Table 7-7 
Central clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, RBC Morphology 
with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
Chemistry - full 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, Glucose, 
Calcium, Chloride, Creatinine, Creatine kinase, GGT, Lactate dehydrogenase (LDH), 
inorganic phosphorus, lipase, amylase, magnesium, potassium, sodium, Total Bilirubin 
(and Direct Bilirubin, Indirect Bilirubin if total Bilirubin is above 1.5 times the upper limit of 
normal), Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid 
Chemistry - partial 
Sodium, potassium, chloride, bicarbonate, Blood Urea Nitrogen (BUN) or Urea, creatinine, 
glucose, calcium, magnesium 
Urinalysis 
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
pH, Protein, Specific Gravity,) 
Coagulation 
Prothrombin time (PT), Activated partial thromboplastin time (APTT) 
Thyroid Panel 
Serum TSH, free T4 
Additional tests 
Pregnancy test: serum (central laboratory testing) and urine dipstick (local laboratory 
testing) 
Serum testosterone and estradiol 
Plasma ACTH, serum cortisol, serum 11-deoxycortisol 
Serum aldosterone 
Renin 
 
Serum 11-Deoxycorticosterone 
Fasting serum insulin and plasma glucose 
HbA1C 
LH, FSH 
Serum Androstenedione, DHEAS, Estrone 
Serum cortisol 
 (Extensive PK subset) (See Section 7.2.2.4.6) 


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Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the [Laboratory Manual]. 
7.2.2.4.1 Hematology 
Hematology tests are to be performed by the central laboratory according to the schedule of 
assessments and collection plan outlined respectively in Table 7-1 to Table 7-5. The 
Hematology panel includes hematocrit, hemoglobin, platelets, red blood cells (RBC), white 
blood cells, RBC morphology with differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils). 
7.2.2.4.2 Clinical chemistry 
Chemistry tests are to be performed by the central laboratory according to the schedule of 
assessments and collection plan outlined respectively in Table 7-1 to Table 7-5. 
The full Chemistry panel includes albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), 
bicarbonate, glucose, calcium, chloride, creatinine, creatine kinase, GGT, LDH, inorganic 
phosphorus, lipase, amylase, magnesium, potassium, sodium, total bilirubin (and direct 
bilirubin, indirect bilirubin, total cholesterol, LDL, HDL, total protein, triglycerides, Blood 
Urea Nitrogen (BUN) or urea, uric acid. 
The partial Chemistry panel includes sodium, potassium, chloride, bicarbonate, Blood Urea 
Nitrogen (BUN) or urea, creatinine, glucose, calcium, magnesium. 
7.2.2.4.3 Urinalysis 
Urinalysis tests are to be performed according to the schedule of assessments and collection 
plan outlined respectively in Table 7-1 to Table 7-5. 
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 esterase and blood. 
7.2.2.4.4 Coagulation 
Prothrombin time (PT), Activated Partial Thromboplastin Time (APTT) will be assessed by the 
central laboratory according to Table 7-1 to Table 7-5. 
7.2.2.4.5 Thyroid panel 
Serum Thyroid Stimulating Hormone (TSH) and free T4 will be assessed by the central 
laboratory according to Table 7-1 to Table 7-5. 
7.2.2.4.6 Additional hormones 
Serum testosterone and estradiol, luteinizing hormone (LH) and follicle stimulating hormone 
(FSH), plasma ACTH, serum cortisol, serum 11-deoxycortisol, renin, serum aldosterone, 
, serum androstenedione, DHEAS, estrone and serum 


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11-deoxycorticosterone will be assessed by the central laboratory according to Table 7-1 to 
Table 7-5. 
For the subset of patients (n~20) participating in extensive PK assessment (See Section 7.2.3), 
serum and salivary cortisol will also be collected at the same time as PK samples; additional 
salivary cortisol samples will be taken the day prior to the visit at 8 am, 12 pm, 6 pm and 
midnight, all with a window of +/- 1 hour. If LCI administration was interrupted prior to a 
planned visit and no study treatment is administered on the day of the planned visit, sampling 
for serum and salivary cortisol will not be required, similarly as the PK sampling. 
For the subset of Chinese patients with extensive PK sampling, serum and salivary cortisol and 
plasma ACTH will be collected at the same time as PK samples; additional salivary cortisol 
samples will be taken the day prior to the visit at 8 am, 12 pm noon, 6 pm and midnight, all 
with a window of +/- 1 hour. Additionally at baseline (Visit 2) these patients will undergo 
sampling for plasma ACTH and serum cortisol at 8 am, 12 pm noon, 4 pm and 8 pm. If LCI 
administration was interrupted prior to a planned visit and no study treatment is administered 
on the day of the planned visit, sampling for serum, salivary cortisol and plasma ACTH will 
not be required, similarly as the PK sampling. 
Collection times for serum cortisol, salivary cortisol and plasma ACTH (when applicable) are 
identical to the PK collection schedule (see Section 7.2.3, Table 7-11) with the exception of the 
additional salivary and serum cortisol and plasma ACTH samples taken prior to the visit. 
7.2.2.4.7 Other laboratory parameters 
Serum fasting insulin and plasma fasting glucose, HbA1C will be assessed by the central 
laboratory according to Table 7-1 to Table 7-5. 
7.2.2.4.8 Pregnancy and assessments of fertility 
Serum pregnancy tests will be performed at screening, baseline. Urine or serum pregnancy 
testing will be performed as indicated in Table 7-1 to Table 7-5. 
If a urine pregnancy test is performed and is found to be positive, this will require immediate 
interruption of study drug until serum β-hCG is performed and found to be negative. If positive, 
the patient must be discontinued from the trial. 
When performed at screening, the result of this test must be received before the patient may be 
dosed. 
7.2.2.5 
Radiological examinations 
Table 7-8 
Imaging assessment collection plan 
Procedure 
Screening/Baseline 
During Treatment/Extension 
Pituitary MRI 
with gadolinium enhancement 
Mandated at baseline 
Mandated at Week 24, 48,72, 120, subsequently 
at the same frequency and at EOT extension 
Pituitary MRI scanning with gadolinium enhancement will be performed at visits according to 
Table 7-1 to Table 7-5. These will be assessed centrally by the imaging vendor to screen for 
pituitary enlargement either by tumor volume or maximum dimension of tumor. If MRI scan 


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with intravenous contrast (gadolinium) is contraindicated for a patient, then a non-contrast MRI 
scan should be performed. If the MRI cannot be performed at all, then a CT of the pituitary 
(with i.v. contrast if not contraindicated) may be performed. Regardless of imaging type, all 
regularly scheduled pituitary imaging will be centrally reviewed by the imaging vendor for 
consistency in the measurement of dimensions. The modality (MRI/CT) should remain 
consistent to that used at baseline unless there is a development of a contraindication. The 
central reading at each time point will include the assessment of invasiveness of the pituitary 
tumor into surrounding structures, and any new finding of measurable pituitary tumor in a 
patient with no measureable tumor at previous scans. Please see the study imaging manual for 
further information. 
7.2.2.6 
Cardiac assessments 
Cardiac monitoring will include 12-lead Safety ECGs, which are the primary assessment of 
safety at study visits, and 24-hour continuous 12-lead Holter recordings, which provide large 
amounts of additional ECG data with central reading, but are not intended to provide real-time 
assessment of cardiac intervals and cardiac rhythm. 
Table 7-9 
ECG collection plan 
Week 
Day 
Time 
ECG Type 
Central or 
Local 
-5 to -2 
-35 to -8 
Pre-dose 
12 Lead 
Local 
-1 
-7 to -1 
Pre-dose 
12 Lead 
Local 
-1 
-7 to -1 
24-hour 
24-hour Holter 
Central 
0 
1 
Pre-dose 
12 Lead 
Local 
0, 2, 4, 6, 8, 10, 12, 16, 20, 
24 
1, 15, 29, 43, 57, 71, 
85, 113, 141, 169 
Post-dose 1.5 hours 
12 Lead 
Local 
Randomized patients: 26, 
28, 30, 32, 34, 36, 40, 44 
183, 197, 211, 225, 
239, 253, 281, 309 
Post-dose 1.5 hours 
12 Lead 
Local 
Non randomized patients: 
26, 30, 34, 36, 40, 44 
183, 211, 239, 253, 
281, 309 
Post-dose 1.5 hours 
12 Lead 
Local 
2, 12, 24, 48 
15, 85, 169, 337 
24-hour 
24-hour Holter 
Central 
Optional Extension: 48, 
60, 72, 84, 96, 108, 120, 
132, 144, subsequently at 
the same frequency and 
EOT extension 
337, 421, 505, 589, 
673, 757, 841, 925, 
1009, subsequently at 
the same frequency and 
EOT extension 
Post-dose 1.5 hours 
12 Lead 
Local 
Optional Extension: 72, 
120, subsequently at the 
same frequency and EOT 
extension 
505, 841, subsequently 
at the same frequency 
and EOT Extension 
24-hour 
24-hour Holter 
Central 
Study completion 
30 days from last dose 
N/A 
12 Lead 
Local 
Unscheduled assessment 
Anytime 
12 Lead 
Local 
7.2.2.6.1 24-hour Holter electrocardiogram 
Twenty-four hour continuous 12-lead Holter recording with central reading of data are done on 
each patient according to the Table 7-1 to Table 7-5 and Table 7-9. 


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7.2.2.6.2 Electrocardiogram (ECG) 
Twelve-lead safety ECGs are collected at the study sites according to Table 7-1 to Table 7-3 
and Table 7-9. 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 the Extension Study, 12-lead safety ECGs will also be done according to the Table 7-
4 and Table 7-5, 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 ECG equipment provided by 
vendor. This ECG must be read on site by a qualified physician (e.g., the investigator, or another 
qualified physician such as a consulting cardiologist) at the time they are collected and 
documented on the ECG CRF. 
Each 12-lead Safety ECG tracing should be labeled with the: 
 study number 
 patient initials 
 patient number 
 date and time 
and kept in the source documents at the study site. The clock on the ECG machine should be 
synchronized with the central clock on a daily basis. 
The CRF will contain: 
 date and time of ECG 
 heart rate 
 PR interval 
 QT and QTcF interval 
 QRS duration 
The Fridericia QT formula (QTcF) to correct for variations in heart rate should be used for 
clinical decisions. 
The purpose of the safety ECG is to identify patients with clinically significant ECG 
abnormalities. On the day of the first study drug administration (day 1), pre-dose ECGs must 
be done in triplicate. The mean of the QTcF from these 3 tracings is used as the baseline QTcF 
to be compared with subsequent ECGs. 
ECGs with clinically significant abnormalities should be reported on the CRF. The overall 
interpretation will be collected with a Yes/No statement to confirm if any clinically significant 
abnormalities are present which need to be specified further. 
A “notable ECG abnormality” is defined as: 
 Day 1 only: an increase in QTcF > 30 msec at 1.5 hours post-dose, compared to the mean 
pre-dose baseline QTcF from the same day 
 QTcF > 480 msec with acute cardiovascular risk, as assessed by a consulting cardiologist 
 Any QTcF > 500 msec, confirmed by a consulting cardiologist 
 QTcF increase > 60 msec from baseline. 


