Clinical trial NCT02697734
Conditions: Cushing's Disease
Keywords: Cushing's disease LCI699 osilodrostat Pituitary Gland Adrenocorticotropic Hormone ACTH UFC
Sponsor: Novartis Pharmaceuticals
Start date: 2016-10-03; Completion date: 2020-12-31
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy.

Detailed description:
The study LCI699C2302 (LINC-4) is a multi-center, randomized, double-blind study to evaluate the safety and efficacy of osilodrostat in patients with Cushing's disease.

Enrolled patients were initially randomized to either osilodrostat or placebo, in a 2:1 ratio, for a 12-week double-blind period (Period 1). Randomization was stratified by history of pituitary radiation. After Week 12, all patients received open-label osilodrostat until the end of the Core phase at Week 48 (Period 2).

After Week 48, patients could join an optional 48 week extension period.

Arms: arm 1: Participants in this arm were randomized to receive the study drug, osilodrostat followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration) arm 2: Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration)
Interventions: intervention 1: osilodrostat intervention 2: osilodrostat Placebo
Intervention descriptions: intervention 1: In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg. intervention 2: Matching Placebo in the form of filmcoated tablets for oral administration

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Clinical Development 
LCI699 (osilodrostat) 
Oncology Clinical Trial Protocol CLCI699C2302 / NCT02697734 
 A Phase III, multi-center, randomized, double-blind, 48 
week study with an initial 12 week placebo-controlled 
period to evaluate the safety and efficacy of osilodrostat in 
patients with Cushing’s disease  
Document type 
Amended Protocol Version 
EUDRACT number 
2014‐004092‐23 
Version number 
02 Clean 
Development phase 
III 
Document status 
Final 
Release date 
20-Dec-2019 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
 
Template version 02-Dec-2013 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 10 
Amendment 2 (20-Dec-2019) ............................................................................................ 11 
Amendment 1 (20-Nov-2017) ........................................................................................... 15 
Protocol summary: ............................................................................................................. 19 
1 
Background ........................................................................................................................ 24 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 24 
1.1.1 
Epidemiology and pathogenesis of Cushing’s syndrome and 
Cushing’s disease .................................................................................. 24 
1.1.2 
Current treatment modalities ................................................................. 25 
1.1.3 
Unmet medical need .............................................................................. 26 
1.2 
Introduction to investigational treatment, osilodrostat .......................................... 26 
1.2.1 
Overview of osilodrostat ....................................................................... 26 
2 
Rationale ............................................................................................................................ 33 
2.1 
Study rationale and purpose................................................................................... 33 
2.2 
Rationale for the study design ............................................................................... 34 
2.2.1 
Overall design ....................................................................................... 34 
2.2.2 
Period 1: Double-blind, placebo-controlled .......................................... 34 
2.2.3 
Period 2: Open-label ............................................................................. 35 
2.2.4 
Optional Extension Phase ..................................................................... 35 
2.2.5 
Steps to ensure reliability of UFC results ............................................. 35 
2.2.6 
ECG Monitoring.................................................................................... 36 
2.3 
Rationale for dose and regimen selection .............................................................. 36 
2.4 
Rationale for choice of combination drugs ............................................................ 37 
2.5 
Rationale for choice of comparators drugs ............................................................ 37 
2.6 
Benefit-Risk Assessment of osilodrostat in study population ............................... 37 
2.7 
Biomarker development......................................................................................... 39 
 
 40 
3 
Objectives and endpoints ................................................................................................... 41 
4 
Study design ...................................................................................................................... 44 
4.1 
Description of study design ................................................................................... 44 
4.2 
Timing of interim analyses and design adaptations ............................................... 47 
4.3 
Definition of end of the study ................................................................................ 47 


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4.4 
Early study termination.......................................................................................... 48 
5 
Population .......................................................................................................................... 48 
5.1 
Patient population .................................................................................................. 48 
5.2 
Inclusion criteria .................................................................................................... 48 
5.3 
Exclusion criteria ................................................................................................... 49 
6 
Treatment ........................................................................................................................... 51 
6.1 
Study drug .............................................................................................................. 51 
6.1.1 
Dosing regimen ..................................................................................... 52 
6.1.2 
Ancillary treatments .............................................................................. 52 
6.1.3 
Rescue medication for co-morbid conditions ....................................... 52 
6.1.4 
Guidelines for continuation of treatment .............................................. 53 
6.1.5 
Treatment duration ................................................................................ 53 
6.2 
Dose titration guidelines ........................................................................................ 54 
6.2.1 
Study Period 1: The double-blind, placebo-controlled period 
(Weeks 1-12). ........................................................................................ 54 
6.2.2 
Study Period 2:  The single-arm, open-label dose titration period 
(Weeks 12-48) ....................................................................................... 56 
6.2.3 
Extension phase (Weeks 48 - 96): ......................................................... 57 
6.3 
Dose modifications ................................................................................................ 57 
6.3.1 
Dose modification and dose delay ........................................................ 57 
6.3.2 
Guidance for evaluation and management of hypocortisolism ............. 61 
6.3.3 
Follow-up for toxicities ......................................................................... 62 
6.3.4 
Anticipated risks and safety concerns of the study drug ....................... 63 
6.4 
Concomitant medications ...................................................................................... 63 
6.4.1 
Permitted concomitant therapy ............................................................. 63 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 63 
6.4.3 
Prohibited concomitant therapy ............................................................ 64 
6.5 
Patient numbering, treatment assignment or randomization ................................. 65 
6.5.1 
Patient numbering ................................................................................. 65 
6.5.2 
Treatment assignment or randomization ............................................... 65 
6.5.3 
Treatment blinding ................................................................................ 66 
6.6 
Study drug preparation and dispensation ............................................................... 66 
6.6.1 
Study drug packaging and labeling ....................................................... 67 
6.6.2 
Drug supply and storage ........................................................................ 68 
6.6.3 
Study drug compliance and accountability ........................................... 68 
6.6.4 
Disposal and destruction ....................................................................... 68 
7 
Visit schedule and assessments ......................................................................................... 69 


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7.1 
Study flow and visit schedule ................................................................................ 69 
7.1.1 
Screening ............................................................................................... 81 
7.1.2 
Run-in period ........................................................................................ 83 
7.1.3 
Treatment phase .................................................................................... 83 
7.1.4 
Discontinuation of Study drug .............................................................. 83 
7.1.5 
Withdrawal of Consent ......................................................................... 85 
7.1.6 
Follow-up period ................................................................................... 85 
7.1.7 
Lost to follow-up ................................................................................... 86 
7.2 
Assessment types ................................................................................................... 86 
7.2.1 
Efficacy assessments ............................................................................. 86 
7.2.2 
Safety and tolerability assessments ....................................................... 88 
7.2.3 
Pharmacokinetics .................................................................................. 96 
 
 98 
7.2.5 
Resource utilization ............................................................................. 101 
7.2.6 
Patient reported outcomes ................................................................... 101 
8 
Safety monitoring and reporting ...................................................................................... 104 
8.1 
Adverse events ..................................................................................................... 104 
8.1.1 
Definitions and reporting .................................................................... 104 
8.1.2 
Laboratory test abnormalities .............................................................. 106 
8.1.3 
Adverse events of special interest ....................................................... 106 
8.2 
Serious adverse events ......................................................................................... 108 
8.2.1 
Definitions ........................................................................................... 108 
8.2.2 
Reporting ............................................................................................. 108 
8.3 
Emergency unblinding of treatment assignment ................................................. 109 
8.4 
Pregnancies .......................................................................................................... 110 
8.5 
Warnings and precautions.................................................................................... 110 
8.6 
Data Monitoring Committee ................................................................................ 110 
8.7 
Steering Committee ............................................................................................. 111 
9 
Data collection and management ..................................................................................... 111 
9.1 
Data confidentiality ............................................................................................. 111 
9.2 
Site monitoring .................................................................................................... 111 
9.3 
Data collection ..................................................................................................... 112 
9.4 
Database management and quality control .......................................................... 112 
10 Statistical methods and data analysis .............................................................................. 113 
10.1 
Analysis sets ........................................................................................................ 114 
10.1.1 
Full Analysis Set ................................................................................. 114 


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10.1.2 
Safety Set ............................................................................................ 114 
10.1.3 
Per-Protocol Set .................................................................................. 114 
10.1.4 
Pharmacokinetic analysis set ............................................................... 114 
10.1.5 
Other analysis sets ............................................................................... 114 
10.2 
Patient demographics/other baseline characteristics ........................................... 114 
10.3 
Treatments (study drug, concomitant therapies, compliance) ............................. 114 
10.4 
Primary objective ................................................................................................. 115 
10.4.1 
Variable ............................................................................................... 115 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 115 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 115 
10.4.4 
Supportive and sensitivity analyses .................................................... 116 
10.5 
Secondary objectives ........................................................................................... 116 
10.5.1 
Key secondary objective(s) ................................................................. 116 
10.5.2 
Other secondary efficacy objectives ................................................... 117 
10.5.3 
Safety objectives ................................................................................. 118 
10.5.4 
Pharmacokinetics ................................................................................ 121 
 
 121 
10.5.6 
Resource utilization ............................................................................. 121 
10.5.7 
Patient-reported outcomes ................................................................... 121 
 
 122 
 
 
 122 
 
 122 
 
 122 
 
 123 
 
 123 
10.7 
Interim analysis .................................................................................................... 123 
10.8 
Sample size calculation........................................................................................ 123 
10.9 
Power for analysis of key secondary variables .................................................... 123 
11 Ethical considerations and administrative procedures .................................................... 124 
11.1 
Regulatory and ethical compliance ...................................................................... 124 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 124 
11.3 
Informed consent procedures ............................................................................... 124 
11.4 
Discontinuation of the study ................................................................................ 125 
11.5 
Publication of study protocol and results............................................................. 125 
11.5.1 
Communication and Publication of Clinical Trial Results ................. 125 


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11.6 
Study documentation, record keeping and retention of documents ..................... 126 
11.7 
Confidentiality of study documents and patient records ..................................... 127 
11.8 
Audits and inspections ......................................................................................... 127 
11.9 
Financial disclosures ............................................................................................ 127 
12 Protocol adherence .......................................................................................................... 127 
12.1 
Amendments to the protocol ................................................................................ 127 
13 References (available upon request) ................................................................................ 128 
14 Appendices ...................................................................................................................... 131 
Appendix 1: List of drugs to be used with caution with osilodrostat .............................. 131 
Appendix 2: Medications with a “Known risk to cause TdP” and with a “Possible 
risk to cause TdP” ................................................................................................ 134 
Appendix 3: 
Normal ranges for cardiovascular risk factors .................................... 135 
 
List of figures 
Figure 1-1 
Mechanism of action of osilodrostat in Cushing’s Disease .................. 27 
Figure 1-2 
Arithmetic mean and SE plots for fold ULN of mUFC (PD analysis 
set) ......................................................................................................... 30 
Figure 1-3 
Mean (+/-SE) mUFC (nmol/24h) over time by cohort ......................... 31 
Figure 4-1 
Schematic of Period 1 ........................................................................... 44 
Figure 4-2 
Timing of study visits, UFC collection, and dose adjustments 
during Period 1 ...................................................................................... 45 
Figure 4-3 
Schematic of Core study design ............................................................ 47 
Figure 6-1 
Appearance of osilodrostat tablets by strength ..................................... 52 
Figure 7-1 
Sequence of cardiovascular data collection .......................................... 94 
Figure 7-2 
QT Monitoring Flow Chart ................................................................... 96 
 


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List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 41 
Table 6-1 
Dose Modification Guidelines for osilodrostat-suspected toxicities .... 58 
Table 6-2 
Criteria for interruption and re-initiation of osilodrostat for 
abnormal liver function ......................................................................... 60 
Table 6-3 
Preparation and dispensing ................................................................... 67 
Table 6-4 
Packaging and labeling ......................................................................... 68 
Table 6-5 
Supply and storage of study drugs ........................................................ 68 
Table 7-1a 
Visit evaluation schedule – Core – Period 1 ......................................... 70 
Table 7-1b 
Visit evaluation schedule– Core (continued) – Period 2 ....................... 75 
Table 7-2 
Visit evaluation schedule – Extension .................................................. 78 
Table 7-3 
Disease and Imaging Assessment collection plan ................................. 86 
Table 7-4 
Central Clinical laboratory parameters ................................................. 90 
Table 7-5 
Imaging Assessment collection plan ..................................................... 91 
Table 7-6 
ECG collection plan .............................................................................. 92 
Table 7-7 
Pharmacokinetic blood collection log ................................................... 97 
 
 99 
 
 100 
 
 100 
Table 7-11 
Patient reported outcomes (PROs) collection plan ............................. 102 
Table 8-1 
CTCAE v4.03 - General grading guideline ......................................... 105 
Table 14-1 
List of medications with potential drug-drug interactions with 
osilodrostat – to be used with caution ................................................. 131 
 


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List of abbreviations 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
BDI 
Beck Depression Inventory 
b.i.d. 
bis in diem/twice a day 
BMI 
Body Mass Index 
CD 
Cushing’s disease 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel 
CNS 
Central Nervous System 
eCRF 
Electronic Case Report/Record Form  
CRO 
Contract Research Organization 
CS 
Cushing’s syndrome 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Reporting Scale 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DHEA(S) 
Dehydroepiandrosterone (Sulfate) 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety and Epidemiology 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FSH 
Follicle-stimulating hormone 
GFR 
Glomerular Filtration Rate 
eGFR 
Estimated Glomerular Filtration Rate 
ICH 
International Conference on Harmonization 
IE  
Independent Endocrinologist 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System 
ITT 
intent-to-treat 
KOL 
key opinion leaders 
LAR 
Long Acting Release 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LFT 
Liver Function Test 
LH 
Luteinizing Hormone 
LLN 
Lower Limit of Normal 
MoA 
Mechanism of Action 
MRI 
Magnetic Resonance Imaging 
mUFC 
mean Urine Free Cortisol 


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PAS 
Pharmacokinetic Analysis Set 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPS 
Per-Protocol Set 
PRO 
Patient-Reported Outcomes 
PT 
Preferred Term 
QoL 
Quality of Life Questionnaire 
QTc(F) 
QT corrected (Fridericia QT formula) 
eSAE 
Electronic Serious Adverse Event 
SAS 
Safety Analysis Set 
SBP 
Systolic Blood Pressure 
s.c. 
Subcutaneous 
SC 
Steering Committee 
SD 
Standard Deviation 
SEC 
Safety Event Categories 
SMR 
standardized mortality ratio  
SOP 
Standard Operating Procedure 
SS 
Safety Set 
TBIL 
Total bilirubin  
TdP 
Torsades des Pointes 
UFC 
Urine Free Cortisol 
ULN 
Upper Limit of Normal 


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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 
Baseline value 
Value from the last assessment prior to first dosing 
Complete Response 
Defined as mUFC ≤ ULN  
Core phase 
Includes both Period 1 and Period 2; Visits Day 1 through Week 48.   
Enrollment 
Point/time of patient entry into the study when informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the 
protocol) 
Escape 
Defined as loss of control of mUFC after week 26 (mean UFC > 1.3 x ULN on 
two consecutive visits on the highest tolerated dose of osilodrostat and not 
related to a dose interruption or dose reduction due to safety reasons) after 
prior mUFC normalization 
Optional extension phase 
Week 48 through Week 96 
Study drug 
Osilodrostat or placebo 
Medication number 
A unique identifier on the label of each blinded study drug package linked to 
one of the treatment groups of a study 
mUFC 
mUFC at a particular visit is the arithmetic mean of the urinary free cortisol 
(UFC) levels calculated from three 24-hour urine samples collected at 
screening, baseline, Week 12, Week 36, Week 48 and Week 12 follow up.  
The arithmetic mean of UFC from two 24-hour urine samples will be 
evaluated at all other study visits 
Overall Response 
Defined as  either complete response (mUFC ≤ ULN ) or partial response 
(mUFC > ULN with ≥ 50% reduction from baseline) during study treatment 
Partial Response 
Defined as  mUFC > ULN with ≥ 50% reduction from baseline during study 
treatment 
Period 
Period 1: Day 1 through Week 12.  
Period 2: Starts immediately after the Week 12 visit through Week 48. 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for any reason  
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time-points 
Withdrawal of Consent 
Withdrawal of consent occurs only when a patient does not want to 
participate in the study any longer, and does not want any further visits or 
assessments, and does not want any further study related contact 