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Notable ECG abnormalities should be recorded on the Adverse Events CRF page. If there is a 
notable abnormality, then a cardiology consult should be called, and the Novartis Medical 
Monitor for this trial notified of the event. 
For any ECGs with clinically significant or notable ECG abnormalities, two additional 12-lead 
ECGs should be performed to confirm the safety finding and the triplicate ECGs collected 
should be transferred for central review. 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and then blood sampling for LCI699 pharmacokinetic (PK) 
assessment (Figure 7-1). ECG procedure may also be performed 30 minutes after PK sampling. 
Figure 7-1 
Sequence of cardiovascular data collection 
 
Original ECG tracings, appropriately signed, will be archived at study site. 
7.2.2.7 
QT monitoring 
QT monitoring will occur as follows: 
 On the first day of the first administration of LCI699 (day 1), pre-dose baseline ECGs 
must be done in triplicate. The mean of the QTcF values from these three ECG tracings is 
used to determine the mean baseline QTcF. 
 On day 1, if the safety ECG (1.5 hours post-first dose of LCI) shows a mean increase in 
QTcF > 30 ms from the mean baseline value, or the mean QTcF is > 480 ms, then the 
patient must be discontinued from the study drug according to the discontinuation 
procedure described in Section 7.1.7 and an unscheduled triplicate ECGs collected at 
approximately 1-2 hours and a PK sample collected. The patient must remain under 
observation until the QTcF is < 480 msec and serum electrolytes, calcium, and magnesium 
are measured and the results normal. 
 If at any follow up visit, a QTcF > 480 msec is observed or an increase of the QTcF 
of >60 msec compared to baseline QTcF assessment, then two additional ECGs, each 2-3 
minutes apart, need to be taken after the initial ECG. The mean QTcF from the triplicate 
ECGs will be determined. If the mean QTcF is > 480 msec or the mean QTcF increase 
is >60 msec compared to baseline, the patient has to interrupt study treatment while an 
urgent cardiology consultation is obtained to re-evaluate the ECG and perform a clinical 
consultation. If immediate treatment is required for patient safety, this should be initiated 
at the study site without delay and without waiting for confirmation by a cardiologist. 
Based on the cardiologist consultation, the following should occur: 


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 If a mean QTcF > 480 msec is NOT confirmed, no further action needs to be taken.If the 
cardiologist confirms a mean QTcF > 500 msec, the patient has to discontinue according 
to the discontinuation procedure described in Section 7.1.7 and an unscheduled PK sample 
collected. The patient must remain under observation until the QTcF is < 480 msec and 
serum electrolytes, calcium, and magnesium are measured and the results normal. This 
observation may be done at the site, in an Emergency Room, or a cardiology clinic, as 
appropriate and depending upon local resources. 
a. If the cardiologist confirms that QTcF > 480 msec, LCI699 treatment is temporarily 
interrupted and a thorough evaluation is performed to assess the patient for acute 
cardiovascular risk, and for possible underlying heart disease that needs additional 
evaluation and management. In addition, an unscheduled PK sample will be collected. 
b. If based upon the assessment by the cardiologist, the investigator considers that there 
is an acute cardiovascular safety risk and that the patient should not continue with 
study medication, the patient needs to be discontinued immediately (discontinuation 
criteria described in Section 7.1.7). 
c. If based upon the assessment by the cardiologist, the investigator considers that there 
is not an acute cardiovascular safety risk; the patient can continue to receive study 
medication. 


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Figure 7-2 
QT Monitoring Flow Chart (except for Day 1) 
 
* Please refer to Section 7.1.5, study treatment must be discontinued under this circumstance. 
7.2.3 
Pharmacokinetics 
Blood samples for LCI699 PK evaluation will be collected from all patients who receive at least 
one dose of study treatment. Pharmacokinetic (PK) blood sampling will be performed in each 
study period as indicated in the Visit Evaluation Schedule (Table 7-1 to Table 7-3). 
Time points of blood sample collection for sparse PK and extensive PK analyses are outlined 
in Table 7-10 and Table 7-1, respectively. The following PK sampling will be performed: 
 Sparse PK assessment in all other patients: trough (predose) and peak (1 – 2 h post-dose). 
(Table 7-10) 


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 Extensive PK assessment (subset of n~20 patients): trough (predose), 0.25 – 0.75 h, 1 – 2 
h, and 3 – 4 h post-dose during dose titration phase; trough (predose) and peak (1 – 2 h 
post-dose) beyond titration phase. (Table 7-11) 
 [(China only): 
 Extensive sampling: trough (predose), 0.5, 1, 1.5, 2, 4, 6, 8 and 12 h post-dose during 
dose titration phase if there is a dose escalation; (Table 7-12) 
 Sparse sampling: trough (predose) and peak (1.5 h post-dose) if there is no dose 
escalation. (Table 7-12) 
If LCI administration was interrupted prior to a planned visit and no study treatment is 
administered on the day of the planned visit, blood draw for PK sampling will not be required. 
All ECG procedures should be taken prior to and/or 30 minutes after any PK blood draws since 
sampling for PK impacts ECG measurements. 
Complete dosing information, including the date and time of actual blood draw and time of the 
last study treatment dose prior to the sampling (24-h clock time), should be obtained on all 
sampling days and recorded on the PK CRF and/or Contract Research Organization (CRO) 
requisition form(s). Sampling problems will be noted in the relevant field in the CRF. 
An additional blood sample (unscheduled) should be collected in the event that a patient 
experiences an AE which requires premature termination from the study treatment. 
Plasma samples remaining after completion of the determination of LCI699 may be used for 
exploratory analysis to further characterize the PK of LCI699 and its metabolite(s), such as 
metabolite profiling, and results will be reported separately. 
7.2.3.1 
Pharmacokinetic blood collection and handling 
Complete instructions for sampling processing, handling and shipment will be provided in the 
[Laboratory Manual]. 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. At specified time points described in Table 7-10 or Table 7-11, blood will be 
collected into tubes containing K2-EDTA and gently inverted several times to thoroughly mix 
the anticoagulant. Tubes will be centrifuged to separate plasma and plasma will immediately be 
transferred into labeled screw-cap polypropylene, cryogenic, freezing vials (e.g. Sarstedt, part# 
72.693, no skirt). Plasma samples will be placed in a freezer in an upright position until 
shipment on dry ice to the Novartis assigned laboratory for analysis. 


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Table 7-10 
Pharmacokinetic blood collection for sparse PK assessment 
Visit 
Week 
Day 
Scheduled time 
point a 
PK collection number 
for dose after trough 
sample b 
PK collection 
number prior to 
trough sample b 
PK 
Sample 
No 
Sample 
volume 
[mL] 
3 
0 
1 
Pre-dose/ 0 h 
1 
 
50 
2.6 
3 
0 
1 
Post-dose 1 - 2 h 
1 
 
51 
2.6 
4 
2 
15 
Pre-dose/ 0 h 
2 
102 
52 
2.6 
4 
2 
15 
Post-dose 1 - 2 h 
2 
 
53 
2.6 
5 
4 
29 
Pre-dose/ 0 h 
3 
103 
54 
2.6 
5 
4 
29 
Post-dose 1 - 2 h 
3 
 
55 
2.6 
6 
6 
43 
Pre-dose/ 0 h 
4 
104 
56 
2.6 
6 
6 
43 
Post-dose 1 - 2 h 
4 
 
57 
2.6 
7 
8 
57 
Pre-dose/ 0 h 
5 
105 
58 
2.6 
7 
8 
57 
Post-dose 1 - 2 h 
5 
 
59 
2.6 
8 
10 
71 
Pre-dose/ 0 h 
6 
106 
60 
2.6 
8 
10 
71 
Post-dose 1 - 2 h 
6 
 
61 
2.6 
9 
12 
85 
Pre-dose / 0 h 
7 
107 
62 
2.6 
9 
12 
85 
Post-dose 1 - 2 h 
7 
 
63 
2.6 
10 
16 
113 
Pre-dose / 0 h 
8 
108 
64 
2.6 
10 
16 
113 
Post-dose 1 - 2 h 
8 
 
65 
2.6 
11 
20 
141 
Pre-dose / 0 h 
9 
109 
66 
2.6 
11 
20 
141 
Post-dose 1 - 2 h 
9 
 
67 
2.6 
12 
24 
169 
Pre-dose / 0 h 
10 
110 
68 
2.6 
12 
24 
169 
Post-dose 1 - 2 h 
10 
 
69 
2.6 
13 
26 
183 
Pre-dose / 0 h 
11 
111 
70 
2.6 
14 
28 
197 
Pre-dose / 0 h 
12 
112 
71 
2.6 
15 
30 
211 
Pre-dose / 0 h 
13 
113 
72 
2.6 
16 
32 
225 
Pre-dose / 0 h 
14 
114 
73 
2.6 
17 
34 
239 
Pre-dose / 0 h 
15 
115 
74 
2.6 
18 
36 
253 
Pre-dose / 0 h 
16 
116 
75 
2.6 
19 
40 
281 
Pre-dose / 0 h 
17 
117 
76 
2.6 
20 
44 
309 
Pre-dose / 0 h 
18 
118 
77 
2.6 
777 
48 
337 
Pre-dose / 0 h 
--- 
119 
78 
2.6 
Unscheduled Sample 
--- 
--- 
--- 
2001+ 
2.6 
a The following PK assessment windows are acceptable: pre-dose sample within 0.5 h before dose administration 
b For the PK pre-dose (trough) samples, the actual date and time of administration of the previous dose of study 
medication should also be recorded with appropriate PK collection number as indicated in the above table. The 
PK collection number series “1, 2, 3…” is for the LCI699 dose administered on study visit day, while PK collection 
number series “102, 103, 104…” is for last LCI699 dose the patient received prior to the collection of the PK pre-
dose (trough) sample 


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Table 7-11 
Pharmacokinetic blood collection for extensive PK assessment 
(subset of approximately 20 patients) 
Visit 
Week 
Day 
Scheduled time point a 
PK collection 
number for dose 
after trough 
sample b 
PK collection 
number prior 
to trough 
sample b 
PK 
Sample 
No 
Sample 
volume 
[mL] 
3 
0 
1 
Pre-dose/ 0 h 
201 
 
1 
2.6 
3 
0 
1 
Post-dose 0.25 - 0.75 h 
201 
 
2 
2.6 
3 
0 
1 
Post-dose 1 - 2 h 
201 
 
3 
2.6 
3 
0 
1 
Post-dose 3 - 4 h 
201 
 
4 
2.6 
4 
2 
15 
Pre-dose/ 0 h 
202 
302 
5 
2.6 
4 
2 
15 
Post-dose 0.25 - 0.75 h 
202 
 
6 
2.6 
4 
2 
15 
Post-dose 1 - 2 h 
202 
 
7 
2.6 
4 
2 
15 
Post-dose 3 - 4 h 
202 
 
8 
2.6 
5 
4 
29 
Pre-dose/ 0 h 
203 
303 
9 
2.6 
5 
4 
29 
Post-dose 0.25 – 0.75 h c 
203 
 
10 
2.6 
5 
4 
29 
Post-dose 1 - 2 h 
203 
 
11 
2.6 
5 
4 
29 
Post-dose 3 - 4 h c 
203 
 
12 
2.6 
6 
6 
43 
Pre-dose/ 0 h 
204 
304 
13 
2.6 
6 
6 
43 
Post-dose 0.25 – 0.75 h c 
204 
 
14 
2.6 
6 
6 
43 
Post-dose 1 - 2 h 
204 
 
15 
2.6 
6 
6 
43 
Post-dose 3 - 4 h c 
204 
 
16 
2.6 
7 
8 
57 
Pre-dose/ 0 h 
205 
305 
17 
2.6 
7 
8 
57 
Post-dose 0.25 – 0.75 h c 
205 
 
18 
2.6 
7 
8 
57 
Post-dose 1 - 2 h 
205 
 
19 
2.6 
7 
8 
57 
Post-dose 3 - 4 h c 
205 
 
20 
2.6 
8 
10 
71 
Pre-dose/ 0 h 
206 
306 
21 
2.6 
8 
10 
71 
Post-dose 0.25 – 0.75 h c 
206 
 
22 
2.6 
8 
10 
71 
Post-dose 1 - 2 h 
206 
 
23 
2.6 
8 
10 
71 
Post-dose 3 - 4 h c 
206 
 
24 
2.6 
9 
12 
85 
Pre-dose / 0 h 
207 
307 
25 
2.6 
9 
12 
85 
Post-dose 0.25 – 0.75 h c 
207 
 
26 
2.6 
9 
12 
85 
Post-dose 1 - 2 h 
207 
 
27 
2.6 
9 
12 
85 
Post-dose 3 - 4 h c 
207 
 
28 
2.6 
10 
16 
113 
Pre-dose / 0 h 
208 
308 
29 
2.6 
10 
16 
113 
Post-dose 1 - 2 h 
208 
 
30 
2.6 
11 
20 
141 
Pre-dose / 0 h 
209 
309 
31 
2.6 
11 
20 
141 
Post-dose 1 - 2 h 
209 
 
32 
2.6 
12 
24 
169 
Pre-dose / 0 h 
210 
310 
33 
2.6 
12 
24 
169 
Post-dose 1 - 2 h 
210 
 
34 
2.6 
13 
26 
183 
Pre-dose / 0 h 
211 
311 
35 
2.6 
14 
28 
197 
Pre-dose / 0 h 
212 
312 
36 
2.6 
15 
30 
211 
Pre-dose / 0 h 
213 
313 
37 
2.6 
16 
32 
225 
Pre-dose / 0 h 
214 
314 
38 
2.6 
17 
34 
239 
Pre-dose / 0 h 
215 
315 
39 
2.6 
18 
36 
253 
Pre-dose / 0 h 
216 
316 
40 
2.6 
19 
40 
281 
Pre-dose / 0 h 
217 
317 
41 
2.6 


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Visit 
Week 
Day 
Scheduled time point a 
PK collection 
number for dose 
after trough 
sample b 
PK collection 
number prior 
to trough 
sample b 
PK 
Sample 
No 
Sample 
volume 
[mL] 
20 
44 
309 
Pre-dose / 0 h 
218 
318 
42 
2.6 
777 
48 
337 
Pre-dose / 0 h 
--- 
319 
43 
2.6 
Unscheduled Sample 
--- 
--- 
--- 
1001+ 
2.6 
a The following PK assessment windows are acceptable: pre-dose sample within 0.5 h before dose administration. 
b For the PK pre-dose (trough) samples, the actual date and time of administration of the previous dose of study 
medication should also be recorded with appropriate PK collection number as indicated in the above table. The 
PK collection number series “201, 202, 203…” is for the LCI699 dose administered on study visit day, while PK 
collection number series “302, 303, 304…” is for last LCI699 dose the patient received prior to the collection of the 
PK pre-dose (trough) sample 
c Required if dose is titrated since last visit. If the LCI699 dose was maintained (i.e. no dose titration since last 
visit), then only pre-dose and 1- 2 h samples are required. 
[(China only) For profiles with extensive sampling, the pharmacokinetic parameters (Table 7-
12) of LCI699 will be calculated from individual plasma concentration versus time profiles 
using non-compartmental analysis (Phoenix WinNonlin v. 6.2). PK parameter derivation will 
be based on actual time points (elapsed time). 
If the LCI699 dose is maintained (i.e. no dose titration since last visit), only pre-dose and 1.5 h 
samples are required from Visit 5 to Visit 9.] 


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Table 7-12 
[(China only) Pharmacokinetic blood collection for Chinese patients] 
Visit 
Week 
Day 
Scheduled time 
point a 
PK collection number 
for dose after trough 
sample b 
PK collection 
number prior to 
trough sample b 
PK 
Sample 
No 
Sample 
volume 
[mL] 
3 
0 
1 
Pre-dose/ 0 h 
401 
 
601 
2.6 
3 
0 
1 
Post-dose 0.5 h 
401 
 
602 
2.6 
3 
0 
1 
Post-dose 1 h 
401 
 
603 
2.6 
3 
0 
1 
Post-dose 1.5 h 
401 
 
604 
2.6 
3 
0 
1 
Post-dose 2 h 
401 
 
605 
2.6 
3 
0 
1 
Post-dose 4 h 
401 
 
606 
2.6 
3 
0 
1 
Post-dose 6 h 
401 
 
607 
2.6 
3 
0 
1 
Post-dose 8 h 
401 
 
608 
2.6 
3 
0 
1 
Post-dose 12 h 
401 
 
609 
2.6 
4 
2 
15 
Pre-dose/ 0 h 
402 
502 
610 
2.6 
4 
2 
15 
Post-dose 0.5 h 
402 
 
611 
2.6 
4 
2 
15 
Post-dose 1 h 
402 
 
612 
2.6 
4 
2 
15 
Post-dose 1.5 h 
402 
 
613 
2.6 
4 
2 
15 
Post-dose 2 h 
402 
 
614 
2.6 
4 
2 
15 
Post-dose 4 h 
402 
 
615 
2.6 
4 
2 
15 
Post-dose 6 h 
402 
 
616 
2.6 
4 
2 
15 
Post-dose 8 h 
402 
 
617 
2.6 
4 
2 
15 
Post-dose 12 h 
402 
 
618 
2.6 
If dose is maintained (i.e. no change from visit 4), only take pre-dose and 1.5 h samples 
5 
4 
29 
Pre-dose/ 0 h 
403 
503 
619 
2.6 
5 
4 
29 
Post-dose 0.5 h c 
403 
 
620 
2.6 
5 
4 
29 
Post-dose 1 h c 
403 
 
621 
2.6 
5 
4 
29 
Post-dose 1.5 h 
403 
 
622 
2.6 
5 
4 
29 
Post-dose 2 h c 
403 
 
623 
2.6 
5 
4 
29 
Post-dose 4 h c 
403 
 
624 
2.6 
5 
4 
29 
Post-dose 6 h c 
403 
 
625 
2.6 
5 
4 
29 
Post-dose 8 h c 
403 
 
626 
2.6 
5 
4 
29 
Post-dose 12 h c 
403 
 
627 
2.6 
If dose is maintained (i.e. no change from visit 5), only take pre-dose and 1.5 h samples 
6 
6 
43 
Pre-dose/ 0 h 
404 
504 
628 
2.6 
6 
6 
43 
Post-dose 0.5 h c 
404 
 
629 
2.6 
6 
6 
43 
Post-dose 1 h c 
404 
 
630 
2.6 
6 
6 
43 
Post-dose 1.5 h 
404 
 
631 
2.6 
6 
6 
43 
Post-dose 2 h c 
404 
 
632 
2.6 
6 
6 
43 
Post-dose 4 h c 
404 
 
633 
2.6 
6 
6 
43 
Post-dose 6 h c 
404 
 
634 
2.6 
6 
6 
43 
Post-dose 8 h c 
404 
 
635 
2.6 
6 
6 
43 
Post-dose 12 h c 
404 
 
636 
2.6 


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Visit 
Week 
Day 
Scheduled time 
point a 
PK collection number 
for dose after trough 
sample b 
PK collection 
number prior to 
trough sample b 
PK 
Sample 
No 
Sample 
volume 
[mL] 
If dose is maintained (i.e. no change from visit 6), only take pre-dose and 1.5 h samples 
7 
8 
57 
Pre-dose/ 0 h 
405 
505 
637 
2.6 
7 
8 
57 
Post-dose 0.5 h c 
405 
 
638 
2.6 
7 
8 
57 
Post-dose 1 h c 
405 
 
639 
2.6 
7 
8 
57 
Post-dose 1.5 h 
405 
 
640 
2.6 
7 
8 
57 
Post-dose 2 h c 
405 
 
641 
2.6 
7 
8 
57 
Post-dose 4 h c 
405 
 
642 
2.6 
7 
8 
57 
Post-dose 6 h c 
405 
 
643 
2.6 
7 
8 
57 
Post-dose 8 h c 
405 
 
644 
2.6 
7 
8 
57 
Post-dose 12 h c 
405 
 
645 
2.6 
If dose is maintained (i.e. no change from visit 7), only take pre-dose and 1.5 h samples 
8 
10 
71 
Pre-dose/ 0 h 
406 
506 
646 
2.6 
8 
10 
71 
Post-dose 0.5 h c 
406 
 