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Amendment 2 (20-Dec-2019)  
Amendment rationale  
As of 10 December 2019, the study is fully enrolled and 45 patients are still on treatment. Of 
the 45 patients on treatment, 10 are active in the core phase of the study and 35 are active in the 
optional extension phase of the study. The last patient enrolled in the study should complete the 
48 week core period by the end of Feb-2020. 
The main purpose of this amendment is to change the end of study definition. After the last 
patient enrolled in the study completes the 48 week core period, protocol amendment 02 should 
be locally approved at participating sites. All remaining patients will then complete the study 
as soon as possible after completion of the 48 week core period, rather than after completion of 
the optional 48 week extension period. After local approval of this protocol amendment 02, 
patients who are still receiving treatment in the optional extension period (i.e. who have not yet 
reached week 96) will be asked to come for an end-of-treatment visit within 4 weeks after the 
local amendment approval date (either at their next scheduled visit if the visit is scheduled 
within 4 weeks after the local amendment approval, or at an unscheduled visit). Patients who 
are still receiving clinical benefit are eligible to join a separate long-term follow-up study.  
At the time when this clinical study was set up, the optional extension phase was implemented 
as an initial measure to ensure that all patients benefiting from treatment during the 48 week 
core period would have a possibility to continue receiving treatment, and to ensure that 
emerging safety and efficacy data would be captured. As of the date of release of this 
amendment, a separate long-term follow-up study collecting long term efficacy and safety data 
is now open at all sites with ongoing patients. This provides a means for long-term safety and 
efficacy data to be collected within a prospective clinical trial setting for all eligible patients, 
without impacting the primary and key secondary objective of this study.  
Other changes include: 
• The Beck Depression Inventory (BDI) was removed from Appendix 3 as BDI is not used 
in the study. For this study, the BDI-II is used 
• Appendix 3, Patient Quality of Life questionnaires, deleted for version control. 
Changes to the protocol 
Changes to specific sections for the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  
• List of abbreviations: the list of abbreviations was updated 
• Protocol Summary table, study design updated language to remove duration of 48 week 
Extension phase. 
• Protocol Summary table study design: updated to add additional parameters to be blinded 
in period 1; urine creatinine, aldosterone, renin, estradiol, estrone, androgens (testosterone, 
delta-4 androstenedione, DHEAS), and precursors 11-deoxycortisol, 11- 
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• Protocol Summary table, extension phase:  defined as optional open label Extension phase 
and patients must end participation in the optional Extension phase within 4 weeks after 
Protocol Amendment 02 is approved at the site, or by Week 96, whichever occurs first 
• Section 1.1.1: Corrected reference from ‘Amaldi, et al 2003’ to ‘Arnaldi, et al 2003’ 
• Section 2.2.4 Optional Extension Phase: updated section title to ‘Optional extension 
phase’ and language added to clarify per Protocol Amendment 02 ongoing patients must 
end participation in the optional extension period within 4 weeks after Protocol 
Amendment 02 is approved at the site or by Week 96, whichever occurs first 
• Section 2.2.6 ECG Monitoring: language added to clarify Holter recordings to be 
performed as applicable at Week 72, and at the end of treatment visit in the optional 
Extension phase.   
• Section 4.1. Description of study design:  deleted language defining optional extension 
period as 48 weeks  
• Section 4.1 Description of study design:  updated to add additional parameters to be 
blinded in period 1; urine creatinine, renin, estradiol, estrone, androgens (testosterone, 
delta-4 androstenedione, DHEAS), precursors 11-deoxycortisol, 11- deoxycorticosterone.  
• Section 4.1 Description of study design:  Extension phase updated to clarify patients 
enrolled in the optional extension period must end study participation within 4 weeks after 
Protocol Amendment 02 is approved at the site or by Week 96, whichever occurs first. 
Patients who are benefitting from study treatment, have the option to enter a separate long-
term safety follow-up study or stop study treatment. Patients who do not enter the long- 
term safety follow-up study will discontinue osilodrostat and conclude the study with a 
Post-Treatment (End of Study) visit after 30 days off study drug  
• Section 4.1 Description of study design:  Clarified that during the extension phase the dose 
of osilodrostat will be maintained at the established effective dose unless a change is 
required based on mUFC results collected at Weeks 48, and if applicable, at Weeks 60, 72, 
and 84 
• Section 4.3 Definition of end of the study:  updated and clarifiedcompletion of the study 
as a whole (last patient last visit) will occur once all patients have completed all 
assessments as per Table 7-1a, Table 7-1b (Core) and, as applicable, Table 7-2 (optional 
Extension), or have discontinued from the study, including Post-treatment follow-up or 
transition into the long-term safety follow-up study, whichever occurs first, and patients 
end participation in the optional extension period within 4 weeks after Protocol 
Amendment 02 is approved at the site, or by Week 96, whichever occurs first 
• Section 6.1.5 Treatment duration:  updated to clarify the optional extension phase will end 
when all patients who were eligible, have transitioned into the long-term safety follow-up 
study, or were discontinued from the study. Patients must end participation in the optional 
extension phase within 4 weeks after Protocol Amendment 02 is approved at the site, or 
by Week 96, whichever occurs first. Patients participating in the optional extension phase 
between Week 48 and Week 72, and who are eligible, should transition into the long-term 
safety follow-up study at the next study visit. Patients participating in the optional 
extension phase between Week 72 and Week 96, and who are eligible, should transition 
into the long-term safety follow-up study within 4 weeks, at an unscheduled visit, of 
Protocol Amendment 02 approval at the site. 


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• Section 6.2.3 Extension phase (weeks 48-96):  changed Week 96 to optional extension 
phase, removed separate long-term safety follow-up study from option b, and updated and 
clarified patients must end participation in the optional extension phase within 4 weeks 
after Protocol Amendment 02 is approved at the site, or by Week 96, whichever occurs 
first 
• Section 6.5.3 Treatment blinding:  updated to add additional parameters to be blinded in 
period 1; urine creatinine, renin, estradiol, estrone, androgens (testosterone, delta-4 
androstenedione, DHEAS), precursors 11-deoxycortisol, 11- deoxycorticosterone. 
• Section 7.1 Study flow and visit schedule:  added language to clarify patients must end 
participation in the optional extension period within 4 weeks after  Protocol Amendment 
02 is approved at the site, or by Week 96, whichever occurs first 
• Section 7.1.3 Treatment phase:  clarified at Week 48, patients have the option to enter an 
optional open-label extension phase; however; patients currently enrolled in the optional 
Extension phase must end study participation within 4 weeks after Protocol Amendment 
02 is approved at the site, or by Week 96 whichever occurs first. If patients are benefitting 
from study treatment, they have the option to enter a separate long-term safety follow-up 
study or stop study treatment.  Patients not entering the long-term safety follow-up study 
will complete the study with a 30 day follow-up. 
• Section 7.1.4 Discontinuation of Study drug: removed Week 96 
• Table 7-3 Disease and Imaging Assessment collection plan: added language for 
clarification, DXA scan mandated at End of Treatment Core and End of Treatment 
Extension, unless EOT occurs less than 6 months before the scheduled Week 96 visit. 
• Section 7.2.1.3 Bone mineral density assessments: clarified if EOT occurs less than 6 
months before the scheduled Week 96 visit, MRI (or CT) and DXA is not mandatory at 
EOT 
• Section 7.2.2.5 Radiological examinations: clarified if EOT occurs less than 6 months 
before the scheduled Week 96 visit, MRI (or CT) and DXA is not mandatory at EOT 
• Table 7-6 ECG collection plan: added language for clarification, Patients end participation 
in the optional extension period study within 4 weeks after Protocol Amendment 02 is 
approved at the site, or by Week 96, whichever occurs first 
• Section 7.2.2.6.1 24-hour Holter Electrocardiogram: Patients should be instructed to return 
their 24-hour Holter flashcards to the site at their next study visit in order to facilitate 
timely central reading of the Holter data 
• Table 7-10 Hair Cortisol sample collection plan: clarified extension phase is optional and 
added language Patients to end study participation once Protocol Amendment 02 is 
approved at the site, or by Week 96, whichever occurs first  
• Section 7.2.6 Patient reported outcomes: removed reference for Appendix 3  
• Table 7-11 Patient reported outcomes (PROs) collection plan: added language for 
clarification, Patients to end study participation within 4 weeks after Protocol Amendment 
02 is approved at the site, or by Week 96, whichever occurs first 
• Section 10: Removed text stating that the results and outcomes of primary analysis will be 
presented in a CSR 


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• Section 10.5.2.2 Assess the change in mUFC during the Core and Extension periods of the 
study: updated the section title to optional Extension periods 
• Section 10.5.3.4 Other safety data: updated to clarify that tumor invasiveness is also 
evaluated 
• Reference:  FDA Guidance for Industry Suicidality corrected from 2015 to 2010 to match 
protocol referenced in Section 10.5.3.4  under the Columbia Suicide Severity Reporting 
Scale (C-SSRS) 
• Reference: added Masri-Iraqi et al, 2014 to match reference in Section 2.6 
• Clarifications were made in the protocol that extension phase is an optional extension 
phase 
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.  
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 1 (20-Nov-2017) 
Amendment rationale 
As of 20 Nov 2017, 18 patients have been enrolled (treated) in the study.  
The main purpose of this amendment is to align the language of all ongoing studies in Cushing’s 
disease indication for prohibited drugs due to TdP risk and to add a statement regarding the risk 
of neutropenia observed in LCI699C2201 and LCI699C2103. These were newly acquired 
information added to the Investigator’s Brochure for transparency, and are thus being added to 
all protocols. New objectives and endpoints on cortisol biomarkers were added to maintain 
consistency between the protocol and data collection occurring in the study, as described in the 
VES.   
The duration of the optional extension period was increased 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 study is set up at 
participating sites.  Based on this extension, the end of study definition has been updated. 
This protocol amendment introduces the following changes: 
• In view of the results of the thorough QT study CLCI699C2105, which showed that the 
increase in QTcF caused by osilodrostat at therapeutic doses is below the threshold of 
regulatory concern, the QT-specific concomitant medication guidance for osilodrostat was 
revised to limit the list of prohibited drugs to medications with a “Known risk to cause 
TdP” and “Possible risk to cause TdP”, instead of all drugs known to prolong QT. This 
change is also in alignment with the terminology used in the QT Drug Lists 
(CredibleMeds®).  
• The risks section was updated to include neutropenia, which is a known effect related to 
the decrease of cortisol in patients with Cushing’s disease in line with cases observed in 
clinical trials with osilodrostat. 
• Addition of the following secondary objective and endpoint to ensure that analyses related 
to changes in other biomarkers of hypercortisolism is part of the protocol. These other 
markers are important to describe changes in disease burden following treatment.  
• Objective: To assess the change from baseline in serum, salivary and hair cortisol 
levels during the Core and Extension periods of the study.  
• Endpoint: Actual and percentage change in biomarkers of hypercortisolism (serum 
cortisol, late night salivary cortisol, morning cortisol and hair cortisol) from baseline 
to each post-baseline visit during the Core and Extension at which cortisol biomarkers 
are collected by treatment arms and for all patients.  
• Language added to clarify that the study will end once all patients have completed all 
assessments as per Table 7-1a and Table 7-1b (Core) and Week 96 visit (extension phase) 
or have discontinued from the study early, whichever occurs first. In addition, visits are 
added for patients who continue to benefit from treatment at Week 96 to continue 
treatment on study until any of the following occurs: 
(a) they no longer benefit from treatment or  


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(b) a separate long-term safety follow-up study or managed access program becomes 
locally available or  
(c) an alternative treatment option becomes locally available or  
(d) all patients have either reached Week 96 or have discontinued from the study before 
Week 96.  
• Specifying sample collection requirement in the event of suspected hypocortisolism or 
adrenal insufficiency during period 1 to allow dose modification by Independent 
Endocrinologist (IE).  
• Specifying that the screening Thyroid Panel, FSH, and Pregnancy (serum) tests should be 
done post wash out during screening period.   
• Columbia Suicide Severity Rating Scale (CSSRS) was removed from Appendix 3 as paper 
CSSRS is not used in the study (electronic version is used in the study) 
• Introduced more flexible wording regarding the description of osilodrostat tablet strengths 
used in the study.  
• The tumor aggressiveness evaluation was added to evaluate the prevalence of tumors with 
extension outside sella turcica and/or invasion into surrounding structures at baseline and 
during the study (new onset/disappearance). 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
• Protocol synopsis: edited to be consistent with the changes made throughout the protocol  
• Section 2.2.6: updated to clarify that the 24-hour continuous 12-lead Holter recordings 
will be performed at baseline, Weeks 2, 12, 14, 36, 72, and at the end of treatment 
Extension visit.  
• Section 2.6: updated to include the possibility of neutropenia based on observed cases 
with osilodrostat.  
• Section 3, Table 3-1, and Section 10.5.2.8: addition of the following secondary objective 
and endpoint: 
Objective: To assess the change from baseline in serum, salivary and hair cortisol levels. 
Endpoint: The actual and percentage change from baseline in serum cortisol, late night salivary 
cortisol, morning salivary cortisol and hair cortisol levels for every visit in the Core and 
extension phases at which the biomarkers of hypercortisolism are collected, by treatment arms 
and for all patients.  
• Section 4.1: added the following statement: Three 24-hr UFC urine samples and two late 
night salivary cortisol samples are to be collected after completion of the washout period 
during screening to assess study eligibility. 
• Section 4.3: Clarified definition of end of the study 
• Section 6.2.3: added the following statement:  
Patients who continue to benefit from treatment at Week 96 have the option to continue 
treatment on study until any of the following occurs: 


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(a) they no longer benefit from treatment or  
(b) a separate long-term safety follow-up study or managed access program becomes locally 
available or  
(c) an alternative treatment option becomes locally available or  
(d) all patients have either reached Week 96 or have discontinued from the study before Week 
96, 
For patients who transition into a separate long-term study or managed access program, the 
EOS (last dose + 30 days) visit is not applicable, as treatment on osilodrostat will not be 
interrupted, and only the EOT visit will be performed. 
Those patients who will not continue treatment will complete the EOT extension visit and an 
EOS (last dose + 30 days) visit, for details of assessments, please refer to Section 7.1.4.  
• Section 6.3.1, Table 6-1, the following statement is added:  
The IE can adjust the dose when sufficient information is provided, i.e., serum cortisol, one or 
more (up to three) 24-hour UFC result, plasma glucose and electrolytes, (as central lab 
assessment) and completed eCRF pages with clinical signs and symptoms associated with 
hypocortisolism/adrenal insufficiency event.  
• Section 6.3.1, Table 6-2, included discontinuation requirement when Isolated AST or ALT 
elevation is > 10.0 - 20.0 x ULN: If not resolved after 4 weeks, discontinue from study 
drug  
• Section 6.3.2: added the following statement:  
In the event of suspected hypocortisolism or adrenal insufficiency during period 1, the site 
should instruct the patient to collect one or more (up to three) 24-hour urine samples for UFC 
assessment and come to the site for tests for serum cortisol, plasma glucose and electrolytes 
(sodium and potassium). These samples should be sent to central laboratory immediately to 
allow an appropriate dose modification by IE. Physical exam is recommended and a record of 
abnormal findings should be annotated in the CRF. 
• Section 6.4.3, Section 6.4.3.1, and Appendix 2: revised to update the QT-specific 
concomitant medication guidance for osilodrostat 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, according to (CredibleMeds®).  
• Table 7-1a: Specifying that the screening Thyroid Panel, FSH, and Pregnancy (serum) 
tests should be done post wash out during the screening.  
• Table 7-2, Table 7-6, 
 and Table 7-11: Additional visits are added for patients 
who continue to benefit from treatment at Week 96 to continue treatment on study until 
any of the following occurs: 
(a) they no longer benefit from treatment or  
(b) a separate long-term safety follow-up study or managed access program becomes locally 
available or  
(c) an alternative treatment option becomes locally available or  
(d) all patients have either reached Week 96 or have discontinued from the study before Week 
96. 


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• Section 7.1.4, amending that hypertension should be defined as office mean supine 
systolic BP > 180 mmHg or mean supine diastolic BP > 110 mmHg (confirmed and 
persistent*). 
• Table 7-7: updated the blood volume to approximately 3mL and the following footnote:  
pre-dose sample within 0.5 h before dose administration, ±10 min for up to the 2 h timepoint, 
and within 0.5h before the 12h post dose sampling.  If patient enters the extension phase of 
study, the 12 h post dose sampling should be taken prior to the first dose in the extension phase 
• Section 10.5.2.8: added the following statement:  
Change in the actual and percentage change from baseline to each post-baseline visit for 
serum cortisol, late night salivary cortisol, morning salivary cortisol and hair cortisol 
levels will be assessed. Descriptive summaries will be provided for every visit in the Core 
and Extension phases at which the biomarkers of hypercortisolism are collected. Salivary 
cortisol samples will only be included if they are collected within the correct time 
window. 95% CIs for the percentage change from baseline will also be provided by 
treatment and for overall patients.• 
Section 10.5.3.4: added the following statement: 
The tumor aggressiveness is also evaluated, in terms of the prevalence of tumors with 
extension outside sella turcica and/or invasion into surrounding structures at baseline and 
during the study (new onset/disappearance). 
• Language “(depending on availability)” was added in front of all text mentioning 20 mg 
tablet strength.  
• Appendix 3: Columbia Suicide Severity Rating Scale (CSSRS) was removed.  
• Editorial changes and clarifications were made at various places in the protocol. 
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 
CLCI699C2302 
Title 
A Phase III, multi-center, randomized, double-blind, 48 week study with an initial 
12 week placebo-controlled period to evaluate the safety and efficacy of 
osilodrostat in patients with Cushing’s disease 
Brief title 
Efficacy and safety evaluation of osilodrostat in Cushing’s disease 
Sponsor and Clinical 
Phase 
Novartis 
Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The study aims to confirm efficacy and safety of osilodrostat for the treatment of 
patients with Cushing’s disease (CD) who are candidates for medical therapy. 
Primary Objective(s) and 
Key Secondary Objective 
Primary: 
To demonstrate the superiority of osilodrostat compared to placebo in achieving a 
complete response (mUFC ≤ ULN) at Week 12. 
Key secondary: 
To assess the complete response rate in both arms combined at Week 36 in 
patients receiving osilodrostat treatment. 
Secondary Objectives 
To assess the proportion of patients with a complete response (mUFC ≤ ULN) or 
a partial response (mUFC decrease ≥50% from baseline and >ULN) at Week 12, 
Week 36, and Week 48. 
To assess the change in mUFC during the Core and Extension periods of the 
study. (Refer to Table 7-1a, Table 7-1b and Table 7-2 for the study visit and 
evaluation schedule during the Core and Extension phases, respectively). 
To compare the time-to-first control of mUFC during the placebo-controlled period 
(Weeks 1-12) between the randomized treatment arms. 
To assess the time-to-escape during osilodrostat treatment up to Week 48.  
To assess cardiovascular and metabolic related parameters associated with CD 
(fasting plasma glucose, HbA1c, fasting lipid profile, blood pressure, weight and 
waist circumference) by assessing actual and percent change from baseline and 
shift table at Weeks 12, 36, and 48. 
To assess the change from baseline at Weeks 12, 36, and 48 in physical features 
of CD. 
To assess the change from baseline in bone mineral density (BMD) by DXA scan 
at the lumbar spine and total hip at Week 48. 
To determine the safety and tolerability of osilodrostat in the study population.  
To assess the change from baseline in Health Related Quality of Life, as 
measured by the CD-specific QoL questionnaire (CushingQoL); by the Beck 
Depression Inventory (BDI-II); and by the general health-related QoL instrument 
EQ-5D-5L, by randomized treatment arm and overall. 
To evaluate pharmacokinetic exposure of osilodrostat in the study population. 
To assess the change in cortisol levels (serum cortisol, late night salivary cortisol, 
morning cortisol and hair cortisol) during the Core and Extension periods of the 
study.  
Study design 
This is a Phase III, global, multi-center, randomized, double-blind, placebo-
controlled study.  The study design is placebo-controlled during the first 12 
weeks, followed by open-label treatment with osilodrostat until week 48, and an 
optional Extension phase. 
Screening (up to 8 weeks):  Written informed consent must be obtained before 
any study specific assessments. Washout of current drug therapy for CD, as well 
as optimization of treatment of co-morbidities is to be completed. Three 24-hr 
UFC urine samples and two late night salivary cortisol samples are to be 
collected after completion of the washout period to assess study eligibility. Other 
assessments needed for eligibility are detailed in Table 7-1a.  


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Core Phase 
Period 1 (Weeks 1-12) Double-blind, placebo-controlled:  
Study visits are performed at Day 1, Week 2, Week 5, Week 8 and Week 12. 
The initial dose of study drug (osilodrostat or placebo) is 2 mg b.i.d. The mean of 
three 24-hr UFC values (mUFC) will be done at screening (prior to Period 1), 
baseline and Week 12. The mean of two 24-hr UFC values (mUFC) is the basis 
for dose titration decisions (See Section 6.2 for details). If the mUFC 
remains >ULN, dose escalation needs to occur according to the following 
sequence: 5 mg b.i.d., 10 mg b.i.d., and 20 mg b.i.d at Weeks 2, 5, or 8, as 
applicable. Dose escalation stops when the mUFC is ≤ ULN.  Doses may be 
down titrated in both the active control and placebo arms (to the previous dose, 
or to below 2 mg b.i.d.) if mUFC is below the LLN or close to the lower limit of 
the normal range and/or the patient has signs or symptoms of adrenal 
insufficiency. Down-titration to doses less than 2 mg b.i.d. (with mock down-
titration in the placebo arm to maintain the treatment blind) could also be used 
(Section 6.2.1 for further details). Intermediate doses may only be used in 
specific circumstances (see Section 6.2.1.3 for details). Dose adjustments will be 
done between study visits to allow the next UFC assessment to reflect the 
impact of the new dose of study drug (see Sections 4.1). In patients 
discontinuing study drug before Week 12, every effort should be made to 
continue visits and assessments up to and including Week 12 (see Section 4.1). 
To maintain the treatment blind, the UFC, urine creatinine, serum and salivary 
cortisol, Adrenocorticotropic Hormone (ACTH), aldosterone, renin, estradiol, 
estrone, androgens (testosterone, delta-4 androstenedione, DHEAS), and 
precursors 11-deoxycortisol, 11-deoxycorticosterone will be kept blinded to 
patients, investigators and the Novartis Clinical Trial Team during Period 1 (see 
Section 6.5.3). A group of independent endocrinologists (IEs) is responsible for 
managing dose titrations during this period. The IE will have access to relevant 
data including UFC, serum cortisol, ACTH and chemistry results, the treatment 
assignment, and clinical signs and symptoms at the most recent study visit.  The 
IE is responsible for determining the dose of study drug as soon as the mUFC 
results are available for individual patients. The IE communicates instructions 
regarding the dose of study drug in a blinded manner via Interactive Response 
Technology (IRT) to the appropriate site. 
 
Period 2 (Weeks 12-48): Open-label treatment:  
All patients receive active, open label drug, osilodrostat, during Period 2. 
Immediately after the Week 12 visit, all patients that were receiving doses of 2 
mg b.i.d. or above, regardless of treatment assignment (active drug or placebo) 
during Period 1, will receive osilodrostat 2 mg b.i.d. Patients treated with either 
osilodrostat or matching placebo at doses less than 2 mg b.i.d. during Period 1 
will receive open label osilodrostat at the same dose.  
As in Period 1, dose escalation in Period 2 will be based on mUFC results 
(mUFC > ULN).  All dose adjustments will be made by the investigator who will 
have access to mUFC and all other lab values from Week 14 onwards. The IE 
does not participate in dose decisions beyond Week 12. The investigator should 
be vigilant for signs or symptoms of adrenal insufficiency or glucocorticoid 
withdrawal between Week 12 and the receipt of Week 14 UFC results, and may 
reduce or temporarily withhold osilodrostat if clinically indicated. The dose 
escalation sequence in all patients in Period 2, regardless of Period 2 starting 
dose (either 2 mg b.i.d. or doses less than 2 mg b.i.d.), is 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 (see Section 6.2.2). 
During Period 2, three 24-hr UFC values will be used to calculate mUFC at 
Week 36 and Week 48; the mean of two 24-hr UFC values will be calculated at 
all other visits to inform dose titrations. 
A patient is considered to have reached a stable efficacious dose when, mUFC 
remains ≤ ULN. The dose may be up-titrated for mUFC > ULN, or down-titrated 
for mUFC values <LLN or close to the lower limit of the normal range and/or if 
the patient has signs or symptoms of adrenal insufficiency. Intermediate doses 


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may be used only in specific circumstances. Please see Section 6.2.1.3 for 
details. 
 
Optional Extension phase (Weeks 48-96):  
At Week 48, patients have the option to enter an optional open-label Extension 
phase. Patients must end participation in the optional Extension phase within 4 
weeks after Protocol Amendment 02 is approved at the site, or by Week 96, 
whichever occurs first. Doses can be adjusted in this phase of the study as 
described above and in Section 6.2.3 
Population 
The study population will be comprised of approximately 69 adult male and 
female patients with Cushing’s disease who are candidates for medical therapy 
(see Section 5.1). 
Inclusion criteria 
Key inclusion criteria are listed below; please refer to Section 5.2 for the full list of 
inclusion criteria.  
• 
Confirmed CD that is persistent or recurrent as evidenced by all of the following 
criteria being met (i.e., a, b and c): 
a. 
mUFC > 1.3 x ULN (Mean of three 24-hour urine samples collected 
preferably on 3 consecutive days, during screening after washout of prior 
medical therapy for CD (if applicable), confirmed by the central laboratory and 
available before Day 1), with ≥2 of the individual UFC values being > 1.3 x 
ULN.  
b. 
Morning plasma ACTH above Lower Limit of Normal  
c. 
Confirmation (based on medical history) of pituitary source of excess 
ACTH as defined by any one or more of the following three criteria: 
i. Histopathologic confirmation of an ACTH-staining adenoma in patients 
who have had prior pituitary surgery. 
OR 
ii. MRI confirmation of pituitary adenoma > 6 mm 
OR 
iii. 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 
• 
Patients that received glucocorticoid replacement therapy must have 
discontinued such therapy for at least seven days or 5 half-lives prior to 
screening, whichever is longer. 
• 
Patients with de novo CD can be included only if they are not considered 
candidates for surgery (e.g., poor surgical candidates due to co-morbidities, 
inoperable tumors, patients who refuse to have surgical treatment, or 
surgical treatment is not available). 
• 
For patients with a history of pituitary irradiation: at least 2 years for 
stereotactic radiosurgery (SRS), and 3 years for conventional (fractionated) 
radiation, respectively, must have elapsed from the time of the most recent 
radiation treatment to the time of enrollment into this study.  
• 
Washout of any current drug therapy for CD. The following minimum 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. 
Mifepristone: 3 weeks 
d. 
Dopamine agonists (e.g., cabergoline), or PPAR-gamma agonists (e.g., 
rosiglitazone, pioglitazone): 4 weeks 


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e. 
Pasireotide LAR: 8 weeks.  Rescreening can be used as needed to 
ensure washout is complete.  
f. 
Mitotane: 6 months. Rescreening can be used as needed to ensure 
washout is complete. 
Exclusion criteria 
Key exclusion criteria are listed below; please refer to Section 5.3 for the full list 
of exclusion criteria.  
• 
Patients with pseudo-Cushing’s syndrome. This may be diagnosed by two 
normal late night salivary cortisol values collected during the screening 
period and after washout of prior CD medication.   
• 
Patients with risk factors for QTc prolongation or Torsade de Pointes, 
including: patients with a baseline QTcF > 450 ms for males and QTcF > 
460 ms for females; personal or family history of long QT syndrome; 
concomitant medications known to prolong the QT interval; patients with 
hypokalemia, hypocalcaemia, or hypomagnesaemia, if not corrected before 
pre-dose Day 1. 
• 
Patients likely to require adrenalectomy, pituitary surgery, or radiation 
therapy during the placebo-controlled period (Weeks 1-12) for the treatment 
of severe hypercortisolism or pituitary tumor growth causing compression of 
the optic chiasm.  
• 
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 any major surgery within 1 month, or 
undergone transsphenoidal pituitary surgery within 3 months, prior to 
screening. 
• 
Hypertensive patients with uncontrolled blood pressure defined as SBP > 
180 and/or DBP > 105 or not optimally treated for hypertension as judged by 
the investigator. 
• 
Diabetic patients with poorly controlled diabetes as evidenced by HbA1c > 
9 % or not optimally treated for diabetes mellitus as judged by the 
investigator. 
• 
Patients who are not euthyroid as judged by the investigator. 
• 
Patients with liver disease such as cirrhosis, chronic active hepatitis, or 
chronic persistent hepatitis, or patients with serum ALT and/or AST > 3 x 
ULN, or total bilirubin > 1.5 x ULN. 
Please refer to Section 5.2 and Section 5.3 for the full list of study inclusion and 
exclusion criteria, respectively. 
Investigational and 
reference therapy 
Osilodrostat 1 mg, 5 mg, 10 mg and (depending on availability) 20 mg film-coated 
tablets, and matching placebo film-coated tablets, for oral administration. Each 
tablet strength is provided in a separate bottle.  
Efficacy assessments 
24-hour Urine Free Cortisol for the primary and key secondary endpoints.  Other 
assessments for secondary endpoints include: weight, waist circumference, blood 
pressure, fasting plasma glucose, HbA1c, fasting lipid profile, Health-related 
Quality of Life questionnaires (CushingQoL, Beck Depression Inventory-II, and 
EQ-5D-5L), 
physical 
features 
of 
Cushing’s 
disease, 
biomarkers 
of 
hypercortisolism, BMD at lumbar spine and total hip (by DXA). 
Safety assessments 
Adverse events 
Laboratory evaluations (chemistry, hematology, coagulation, Thyroid Panel, FSH, 
LH, fasting plasma glucose, urinalysis and pregnancy test);  
ECG, Holter recordings, MRI of pituitary, vital signs, physical exam and C-SSRS.  


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Data analysis 
The primary efficacy variable is the proportion of randomized patients in each 
treatment arm that are complete responders at Week 12. A complete responder 
is defined as a patient who has mUFC ≤ ULN (based on central laboratory result) 
at Week 12. The primary analysis will be based on a Cochran–Mantel–Haenszel 
(CMH) exact test stratified by the history of pituitary irradiation (yes/no) using the 
FAS. Following the ITT principle, patients are analyzed according to the drug 
and stratum they were assigned to at randomization.  
The statistical null hypothesis states that the complete response rates at the end 
of the 12-week placebo-controlled period (i.e., at Week 12) are the same 
between the two randomized arms. If the 1-sided p-value is ≤ 0.025, and the 
odds ratio (osilodrostat vs. placebo) is > 1, the null hypothesis will be rejected 
and the complete response rate in the osilodrostat arm is considered higher than 
that in the placebo arm. 
The key secondary objective is to assess the complete response rate (proportion 
of patients with mUFC ≤ ULN)  in both arms combined at Week 36 in patients 
receiving osilodrostat treatment, i.e., patients randomized to placebo who do not 
switch to osilodrostat will not be included. In this analysis, patients with missing 
mUFC assessments at Week 36 will be considered as non-responders. 
For the key secondary objective, the statistical null hypothesis states that the 
complete response rate at Week 36 is < 30%. The analysis of the key secondary 
objective will be based on the 2-sided 95% exact confidence interval (CI) 
constructed using the Clopper-Pearson method in FAS patients receiving 
osilodrostat treatment. 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% at Week 36.  
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 analysis of the key secondary endpoint will be performed in FAS patients 
receiving osilodrostat treatment and will be repeated using PPS patients 
receiving osilodrostat treatment as supportive analysis.  In addition, the key 
secondary endpoint will also be analyzed using the patients randomized to the 
osilodrostat arm only. 
Key words 
Cushing’s disease, LCI699, osilodrostat, Pituitary Gland, Adrenocorticotropic 
Hormone, ACTH, UFC 


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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 
Endogenous Cushing’s syndrome (CS) is rare (estimated prevalence of less than 1 in 10,000 
inhabitants) (Feelders, et al 2012). 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 (CD), which occurs in about 70% of cases, and is due 
to an ACTH-secreting pituitary corticotroph adenoma. Cushing’s disease most commonly 
affects adults aged 20-50 years, with a marked female preponderance. 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 
(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 in both gender, 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 
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 


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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 CD 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). 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 primary pituitary surgery with or without radiation, and 
patients with de novo CD who are not surgical candidates for medical reasons, refuse to undergo 
surgery, or do not have access to a specialized center with experience in pituitary surgery. 
Pasireotide (Signifor®), a second generation somatostatin analogue, is currently approved in the 
US and in EU for the treatment of Cushing’s disease. 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 0.6 mg s.c. b.i.d. and 0.9 mg s.c. b.i.d., respectively. 
Mifepristone, a glucocorticoid receptor antagonist, is 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. 


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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). 
Bilateral adrenalectomy is deferred until all other options have been exhausted (Biller, et al 
2008). A 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 
There is still much room for improvement beyond the existing medical therapies, because 
substantial subsets of patients either do not achieve normalization of mUFC or have adverse 
reactions from the medical therapy. 
Therefore, there is an unmet medical need to develop new drugs with improved safety and 
efficacy. Based on the data from study LCI699C2201 in patients with Cushing’s disease, 
osilodrostat shows promise in fulfilling this unmet medical need. 
1.2 
Introduction to investigational treatment, osilodrostat 
1.2.1 
Overview of osilodrostat 
Osilodrostat (company research code: 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.  
Osilodrostat is a potent, oral inhibitor of 11β-hydroxylase (CYP11B1), the enzyme that 
catalyzes the last step in the biosynthesis of cortisol. This provides the rationale for investigating 
the use of osilodrostat in endogenous causes of Cushing’s syndrome. The current development 
activity of osilodrostat 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 of Cushing’s syndrome and it is a relatively homogeneous patient group. This drug also 
inhibits aldosterone synthase (CYP11B2), and therefore is a dual inhibitor of both cortisol and 
aldosterone synthesis.  It is manufactured as a phosphate salt and available in film-coated tablets 
of 1 mg, 5 mg, 10 mg and 20 mg for this phase III study.  
The mechanism of action of osilodrostat is depicted in Figure 1-1 below.  


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Figure 1-1 
Mechanism of action of osilodrostat 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 Pharmacology 
The oral absorption of osilodrostat in rat and dog was rapid with complete bioavailability 
indicating a minimal first-pass effect. The plasma half-life of osilodrostat in rat and dog was 
short (~ 2 h). Exposure was dose-proportional within the dose range investigated in the rat but 
over-proportional in dogs and mice. No accumulation or gender differences were observed in 
either species. Protein binding of osilodrostat in animals and humans was low (26.6–36.4%). 
Osilodrostat rapidly and extensively distributed to rat tissues. The highest tissue-to-blood ratios 
(≥ 9) were observed in the uveal tract, skin, eye, glandular stomach, small intestine, liver, and 
adrenal cortex. Drug-related radioactivity showed a significant affinity to melanin in the skin 
and uveal tract. Drug-related radioactivity showed a moderate distribution to brain, spinal cord 
and the testis with tissue-to-blood concentration ratio of 0.73-1.7. The elimination of 
osilodrostat is mainly through metabolism and excretion in urine (~79% in rats and ~90% in 
dogs; unchanged osilodrostat ~ 5-10% in urine and < 3% in feces).  
Based on the in vitro CYP P450 inhibition profile and predicted steady state maximum 
concentration of 1.54 μM at 30 mg twice daily in humans, there is potential of drug- drug 
interaction for osilodrostat. Results from a clinical drug-drug interaction study [LCI699C2102] 
are summarized in Section 1.2.1.2.1. It is unlikely that osilodrostat will increase the systemic 
exposure of co-medications whose clearance is mediated by P-gp, BCRP, OAT1, OAT3, OCT1, 
and OCT2 transport activity. 