647 
2.6 
8 
10 
71 
Post-dose 1 h c 
406 
 
648 
2.6 
8 
10 
71 
Post-dose 1.5 h 
406 
 
649 
2.6 
8 
10 
71 
Post-dose 2 h c 
406 
 
650 
2.6 
8 
10 
71 
Post-dose 4 h c 
406 
 
651 
2.6 
8 
10 
71 
Post-dose 6 h c 
406 
 
652 
2.6 
8 
10 
71 
Post-dose 8 h c 
406 
 
653 
2.6 
8 
10 
71 
Post-dose 12 h c 
406 
 
654 
2.6 
If dose is maintained (i.e. no change from visit 8), only take pre-dose and 1.5 h samples 
9 
12 
85 
Pre-dose/ 0 h 
407 
507 
655 
2.6 
9 
12 
85 
Post-dose 0.5 h c 
407 
 
656 
2.6 
9 
12 
85 
Post-dose 1 h c 
407 
 
657 
2.6 
9 
12 
85 
Post-dose 1.5 h 
407 
 
658 
2.6 
9 
12 
85 
Post-dose 2 h c 
407 
 
659 
2.6 
9 
12 
85 
Post-dose 4 h c 
407 
 
660 
2.6 
9 
12 
85 
Post-dose 6 h c 
407 
 
661 
2.6 
9 
12 
85 
Post-dose 8 h c 
407 
 
662 
2.6 
9 
12 
85 
Post-dose 12 h c 
407 
 
663 
2.6 
10 
16 
113 
Pre-dose / 0 h 
408 
508 
664 
2.6 
10 
16 
113 
Post-dose 1.5 h 
408 
 
665 
2.6 
11 
20 
141 
Pre-dose / 0 h 
409 
509 
666 
2.6 
11 
20 
141 
Post-dose 1.5 h 
409 
 
667 
2.6 
12 
24 
169 
Pre-dose / 0 h 
410 
510 
668 
2.6 
12 
24 
169 
Post-dose 1 - 2 h 
410 
 
669 
2.6 
13 
26 
183 
Pre-dose / 0 h 
411 
511 
670 
2.6 
14 
28 
197 
Pre-dose / 0 h 
412 
512 
671 
2.6 
15 
30 
211 
Pre-dose / 0 h 
413 
513 
672 
2.6 
16 
32 
225 
Pre-dose / 0 h 
414 
514 
673 
2.6 
17 
34 
239 
Pre-dose / 0 h 
415 
515 
674 
2.6 
18 
36 
253 
Pre-dose / 0 h 
416 
516 
675 
2.6 
19 
40 
281 
Pre-dose / 0 h 
417 
517 
676 
2.6 
20 
44 
309 
Pre-dose / 0 h 
418 
518 
677 
2.6 


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Visit 
Week 
Day 
Scheduled time 
point a 
PK collection number 
for dose after trough 
sample b 
PK collection 
number prior to 
trough sample b 
PK 
Sample 
No 
Sample 
volume 
[mL] 
777 
48 
337 
Pre-dose / 0 h 
--- 
519 
678 
2.6 
Unscheduled Sample 
--- 
--- 
--- 
3001+ 
2.6 
a The following PK assessment windows are acceptable: pre-dose sample within 0.5 h before dose 
administration, ±10 min for up to the 2 h time points; ± 30 min for time points beyond 2 h. 
b For the PK pre-dose (trough) samples, the actual date and time of administration of the previous dose of study 
medication should also be recorded with appropriate PK collection number as indicated in the above table. The 
PK collection number series “401, 402, 403…” is for the LCI699 dose administered on study visit day, while PK 
collection number series “502, 503, 504…” is for last LCI699 dose the patient received prior to the collection of 
the PK pre-dose (trough) sample 
c Required if dose is titrated since last visit. If the LCI699 dose was maintained (i.e. no dose titration since last 
visit), then only pre-dose and 1.5 h samples are required. 
Table 7-13 
[(China only) Non-compartmental pharmacokinetic parameters] 
AUClast 
The area under the concentration-time curve from time zero to the last measurable 
concentration [ng*h/mL] 
AUCinf 
The area under the plasma concentration-time curve from time zero extrapolated to infinity 
when feasible [ng*h/mL] 
Cmax 
The maximum (peak) plasma concentration after single dose administration [ng/mL] 
Tmax 
The time to reach maximum plasma concentration following drug administration [h] 
T1/2 
The elimination half-life [h] 
Cl/F 
Apparent systemic clearance of drug from plasma [L/h] 
Vz/F 
Apparent volume of distribution during terminal phase [L] 
7.2.3.2 
Analytical method 
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 lower 
limit of quantitation (LLOQ) will be 0.10 ng/mL for LCI699; values below LLOQ will be 
reported as zero ng/mL, and missing samples will be labeled accordingly. Concentrations of 
LCI699 will be expressed in mass per volume units (ng/mL). Placebo samples will be analyzed. 
A further refinement of this bioanalytical method may be conducted during the course of the 
study. 


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7.2.5 
Resource utilization 
Not applicable. 
7.2.6 
Patient reported outcomes 
Three patient reported outcome instruments will be used to assess the impact of treatment on 
patient quality of life and symptom burden (see Appendix 4). Patients must be asked to complete 
each questionnaire prior to clinical assessments being undertaken, and these must be completed 
in accordance with the schedules listed in Table 7-1 to Table 7-3 and Table 7-16. Patient’s 
refusal to complete all or any part of a questionnaire should be documented in the study data 
capture system and should not be captured as a protocol deviation. Patient questionnaires should 
be completed in the language most familiar to the patient. The patient should be given sufficient 
space and time to complete the questionnaire. The site personnel should check the questionnaire 
for completeness and ask the patient to complete any missing responses. The original 
questionnaire will be kept with the patient’s file as the source document. 
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs before any clinical study examinations. This assessment should be documented in study 
source records. If AEs or SAEs are confirmed, study investigators should not encourage the 
patient to change responses reported in the completed questionnaires. Study investigators must 
follow reporting instructions outlined in Section 8 (e.g. reference “Adverse Events” section) of 
the study protocol. 


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Table 7-16 
Patient reported outcomes (PROs) collection plan 
Patient Questionnaires1 
Week 
Day 
Time 
CushingQoL 
Beck Depression Inventory-II 
EQ-5D-5L 
Mandated, week -1 
Day -7 to -1 
Prior to any clinical 
assessments or diagnostic 
testing. 
CushingQoL 
Beck Depression Inventory-II 
EQ-5D-5L 
Mandated, Week 4, 8, 
12, 24, 26,28, 30,32 34, 
48 (see Section 7.1) 
Day 29, 57, 85, 169, 
183, 197, 211, 225, 
239, 337 
Prior to any clinical 
assessments, drug dosing or 
diagnostic testing. 
CushingQoL 
Beck Depression Inventory-II 
EQ-5D-5L 
Optional Extension: 
Mandated, Week 72, 
96, EOT extension 
Day 505, 673, EOT 
extension 
Prior to any clinical 
assessments, drug dosing or 
diagnostic testing. 
1 Patient Questionnaires should be completed in the sequence from most specific to most general: Cushing QoL 
→ Beck Depression Inventory-II → EQ-FD-5L 
CushingQoL 
The Cushing’s Disease Health-Related Quality of Life Questionnaire (CushingQoL) (version 
1.0) that was developed to evaluate quality of life in patients with Cushing’s syndrome (Webb 
et al 2008). The CushingQoL is comprised of 12 items that capture patient responses on seven 
concepts: daily activities, healing and pain, mood and self-confidence, social concerns, physical 
appearance, memory and concern about the future. Content reliability, sensitivity to change and 
psychometric properties have been validated in patients with Cushing’s disease (Nelson et al 
2013). 
For this study, the CushingQoL has been modified from the standard four-week recall to a one-
week recall in order to be more sensitive to the changes in patient quality of life, specifically 
during the randomized withdrawal period, where it is believed that changes in Cushing’s disease 
symptoms will occur rapidly once patients stop treatment. 
BDI-II 
The Beck Depression Inventory II (BDI-II) is a patient reported instrument that consists of 21 
items designed to assess the intensity of depression in clinical and normal patients in the 
preceding two weeks. Each item is a list of four statements arranged in increasing severity about 
a particular symptom of depression. 
EQ-5D-5L 
The EQ-5D-5L questionnaire is a standardized measure of health status developed by the 
EuroQol Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal. The EQ-5D-5L is applicable to a wide range of health conditions and 
treatments; it provides a simple descriptive profile and a single index value for health status that 
can be used in the clinical and economic evaluation of health care as well as in population health 
surveys. 
The EQ-5D-5L is designed for self-completion by respondents and is ideally suited for use in 
postal surveys, in clinics, and in face-to-face interviews. It is cognitively undemanding, taking 
only a few minutes to complete. 
Instructions to respondents are included in the questionnaire. The EQ-5D-5L measures 5 items 
on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 


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levels: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with on 
a scale of 0-100, with endpoints labeled ‘the best health you can imagine’ and ‘the worst health 
you can imagine’. A single index value is analyzed for the EQ-5D-5L and VAS score. 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Except for screening failures, adverse events that begin or worsen after informed consent should 
be recorded in the Adverse Events CRF. Conditions that were already present at the time of 
informed consent should be recorded in the Relevant Medical History/Current Medical 
Conditions CRF page of the patient’s CRF. Adverse event monitoring should be continued for 
at least 30 days following the last dose of study treatment. Adverse events (including laboratory 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected through a End Of Treatment / Study Evaluation completion CRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates, or Ongoing at End of Study) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given 


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6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the laboratory abnormality may be 
required by the protocol in which case the laboratory abnormality would still, by definition, be 
an adverse event and must be reported as such. 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are of scientific and medical concern specific to the sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. Adverse events of special interest are defined on the basis of an ongoing 
review of the safety data. AESI are discussed in detail in the Investigator Brochure. 
In addition to the AEs listed earlier (Section 1.2.1.2.2 and Section 1.2.1.2.3), other AEs are 
predicted by the underlying disease or the mechanism of action (MoA) of LCI699, specifically 
in patients with Cushing’s disease. Many, but not all, of these AEs have been observed in 
preclinical and/or clinical studies. 
These “AEs of Special Interest” includes the following mechanistic groups: 
 Adrenal Hormone Precursor Accumulation-related AEs 
 Hypocortisolism related AEs 
 Pituitary tumor enlargement-related AEs 


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 QT-prolongation-related AEs 
 Arrythmogenic potential AEs 
Two of the AEs of special interest, the potential for QT prolongation and glucocorticoid 
withdrawal/hypocortisolism/adrenal insufficiency are described in greater detail below. 
8.1.3.1 
Risk of QT prolongation 
Preclinical cardiac safety studies have revealed a signal of QT prolongation with LCI699 that 
is consistent across in vitro and in vivo studies. The risk was quantified in an ICH E-14 
compliant thorough QT/QTc study conducted in healthy volunteers (see Section 1.2.1.2.4 for a 
summary of the results). The results support the use of LCI699 in doses up to 30 mg 
[LCI699C2105]. 
8.1.3.2 
Glucocorticoid withdrawal/hypocortisolism/adrenal insufficiency 
Important and closely related AEs of special interest are glucocorticoid withdrawal, 
hypocortisolism, and adrenal insufficiency. These AEs are a consequence of the potent activity 
of LCI699 to inhibit cortisol synthesis. In patients Cushing’s disease, the relatively rapid 
correction of hypercortisolism can result in symptoms of glucocorticoid withdrawal. If the 
inhibition of cortisol synthesis is excessive, hypocortisolism or adrenal insufficiency may 
develop. 
The patient should be questioned on the signs and symptoms of glucocorticoid 
withdrawal/hypocortisolism/adrenal insufficiency during all phone communications and during 
visits at the site. If any potential signs or symptoms are reported, they should be graded for 
severity and reported as an AE. 
8.1.3.3 
Definitions and reporting 
Groupings of adverse event of special interest will be considered and the number of patients 
with at least one event in each grouping will be reported. Such groups consist of AEs for which 
there is a specific interest in connection with LCI699 treatment (i.e. where LCI699 may 
influence a common mechanism of action responsible for triggering them) or adverse event that 
are very similar although not identical. The groups will be defined according to criteria 
described in MedDRA. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
 Is fatal or life-threatening 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 


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 Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department. 
The telephone and telefax number of the contact persons in the local department of Drug Safety 
and Epidemiology (DS&E), 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 contact(s) 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. Each re-occurrence, complication, or progression of the original event should 
be reported as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated, 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] and is thought to be 
related to the Novartis study treatment, an oncology Novartis Drug Safety and Epidemiology 
(DS&E) 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 


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reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries. 
8.3 
Emergency unblinding of treatment assignment 
Emergency unblinding should only be undertaken when it is essential for effective treatment of 
the patient. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IRT. When the investigator contacts 
the IRT to unblind a patient, he/she must provide the requested patient identifying information 
and confirm the necessity to unblind the patient. The investigator will then receive details of 
the drug treatment for the specified patient and a fax confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Lead that the code has 
been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT. 
Unblinding would only be considered if the emergency occurs during the randomized 
withdrawal period. 
Study treatment must be interrupted once emergency unblinding has occurred. 
An assessment will be done by the appropriate site personnel and the Study Lead/Medical Lead 
after an emergency unblinding to assess whether or not study treatment should be discontinued 
for a given patient and, if applicable, whether the patient can continue to receive study treatment 
and be followed as described in the protocol. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes 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. 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 


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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. 
8.6 
Data Monitoring Committee 
Not applicable. 
8.7 
Steering Committee 
A Steering Committee (SC) will be established prior to the enrollment of the first patient. Most 
SC members will be investigators participating in the trial. Novartis representatives from the 
Clinical Trial Team may be present at SC Meetings as non-voting participants. 
It is expected that the SC will consist of eight members, seven of whom are experts in the 
treatment and investigation of patients with Cushing’s disease and one cardiologist with 
expertise in drug-related QT prolongation. The membership will represent the following 
countries and/or regions: the US, Europe, and Asia. 
Since nearly all the safety data in this trial is from open-label treatment with LCI699 (except 
for the 8-week randomized withdrawal period), it is not necessary to have a separate Data 
Monitoring Committee. 
The SC will also ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter, 
which must be approved and signed by each member of the SC. 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 


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information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. 
9.3 
Data collection 
The designated investigator staff will enter the data required by the protocol into the Case 
Report Forms. The CRFs have been built using fully validated secure web-enabled software 
that conforms to 21 CFR Part 11 requirements, Investigator site staff will not be given access 
to the EDC system until they have been trained. Automatic validation programs check for data 
discrepancies in the CRFs and, allow modification or verification of the entered data by the 
investigator staff. 
The Principal Investigator is responsible for assuring that the data entered in the CRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
Pharmacokinetic (PK) 
 (blood) samples drawn during the course of the 
study will be collected from the investigator sites and analyzed by Novartis or a central 
laboratory contracted by Novartis. The site staff designated by the investigator will enter the 
information required by the protocol onto the PK 
 Sample Collection CRFs, as 
well as onto the designated CRO’s requisition form. One copy of the requisition form will be 
sent to the CRO with the relevant information (including study number, patient ID, etc.) and 
one copy will be retained by the site. 
IRT, ECG tracings and Imaging (MRI and DXA) will be transferred to central readers. Method 
for data collection will be described in respective manuals. A [Laboratory Manual] will also be 
available for Central laboratory. 


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9.4 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staffs are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples for hematology, biochemistry, coagulation, thyroid panel, serum pregnancy 
test and others assessments (Testosterone, estradiol, Plasma ACTH, cortisol, 11-deoxycortisol 
Plasma and serum aldosterone, 
, Plasma 11-
Deoxycorticosterone, Fasting Insulin and plasma glucose, HbA1C, Serum Androstenedione, 
DHEAS, Estrone) will be performed by a Central Laboratory. Results of analysis tested 
centrally will be reconciled and sent electronically to Novartis (or a designated CRO). 
Unscheduled laboratory analysis performed locally will be collected directly in CRF by the 
sites. 
Samples and/or data for 
 PK sampling, imaging and IRT will be processed 
centrally and the results will be sent electronically to Novartis (or a designated CRO). 
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The system 
will be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Novartis personnel (or designated CRO). 
At the conclusion of the core study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis personnel 
(or designated CRO). The occurrence of any protocol violations will be determined. After these 
actions have been completed and the data has been verified to be complete and accurate, the 
database will be declared locked and the treatment codes will be unblinded and made available 
for data analysis. Authorization is required prior to making any database changes to locked data, 
by joint written agreement between the Global Head of Biostatistics and Data Management and 
the Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
The primary analysis will be performed based on cumulative data collected up to the date when 
all enrolled patients have either completed or prematurely withdrawn from the core phase of 
study. The results and outcomes of this analysis will be presented in a CSR. All additional data 
collected subsequently to the cutoff date for the primary analysis will be included in the analysis 
for the final CSR, which will be performed once all patients have either completed the extension 


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phase or discontinued earlier. Additional database lock/analysis could be performed after the 
primary analysis to support the publication of manuscripts. 
Novartis or designated CRO will analyze all data using the Statistical Analysis System (SAS) 
for data analysis V9.3 or higher. Any data analyses carried out independently by an investigator 
should be submitted to Novartis before publication or presentation. 
The data from all centers participating in the trial will be combined, so that an adequate number 
of patients will be available for analysis. The statistical analysis methods described in this 
section will focus on the analysis of the data in the core study. Similar methods will be applied 
to the analyses in the extension phase as appropriate. 
10.1 
Analysis sets 
10.1.1 
Randomized Analysis Set 
The Randomized Analysis Set (RAS) comprises all randomized patients who have received at 
least one dose of randomized drug (LCI699 or placebo). According to the ITT principle, patients 
will be analyzed according to the treatment and stratum they have been assigned to during the 
randomization. 
10.1.2 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all enrolled patients who receive at least one dose of 
LCI99. This is the default analysis set for efficacy. 
10.1.3 
Safety set 
There are two safety sets defined in this study: 
Safety Analysis Set (SAS) includes all patients who received at least one dose of LCI699 and 
had at least one valid post-baseline safety assessment. 
Safety Analysis Set for randomized withdrawal period (SASR) includes only randomized 
patients who received at least one dose of randomized treatment (LCI699 or placebo) and had 
at least one valid safety assessment during the randomized withdrawal period. 
Please note: the statement that a patient had no adverse events (on the Adverse Event CRF) 
constitutes a safety assessment. 
For safety analysis, patients will be analyzed according to the study treatment received, where 
treatment received is defined as the randomized/assigned treatment if the patient took at least 
one dose of that treatment or the first treatment (first dose of the study for SAS and first dose 
of randomized withdrawal period for SASR) received if the randomized/assigned treatment was 
never received. 
10.1.4 
Per-Protocol set 
There are two per-protocol sets defined in this study: 


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Per-Protocol Set for Randomized Analysis Set (PPRAS) consists of a subset of the patients in 
the RAS who are compliant with the requirements of the Clinical Study Protocol (CSP) and 
have no selected CSR-reportable protocol deviations. 
Per-Protocol Set for Full Analysis Set (PPFAS) consists of a subset of the patients in the FAS 
who are compliant with the requirements of the CSP and have no selected CSR-reportable 
protocol deviations. 
The details of selected CSR-reportable protocol deviations will be provided in the SAP. 
10.1.5 
Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PAS) consists of all patients who receive at least one dose of 
LCI699 and have at least one evaluable pharmacokinetic concentration (post-first-dose) at any 
visit. 
Additional definition of an evaluable PK blood sample will be further specified in the SAP. 
10.1.6 
Other analysis sets 
Not Applicable. 
10.1.6.1 Efficacy/evaluable set 
Not Applicable. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data will be summarized descriptively for the FAS and RAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group using FAS and RAS. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
When appropriate, patients in a given analysis set can be classified into mutually exclusive 
treatment groups as described below: 
For patients in RAS/PPRAS 
 LCI699 group: patients randomized to continued treatment of LCI699 for the randomized 
withdrawal period of the study 
 Placebo group: patients randomized to placebo for the randomized withdrawal period of 
the study 
For patients in FAS/PPFAS 
 LCI699 group: patients randomized to continued treatment of LCI699 for the randomized 
withdrawal period of the study 


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 Placebo group: patients randomized to placebo for the randomized withdrawal period of 
the study 
 Non-randomized patients: patients who do not enter randomized withdrawal period of the 
study 
For patients in SAS 
 LCI699 group: patients receiving continued treatment of LCI699 for the randomized 
withdrawal period of the study 
 Placebo group: patients receiving placebo for the randomized withdrawal period of the 
study 
 Non-randomized patients: patients who do not enter randomized withdrawal period of the 
study 
For patients in SASR 
 LCI699 group: patients receiving continued treatment of LCI699 for the randomized 
withdrawal period of the study 
 Placebo group: patients receiving placebo for the randomized withdrawal period of the 
study 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure (Week) to study drugs will be summarized by means of descriptive 
statistics. 
The number of patients with dose reductions, interruption, or permanent discontinuation and 
the reasons will be listed and summarized by treatment arms, and all dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, preferred term and treatment groups. The doses and 
dosing frequency of concomitant medications for the treatment of hypertension, diabetes, and 
dyslipidemia captured on the concomitant medication CRF, will be taken into account in the 
analysis of safety and efficacy. 
10.4 
Primary objective 
The primary objective is to compare the complete response rates at the end of the 8 weeks period 
of randomized withdrawal (Week 34) between patients randomized to continued LCI699 
therapy vs. placebo. 
10.4.1 
Variable 
The primary efficacy variable is the proportion of randomized patients in each treatment arm 
that are complete responders at the end of the 8 weeks of the randomized withdrawal period 
(Week 34). A complete responder is defined as a patient who has mUFC ≤ ULN (based on 
central laboratory result) at Week 34 and was neither discontinued nor had LCI699 dose 
increase above the level at week 26 during the randomized withdrawal period of the study. 