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


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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, 
osilodrostat was rapidly absorbed with a Tmax of approximately 1 hour. The elimination half-
life of osilodrostat was 3-5 hours across all doses examined. The pharmacokinetics of 
osilodrostat were over-dose proportional in the dose range of 0.5 to 200 mg (single dose); for a 
2-fold increase in dose, the AUC increase would be about 2.4-fold, and Cmax increase would 
be 2.1-to 2.4-fold [LCI699A2101]. Metabolism was the major clearance pathway for 
osilodrostat in humans with renal clearance making only a minor contribution. Metabolism of 
osilodrostat was extensive in humans via multiple pathways (and combination of pathways) 
[LCI699C2101]. Results from a cocktail drug-drug interaction study [LCI699C2102] showed 
that at a single dose of 50 mg which covers the exposure at the highest therapeutic dose of 30 
mg b.i.d. at steady state, osilodrostat is a moderate inhibitor of CYP1A2, a weak to moderate 
inhibitor of CYP2C19, and a weak inhibitor of CYP2D6 and CYP3A4/5.  
1.2.1.2.2 Results of LCI699C2201 study in Cushing’s disease 
The purpose of the LCI699C2201 study was to determine whether the ability of osilodrostat to 
inhibit 11β-hydroxlase 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 and a new cohort (Expansion cohort) 
of patients, and evaluating the long-term efficacy and safety of osilodrostat treatment. 
In Part I, osilodrostat was effective in controlling cortisol production in all 12 patients studied. 
At daily osilodrostat doses between 2 mg b.i.d. and 50 mg b.i.d., 24-hour mean UFC (mUFC) 
decreased rapidly and normalized at least once in all patients studied. In general at 5 mg b.i.d. 
patients showed mUFC reduction after 2 weeks (at first mUFC measurement after dose 
titration). 
The primary endpoint, defined as mUFC ≤ ULN or ≥ 50% decrease from baseline at Day 70, 
was achieved by all patients. Overall, the mean time to response (UFC normalization or ≥ 50% 
reduction from baseline) was 34.3±14.1 days. The mean daily dose (± SD) of osilodrostat 
required to reach the primary endpoint was 13.5±13.9 mg b.i.d. with 75% of patients 
normalizing mUFC on ≤ 10 mg b.i.d. At Day 84, two weeks after osilodrostat was withdrawn, 
mUFC levels increased to a mean of 4-fold above upper limit of normal (ULN) (Figure 1-2). 


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Figure 1-2 
Arithmetic mean and SE plots for fold ULN of mUFC (PD analysis set) 
 
Source: In-text Figure 11-2, 10-week interim CSR study [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 22 weeks of treatment and 15 had normal mUFC 
levels at week 22 (79%). During treatment with osilodrostat, the mean mUFC levels decreased 
quickly and stabilized to a normal level (11 to 138 nmol/24h) at Week 4 (Figure 1-3). After 
Week 4, normal mean mUFC levels were observed through the study up to Week 22. All 
patients attained UFC normalization at least once during the study, and no patient “escaped” 
UFC control. 


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Figure 1-3 
Mean (+/-SE) mUFC (nmol/24h) over time by cohort 
 
 
 
Source: In-text Figure 11-1, 22-week interim CSR study [LCI699C2201] 
1.2.1.2.3 Overview of safety 
In the clinical trials for the treatment of hypertension or primary hyperaldosteronism, 
osilodrostat was tolerated with the overall incidence of adverse events being similar to placebo. 
Adverse events (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 Study [CLCI699C2201], in patients with Cushing’s disease, safety data from the 10-week 
analysis also showed that osilodrostat was well tolerated with similar common adverse events 
to those in the hypertension trials, including: fatigue, nausea, vomiting, diarrhea, headache, 
dizziness, hypokalemia and muscle spasms. 
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, osilodrostat was generally well tolerated throughout the study. Of the 19 enrolled 
patients, 17 patients completed the 22 weeks treatment period with a median duration of 
exposure of 25.1 and 38.9 weeks in the Expansion cohort and Follow-up cohort, respectively. 
The safety findings identified in the interim analysis (data cut-off date: 23-Dec-2013) that was 


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performed after the last patient had completed 22 weeks of treatment in this ongoing study are 
summarized below. 
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 increase levels of oxycorticosteroids, 
blood corticotrophin, and blood testosterone were the most common AEs suspected to be drug 
related (by PT). 
Two patients experienced a total of 3 SAEs.  
One patient was reported to have grade 3 pituitary-dependent Cushing's syndrome (preferred 
term [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 (Preferred Term (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 electrocardiogram QT prolongation SAE 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. 
Nine patients reported AEs requiring dose adjustment or study drug interruption with adrenal 
insufficiency and fatigue being the most commonly reported. The majority of AEs requiring 
does adjustment or study-drug interruption was suspected to be related to study drug, were 
mainly grade 1 and resolved after the dose was adjusted or temporarily interrupted.  
Nine patients reported AEs of special interest with adrenal insufficiency, acne, and hirsutism 
(female only) being the most commonly reported. The majority of AEs of special interest were 
suspected to be related to study drug, were mainly grade 1/2 and resolved after the dose was 
adjusted or temporarily interrupted, with concomitant medication or without any action being 
taken. 
All patients in the study had at least one clinical laboratory test result outside the normal range 
at some point, changes were grade 1/2 in most of the cases. There were no clinically relevant 
changes over time observed for mean values of clinical laboratory tests. No patients 
discontinued the study drug due to abnormal clinical laboratory parameters. There were trends 
towards decreased fasting plasma glucose, HbA1c, cholesterol and triglyceride levels. 
There were no clinically relevant changes in mean vital signs. There were no clinically relevant 
changes from baseline in mean QTcF or in the other mean ECG intervals. 
In reviewing the clinical trial experience with osilodrostat to date, AEs have been identified that 
are consistent with the mechanism of action of the drug as an inhibitor of both cortisol and 
aldosterone synthesis.  These can be summarized as follows: 


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• 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) 
A more detailed list of potential AEs related to the mechanism of action of osilodrostat can be 
found in Section 8.1.3 AEs of Special Interest. For a comprehensive review of clinical safety 
data with osilodrostat, see the [Investigator’s Brochure]. 
1.2.1.2.4 Osilodrostat: QT/QTc in healthy volunteers  
The cardiac repolarization liability of osilodrostat was assessed in the definitive ICH E14 
compliant thorough QT Study (TQT) study CLCI699C2105 in 86 healthy male and female 
subjects. A maximum mean ∆∆QTcF of 25.4 ms was observed on osilodrostat 150 mg (5-fold 
higher than the maximum clinical dose of 30 mg), with absence of a relevant QT effect on 
osilodrostat 10 mg (∆∆QTcF 0.3 ms; 90% CI −1.50, 2.16).  No subject experienced QTcF 
values >500 ms, or 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 osilodrostat 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 osilodrostat (20 mg and 30 mg), based on the pooled PK data from the 
osilodrostat studies A2101, C2105, and C2201 (total N=178). The predicted arithmetic mean 
and geometric mean Cmax,ss of osilodrostat 20 mg was 174 and 168 ng/mL, and on osilodrostat 
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 osilodrostat 20 mg and 30 mg from the Population-PK 
analysis.  Based on the predicted exposure levels, the predicted maximum mean QTcF on 
osilodrostat 20 mg is 4.1 ms (CI 2.98, 5.28), and the predicted maximum mean QTcF on 
osilodrostat 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 osilodrostat doses up to 30 mg. 
2 
Rationale 
2.1 
Study rationale and purpose 
Osilodrostat is a potent, oral inhibitor of 11β-hydroxylase (CYP11B1), the enzyme that 
catalyzes the last step in the biosynthesis of cortisol. This provides the rationale for investigating 
the use of osilodrostat in endogenous causes of Cushing’s syndrome (CS) of which the most 
common cause is an ACTH-secreting pituitary adenoma (Cushing’s disease [CD]).  


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This is a pivotal, Phase III, global, multi-center, randomized, double-blind, placebo-controlled 
study to confirm the results of the phase II [LCI699C2201] study and intended to support the 
registration of osilodrostat for the treatment of patients with CD who are candidates for medical 
therapy.  
2.2 
Rationale for the study design 
2.2.1 
Overall design 
The study aims to demonstrate the superiority of osilodrostat compared to placebo in achieving 
a complete response (mUFC ≤ ULN) at Week 12, to evaluate the safety of osilodrostat 
compared to placebo, and to evaluate the long-term safety and efficacy of osilodrostat.   
2.2.2 
Period 1: Double-blind, placebo-controlled 
At the beginning of the 12-week placebo-controlled period, eligible patients will be randomly 
assigned in a double-blinded fashion, either to osilodrostat treatment or to placebo (2:1 ratio).  
The duration of the placebo-controlled period in the current study is optimized to allow for 
appropriate dose titration and collection of placebo-controlled data, while minimizing the 
duration of time without cortisol-lowering therapy to protect patient safety. Furthermore, over 
75% of patients in the Phase II study [LCI699C2201] had UFC controlled by Week 6 and all 
patients had completed up-titration by Week 8. 
The placebo-controlled study design assesses efficacy and safety in patients randomized to 
treatment with osilodrostat versus placebo during the first 12 weeks of the study. The double-
blind design minimizes the risk of potential bias. It also provides data to distinguish adverse 
effects related to the study drug from those resulting from underlying disease.  
In order to maintain the integrity of the blind during the first 12 weeks of the study: 
1. UFC and related laboratory tests obtained during Period 1 that may disclose treatment 
assignment will remain blinded (as described in Section 6.5.3) to patients, investigators 
and Novartis Clinical Trial Team until after the 48-week Core database lock.   
2. Matching placebos will be provided for all tablet strengths used during Period 1 
(osilodrostat 1 mg, 5 mg, 10 mg, and (depending on availability) 20 mg).   
3. Patients randomized to placebo will undergo mock titration (simulating both up and down-
titrations) consistent with what may occur in patients treated with active drug during 
Period 1. Please see Section 6.2.1 for details.  
In addition, to reduce the risk of premature discontinuation during the placebo-controlled 
period, comorbidities (such as hypertension, hyperglycemia, hyperlipidemia and hypokalemia), 
should be optimally treated prior to study entry and during the entire study. Rescue therapy for 
co-morbid conditions should also be implemented before a decision is made to discontinue a 
patient from study drug (see rescue plan in Section 6.1.3). During this period, the investigator 
may temporarily interrupt study drug in the event of an AE of suspected adrenal insufficiency, 
or any AE that requires replacement or stress doses of glucocorticoid therapy (for additional 
information, see Section 6.2, Section 6.3.1 and Section 6.3.2). 


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2.2.3 
Period 2: Open-label  
The objective of the open-label period, during which all patients receive active drug, is to 
elucidate the long-term efficacy and safety profile of osilodrostat while allowing for dose 
titration as needed by the investigator to achieve optimal control. 
To maintain the integrity of the blind during Period 1 (double-blind period), at the beginning of 
Period 2 (Week 12, open-label period) all patients will start open-label osilodrostat 2 mg b.i.d., 
except those treated with doses < 2 mg b.i.d. at the end of Period 1. The first UFC results 
available to investigators will be for the Week 14 assessment, which occurs 2 weeks after these 
patients have received osilodrostat 2 mg b.i.d. Based on experience from the Phase II study, the 
majority of patients treated with active drug during Period 1 are expected to have been titrated 
to doses of > 2 mg b.i.d. by week 12. Decreasing the dose to 2 mg b.i.d. in these patients at the 
beginning of Period 2 is likely to lead to increased mUFC values in the Week 14 urine sample. 
On the other hand, patients randomized to placebo would have been on active treatment for 2 
weeks and their mUFC values will likely have fallen from baseline. Thus, it is expected that 
mUFC values at Week 14 will overlap significantly between the two treatment groups, thereby 
maintaining the integrity of the blind.  
During Period 1, a small subset of osilodrostat- and placebo-treated patients may have been 
down-titrated to doses lower than 2 mg b.i.d. by week 12.  At the start of Period 2 (after Week 
12 assessments have been completed), these patients will continue or start treatment with open-
label osilodrostat at their last dose of Period 1 with dose titrations based on mUFC at Week 14 
onwards (as described in Section 6.2).  
2.2.4 
Optional Extension Phase 
At the end of the Core study (Week 48) patients receiving clinical benefit from osilodrostat 
have the option to enter a 48-week optional Extension phase (Weeks 48 to 96). Additional safety 
and efficacy data will be collected during this period. Patients currently enrolled in the optional 
extension phase must end study participation within 4 weeks after Protocol Amendment 02 is 
approved at the site, or by Week 96, whichever occurs first. Refer to Section 4.1 for more 
details. 
2.2.5 
Steps to ensure reliability of UFC results 
As UFC, measured in a 24-hour urine collection is the biomarker used for both the primary and 
key secondary assessments, special care is taken to ensure that the results are reliable (Section 
7.2.1.1).  The 24-hour urine collection must be within defined upper and lower limits for urine 
volume (>500mL - <3000mL) and urine creatinine (see Laboratory Manual for the most current 
reference ranges). These limits are intended to avoid the reporting of misleading results because 
of incomplete urine collections or extremes of urine concentration from under-treatment 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 (Chan, et al 2004; Issa, et al 1999; and Sharp, et al 
1996).  Additionally, 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 


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interference by cross-reactivity of accumulating cortisol precursors (e.g., 11-DOC) with 
osilodrostat therapy (Trainer, et al 2014; Monaghan, et al 2011). 
2.2.6 
ECG Monitoring 
Cardiac monitoring will include 12-lead Safety ECGs at pre-dose (Day 1) and 1.5 hours post-
dose at each visit the patient receives study drug. The Safety ECGs are the primary cardiac 
safety assessment, and their rationale is to assess the maximum change in QTcF in each 
individual patient each time they receive study drug at the site. The 12-lead safety ECGs are 
read in real-time on-site by the PI or other qualified physician (e.g., cardiologist), and if there 
is QT prolongation (QTcF > 480 ms or increase > 60 ms from baseline assessment), patients 
are to be managed according to the QT Monitoring Flow Chart in Figure 7-2. 
In addition, 24-hour continuous 12-lead Holter recordings will be performed at baseline, Weeks 
2, 12, 14, 36, and as applicable at Week 72 and at the end of treatment visit in the optional 
Extension phase.  The 24 hour Holter assessments are not intended to provide real-time 
assessment of cardiac intervals and cardiac rhythm; the recordings are read centrally.  
2.3 
Rationale for dose and regimen selection 
The rationale for b.i.d. dosing of osilodrostat is based on its half-life of 3-5h. This dosing 
regimen was used in study [LCI699C2201].  The original modeling of PK exposure estimated 
that a dose of 4-5 mg b.i.d. was expected to achieve a plasma concentration above the in vitro 
IC50 for CYP11B1 (2.5 nM) for a full 24 hours for efficacy; however, 2 mg b.i.d was chosen 
to be the starting dose in the proof-of-concept study based on safety considerations. 
In the Phase II study [LCI699C2201], Part I, evaluating osilodrostat in patients with 
uncontrolled CD over a 10 week period (N=12), osilodrostat was initiated at 2 mg b.i.d with 
dose escalation every 2 weeks to 5, 10, 20, and 50 mg b.i.d until UFC was normalized. All 
patients normalized UFC at least once during the study and 11/12 patients had a normal UFC 
at week 10.  The mean dose at the time of response was 13.5 mg/day (SD = 13.9 mg), and the 
mean time to response was 34.3 days (SD = 14.1 days). The daily dose required to first reach 
UFC normalization was ≤ 20 mg/day in 75% of the patients, with at least 50% of the patients 
requiring 10-20 mg/day (5-10 mg, b.i.d).   
In Part II (N=19), osilodrostat was initiated at 2 or 5 mg b.i.d. in 15 new patients with dose 
escalation every 2 weeks to 5, 10, 20 and 30 mg b.i.d until UFC normalization, and at  the  
penultimate  effective dose in 4 patients from Part 1 with escalation if needed. All patients 
normalized UFC at least once during the study; 16/19 (84%) patients had a normal UFC at 
Week 10, and 15/19 (79%) had a normal UFC at Week 22.  The distribution of total daily doses 
was similar to that of study Part I.  The mean total daily dose for the 17 patients that remained 
in the study at Week 22 was 16.9 mg; the total daily dose at Week 22 was ≤ 20mg in 14/17 
(82.3%) of patients.  
Hypocortisolism was reported in 4 patients in Part I of study [LCI699C2201], and in 6 patients 
in Part II (Core).  Hypocortisolism resolved in all patients with dose reduction and/or 
interruption.  In addition, during Part II of study [LCI699C2201], one patient had biochemical 
evidence of hypocortisolism on 2 mg b.i.d., and the dose was reduced to 1 mg b.i.d. Therefore, 
the individual dose titration starting at 2 mg b.i.d. is an appropriate method to assess the efficacy 