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Patients who discontinued during the randomized withdrawal period will be counted as non-
responders for the primary endpoint. Dose reductions and temporary dose interruptions for 
safety reason during randomized withdrawal period do not preclude patients from being 
complete responder for primary endpoint. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
For the primary objective, the statistical null hypothesis states that the complete response rates 
at the end of 8-week randomized withdrawal period (i.e., at Week 34) are the same between the 
two randomized arms. To test this hypothesis, a Cochran–Mantel–Haenszel exact test stratified 
by the two stratification factors considered for randomization will be performed using the RAS 
following the intent-to-treat principle. 
If the 2-sided p-value is ≤ 0.05 and the odds ratio (LCI699 vs. Placebo) is > 1, the null 
hypothesis will be rejected and the complete response rate in the LCI699 arm will be considered 
higher than that in the placebo arm. 
10.4.3 
Handling of missing values/censoring/discontinuations 
The mUFC will be determined at a central laboratory from three 24-hour urine specimens 
collected within 7 days from scheduled visit date. The mean of the results from the 3 samples 
will be used to obtain the corresponding mUFC level for a given assessment. If a patient has 
two or more missing UFC values for a particular visit, the mUFC assessment for that patient at 
that visit will be considered missing. Otherwise, the mean of UFC collections will be considered 
as the mUFC level for that visit. 
Randomized patients who discontinued during the randomized withdrawal period or had a 
missing mUFC assessment at end of the randomized withdrawal period (Week 34) will be 
counted as non-responders for the primary endpoint. 
10.4.4 
Supportive and sensitivity analyses 
As a supportive analysis to the primary analysis, an un-stratified Fisher’s exact test of the 
primary endpoint will be performed using RAS. 
In addition, both stratified CMH exact test and un-stratified Fisher’s exact test of the primary 
endpoint will be performed using PPRAS. 
10.5 
Secondary objectives 
10.5.1 
Key secondary objective(s) 
The key secondary objective is to assess the complete response rate (proportion of enrolled 
patients with mUFC ≤ ULN) at the end of 24 weeks of dose-titration and treatment with LCI699 
in the initial single-arm, open label part of this trial. 
The key secondary efficacy variable is the proportion of complete responders at Week 24. A 
complete responder is defined as an enrolled patient who has mUFC ≤ ULN at Week 24 and 
the dose of LCI699 during Study Period 2 (Weeks 13-24) was not increased above the level 
established at the end of Study Period 1 (Week 12). 


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Dose reductions and temporary dose interruptions for safety reasons do not preclude patients 
from being complete responder for the key secondary endpoint. 
Enrolled patients who had missing mUFC assessment at Week 24 will be counted as non-
responders for the key secondary endpoint. 
For the key secondary objective, the statistical null hypothesis states that the complete response 
rate at the end of 24 weeks open label period of LCI699 treatment is ≤ 30%. The analysis of the 
key secondary objective will be based on the 2-sided 95% exact confidence interval (Clopper-
Pearson method). If the lower bound of this 95% confidence interval is ≥ 30%, the null 
hypothesis will be rejected and the complete response rate will be considered at least 30% after 
24 weeks of treatment with LCI699. 
The above testing on the key secondary objective will only be carried out if the null hypothesis 
for the primary objective is rejected. This sequential procedure will ensure preservation of the 
overall 2-sided type 1 error at 5%. 
The primary analysis of the key secondary endpoint will be performed using FAS. An additional 
analysis will be performed using PPFAS. 
10.5.2 
Other secondary efficacy objectives 
10.5.2.1 Compare the time-to-last control of mUFC during the randomized 
withdrawal period between patients randomized to continued LCI699 
and placebo 
Time-to-last control of mUFC during the randomized withdrawal period will be analyzed using 
K-M plot and stratified logrank test. Time-to-last control of mUFC is defined as the time (in 
days) from randomization to the time of the last normal UFC assessment (mUFC ≤ ULN based 
on central laboratory result) before early discontinuation or completion of randomized 
withdrawal period, whichever is earlier. RAS will be used for this analysis. 
10.5.2.2 Assess the complete, partial, and overall response rate at Week 12, 
Week 24,Week 48, and during the extension period 
Proportion of complete responder (enrolled patients with mUFC ≤ ULN), partial responder 
(enrolled patients with mUFC > ULN and at least 50% reduction from baseline), and overall 
responder (enrolled patients with mUFC ≤ ULN or have at least 50% reduction from baseline) 
at Week 12 (end of period 1), Week 24 (end of period 2) and Week 48 (end of period 4) as well 
as at scheduled time points during the extension period (provided adequate follow-up as 
specified in the SAP) and the last available assessment will be summarized using point estimates 
and 95% CIs. 
10.5.2.3 Assess the change in mUFC during the core and extension period of 
the study 
For the actual and percentage change in mUFC from baseline, descriptive summaries will be 
provided for every visit in core and extension (provided adequate follow-up as specified in the 
SAP) at which UFC is collected. 95% CIs for the percentage change from baseline will also be 
provided. 


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For the actual and percentage change in mUFC from the randomization (Week 26) to the end 
of randomized withdrawal period, or the last mUFC measurement prior to early discontinuation, 
whichever occurs earlier, in addition to the descriptive summaries, the difference between two 
randomized arm and associated 95% C.I. will be estimated with adjustment for mUFC at 
randomization. RAS will be used for the analysis. 
10.5.2.4 Assess the change in cardiovascular-related metabolic parameters 
associated with Cushing’s disease during the core and extension 
period of the study 
For cardiovascular-related metabolic parameters associated with Cushing’s disease (e.g. fasting 
glucose, HbA1c, fasting lipid profile, SBP, DBP, weight, waist circumference and BMI): 
For actual and percentage change from baseline during the core and extension period (provided 
adequate follow-up as specified in the SAP) of the study, descriptive summaries will be 
provided. 
For the actual and percentage change from the randomization (Week 26) to the end of 
randomized withdrawal period, or the last measurement available prior to early discontinuation, 
whichever occurs earlier, in addition to the descriptive summary, the difference between two 
randomized arm and associated 95% C.I. will be estimated with adjustment for corresponding 
parameter value at randomization. RAS will be used for the analysis. 
10.5.2.5 Assess the change from baseline in physical features of Cushing’s 
disease by photography 
For each of physical features of Cushing’s disease: facial rubor, hirsutism, striae, 
supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) 
obesity, and ecchymoses (bruises). The change from baseline at Week 12, 24, 34 and 48 as well 
as during the extension at Week 72 and EOT extension will be assessed using shift table. 
10.5.2.6 Assess the change from baseline in bone mineral density by DXA scan 
at Week 48 and the last available assessment 
For bone mineral density measured by DXA scan at the lumbar spine and total hip, descriptive 
summaries of actual and percentage change from baseline at Week 48 and the last available 
assessment will be provided. 
10.5.2.7 Assess the time-to-escape under treatment of LCI699 
Escape is defined as the first loss of control of UFC that meets all of the following criteria: 
 prior normalization of mUFC has occurred (mUFC≤ULN) 
 both the mean UFC and at least 2 individual values contributing to that mUFC have to be 
>1.5 x ULN 
 the loss of control of UFC is not related to a dose interruption or dose reduction due to 
safety reasons 
 happens beyond 12-week dose titration period (Study Period 1). 


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For patients who attained normal mUFC (≤ ULN), time-to-escape will be analyzed using K-M 
plot. Time-to-escape is defined as the time (in days) between the first UFC assessment with 
mUFC ≤ ULN and either the UFC assessment of escape (event) or last UFC assessment before 
discontinuation of LCI699 treatment (censored), whichever occurs earlier. 
Patients randomized to placebo are not included in this analysis. 
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
Analysis set and treatment groups (see Section 10.1 and Section 10.3) used for safety analyses 
will be described below: 
 For study period up to Week 26: SAS by All patients only. 
 For randomized withdrawal period: SASR by LCI699 group and Placebo group 
 For overall study period while on LCI699: SAS by LCI699 group, Placebo group, Non-
randomized patients, and all patients. 
 In addition to the above mentioned analysis, other post-treatment safety data collected will 
be included in listings and flagged as appropriate. 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 31 after last dose of study medication 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. However, all safety data (including 
those from the pre and post-treatment periods) will be listed and those collected during the pre-
treatment and post-treatment period are to be flagged. The incidence of treatment-emergent 
adverse events (new or worsening from baseline) will be summarized by system organ class 
and or preferred term, severity (based on CTCAE version 4.03 grades), type of adverse event, 
relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated. 
All deaths will be listed. 
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 


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10.5.3.3 Laboratory abnormalities 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry and 
urinary laboratory tests: 
 Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE v4.03 
 Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 
 Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
value 
For laboratory tests where grades are not defined by CTCAE v4.03, shift tables based on the 
low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value. In addition to the above mentioned tables and listings, other exploratory 
analyses, for example figures plotting time course of raw or change in laboratory tests over time 
or box plots might be specified in the SAP. 
10.5.3.4 Other safety data 
ECG 
ECG data will be summarized with 
 shift table baseline to worst on-treatment result for overall assessments 
 Number and percentage of patients with clinically notable QT/QTcF interval values will 
be summarized. 
 listing of ECG evaluations for all patients with at least one abnormality. 
Vital signs 
Vital signs (supine BP, HR & temperature) reporting of results will include 
 shift table baseline to worst on-treatment result 
 table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 