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and safety of osilodrostat. In the event that hypocortisolism (24-hour mUFC < LLN, or mUFC 
in the lower part of the normal range with signs and symptoms of adrenal insufficiency) is 
observed on a dose of 2 mg b.i.d., the dose may be reduced to < 2 mg b.i.d. (i.e., 1 mg b.i.d., 1 
mg q.d., or 1 mg q.o.d. (every other day)) to mitigate the risk of persistent hypocortisolism.  
In both parts of this study, the interpatient variability in dose requirements to normalize cortisol 
is broad (e.g. 2 mg b.i.d. to 30 mg b.i.d.). Fixed-dose comparisons of treatment groups with 
various doses of osilodrostat are not appropriate because this would carry the potential risk of 
acute adrenal insufficiency if a relatively high dose is administered to a patient that is sensitive 
to osilodrostat. 
This study will start individual dose titration with 2 mg b.i.d., and up-titration to 5 mg b.i.d., 10 
mg b.i.d., and 20 mg b.i.d. primarily on the basis of the mUFC levels. Similar dose titration will 
be performed in Period 2 with dose escalation up to 30 mg b.i.d.  
2.4 
Rationale for choice of combination drugs 
Not applicable.  
2.5 
Rationale for choice of comparators drugs 
The placebo-controlled study design assesses efficacy and safety in patients randomized to 
treatment with osilodrostat versus placebo during the first 12 weeks of the study. The double-
blind design minimizes the risk of potential bias.  
2.6 
Benefit-Risk Assessment of osilodrostat 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. Phase 2 data demonstrated normalization of 
mean UFC in 11/12 patients after 10 weeks of therapy (LCI699C2201, Part 1) and 15/19 
patients after 22 weeks of therapy ((LCI699C2201, Part II Core). There was a trend toward 
improved fasting glucose and HbA1c in patients with diabetes at baseline, and an improved 
fasting lipid profile in patients with dyslipidemia at baseline. Based on these results osilodrostat 
is a promising potential new therapy in patients with uncontrolled Cushing’s disease. 
Study-specific risks 
Study-specific risks in study LCI699C2302 include the potential for prolonged periods of 
uncontrolled hypercortisolism during washout, blinded placebo and dose titration with a 
maximum combined duration of under-treatment of 7 months.    
To mitigate the risk of uncontrolled hypercortisolism during drug washout, patients are to be 
monitored closely with specific attention to controlling co-morbidities. In addition, specific 
exclusion criteria with regard to blood pressure and diabetes control are used.  For patients who 
require washout periods of 4 weeks or longer, treatment with drugs that require a short washout 
period (e.g., 1 week) is recommended (see Section 5.2). 
To reduce the probability of treatment with placebo, a 2:1 randomization ratio (osilodrostat: 
placebo) has been implemented. In addition, close clinical monitoring of co-morbidities during 


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the placebo-controlled period, specific rescue therapies to treat uncontrolled co-morbidities, and 
criteria for early discontinuation have been implemented.  In addition, the threshold for mUFC 
to enter the study is > 1.3 x ULN (compared to > 1.5 x ULN in other studies) allowing patients 
with less severe Cushing’s disease to participate in the study. Furthermore, the placebo-
controlled period has been kept to a minimum at 12-weeks after which patients randomized to 
placebo will be treated with active drug.    
In addition, treatment with osilodrostat can potentially result in neutropenia, which is 
considered to be an indirect effect of cortisol reduction, as reported in the literature. During 
hormonal control, a significant decrease of neutrophil count, which is commonly elevated in 
patients with Cushing’s disease, has been reported demonstrating the effect of glucocorticoids 
on these blood cells (Masri-Iraqi et al, 2014). This effect has also been observed with 
osilodrostat in the Cushing’s disease trials and has included cases of neutropenia which were 
associated with mUFC levels that were either below normal or have had a rapid and substantial 
decline from baseline. In the cases observed, neutropenia has rapidly reversed with 
discontinuation of osilodrostat, and has also reversed when osilodrostat was continued, typically 
with decreasing doses. 
Potential risks of osilodrostat treatment in study population 
Potential risks of treatment with osilodrostat 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 men and 
women. Corticotroph tumor progression, with or without compressive symptoms, is another 
potential risk.  Skin rash has also been observed.   
Mitigation of the potential risks related to osilodrostat treatment include: frequent study visits 
with careful monitoring for adverse events and toxicities including those that have been 
observed in previous studies with osilodrostat; vital signs, blood chemistry including urine, 
serum, and salivary cortisol levels, plasma ACTH, electrolytes, renal and liver function, fasting 
lipid profiles, HbA1c, sex steroid levels (testosterone, estradiol, adrenal androgens), aldosterone 
and immediate precursor levels, safety ECGs at the time of Cmax, pituitary MRI scans, and 
bone mineral density.   
In addition, the protocol provides specific guidance for safety follow-up for liver toxicity 
(increased transaminases, increased total bilirubin) and an algorithm for monitoring and 
management of QT prolongation.  PK sampling will be conducted in all patients to measure 
osilodrostat plasma concentrations and assess for any correlation with adverse events or for 
potential drug-drug interaction. 
Oversight Committees  
A Steering Committee has been established comprising investigators who are Cushing’s disease 
experts, whose role is to contribute to the study design, oversee the conduct of the study and to 
ensure the transparent management of the study according to the protocol. An independent data 
monitoring committee (DMC) comprising external endocrinologists with expertise in 
Cushing’s disease, a cardiologist and a statistician will be established before FPFV to monitor 


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unblinded safety data periodically as the study proceeds, and to oversee the functioning of the 
IEs. 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. 
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 the 
placebo arm.   
2.7 
Biomarker development 
24-hour UFC is currently the standard test for screening and monitoring Cushing’s disease. 
Since cortisol is not uniformly secreted during the day, a quantitatively exact collection and 
measurement of 24-hour urine is required to detect abnormal cortisol levels. 
Although this method has been used in routine clinical practice for many years, there are several 
practical/methodological difficulties accompanying the collection and analyses of 24-hour UFC 
samples. For instance, patient education and compliance is essential to ensure that 24-hour urine 
samples are collected correctly, and consequently the UFC results are reliable. UFC levels could 
be elevated by physiological or pathological conditions other than Cushing’s disease (pseudo-
Cushing’s syndrome, e.g., due to major depression or chronic alcoholism).  Multiple UFC 
collections are required to assess the possibility of cyclic hypercortisolism.  Salivary cortisol 
may allow an easier method of assessing cortisol that reflects the concurrent free cortisol level 
in serum. Hair cortisol levels may be useful to assess longer-term overall cortisol secretion. 
This study will assess the value of additional pharmacodynamic markers such as the 
 
 salivary cortisol, and hair cortisol.   


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3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4 
To demonstrate the superiority of osilodrostat compared to placebo 
in achieving a complete response (mUFC ≤ ULN) at Week 12.   
The proportion of randomized patients with a complete response, 
i.e. mUFC ≤ ULN at Week 12.   
 
Key secondary 
 
Refer to Section 10.5.1 
To assess the complete response rate in both arms combined at 
Week 36 in patients receiving osilodrostat treatment.  
The proportion of patients with mUFC ≤ ULN at Week 36 for  
combined randomized patients who receive osilodrostat treatment. 
 
Other secondary 
 
Refer to Section 10.5.2 
To assess the proportion of patients with a complete response 
(mUFC ≤ ULN) or a partial response (mUFC decrease ≥ 50% from 
baseline and > ULN) at Week 12, Week 36, and Week 48.  
 
The overall response rate defined as proportion of complete 
responders (mUFC ≤ ULN) plus partial responders (≥ 50% 
reduction in mUFC from baseline and > ULN) at Week 12, Week 
36, and Week 48 by treatment arms and for all patients. 
 
To assess the change in mUFC during the Core and Extension 
periods of the study. (Refer to Table 7-1a and Table 7-2 for the 
study visit and evaluation schedule during the Core and optional 
Extension phases, respectively). 
Actual and percentage change in mUFC from baseline to each 
post-baseline visit during the Core and Extension at which UFC is 
collected by treatment arms and for all patients. 
 
To compare the time-to-first control of mUFC during the placebo-
controlled period (Weeks 1-12) between the randomized treatment 
arms. 
 
Time-to-first control of mUFC, which is defined as the time (in days) 
from randomization to the first mUFC collection that was ≤ ULN 
before completion or discontinuation of placebo-controlled period, 
whichever is earlier. 
 
To assess the time-to-escape during osilodrostat treatment up to 
Week 48.  
 
Time-to-escape is defined as the time (in weeks) from the first 
collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN 
on two consecutive visits on the highest tolerated dose of 
osilodrostat and not related to a dose interruption or dose reduction 
due to safety reasons. Escape will not be assessed for patients 
during the first 26 weeks. 
 


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Objective 
Endpoint 
Analysis 
To assess cardiovascular and metabolic related parameters 
associated with CD (fasting plasma glucose, HbA1c, fasting lipid 
profile, blood pressure, weight and waist circumference) by 
assessing actual and percent change from baseline and shift table 
at Weeks 12, 36, and 48. 
The actual and percent change from baseline in fasting plasma 
glucose (FPG), HbA1c, fasting lipid profile, blood pressure (BP), 
weight and waist circumference at Week12, Week 36, and Week 48 
by treatment arms and for the overall patient population. 
 
 
To assess the change from baseline at Weeks 12, 36, and 48 in 
physical features of CD. 
Mean change from baseline to Week 12, Week 36, and Week 48 in 
each of the following clinical signs of Cushing’s disease, captured 
by: a semi-quantitative Likert scale for facial rubor, striae, 
supraclavicular fat pad, dorsal fat pad, proximal muscle wasting 
(atrophy), central (abdominal) obesity, and ecchymoses (bruises) 
by randomized treatment arm and overall population.   
 
To assess the change from baseline in bone mineral density (BMD) 
by DXA scan at the lumbar spine and total hip at Week 48.   
The change from baseline in bone mineral density, and BMD T-
score, at the lumbar spine (L1-L4) and total hip at Week 48 by 
treatment arm and for overall patient population.  
 
To determine the safety and tolerability of osilodrostat in the study 
population. 
Adverse events and laboratory abnormalities.  Assessed events 
include: AEs of special interest, laboratory evaluation, ECG, Holter 
recording, and pituitary MRI. 
 
To assess the change from baseline in Health Related Quality of Life, 
as measured by the CD-specific QoL questionnaire (CushingQoL); 
by the Beck Depression Inventory (BDI-II); and by the general health-
related QoL instrument EQ-5D-5L, by randomized treatment arm and 
overall. 
 
Change in standardized score of CushingQoL, Beck Depression 
Inventory-II, and EQ-5D-5L, from baseline to Week 12 and Week 
48, from Week 12 to Week 36, and from Week 36 to Week 48, or 
the last measurement prior to early discontinuation, whichever 
occurs earlier.  
 
To evaluate pharmacokinetic exposure of osilodrostat in the study 
population. 
Plasma concentrations (pre-dose, 1-2 h post-dose) of osilodrostat. 
 
To assess the change from baseline in serum, salivary and hair 
cortisol levels 
The actual and percentage change from baseline in serum cortisol, 
late night salivary cortisol, morning salivary cortisol and hair cortisol 
levels for every visit in the Core and extension phases at which the 
biomarkers of hypercortisolism are collected, by treatment arms and 
for all patients.  
 


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Objective 
Endpoint 
Analysis 


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4 
Study design 
4.1 
Description of study design 
This is a Phase III, global, multi-center, randomized, double-blind, placebo-controlled study.  
The study design is placebo-controlled during the first 12 weeks, followed by open-label 
treatment with osilodrostat until week 48, and an optional Extension phase.  
Screening period (up to 8 weeks): 
The screening period will have a maximum duration of 8 weeks to enable patients to washout 
their current treatment for Cushing’s disease. Patients will be evaluated for trial eligibility after 
the washout period is completed. 
During washout, some patients may have loss of control of co-morbidities such as hypertension 
and diabetes. Therefore the screening period should be viewed as a “run-in” period in which 
the treatment of co-morbidities is optimized. Patients should be closely monitored and treated 
accordingly, aiming ideally for normalization of blood pressure, fasting glucose and potassium. 
Control of co-morbidities in this “run-in” is important for patient safety and to ensure the 
majority of patients can complete the 12-week placebo-control period and therefore minimize 
loss of data. Three 24-hr UFC urine samples and two late night salivary cortisol samples are to 
be collected after completion of the washout period to assess study eligibility. 
Period 1 (Weeks 1-12): double-blind, placebo-controlled period 
This is the randomized, double-blind, placebo-controlled period (Weeks 1-12).  Eligible 
patients are randomized in a 2:1 ratio to treatment with study drug (osilodrostat or placebo, 
respectively). Patients are stratified at randomization according to history of pituitary irradiation 
(yes/no).  
Figure 4-1 
Schematic of Period 1 
 
Study visits occur at Day 1, and Weeks 2, 5, 8, and 12 (Figure 4-1).  Study drug is started on 
Day 1 at a dose of 2 mg b.i.d., and titrated according to the regimen described in Section 6.2, to 
a dose which lowers mUFC to within the normal range.  Dose adjustments, if required, will be 
determined between study visits allowing the UFC samples collected just prior to the next visit 
to reflect the dose adjustment. The maximum dose that can be reached in Period 1 is 20 mg 
b.i.d. After Week 2, visit intervals are increased to three or more weeks to ensure adequate time 


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to execute the required steps for dose adjustment, which include provision of the laboratory data 
and clinical information to the IE, time for the IE to determine study drug dose and 
communicate this to sites, and for sites to contact the patient to implement the dose to patients. 
Figure 4-2 
Timing of study visits, UFC collection, and dose adjustments during 
Period 1 
 
Legend: During Period 1, study visits are at Day 1 and Weeks 2, 5, 8, and 12. The IE determines the 
study dose once UFC results become available.  Patients may be informed of dose changes by a site 
phone contact or at a visit if the patient needs to receive new study drug supplies or for safety issues. 
See text for additional details.   
Three 24-hour urine samples will be collected by patients, preferably on consecutive days at 
screening, immediately prior to Day 1 and the Week 12 visit (primary endpoint) during this 
study period. Two 24-hour urine samples will be collected preferably on consecutive days 
immediately prior to each of the other visits (i.e. at Weeks 2, 5, and 8).  
In order to maintain the treatment blind during Period 1, all laboratory results obtained during 
Period 1 that may disclose the randomized treatment assignment are blinded to patients, 
investigators and the Novartis Clinical Trial Team (see Section 6.5.3 for further details). The 
relevant laboratory results that are blinded include: UFC, urine creatinine, serum and salivary 
cortisol, ACTH, aldosterone,  renin, estradiol, estrone, androgens (testosterone, delta-4 
androstenedione, DHEAS), and precursors 11-deoxycortisol, 11- deoxycorticosterone. 
A group of independent endocrinologists (IEs) is responsible for managing dose titrations 
during Period 1 between visits. Titrations for patients assigned to placebo will aim to simulate 
the active arm. Refer to Section 6.2 for details on dose titration. The IE communicates study 
drug dosing instructions to the site for all patients (active and placebo) in a blinded manner 
through the IRT system. If a dose adjustment is required, sites may inform patients of a dose 
change by phone or at a visit if the change can be managed with the patients’ current supplies. 
If a different tablet strength is needed to implement the dose change, patients need to return to 
the site to collect the required study drug supplies and instructions on how to administer the 
dose. To minimize dosing errors for patient safety, it is very important that these instructions 
are clear, simple and written legibly (see Section 6.2.1.4. and Section 6.6 for further details).  
If patients discontinue study drug treatment before the Week 12 visit, investigators should make 
reasonable efforts to follow patients and perform assessments for all scheduled visits up to and 


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including the Week 12 visit (as listed in Table 7-1a, Post-treatment Follow-up), even if 
alternative cortisol lowering therapy has been initiated.  
During Period 1, the investigator may temporarily interrupt study drug in the event of an AE of 
suspected adrenal insufficiency, or any AE that requires replacement or stress doses of 
glucocorticoid therapy (for additional information, see Section 6.2.1.2 and Section 6.3.1).  
Period 2 (Weeks 12-48): single arm, open-label treatment period 
Period 2 starts immediately after the Week 12 visit, when the trial becomes open-label with all 
patients receiving the active drug, osilodrostat. During Period 2 patients randomized to placebo 
switch to osilodrostat and undergo their first dose titration with active drug, while patients 
randomized to osilodrostat continue this treatment and undergo a “second” dose titration.   
• All patients on doses of ≥2 mg b.i.d. at the Week 12 visit will receive open-label 
osilodrostat at a starting dose of 2 mg b.i.d. at the beginning of Period 2, regardless of 
treatment assignment in Period 1.  
• Patients on <2 mg b.i.d. at the Week 12 visit will continue the same dose they were on at 
the end of Period 1, regardless of treatment assignment during Period 1.  
• Placebo-treated patients on a dose of < 2 mg b.i.d. at the end of Period 1, will continue this 
dose but with active drug at the beginning of Period 2.   
During Period 2, the investigator is responsible for dose titration, which will be based on mUFC 
and other relevant patient data (as described in Section 6.2.2). Osilodrostat can be titrated up to 
a maximum dose of 30 mg b.i.d. during this period. The investigator has access to all laboratory 
results from the Week 14 assessments onward.   The IE does not participate in dose decisions 
beyond Week 12.  
Three 24-hour urine samples will be collected by patients, preferably on consecutive days 
immediately prior to the Week 36 visit (key secondary endpoint) and Week 48 (end of Core 
phase). Two 24-hour samples will be collected prior to all other visits in Period 2.  A patient is 
considered to have reached a stable efficacious dose when mUFC remains ≤ ULN. This dose is 
continued, unless a change is needed (see Section 6.2.2 for details). As in Period 1 dose 
adjustments may be managed via a phone call, however if a different tablet strength is needed 
patients should return to the site to collect the new supplies. 
Optional Extension phase: 
 
At Week 48, patients have the option to enter an optional  open-label Extension phase.  Patients 
who do not enter the optional extension discontinue osilodrostat at Week 48 and conclude with 
a Post-Treatment (End of Study) visit after 30 days off study drug.  Patients enrolled in the 
optional extension phase must end study participation within 4 weeks after Protocol 
Amendment 02 is approved at the site, or by Week 96, whichever occurs first. If Patients who 
are benefitting from study treatment, have the option to enter a separate long-term safety follow-
up study or stop study treatment. Patients who do not enter the long-term safety follow-up study 
will discontinue osilodrostat  and  conclude the study with a Post-Treatment (End of Study) 
visit after 30 days off study drug. Refer to Section 6.1.5 for more details. During the optional 
extension phase the dose of osilodrostat will be maintained at the established effective dose 


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unless a change is required based on mUFC results collected at Weeks 48, and if applicable, at 
Weeks 60, 72, and 84 (see Section 6.2.3 for details on dose adjustment).  
Additionally, patients are allowed to have unscheduled visits at any time in the study if needed, 
e.g. if they report signs and/or symptoms of hypercortisolism, adrenal insufficiency, other AEs, 
or need additional study drug supplies. 
For more details on dosing titration, Independent Endocrinologists (IE) and Investigator 
interventions, please refer to Section 6.2. 
A schematic diagram of the Core study design is shown below in Figure 4-3. 
Every effort will be made to continue provision of osilodrostat treatment beyond this study as 
described in Section 4.3. 
Figure 4-3 
Schematic of Core study design 
 
 
4.2 
Timing of interim analyses and design adaptations 
The study will have no interim analysis for efficacy. The DMC will conduct periodic safety 
data reviews as outlined in Section 8.6. 
4.3 
Definition of end of the study 
Completion of the study as a whole (last patient last visit) will occur once all patients have 
completed all assessments as per Table 7-1a, Table 7-1b (Core) and, as applicable, Table 7-2 
(optional Extension), or have discontinued from the study, including Post-treatment follow-up 
or transition into the long-term safety follow-up study, whichever occurs first.  
Patients to end participation in the optional Extension period within 4 weeks after Protocol 
Amendment 02 is approved at the site, or by Week 96, whichever occurs first. Refer to Section 
6.1.5 for details. 