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Tumor volume 
For tumor volume evaluated by MRI (or CT) scanning, descriptive summary of actual tumor 
volumes as well as its actual and percent change from baseline will be provided. The number 
and percentage of patients with newly occurring measurable tumor and/or new evidence of 
tumor invasion into surrounding structures during the study will be calculated. For MRI (or CT) 
images that are not interpretable for tumor volume, the longest dimension (in mm) will be 
summarized instead. 
10.5.3.5 Supportive analyses for secondary objectives 
Not applicable. 
10.5.3.6 Tolerability 
Tolerability will be studied in terms of dose reductions or drug interruption due to an AE. 
10.5.4 
Pharmacokinetics 
The PAS will be used in all pharmacokinetic data analysis and summary statistics. 
As sparse pharmacokinetic sampling is performed in this study, traditional non-compartmental 
analysis will not be performed to calculate pharmacokinetic parameters. Plasma concentration 
data of LCI699 will be listed by patient, visit, incident dose and nominal sampling times. 
Descriptive statistics of plasma concentrations will be provided by incident dose, visit and 
nominal sampling times. Graphical depiction (mean and individual) for LCI699 concentrations 
and/or profiles (if applicable) during the course of the study will be performed by incident dose 
and visit. Additional details on PK data analysis will be specified in the SAP. 
PK data generated from this study will be used in conjunction with PK data from other clinical 
studies in population PK assessment. Patient demographics (e.g. age, gender, ethnicity, weight) 
will be explored as covariates, if appropriate. The broad principles outlined in the FDA 
“Guidance for Industry: Population Pharmacokinetics” will be followed during the population 
PK analysis. The results of population PK assessment will be presented in a separate report. 
[(China only) Plasma concentration data of LCI699 will be listed by patient, visit, incident dose 
and nominal sampling times. Descriptive statistics of plasma concentrations will be provided 
by incident dose, visit and nominal sampling times. For the extensive sampling profiles, 
graphical depiction (mean and individual) for LCI699 concentrations and/or profiles (if 
applicable) during the course of the study will be performed by incident dose and visit. 
Descriptive statistics will be reported for all PK parameters (including AUClast, AUCinf, 
Cmax, Tmax, T1/2, Cl/F, Vz/F) for LCI699 from the extensive sampling profiles. For sparse 
sampling data, traditional non-compartmental analysis will not be performed. PK data from this 
study will be used in conjunction with PK data from other clinical studies in population PK 
assessment.] 
10.5.4.1 Data handling principles 
Plasma concentrations of LCI699 will be expressed in ng/mL. Missing concentration values 
will be labeled as such in data listings. Concentrations below the limit of quantitation (LLOQ) 
will be treated as zero in summary statistics and reported as zero in data listings. 


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10.5.6 
Resource utilization 
Not Applicable. 
10.5.7 
Patient-reported outcomes 
The CushingsQoL score is identified as the primary PRO variable of interest. EQ-5D utility 
index and visual analogue scale (VAS) scores, and Beck Depression Inventory-II (BDI) total 
score are identified as secondary PRO variables of interest. The FAS will be used for analyzing 
PRO data. No multiplicity adjustment will be applied. 
Change from Week 24 in the CushingsQoL score during Study Period 3 will be analyzed using 
a linear mixed effect model for longitudinal data to assess the treatment effect over time 
including terms for treatment, stratification factors, time of visit (in weeks counting from the 
time of randomization to the time of a particular post baseline measurement), treatment by time 
of visit interaction, and Week 24 score. The differences in least square means between LCI699 
and placebo group, and the corresponding 2-sided 95% confidence interval (CI) at each 
timepoint will be presented. Descriptive statistics will be used to summarize the raw and 
absolute change from baseline for the scores at each scheduled assessment during the core and 
extension periods (Week 72, 96, and EOT extension) of the study. 
Similar analyses will be performed for EQ-5D utility index and visual analogue scale (VAS) 
scores, and Beck Depression Inventory-II (BDI) total score. 
Missing items data in a scale will be handled based on each instrument manual. Additional 
details for handling missing items data will be specified in the analysis plan for instruments 
with no missing data handling criteria in the instrument manual. 
No imputation will be applied if the total scores are missing at a visit. Patients with Week 26 
and at least one non-missing post-Week 24 assessments during the Study Period 3 will be 
included in the linear mixed effect model analysis. All available data until completion or early 
discontinuation during Period 3 will be used in the linear mixed effect models analyses which 
assume that the missing scores at any time point are missing-at-random. Additional sensitivity 
analysis may be performed to assess the possible violation of missing-at-random assumption 
for the missing data mechanism if deemed appropriate. Details will be specified in the SAP. 


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10.7 
Interim analysis 
The study has no planned interim analysis for efficacy. 


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10.8 
Sample size calculation 
Eligible patients will be stratified at randomization according to: LCI699 dose at Week 24 (≤ 
5mg bid vs. > 5mg bid); and history of pituitary irradiation (yes/no). It is estimated that 10 %, 
40%, 10% and 40 % of randomized patients respectively will be in the 4 strata defined by two 
randomization stratification factors (≤ 5mg b.i.d and Yes; ≤ 5mg b.i.d and No; > 5mg b.i.d. and 
Yes; and > 5mg b.i.d. and No) based on the following considerations: 
1. LCI699 dose at week 24 (≤ 5mg b.i.d. vs. > 5mg b.i.d.): Based on the data from the PoC 
study, 5mg b.i.d. is estimated to be the median LCI dose at week 24 for this phase 3 trial. 
2. History of pituitary irradiation (Yes/No): Although supportive data is not available, it is 
assumed that approximately 20% of randomized patients will have a history of pituitary 
radiation. 
3. In the absence of data to expect otherwise, it is assumed that these two stratification 
factors are independent of each other. 
To detect a difference of 40% in complete response rate between 70% in LCI699 arm and 30% 
in placebo arm (equivalent odds ratio equals 5.444), a sample size of 33 patients per arm will 
be considered adequate based on a two-sided Cochran-Mantel-Haenszel (CMH) test at the 0.05 
level with 87% power. Assuming that ≥ 50% of enrolled patients will be eligible for 
randomization (mUFC ≤ ULN at the end of the 24 week open-label LCI699 study period), 132 
patients need to be enrolled into the study. 
10.9 
Power for analysis of key secondary variables 
The analysis of the key secondary objective will be based on the 2-sided 95% confidence 
interval constructed using the Clopper-Pearson exact method. If the lower bound of this 95% 
confidence interval is ≥ 30%, the null hypothesis will be rejected and the complete response 
rate will be considered at least 30% after 24 weeks of treatment with LCI699. 
The above testing on the key secondary objective will only be carried out if the null hypothesis 
for the primary objective is rejected. This sequential procedure will ensure preservation of the 
overall 2-sided type 1 error at 5%. 
Assuming a 50% complete response rate (mUFC ≤ ULN) at end of 24 weeks of LCI699 
treatment, for 132 enrolled patients, there is 99.7% chance that the lower bound of 95% 2-sided 
C.I. of observed response rate (based on Clopper-Pearson Exact method) is larger than 30.0%. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 


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11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4. 


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11.5 
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 study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.5.1 
Communication and publication of clinical trial results 
Novartis is committed to upholding the highest ethical standards for reporting the results of 
medical research, including the timely communication and publication of clinical trials results, 
whatever their outcome. 
Novartis complies with the authorship guidelines of the International Committee of Medical 
Journal Editors (ICMJE) uniform requirements for manuscripts submitted to biomedical 
journals and other specific guidelines of the journal or congress to which the document will be 
submitted. These guidelines apply to any clinical trial publication including but not limited to 
manuscripts, abstracts, posters, and oral presentations. For more information regarding the 
ICMJE guidelines, visit http://www.ICMJE.org/index.html#author. 
Accordingly, ALL AUTHORS MUST HAVE: 
 Contributed substantially to the study concept, design and/or conduct of the study or to the 
acquisition, analysis, and interpretation of the data AND 
 Drafted or critically revised the proposed clinical publication for important intellectual 
content AND 
 Approved the final proposed clinical publication for submission AND 
 Have intimate knowledge of trial implementation/analysis 
Substantial contribution for primary publication is defined as having active and ongoing 
participation in the study. Study steering committee members must have significant 
involvement to study concept, design, and data interpretation and patient recruitment. Each 
steering committee member must have attended the majority of the steering committee meetings 
and recruited patients into the trial from his/her own center to be included as an author. Study 
investigators must have significant contribution to patient recruitment based on number of 
eligible patients upon study entry and data quality. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 


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clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Consult with DRA whether the study need to be covered by financial disclosures. 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 


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to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
References (available upon request) 
 
 
 
Arnaldi G, Angeli A, Atkinson AB, et al (2003). Diagnosis and Complications of Cushing’s 
Syndrome: A Consensus Statement. J Clin Endocrinol Metab; 88(12):5593-5602. 
Arnaldi G, Mancini T, et al (2012). Advances in the epidemiology, pathogenesis, and 
management of Cushing's syndrome complications. J Endocrinol Invest. 35: 434-448. 
Arnardottir S, Sigurjonsdottir H (2011). The incidence and prevalence of Cushing’s disease 
may be higher than previously thought: results from a retrospective study in Iceland 1955 
through 2009. Clin Endocrinol. 74(6): 792-793. 
Assie G, Bahurel H, Coste J, et al (2007). Corticotroph tumor progression after adrenalectomy 
in Cushing’s disease: a reappraisal of Nelson’s syndrome. J Clin Endocrinol Metab 
92(1):172–179. 
Ayuk J (2012). Does Pituitary Radiotherapy Increase the Risk of Stroke and, if so, What 
Preventative Actions Should be Taken? Clin Endocrinol. 76(3):328-331. 
Biller BMK, Grossman AB, Stewart PM, et al (2008). Treatment of 
adrenocorticotropindependent Cushing’s Syndrome: a consensus statement. J Clin Endocrinol 
Metab; 93(7):2454-62. 
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. 
Bolland M, Holdaway I, et al (2011). Mortality and morbidity in Cushing’s syndrome in New 
Zealand. Clin Endocrinol. 75: 436-442. 
Broder M, Neary M, Chang E, et al (2013). Incidence of Cushing’s Disease in the United 
States. Endocr Rev, 34: (Abstract MON-91). 
Chan K, Lit L, Law E, et al (2004). Diminished Urinary Free Cortisol Excretion in Patients 
with Moderate and Severe Renal Impairment. Clinical Chemistry, 50 (4): 757-759. 
Clayton R, et al (2011). Mortality and Morbidity in Cushing’s Disease over 50 Years in 
Stoke-on-Trent, UK: Audit and Meta-Analysis of Literature. J Clin Endocrinol Metab. 96(3): 
632-642. 
Daly A, Rixhon M, et al (2006). High Prevalence of Pituitary Adenomas: A Cross-Sectional 
Study in the Province of Lie`ge, Belgium. J Clin Endo and Met. 91(12): 4769-4775. 
Etxabe J, Vazquez JA (1994). Morbidity and mortality in Cushing's disease: an 
epidemiological approach.Clin Endocrinol (Oxf) 40 (4):479–484. 
FDA Draft Guidance for Industry on Enrichment Strategies for Clinical Trials to Support 
Approval of Human Drugs and Biological Products, December 2012. 
Feelders R, Pulgar S, Kempel A, et al (2012). The burden of Cushing’s disease: clinical and 
health-related quality of life aspects. Eur J Endocrinol 167: 311–326. 