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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 assessments should be performed as described in Section 7 for a 
discontinued or withdrawn patient. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing IRBs and/or ECs of the 
early termination of the trial. 
5 
Population 
5.1 
Patient population 
The study population will be comprised of approximately 69 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 or do not have access to a 
specialized center with experience in pituitary surgery.  
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are randomized to treatment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent obtained before any assessment is performed. 
2. Male or female patients aged 18 - 75 years. 
3. Confirmed CD that is persistent or recurrent as evidenced by all of the following criteria 
being met (i.e., a, b, and c): 
a. mUFC > 1.3 x ULN (Mean of three 24-hour urine samples collected preferably on 3 
consecutive days during screening after washout of prior medical therapy for CD (if 
applicable), confirmed by the central laboratory and available before Day 1), with ≥ 2 
of the individual UFC values being > 1.3 x ULN. 
b. Morning plasma ACTH above Lower Limit of Normal  
c. Confirmation (based on medical history) of pituitary source of excess ACTH as defined 
by any one or more of the following three criteria: 
i. 
Histopathologic confirmation of an ACTH-staining adenoma in patients who have 
had prior pituitary surgery. 
OR 
ii. 
MRI confirmation of pituitary adenoma > 6 mm 
OR 
iii. 
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; 


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• Post-dose central to peripheral ACTH gradient > 3 after either CRH or DDAVP 
stimulation 
4. Patients that received glucocorticoid replacement therapy must have discontinued such 
therapy for at least seven days or 5 half-lives prior to screening, whichever is longer. 
5. Patients with de novo CD can be included only if they are not considered candidates for 
surgery (e.g., poor surgical candidates due to co-morbidities, inoperable tumors, patients 
who refuse to have surgical treatment, or surgical treatment is not available) 
6. For patients with a history of pituitary irradiation: at least 2 years for stereotactic 
radiosurgery (SRS), and 3 years for conventional (fractionated) radiation, respectively, must 
have elapsed from the time of the most recent radiation treatment to the time of enrollment 
into this study.  
7. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
8. Washout of any current drug therapy for CD. The following minimum 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. Mifepristone: 3 weeks 
d. Dopamine agonists (e.g., cabergoline), or PPAR-gamma agonists (e.g., rosiglitazone, 
pioglitazone): 4 weeks 
e. Pasireotide LAR: 8 weeks.  Rescreening can be used as needed to ensure washout is 
complete.  
f. Mitotane: 6 months. Rescreening can be used as needed to ensure washout is 
complete. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
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. Patients with pseudo-Cushing’s syndrome. This may be diagnosed by two normal late 
night salivary cortisol value collected during the screening period and after washout of 
prior CD medication. 
3. History of hypersensitivity to drugs of the same or similar chemical classes as osilodrostat. 
4. 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. 
5. Patients with risk factors for QTc prolongation or Torsade de Pointes, including:  
• patients with a baseline QTcF > 450 ms for males and QTcF > 460 ms for females 
• personal or family history of long QT syndrome 
• concomitant medications known to prolong the QT interval 


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• patients with hypokalemia, hypocalcaemia, or hypomagnesaemia, if not corrected 
before pre-dose Day 1. 
6. Patients who have a history of: congestive heart failure (NYHA Class III or IV), unstable 
angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart 
block, acute myocardial infarction less than one year prior to study entry, or clinically 
significant impairment in cardiovascular function. 
7. Pregnant or nursing (lactating) women. 
8. 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: 
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 drug. 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 drug. 
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 (i.e., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy,  or tubal ligation at least six weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment is she considered not of child bearing 
potential. 
9. Patients likely to require adrenalectomy, pituitary surgery, or radiation therapy during the 
placebo-controlled period (Weeks 1-12) for the treatment of severe hypercortisolemia or 
pituitary tumor growth causing compression of the optic chiasm.   
10. 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). 
11. Patients who have a known inherited syndrome as the cause for hormone over secretion 
(i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP). 


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12. Patients with Cushing’s syndrome due to ectopic ACTH secretion or ACTH-independent 
(adrenal) Cushing’s syndrome. 
13. Patients who have undergone any major surgery within 1 month, or undergone 
transsphenoidal pituitary surgery within 3 months, prior to screening.  
14. Hypertensive patients with uncontrolled blood pressure defined as SBP > 180 and/or DBP > 
105 or not optimally treated for hypertension as judged by the investigator. 
15. Diabetic patients with poorly controlled diabetes as evidenced by HbA1c > 9 % or not 
optimally treated for diabetes mellitus as judged by the investigator. 
16. Patients who are not euthyroid as judged by the investigator. 
17. Patients with moderate to severe renal impairment (estimated GFR < 60 mL/min by the 
MDRD formula). 
18. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent 
hepatitis, or patients with serum ALT and/or AST > 3 x ULN, or total bilirubin > 1.5 x 
ULN. 
19. Any ongoing or prior medical condition, drug or alcohol abuse, non-compliance behavior, 
or inability to complete the entire trial that can negatively interfere with the conduct of the 
study or the evaluation of its results as judged by the investigator.  
20. Previous exposure to osilodrostat for the treatment of CD. 
21. History of stroke, or pulmonary embolism within the prior year.   
22. Repeated history of deep venous thrombosis unrelated to prolonged bed rest, recent surgery, 
or pregnancy. 
23. History of psychiatric hospitalization within the prior 6 months.      
24. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the Colombia Suicide 
Severity rating Scale (C-SSRS), if this ideation occurred in the past 6 months, or “yes” on 
any item of the Suicidal Behavior section, except for the “Non-Suicidal Self-Injurious 
Behavior” (item also included in the Suicidal Behavior section), if this behavior occurred 
in the past 2 years. 
6 
Treatment 
6.1 
Study drug 
The study drug consists of osilodrostat (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, imprint and color (Figure 6-1). The osilodrostat 1 mg, 5 mg, 
10 mg and 20 mg film coated tablets are approximately 6 mm, 7 mm, 9 mm, and 11 mm 
respectively in diameter and pale yellow, yellow, pale orange brown and light brown 
respectively in color. 


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Figure 6-1 
Appearance of osilodrostat tablets by strength 
 
Legend: Each strength of osilodrostat (and matching placebo) has a unique size and color to aid in 
recognition. The appearance of the actual tablets may vary slightly from the picture.  
6.1.1 
Dosing regimen 
Study drug should be taken twice a day (b.i.d.). For example a patient on a 2 mg b.i.d. dose will 
take 2 mg in the morning and 2 mg 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. Osilodrostat can be dosed without regard to food. The patient will 
maintain a diary of each drug self-administration in order to track compliance. 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. A missed dose 
is defined as a case when the dose is not taken within 4 hours after the usual dosing time.  
On study visit days, patients should be reminded not to take the study drug prior to the site visit 
to ensure compliance with the ECG and pre-dose PK sampling procedure. The morning dose of 
study drug on the visit days should be administered at the site after the ECG and pre-dose PK 
sampling has been completed. 
6.1.2 
Ancillary treatments 
Not applicable. 
6.1.3 
Rescue medication for co-morbid conditions 
Patients should receive optimal treatment for co-morbidities (hyperglycemia, hypertension, 
dyslipidemia, hypokalemia) both during the screening period and study treatment period.  
During the placebo-controlled period (Weeks 1-12), if patients’ comorbidities for CD worsen, 
rescue treatment for co-morbidities should be initiated and optimized to retain the patient in the 
study if possible, before a decision is made to discontinue study medication.    
It is suggested that the following glycemic thresholds be used for initiation or intensification of 
glucose-lowering therapy: 
• Fasting plasma glucose > 200 mg/dL (11.1 mmol/L) from baseline to Week 6  


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• Fasting plasma glucose > 160 mg/dL (8.88 mmol/L) from Week 6 to Week 12. 
It is suggested that certain classes of agents be used to treat co-morbidities.  For the treatment 
of hyperglycemia, metformin should be considered first and the dose increased, if tolerated, to 
the maximally effective dose (i.e., ≥1500 mg daily) prior to adding another agent.   
For the treatment of hypertension, ACE inhibitors should be used over diuretics known to cause 
hypokalemia (e.g., hydrochlorothiazide) and dose should be optimized.  Mineralocorticoid 
receptor antagonists (e.g., spironolactone) should be used as second line agents for hypertension 
and to prevent hypokalemia; however the concomitant use of ACE inhibitors and 
spironolactone or eplerenone is prohibited. Serum potassium should be monitored closely and 
hypokalemia should be treated promptly if it occurs. Oral or intravenous potassium supplements 
can be used to treat hypokalemia, and spironolactone should be considered to prevent 
hypokalemia in patients with edema and/or hypertension.  It is suggested that oral potassium 
supplementation be initiated if the serum potassium level is even mildly decreased (e.g., ≤ 3.3 
mg/dL [≤ 3.3 mEq/L]), and more aggressively treated (e.g., consider intravenous potassium 
replacement) if the patient is symptomatic or serum potassium level falls to < 3.0 mg/dL [< 3.0 
mEq/L]). 
Serum lipid levels should be monitored and treated as appropriate.   
Thresholds for considering discontinuation of patients from study drug or from the study are 
discussed in Section 7.1.4. 
6.1.4 
Guidelines for continuation of treatment 
Osilodrostat 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 study (Periods 1 and 2), and up to an additional 
48 weeks for patients who agree to continue on the optional extension phase. Patients may 
continue treatment with the study drug until unacceptable toxicity has been experienced, and/or 
treatment is discontinued at the discretion of the investigator or withdrawal of consent.  In the 
absence of study drug discontinuation, patients will receive osilodrostat for a minimum of 36 
weeks to a maximum of 48 weeks during the Core phase. 
The optional extension phase will end when all patients who were eligible have transitioned 
into the long-term safety follow-up study, or were discontinued from the study. Patients must 
end participation in the optional extension phase within 4 weeks after Protocol Amendment 02 
is approved at the site, or by Week 96, whichever occurs first. Patients participating in the 
optional extension phase between Week 48 and Week 72, and who are eligible, should transition 
into the long-term safety follow-up study at the next study visit. Patients participating in the 
optional extension phase between Week 72 and Week 96, and who are eligible, should transition 
into the long-term safety follow-up study within 4 weeks, at an unscheduled visit if needed, of 
Protocol Amendment 02 approval at the site. 


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6.2 
Dose titration guidelines 
6.2.1 
Study Period 1: The double-blind, placebo-controlled period (Weeks 1-
12). 
For patients on osilodrostat arm, the IE is responsible for study drug dose titrations during 
Period 1, as the Investigators will not have access to UFC, serum cortisol, and other related 
laboratory results (as described in Section 4.1) that could disclose the randomized treatment 
assignment. The IE will determine the study drug dose once the mUFC level is available from 
scheduled study visits at Week 2, Week 5 and Week 8, and has access to following data:  
• treatment allocation 
• mUFC and individual 24-hour UFC values from the most recent study visit (see Table 7-
1a), and mUFC values since the beginning of the trial (as reported by the central 
laboratory) 
• other relevant laboratory data (i.e., serum cortisol, ACTH, and chemistry) 
• data on the presence or absence of clinical signs and symptoms of adrenal insufficiency 
(AI; as recorded on the clinical signs and symptoms of AI eCRF page from the most 
recent study visit) (see Section 7.2.2.1.1 for details). 
• vital signs as recorded in the eCRF 
• study drug doses since the beginning of the trial (as recorded on the Drug Administration 
Record (DAR) eCRF). 
In order to maintain the study blind, communication from the IE to the investigator must be 
limited to communication of study drug dose decisions through the IRT system.   
For patients in the placebo arm, a simulated dose titration sequence will be used to maintain 
the blind.  
6.2.1.1 
Dose up-titration during Period 1 
The initial study drug dose in Period 1 is osilodrostat or placebo 2 mg b.i.d.  The dose escalation 
sequence is: 5 mg b.i.d., 10 mg b.i.d. and 20 mg b.i.d. The IE will up-titrate the osilodrostat 
dose to the next dose in the sequence, based on the mUFC value until mUFC is normalized.  
While the goal is to normalize mUFC, decision to up-titrate dose will take into consideration 
the totality of the data available on each patient e.g. level of mUFC, rate of decrease of mUFC 
and tolerability of study drug (see Section 6.3). 
Once mUFC is in the normal range (i.e., mUFC ≤ ULN and ≥ LLN), the dose should be 
maintained, provided there are no safety concerns requiring a dose reduction or interruption (as 
described below and in Section 6.3).  
6.2.1.2 
Dose down-titration during Period 1  
The dose of study drug may be down-titrated or interrupted by the IE in patients with mUFC 
values < LLN or close to LLN together with signs and/or symptoms of adrenal insufficiency. 
However, it is expected that the investigator will take immediate action to temporarily withhold 
study medication, without waiting for instructions from the IE, if their patient had suspected 
adrenal insufficiency, or any AE that requires replacement therapy with glucocorticoids (see 


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Section 6.3.1 for details). In the event the investigator interrupts study drug, this information 
must be recorded in the eCRF as soon as possible, so that the IE can take this into account when 
selecting the next scheduled study drug dose.  
6.2.1.3 
Intermediate doses for dose adjustment 
The preferred doses for either up or down-titration are the standard recommended doses of 2, 
5, 10 and 20 mg b.i.d. during Period 1. The preferred intermediate doses are: 3, 7, and 15 mg 
b.i.d., but other doses may be selected if necessary. 
Examples of the appropriate use of intermediate study drug doses are described below:     
• A patient previously down titrated from a higher dose for signs and symptoms of adrenal 
insufficiency to the next lower standard dose (e.g., down titrated from 10 mg b.i.d. to 5 mg 
b.i.d.), and who experienced an increase in mUFC > ULN, or developed signs and 
symptoms of hypercortisolism at the lower dose, may be up titrated to an intermediate 
dose (e.g. 7 mg b.i.d., or, if needed, another intermediate dose between 5 mg and 10 mg 
b.i.d.) to optimize control.  
• A patient who had mUFC > ULN, with or without signs and symptoms of 
hypercortisolism at one dose, and subsequently had mUFC < LLN or close to the LLN, 
accompanied by signs and symptoms of hypocortisolism at the next standard higher dose 
(e.g., after up-titration from 5 mg b.i.d. to 10 mg b.i.d.) may be down titrated to an 
intermediate dose (e.g., 7 mg b.i.d., or, if needed, other doses between 5 mg and 10 mg 
b.i.d.) to optimize control.  
In patients treated with either osilodrostat or placebo, the study drug could be down-titrated to 
a dose lower than 2 mg b.i.d., if indicated.  In addition, doses of 1 mg b.i.d. or lower can be 
used, e.g., 1 mg q.d. or 1mg q.o.d. (every other day), if needed for patients that are sensitive to 
osilodrostat. Importantly, only placebo-treated patients with mUFC < 1.5 x ULN will be down-
titrated to doses below 2 mg b.i.d., to avoid unblinding and prolonged hypercortisolism after 
the Week 12 visit for patients with severely uncontrolled hypercortisolism.  
The IEs, 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 (see Section 6.6 for details). 
6.2.1.4 
Communication and implementation of dose changes 
As soon as possible (e.g. within 48 hours, if feasible) after the receipt of UFC values for each 
patient: 
1. The IE must determine the next study drug dose (as described in the dosing guidelines, 
above)  
2. The IE must communicate the dose decision for each patient to the corresponding site, 
through the IRT system in a blinded manner.  
3. If a dose change is needed and can be accommodated with the patients’ current supplies, 
the IRT system will provide instructions for the new dose,  with the option for this dose 
change communication to be either via the phone or during an unscheduled visit (per 
investigator judgment). If a different tablet strength is needed to implement the dose 
change, the IRT system will recommend that the patient returns to the site (unscheduled 