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Fleseriu M, Loriaux DL, Ludlam WH (2007). Second-line treatment for Cushing's disease 
when initial pituitary surgery is unsuccessful. Curr Opin Endocrinol Diabetes Obes 2007 Aug; 
14(4):323-8. 
Friedman R, et al (1989). Repeat transsphenoidal surgery for Cushing’s disease. J 
Neurosurgery 71(4):520–527. 
Issa B, Page M, Read G, et al (1999). Undetectable urinary free cortisol concentrations in a 
case of Cushing’s disease. European Journal of Endocrinology 140: 148–151. 
Lindholm J, Juul S, et al (2001). Incidence and Late Prognosis of Cushing’s Syndrome: A 
Population-Based Study*. J Clin Endo & Metab. 86(1): 117-123. 
Loeffler J, Shih H (2011). Radiation Therapy in the Management of Pituitary Adenomas. J 
Clin Endocrinol Metab: 96(7):1992–2003. 
Losa M, et al (2010). Pituitary Radiotherapy for Cushing’s Disease. Neuroendocrinology 92 
(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, et al (2007). Long-term follow-up results of postoperative radiation therapy for 
Cushing’s disease. J Neurooncol 84(1):79–84. 
Monaghan P, Keevil B, Stewart P, et al (2014). Case for the Wider Adoption of Mass 
Spectrometry- Based Adrenal Steroid Testing, and Beyond. J Clin Endocrinol Metab 99 (12): 
4434–4437. 
Nelson L, Forsythe A, McLeod L, et al (2013). Psychometric Evaluation of the Cushing’s 
Quality-of-Life. The Patient - Patient-Centered Outcomes Research; 6(2): 113-124. 
Newell-Price J, Bertagna X, Grossman AB, et al (2006). Cushing’s syndrome. Lancet 2006; 
367(9522): 1605–17. 
Sedney C, Morris J, Giannini C, et al (2012). Radiation-associated sarcoma of the skull base 
after irradiation for pituitary adenoma. Rare Tumors 4(1): e7. 
Sharp N, Devlin J, Rimmer J, et al (1986). Renal Failure Obfuscates the Diagnosis of 
Cushing's Disease. JAMA – Vol. 256 (18): 2564-2565. 
Sheehan J, Xu Z, Salvetti D, et al (2013). Results of Gamma Knife surgery for Cushing’s 
disease. J Neurosurg 119:1486–1492. 
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(7), 
2647-2652. 
Valassi E, et al (2012). Clinical consequences of Cushing’s syndrome. Pituitary. 15: 319-329. 
Webb S, Badia X, Barahona M, et al (2008). Evaluation of health-related quality of life in 
patients with Cushing’s syndrome with a new questionnaire. European Journal of 
Endocrinology; 158: 623–630. 
Zhang G, Wang B, Ouyang J, et al (2010). Polymorphisms in CYP11B2 and CYP11B1 genes 
associated with primary hyperaldosteronism. Hypertension Research; 33: 478–484. 


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14 
Appendices 
14.1 
Appendix 1: Summary of Common Toxicity Criteria for Adverse 
Events v4.03 (CTCAE) 
Table 14-1 
List of summary of Common Toxicity Criteria for Adverse Events 
v4.03 (CTCAE) 
Grade 
Definition of Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL* 
3 
Severe or medically significant but not immediately life-threatening hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL** 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 


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14.2 
Appendix 2: List of drugs to be used with caution with LCI699 
Table 14-2 
List of medications with potential drug-drug interactions with LCI699 – 
to be used with caution 
CYP1A2 
substrates 
CYP2C19 
substrates 
CYP2D6 substrates 
CYP3A4/5 substrates 
CYP2E1 substrates 
Atypical 
antipsychotics: 
Clozapine 
Olanzapine 
Xanthines: 
Caffaine1 
Theophylline2 
Others: 
Nabumetone 
Riluzole 
Ropivacaine 
Zolmitriptan 
Alosetron1 
Duloxetine1 
Melatonin1 
Ramelteon1 
Tacrine1 
Tizanidine1,2 
Anti-epileptics: 
Diazepam 
Phenytoin 
Phenobarbitone 
S-mephenytoin1,2 
Benzodiazepines: 
Clobazam1 
Proton pump 
inhibitors: 
Lansoprazole1 
Omeprazole1 
Pantoprazole 
Rabeprazole 
Esoprazole 
Antidepressants: 
Amitriptyline 
Clomipramine 
Others: 
Clopidogrel 
Moclobemide 
Proguanil 
Antipsychotics: 
Aripiprazole 
Chlorpromazine 
Clozapine 
Fluphenazine 
Haloperidol 
Iloperidone 
Pimozide 
Risperidone 
Perphenazine1 
Thioridazine2 
Antiarrhythmics: 
Encainide 
Flecaninide 
Mexilletine 
Prajmaline 
Procainamide 
Propafenone 
Sparteine 
Vernakalant 
Alpha/Beta-
adrenergic 
antagonists: 
Metoprolol1 
Nebivolol1 
Carvedilol 
Propranolol 
Tamsulosin 
Timolol 
Serotonin 
modulators: 
Venlafaxine1 
Citalopram 
Duloxetine 
Fluoxetine 
Fluvoxamine 
Nefazodone 
Ondansetron 
Paroxetine 
Repinotan 
Trazodone 
Tropisetron 
Tricyclics/ 
tetracyclics: 
Desipramine1 
Antiarrhythmics: 
Quinidine2 
Dronedarone1 
Antihistimines: 
Astemizole2 
Ebastine1 
Terfenadine1,2 
Benzodiazepines: 
Brotizolam1 
Midazolam1 
Triazolam1 
Alprazolam 
Diazepam 
Calcium channel 
blockers: 
Felodipine1 
Nisoldipine1 
Amlodipine 
Diltiazem 
Nifedipine 
Nitrendipine 
Verapamil 
Protease inhibitors: 
Brecanavir1 
Capravirine1 
Darunavir1 
Indinavir1 
Lopinavir1 
Saquinavir1 
Tipranavir1 
Boceprevir 
Ritonavir 
Telaprevir 
HMG CoA reductase 
inhibitors: 
Atorvastatin1 
Lovastatin1 
Simvastatin1 
Antibiotics: 
Clarithromycin 
Erythromycin 
Telithromycin 
Antipsychotics: 
Aripiprazole 
Haloperidol 
Enflurane 
Halothane 
Isoflurane 
Methoxyflurane 
Sevoflurane 
Acetaminophen 
Chlorzoxazone 
Ethanol 
N, N-
Dimethylformamide 
Theophylline 


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Amitriptyline 
Clomipramine 
Doxepin 
Imipramine 
Maprotiline 
Mianserin 
Mirtazapine 
Nortriptyline 
Trimipramine 
Opiods: 
Codeine 
Dihydrocodeine 
Hydrocodone 
Methadone 
Oxycodone 
Tramadol 
Others: 
Atomoxetine1 
Dextromethorphan1 
Tolterodine1 
Amiflamine 
Brofaromine 
Chlorpheniramine 
Debrisoquine 
Dexfenfluramine 
Donepezil 
Fesoterodine 
Gefitinib 
Lasofoxifene 
Loratadine 
Methamphetamine 
Methoxyphenamine 
Methylphenidate 
Nicergolin 
Pactimibe 
Phenformin 
Ranolazine 
Ratonavir 
Sabeluzole 
Tamoxifen 
Traxoprodil 
Lurasidone1 
Perospirone1 
Pimozide2 
Quetiapine1 
Immune Modulators: 
Cyclosporine2 
Everolimus1 
Sirolimus1,2 
Tacrolimus1,2 
Tyrosine Kinase 
Inhibitors: 
Dasatinib1 
Neratinib1 
Imatinib 
Nilotinib 
Opioids: 
Alfentanil1,2 
Fentanyl2 
Levomethadyl1 
Methadone 
Others: 
Quinine 
Tamoxifen 
Trazodone 
Vincristine 
Ergot derivatives: 
Diergotamine/ 
Dihydroergotamin2 
Ergotamine2 
Erectile dysfunction 
agents: 
Sildenafil1 
Vardenafil1 
Antiemetics: 
Aprepitant1 
Casopitant1 
Others: 
Alpha-
dihydroergocryptine1 
Aplaviroc1 
Buspirone1 
Cisapride2 
Conivaptan1 
Darifenacin1 
Eletriptan1 
Eplerenone1 
Lumefantrine1 
Maraviroc1 
Ridaforolimus1 
Ticagrelor1 
Tolvaptan1 


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Vicriviroc1 
1 Sensitive substrates: drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor. 
2 Substrates with narrow therapeutic index: drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns. 
This database of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; from the FDA’s “Guidance for Industry, Drug Interaction Studies” and from the University of 
Washington’s Drug Interaction Database. 


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14.3 
Appendix 3: Medications with a “Known risk to cause TdP” and 
with a “Possible risk to cause TdP” 
The following e-link provides a list of medications with a “known risk to cause TdP” and with 
a “possible risk to cause TdP”. These medications are prohibited to be used concomitantly with 
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. If necessary, a discussion can be 
held with the Novartis Medical Monitor when considering the use of medications with a “known 
risk to cause TdP” and with a “possible risk to cause TdP”. 


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14.4 
Appendix 4: Patient Quality of Life questionnaires 
EQ-5D-5L Questionnaire 
Under each heading, please check the ONE box that best describes your health TODAY 
MOBILITY 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 


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


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


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


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


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


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