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visit) for a dose change. The following need to be completed during both at scheduled and 
unscheduled site visits:  
a. Patients should return all unused tablets to the site for drug accountability 
b. Patients will receive adequate quantities of medication at the new dose to last until the 
next scheduled visit.   
c. Patients must receive written instructions regarding the new dose and dosing schedule.    
Phone contact: Sites should also initiate a patient contact via the phone approximately 2-5 days 
after a visit, regardless of whether a dose change was made to assess the following: 
1. verify the dose the patient is taking   
2. assess the presence or absence of signs and symptoms of adrenal insufficiency or 
glucocorticoid withdrawal.  
Note: If the dose is maintained without change, the patient does not need to return to the site 
until the next scheduled study visit.  
As a general rule, the patient must be on a dose of study medication for at least 4 days before 
starting a UFC sample collection, in order to ensure that the UFC results reflect adequate 
exposure to the dose. Therefore, if the time interval between availability of the new dose and 
next scheduled visit is less than 6 days (when 2 x 24-hour urine collections are required for dose 
titration) or 7 days (when 3 x 24-hour urine collections are required, e.g. Week 12 visit), patients 
should not be requested to change their dose until the next scheduled visit when new dosing 
instructions will be provided and study drug dispensed.  
The above guidance is not applicable when urgent dose changes need to be made to ensure 
patient safety. All study drug dose changes must be documented in the eCRF. 
6.2.2 
Study Period 2:  The single-arm, open-label dose titration period 
(Weeks 12-48) 
Immediately after the Week 12 visit, all patients (in both treatment groups) will receive open-
label osilodrostat (as described in Section 4.1).  
Investigators will up-titrate osilodrostat doses to achieve mUFC normalization, according to the 
following dose escalation sequence: 2 mg b.i.d., 5 mg b.i.d., 10 mg b.i.d., 20 mg b.i.d., and then 
30 mg b.i.d.. For any patients on less than 2 mg b.i.d. at the beginning of Period 2, the 
investigator can increase the dose to 2 mg b.i.d. when the results of the Week 14 visit are 
available, and then follow the above dose escalation sequence as needed to normalize mUFC. 
The investigator will follow the same dosing guidelines as described above for the IE (Section 
6.2.1: Study Period 1).  
The investigator must remain vigilant to signs and symptoms of adrenal insufficiency and 
glucocorticoid withdrawal between Week 12 and receipt of the Week 14 UFC results and take 
appropriate action with regard to the osilodrostat dose, if needed. An unscheduled visit during 
this time may facilitate assessment of the patient.    
Osilodrostat treatment continues until the Week 48 visit with dose-titration to the minimum 
effective dose that maintains UFC ≤ULN. This dose is continued unless a change is required 
based on mUFC results, or an AE occurs that requires dose reduction or temporarily 


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withholding osilodrostat. Dose adjustments are to be performed by the investigator as described 
in the dosing guidelines above for the IE (Section 6.2.1: Study Period 1). 
6.2.3 
Extension phase (Weeks 48 - 96): 
Osilodrostat treatment continues for  up to 48 weeks at the established effective dose unless a 
change is required based on mUFC results, or an AE occurs that requires dose reduction or 
temporarily withholding osilodrostat. Dose adjustments are to be performed as described for 
Period 2. 
Patients who continue to benefit from treatment during the optional extension phase, have the 
option to continue treatment on study until any of the following occurs: 
a) they no longer benefit from treatment or  
b) managed access program becomes locally available or  
c) an alternative treatment option becomes locally available or  
d) within 4 weeks after Protocol Amendment 02 is approved at the site, since a separate long 
term follow up study is now available  or by Week 96, whichever comes first. Refer to 
Section 6.1.5 for details  
For patients who transition into a separate long-term study or managed access program, the 
EOS (last dose + 30 days) visit is not applicable, as treatment on osilodrostat will not be 
interrupted, and only the EOT visit will be performed. 
Those patients who will not continue treatment will complete the EOT extension visit and an 
EOS (last dose + 30 days) visit, for details of assessments, please refer to Section 7.1.4. 
6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
Please refer to Section 4.1 “Description of study design” and Section 6.2  “Dose titration 
guidelines” for further information about dose and dosing regimen during various periods of 
the trial. 
In the event of a major safety issue, the investigator may order any laboratory, radiology, or 
other diagnostic testing required in the safety assessment. In the case of suspected acute adrenal 
insufficiency or adrenal crisis, the investigator may order and see the results of an urgent serum 
cortisol level during the double-blind phase of the trial (Weeks 1-12).  However, since 
knowledge of the serum cortisol level could, in effect, unblind the investigator, this action 
should be reserved for situations in which the clinical diagnosis is in doubt, and the serum 
cortisol level is considered necessary in the evaluation and treatment of the patient. 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study drug. The following guidelines 
(Table 6-1 and Table 6-2) need to be applied.  These changes must be recorded in the eCRFs. 


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Table 6-1 
Dose Modification Guidelines for osilodrostat-suspected 
toxicities 
Toxicity 
Suggested actions 
 
From Week 1 to 12 
The investigator must immediately 
inform the IE about AEs and actions 
taken with study drug by completing 
the appropriate eCRF. 
From Week 12 Onward 
Symptomatic adrenal 
insufficiency 
See Section 6.3.2 for 
additional detail. 
If the investigator at any time suspects adrenal insufficiency, they can 
immediately interrupt study drug and initiate replacement with glucocorticoids. 
Upon recovery as assessed by the investigator*, glucocorticoid therapy can be 
tapered as tolerated, and study drug can be re-started. The decision to restart 
study drug will be made by the investigator. The AE and associated treatments 
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.   
The IE can adjust the dose when sufficient information is provided, i.e., serum 
cortisol, one or more (up to three) 24-hour UFC result, plasma glucose and 
electrolytes (as central lab assessment) and completed eCRF pages with 
clinical signs and symptoms associated with hypocortisolism/adrenal 
insufficiency event.  
Persistent asymptomatic 
hypocortisolism (mUFC < 
LLN) at the lowest dose of 
osilodrostat (1 mg every 
other day) 
See Section 6.3.2 for 
additional detail. 
The IE can interrupt study drug and 
restart at the same dose as clinically 
indicated (based on information in the 
eCRF).  
The investigator can interrupt study 
drug and restart at the same dose as 
clinically indicated.  
Glucocorticoid withdrawal 
syndrome 
See Section 6.3.2 for 
additional detail. 
The investigator can interrupt dose 
until withdrawal symptoms have 
improved. 
The investigator can reduce or 
interrupt dose until withdrawal 
symptoms have improved. 
*Hypotension (mild, 
reversible) 
The investigator can interrupt dose 
until blood pressure levels have 
improved. 
The investigator can reduce or 
interrupt dose until blood pressure 
levels have improved. 
*Hypertension 
The investigator can interrupt dose 
until blood pressure levels have 
improved; consider ACE inhibitors for 
treatment of hypertension, or 
spironolactone as second line 
treatment, particularly if hypokalemia 
is present. ACE inhibitors and 
spironolactone should not be used 
in combination. 
The investigator can reduce or 
interrupt dose until blood pressure 
levels have improved; consider ACE 
inhibitors for treatment of 
hypertension, or spironolactone as 
second line treatment, particularly if 
hypokalemia is present. ACE 
inhibitors and spironolactone 
should not be used in combination. 
*Weight gain, edema 
The investigator can interrupt dose 
until improved; consider 
spironolactone for treatment of 
edema. 
The investigator can reduce or 
interrupt dose until improved; 
consider spironolactone for treatment 
of edema. 
*Hypokalemia 
The investigator can interrupt dose 
until improved; replace potassium; 
consider spironolactone or 
eplerenone for prevention and 
treatment of hypokalemia 
The investigator can reduce or 
interrupt dose until improved; replace 
potassium; consider spironolactone or 
eplerenone for prevention and 
treatment of hypokalemia 


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Toxicity 
Suggested actions 
 
From Week 1 to 12 
The investigator must immediately 
inform the IE about AEs and actions 
taken with study drug by completing 
the appropriate eCRF. 
From Week 12 Onward 
*Hyperkalemia 
The investigator can interrupt dose 
until improved; if on spironolactone or 
eplerenone, reduce or interrupt; treat 
with kayexalate and other potassium 
lowering therapies as needed.  
The investigator can reduce or 
interrupt dose until improved; if on 
spironolactone or eplerenone, reduce 
or interrupt; treat with kayexalate and 
other potassium lowering therapies as 
needed. 
*Hirsutism (women only) 
The investigator can interrupt dose 
until improved; review testosterone 
level; consider treatment with 
spironolactone, cyproterone acetate 
or finasteride per local guidelines 
The investigator can reduce or 
interrupt dose until improved; review 
testosterone level; consider treatment 
with spironolactone, cyproterone 
acetate or finasteride per local 
guidelines 
*Acne (women or men) 
The investigator can interrupt dose 
until improved; review testosterone 
level; consider treatment with 
spironolactone, cyproterone acetate 
or finasteride per local guidelines 
The investigator can reduce or 
interrupt dose until improved; review 
testosterone level; consider 
spironolactone, cyproterone acetate 
or finasteride per local guidelines  
* Treatment of co-morbidities should be optimized during the screening period and may be considered in these 
situations and throughout the study treatment period (see Section 6.1.3 for details).   
Instructions for monitoring liver function, and the criteria for withholding, re-initiating, 
reducing dose or discontinuation of study medication are provided in Table 6-2 below. 


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Table 6-2 
Criteria for interruption and re-initiation of osilodrostat for abnormal 
liver function 
Isolated total Bilirubin elevation 
> ULN – 1.5 x ULN 
Maintain dose level 
> 1.5 - 3.0 x ULN  
lnterrupt study drug dose. Monitor LFTs weekly, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN: 
If resolved in ≤ 14 days, restart study drug and maintain dose level  
If resolved in > 14 days, restart study drug and decrease by one dose level. 
> 3.0 - 10.0 x ULN*  
Interrupt study drug. Monitor LFTsa  weekly, or more frequently if clinically indicated, 
until resolved to ≤ 1.5 x ULN: 
If resolved in ≤ 14 days, restart study drug and decrease by one dose level. 
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 
 
 
 
 
 
Interrupt study drug.  Repeat LFTsa as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; monitor LFTsa weekly, or more frequently if 
clinically indicated, until resolved to ≤ 3.0 x ULN.  Then: 
If resolved in ≤ 14 days, restart study drug and maintain dose level 
If resolved in > 14 days, restart study drug and decrease dose by one level 
If not resolved after 4 weeks, discontinue patient from study drug 
> 10.0 - 20.0 x ULN  
Interrupt study drug. Repeat LFTsa as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; monitor LFTsa weekly, or more frequently if 
clinically indicated, until resolved to ≤3 x ULN. Then restart study drug and decrease 
dose by one level.  
If not resolved after 4 weeks, discontinue patient from study drug 
> 20.0 x ULN 
 
 
 
Discontinue patient from study drug treatment.  
Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; monitor LFTsa weekly, or more frequently if clinically indicated, 
until returned to baseline or stabilized over 4 weeks. 
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 6.3.3.1 for additional follow-up evaluations 
as applicable. 


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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 study drug at the situation when interrupt study 
drug is needed for one parameter and discontinue study drug is required for another parameter).  After all 
elevations resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the 
same dose or at one dose lower if meeting a criterion for dose reduction 
c. “Cholestasis” defined as: ALP elevation (>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. 
In addition, any AE per investigator judgment, regardless of suspected drug causality, may 
require interruption of study drug and replacement therapy with glucocorticoids until 
improvement of the event. These events, associated treatments along with changes to the dosing 
regimen of study drug need to be documented in the eCRF as soon as possible to enable the IE 
(up to Week 12) to make the appropriate dose decisions.  
If the patient has interruption of study drug for more than 4 weeks, the investigator should 
consider early discontinuation from the study drug. Patients who had interruption of study drug 
and mUFC remains ≤ ULN off study drug should remain on study. 
6.3.2 
Guidance for evaluation and management of hypocortisolism 
Patients with Cushing’s disease treated with osilodrostat may experience a broad range of 
symptoms, signs, and/or lab abnormalities associated with relative or absolute hypocortisolism.  
Glucocorticoid withdrawal syndrome may occur with the rapid fall of cortisol levels, even while 
the patient’s serum and/or urine cortisol levels are normal or elevated.  Patients may also present 
with serum and/or urine cortisol levels that are below normal or in the lower part of the normal 
range, in the absence of symptoms. Non-specific symptoms that may be suggestive of 
hypocortisolism or glucocorticoid withdrawal are described in Section 7.2.2.1.1. 
In patients suspected to have adrenal insufficiency, treatment with replacement or stress doses 
of glucocorticoids should be initiated as soon as possible as clinically indicated and consistent 
with local treatment guidelines. 
In the event of suspected hypocortisolism or adrenal insufficiency during the period 1, the site 
should instruct the patient to collect one or more (up to three) 24-hour urine samples for UFC 
assessment and come to the site for tests for serum cortisol, plasma glucose and electrolytes 
(sodium and potassium). These samples should be sent to central laboratory immediately to 
allow the appropriate dose modification by IE. Physical exam is recommended and record of 
abnormal findings to the CRF.  


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6.3.3 
Follow-up for toxicities 
Table 6-1 and Table 6-2 outline the follow-up evaluation recommended for toxicities of specific 
types. 
6.3.3.1 
Follow-up on potential drug-induced liver injury (DILI) cases 
Transaminase increase combined with TBIL increase may be indicative of potential DILI, and 
should be considered as clinically important event.  
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN  
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2.  
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury). 
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver lesions, obstructions/compressions, etc.  
• Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/ international normalized ratio (INR) 
and alkaline phosphatase.  
•  A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.  
• Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.  
• 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 (Section 7.2.2.6 and Section 7.2.2.7). 


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6.3.4 
Anticipated risks and safety concerns of the study drug 
Many of the anticipated drug-related safety concerns and recommendations for actions are 
reviewed in Section 6.3.1 “Dose modification and dose delay.” 
In case of placebo treatment it is possible that patients will present symptoms related to high 
cortisol. 
Additional anticipated risks are summarized in Section 8.1.3 “Adverse events of special 
interest.”  
For a comprehensive review of safety, see the [Investigator’s Brochure]. 
6.4 
Concomitant medications 
Stable doses of concomitant medications (except those for hypercortisolism) are allowed during 
the study. All pre-existing concomitant medications should be recorded at study start. The 
investigator should instruct the patient to notify the study site about any new medications he/she 
takes after the start of the study. All medications and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the patient signs the informed 
consent must be listed on the Concomitant medications/Significant non-drug therapies after 
start of study eCRF. 
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 
Prior and Concomitant Medications page of the eCRF. 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. 
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 
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. Eplerenone may be used if required in acute myocardial infarction management. 
Spironolactone, cyproterone acetate or finasteride for the prevention and/or treatment of 
hirsutism are approved in some countries and are not prohibited in this study. ACE inhibitors 
can be used for the treatment of hypertension, but cannot be used concomitantly with 
spironolactone or eplerenone. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
Medications that are metabolized by CYP450 enzymes 
The clinical inhibitory potential of osilodrostat on CYP450 enzymes was assessed with a drug-
drug interaction study using a cocktail of CYP1A2, CYP2C19, CYP2D6, and CYP3A4/5 probe 
substrates (caffeine, omeprazole, dextromethorphan, and midazolam respectively). Results 


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showed that at a single dose of 50 mg, which covers the maximum extent of interaction of 30 
mg b.i.d., osilodrostat is 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).  
In addition, in vitro drug metabolism studies show that osilodrostat is a potential inhibitor of 
CYP1A2, CYP2C19, CYP2D6, CYP3A4/5 and CYP2E1, and may consequently increase 
exposure to drugs metabolized by these enzymes.  
Therefore concomitant medications that are known substrates of these enzymes (see Appendix 
1) should be used with caution.  
The patient and the Investigator should be aware of potential signs of overdose of the 
concomitant medication and in the event of suspected toxicities; administration of either the 
substrate or osilodrostat should be discontinued according to Investigators’ judgment. 
6.4.3 
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 (except under certain conditions as explained below in Section 6.4.3.2). 
6.4.3.1 
Concomitant medications with a “Known risk to cause TdP” and with 
a “Possible risk to cause TdP”. 
Preclinical data and preliminary clinical data indicate that there is a risk of QTc prolongation in 
humans (see Section 8.1.3.1). Therefore, the use of medications with a “Known risk to cause 
TdP” and with a “Possible risk to cause TdP” concomitantly with osilodrostat is prohibited. 
If a patient requires a long-term medication from the two categories mentioned above, and there 
is no appropriate alternative medication available, 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 osilodrostat may be interrupted temporarily while this drug is administered after 
a thorough risk-benefit assessment. This does not require the patient to discontinue from the 
study prematurely. Washout periods for osilodrostat and the short-term prohibited drug in many 
cases may not be possible; this is acceptable if the benefit of the drug outweighs the risk of 
withholding osilodrostat therapy in the investigator’s judgment. In such cases, a discussion with 
the Novartis Medical Monitor is recommended. 
Please refer to Appendix 2 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. 


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If necessary, a discussion can be held with the Novartis Medical Monitor when considering the 
use of medications with a “Known risk to cause TdP” and with a “Possible risk to cause TdP”  
6.4.3.2 
Glucocorticoids 
Glucocorticoids may be used as required for the short-term treatment of adrenal insufficiency 
(See Section 6.3.2 for a detailed discussion). If glucocorticoids are used in stress doses, or as 
replacement therapy, for > 4 weeks, then the investigator should consider early discontinuation 
from osilodrostat or discontinuation from the trial. 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface. 
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 Subject No. must 
not be reused for any other subject and the Subject 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 Disposition page. 
IRT must be notified within 2 days that the patient was not randomized. 
6.5.2 
Treatment assignment or randomization 
Eligible patients will be assigned to one of the 2 treatment arms (Section 4.1 and Section 6.1) 
in a ratio of 2:1 (osilodrostat: placebo respectively). 
Randomization will be stratified at Day 1 according to 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 subject number 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 Drug Supply Management using a 
validated system that automates the random assignment of medication numbers to medication 
packs containing each of the study drugs. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the 2 treatment arms. The investigator or his/her delegate will call or log on to 
the IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will 


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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 drug 
to be dispensed to the patient. The randomization number will not be communicated to the 
caller. 
6.5.3 
Treatment blinding 
Patients, investigators, other site personnel, and the Novartis Clinical Trial Team will remain 
blinded to the identity of the randomized treatment assignments until after the 48-week Core 
study database lock, using the following methods:  
(1) randomization data are kept strictly confidential until the time of treatment unblinding. The 
bioanalyst and the pharmacokineticist will be unblinded to avoid the unnecessary analysis of 
placebo samples. Novartis Drug Supply Management department members will be unblinded 
in order to prepare the study drug supplies. The Independent Endocrinologists will have access 
to treatment assignment to determine dose titrations during Period 1 of the study. The DMC 
may also have access to treatment assignment, if needed, because they are overseeing the dose 
decisions of the IEs.   
(2) The identity of the randomized treatment assignments will be concealed by the use of 
matching placebo during the randomized withdrawal period. Each dose of osilodrostat will have 
a matching placebo identical in packaging, labeling, schedule of administration, and appearance 
(color, size, and weight).  
(3) The Period 1 laboratory results that could disclose the randomized treatment assignment 
(UFC, urine creatinine, serum and salivary cortisol, ACTH, aldosterone, renin, estradiol, 
estrone, androgens (testosterone, delta-4 androstenedione, DHEAS), precursors 11-
deoxycortisol, 11- deoxycorticosterone)) from this period of the trial, will be kept blinded from 
patients, investigators and other site personnel until the 48-week Core study database lock is 
complete.  Blinded laboratory data (e.g. UFC, serum cortisol, ACTH, etc.) will however be 
available to IEs responsible for dose titration during Period 1, as well as the DMC if needed. 
Unblinding before database lock will only occur in the case of emergencies (Section 8.3 
“Emergency unblinding”), for regulatory reporting purposes and at the conclusion of the study. 
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 eCRF. 
Study drug use in this study includes 1 mg, 5 mg, 10 mg and (depending on availability) 20 mg 
tablets and matching placebo tablets. There is a unique size and color for each tablet strength 
(see Figure 6-1).  Study drug is dispensed in a unique set of kits (bottles) for each patient at 
each visit.  Osilodrostat (or matching placebo) is dispensed in separate bottles for each tablet 
strength.  The label on each bottle indicates the dose strength.    
Patients may be dispensed bottles of more than one tablet strength at the same visit. For 
example, if a patient is on the preferred intermediate dose of 7 mg b.i.d., the patient would be 


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provided with both 1 mg and 5 mg tablet strengths and instructed to take 2 x 1 mg tablets and a 
1 x 5 mg tablet, twice a day.  Consequently, to ensure patient safety, it is very important that 
site staff educate the patient on how to recognize the tablet strength dispensed at each visit, both 
on the bottle labels, and by the appearance of tablets by strength.  Patients are given a dosing 
card that includes general instructions and an image displaying the color and size of each tablet 
strength. Clear, simple, written instructions must be provided to the patient at the visit; these 
instructions must include the dose and the number of tablets of each strength to be taken in the 
morning and in the evening. The IRT system ensures that enough study drug is dispensed to 
treat the patient until the next scheduled visit by specifying the unique set of kits (bottles) for 
each patient at each visit. A minimal number of strengths will be dispensed at any one visit, as 
feasible. 
At each study visit during Period 1 (Weeks 1-12), Period 2 (Weeks 12-48) and in Extension, 
the site will contact Interactive Response Technology (IRT) for identification of the specific 
drug supply to be used by the patient until the following visit.   IRT will provide the site with 
study drug kit number(s) specific to the patient and the visit. For dose changes, IRT will indicate 
if a patient visit to the site is needed to collect study drug supplies to implement the dose change 
or if it may be implemented via a phone contact. Patients requiring a different tablet strength to 
implement a dose change between scheduled study visits, will need to return to the site 
(unscheduled visit) to collect the new study drug supplies. The site pharmacist will dispense the 
corresponding kit(s) to the patient, to provide drug supply until the next study visit.  
Table 6-3 
Preparation and dispensing 
Study drugs 
Dispensing 
Preparation 
Osilodrostat (LCI699) 
or placebo (1 mg, 5 mg, 
10 mg and 20 mg) 
Tablets including instructions for administration are 
dispensed by study personnel on an outpatient basis. 
Patients will be provided with adequate supply of study drug 
for self-administration at home until at least their next 
scheduled study visit (including any dose change required 
in between visits). More than one tablet strength may be 
dispensed to patients at the same visit.   
Not applicable 
6.6.1 
Study drug packaging and labeling 
Osilodrostat/placebo will be supplied as film coated tablets packaged in bottles. 
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 dose. Responsible 
site personnel will identify the study drug package(s) to dispense to the patient by using the IRT 
and obtaining the medication number(s). Site personnel will add the subject number onto 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 subject 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. 


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Table 6-4 
Packaging and labeling 
Study drugs 
Packaging 
Labeling (and dosing frequency) 
Osilodrostat (LCI699) or placebo 
(1 mg, 5 mg, 10 mg and 20 mg) 
Tablets in bottles with 
labels 
LCI699, LCI699/Placebo (b.i.d., o.d., once 
every other day) 
6.6.2 
Drug supply and storage 
Study drugs 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 drug 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 drugs 
Study drugs 
Supply 
Storage 
Osilodrostat (LCI699) or 
placebo 
Centrally supplied by Novartis 
Refer to study drug 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 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 drug 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 drug and packaging on a regular basis, at the end of the study or at the time of study drug 
discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study drug, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.6.3.3 
Handling of other study treatment 
Not applicable. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 


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Novartis 
Confidential 
Page 70 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
Table 7-1a 
Visit evaluation schedule – Core – Period 1 
 
Category 
Protocol 
Section 
Screening 
Core Treatment 
Post-Treatment Follow-up 
 
Wash-
out 
Post 
wash-
out 
 
Period 1 
For patients discontinuing 
during Period 1 
 
Day 
 
 
from 
-56 
up to 
-15 
-14 to  -
1 
1 
15 
36 
57 
85 
15 
36 
57 
85 
Last 
dose 
+30d 
Week 
 
 
from -8 
up to 
-3 
-2 to -1 
1 
2 
5 
8 
12 
2 
5 
8 
12 
 
Obtain Informed consent 
D 
7.1.1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
IRT Contact 
S 
 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
x 
 
IRT Randomization 
S 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Patient history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.1.3 
x 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
D 
5.2 & 5.3 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Relevant medical history/Current medical 
conditions 
D 
7.1.1.3 
x 
 
 
 
 
 
 
 
 
 
 
 
Cushing's Disease history 
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 and Waist Circumference 
D 
7.2.2.3 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical features of Cushing’s disease  
D 
7.2.1.2 
x 
 
 
 
 
x 
 
 
 
x 
 
  Signs and symptoms of adrenal insufficiency  
D 
7.2.2.1.1 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body temperature/ Blood pressure/Pulse rate 
D 
7.2.2.2 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 71 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
 
Category 
Protocol 
Section 
Screening 
Core Treatment 
Post-Treatment Follow-up 
 
Wash-
out 
Post 
wash-
out 
 
Period 1 
For patients discontinuing 
during Period 1 
 
Day 
 
 
from 
-56 
up to 
-15 
-14 to  -
1 
1 
15 
36 
57 
85 
15 
36 
57 
85 
Last 
dose 
+30d 
Week 
 
 
from -8 
up to 
-3 
-2 to -1 
1 
2 
5 
8 
12 
2 
5 
8 
12 
 
 
Hematology 
D 
7.2.2.4.1 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry  
D 
7.2.2.4.2 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Thyroid Panel, FSH 
D 
7.2.2.4.5 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
LH 
D 
7.2.2.4.7 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
Coagulation 
D 
7.2.2.4.4 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
Urinalysis 
D 
7.2.2.4.3 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Pregnancy test (serum) 
D 
7.2.2.4.8 
 
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 
x 
 
Serum testosterone and estradiol 
D 
7.2.2.4.6 
 
 
 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
Plasma ACTH and serum cortisol 
D 
7.2.2.4.6 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum aldosterone and serum 11-
deoxycortisol 
D 
7.2.2.4.6 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Androstenedione, DHEAS, Estrone 
D 
7.2.2.4.6 
 
 
 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
  Plasma Renin 
D 
7.2.2.4.6 
 
 
 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
Salivary Cortisol (morning and late night) 
D 
7.2.2.4.6 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum 11-Deoxycorticosterone 
D 
7.2.2.4.6 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fasting serum Insulin, plasma glucose and 
lipids 
D 
7.2.2.4.7 
 
 
 
x 
 
 
x 
x 
 
 
x 
x 
x 


Novartis 
Confidential 
Page 72 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
 
Category 
Protocol 
Section 
Screening 
Core Treatment 
Post-Treatment Follow-up 
 
Wash-
out 
Post 
wash-
out 
 
Period 1 
For patients discontinuing 
during Period 1 
 
Day 
 
 
from 
-56 
up to 
-15 
-14 to  -
1 
1 
15 
36 
57 
85 
15 
36 
57 
85 
Last 
dose 
+30d 
Week 
 
 
from -8 
up to 
-3 
-2 to -1 
1 
2 
5 
8 
12 
2 
5 
8 
12 
 
 
HbA1C 
D 
7.2.2.4.7 
 
x 
 
x 
 
 
x 
x 
 
 
x 
x 
x 


Novartis 
Confidential 
Page 73 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
 
Category 
Protocol 
Section 
Screening 
Core Treatment 
Post-Treatment Follow-up 
 
Wash-
out 
Post 
wash-
out 
 
Period 1 
For patients discontinuing 
during Period 1 
 
Day 
 
 
from 
-56 
up to 
-15 
-14 to  -
1 
1 
15 
36 
57 
85 
15 
36 
57 
85 
Last 
dose 
+30d 
Week 
 
 
from -8 
up to 
-3 
-2 to -1 
1 
2 
5 
8 
12 
2 
5 
8 
12 
 
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 
 
 
x 
 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Hair Cortisol 
D 
7.2.4.2 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pituitary MRI (or CT) 
D 
7.2.2.5 
x 
 
 
 
 
 
 
 
 
 
 
 
DXA scan 
D 
7.2.1.3 
x 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
D 
7.2.6 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Cushing QoL 
D 
7.2.6 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Beck Depression Inventory 
D 
7.2.6 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
EQ-5D-5L 
D 
7.2.6 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
Patient diary 
S 
7.1.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Drug administration 
D 
6.1 
 
 
 
continuous b.i.d. dosing 
 
 
 
 
 
  Phone contact 
S 
6.2.1.4 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 


Novartis 
Confidential 
Page 74 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
 
Category 
Protocol 
Section 
Screening 
Core Treatment 
Post-Treatment Follow-up 
 
Wash-
out 
Post 
wash-
out 
 
Period 1 
For patients discontinuing 
during Period 1 
 
Day 
 
 
from 
-56 
up to 
-15 
-14 to  -
1 
1 
15 
36 
57 
85 
15 
36 
57 
85 
Last 
dose 
+30d 
Week 
 
 
from -8 
up to 
-3 
-2 to -1 
1 
2 
5 
8 
12 
2 
5 
8 
12 
 
PK sampling 
D 
7.2.3 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
End of Phase disposition 
D 
 
 
 
x 
 
 
 
 
 
 
 
 
x 


Novartis 
Confidential 
Page 75 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
Table 7-1b 
Visit evaluation schedule– Core (continued) – Period 2 
 
Category 
Protocol 
Section 
Core Treatment 
Post-
Treatment 
Follow-up 
 
Period 2 
EOT 
Core 
All 
Patients 
Day 
 
 
99 
120 
141 
162 
183 
204 
225 
253 
281 
309 
337 
Last dose 
+30d 
Week 
 
 
14 
17 
20 
23 
26 
29 
32 
36 
40 
44 
48 
 
IRT Contact 
S 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Patient history 
 
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 
x 
 
Body weight and Waist Circumference 
D 
7.2.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical features of Cushing’s disease 
D 
7.2.1.2 
 
 
 
 
x 
 
 
x 
 
 
x 
 
Signs and symptoms of adrenal insufficiency  
D 
7.2.2.1.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body temperature/ Blood pressure/Pulse rate 
D 
7.2.2.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
D 
7.2.2.4.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry 
D 
7.2.2.4.2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Thyroid Panel, FSH 
D 
7.2.2.4.5 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
LH 
D 
7.2.2.4.7 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
Coagulation 
D 
7.2.2.4.4 
x 
 
x 
 
x 
 
  
x 
 
 
x 
 
 
Urinalysis 
D 
7.2.2.4.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Pregnancy test (serum)  
D 
7.2.2.4.8 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Pregnancy test (urine)  
D 
7.2.2.4.8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 


Novartis 
Confidential 
Page 76 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
 
Category 
Protocol 
Section 
Core Treatment 
Post-
Treatment 
Follow-up 
 
Period 2 
EOT 
Core 
All 
Patients 
Day 
 
 
99 
120 
141 
162 
183 
204 
225 
253 
281 
309 
337 
Last dose 
+30d 
Week 
 
 
14 
17 
20 
23 
26 
29 
32 
36 
40 
44 
48 
 
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 
x 
Serum testosterone and estradiol 
D 
7.2.2.4.6 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
Plasma ACTH and serum cortisol 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum aldosterone and serum 11-
deoxycortisol 
D 
7.2.2.4.6 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
Serum Androstenedione, DHEAS, Estrone 
D 
7.2.2.4.6 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
Plasma Renin 
D 
7.2.2.4.6 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
Salivary Cortisol (morning and late night) 
D 
7.2.2.4.6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 11-Deoxycorticosterone 
D 
7.2.2.4.6 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
Fasting serum Insulin, plasma glucose and 
lipids 
D 
7.2.2.4.7 
x 
 
x 
 
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 
x 
x 
x 
x 
x 
x 
x 
 
12-Lead 24-hour Holter ECG recording 
D 
7.2.2.6.1 
x 
 
 
 
 
 
 
x 
 
 
 
 
Biomarkers 
  Hair Cortisol 
D 
7.2.4.2 
 
 
 
 
x 
 
 
 
 
 
x 
x 


Novartis 
Confidential 
Page 77 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
 
Category 
Protocol 
Section 
Core Treatment 
Post-
Treatment 
Follow-up 
 
Period 2 
EOT 
Core 
All 
Patients 
Day 
 
 
99 
120 
141 
162 
183 
204 
225 
253 
281 
309 
337 
Last dose 
+30d 
Week 
 
 
14 
17 
20 
23 
26 
29 
32 
36 
40 
44 
48 
 
Imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pituitary MRI (or CT) 
D 
7.2.2.5 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
DXA scan 
D 
7.2.1.3 
 
 
 
 
 
  
 
 
 
 
x 
 
Patient Reported Outcomes 
 
C-SSRS 
D 
7.2.6 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Cushing QoL 
D 
7.2.6 
x 
x 
x 
x 
x 
 
 
x 
 
 
x 
x 
 
Beck Depression Inventory 
D 
7.2.6 
x 
x 
x 
x 
x 
 
 
x 
 
 
x 
x 
 
EQ-5D-5L 
D 
7.2.6 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Patient diary 
S 
7.1.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Drug administration 
D 
6.1 
continuous b.i.d. dosing 
 
 
Phone contact 
S 
6.2.1.4 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
PK sampling 
D 
7.2.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
End of Phase disposition 
D 
 
 
 
 
 
 
 
 
 
 
 
x 
x 


Novartis 
Confidential 
Page 78 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
Table 7-2 
Visit evaluation schedule – Extension 
  
Category 
Protocol 
Section 
Extension-Treatment 
Post-
Treatment 
Follow-up 
  
 
EOT 
Extension 
Day 
  
  
337 
365 
393 
421 
449 
477 
505 
589 
673 
757, 
then 
every 
168 
days 
 
Last dose 
+30d 
Week 
  
  
48 
52 
56 
60 
64 
68 
72 
84 
96 
108, 
then 
every 
24 
weeks  
 
Obtain Informed consent 
S 
7.1.1 
x 
  
   
   
    
  
   
  
  
 
  
  
IRT Contact / Drug Dispensing 
S 
  
  
x 
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 
x 
x 
x 
Body weight and Waist Circumference 
D 
7.2.2.3 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical features of Cushing’s disease 
D 
7.2.1.2 
 
 
 
 
 
 
x 
 
x 
x 
x 
 
Signs and symptoms of adrenal 
insufficiency  
D 
7.2.2.1.1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body temperature / 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 
x 
x 
x 
Chemistry 
D 
7.2.2.4.2 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Thyroid Panel, FSH 
D 
7.2.2.4.5 
  
  
  
x 
  
  
x 
x 
x 
x 
x 
  
 
LH 
D 
7.2.2.4.7 
 
 
 
x 
 
 
x 
x 
x 
 
x 
 


Novartis 
Confidential 
Page 79 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
  
Category 
Protocol 
Section 
Extension-Treatment 
Post-
Treatment 
Follow-up 
  
 
EOT 
Extension 
Day 
  
  
337 
365 
393 
421 
449 
477 
505 
589 
673 
757, 
then 
every 
168 
days 
 
Last dose 
+30d 
Week 
  
  
48 
52 
56 
60 
64 
68 
72 
84 
96 
108, 
then 
every 
24 
weeks  
 
 
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 (serum) 
D 
7.2.2.4.8 
 
 
 
 
 
 
 
 
 
 
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 
Serum testosterone and estradiol 
D 
7.2.2.4.6 
  
  
  
x 
  
  
x 
x 
x 
x 
x 
x 
Plasma ACTH and serum cortisol 
D 
7.2.2.4.6 
  
  
  
x 
  
  
x 
x 
x 
x 
x 
x 
Serum aldosterone and 11-deoxycortisol  
D 
7.2.2.4.6 
  
  
  
x 
  
  
x 
x 
x 
x 
x 
x 
Serum androstenedione, DHEAS, estrone 
D 
7.2.2.4.6 
  
  
  
x 
  
  
x 
x 
x 
x 
x 
x 
Plasma Renin 
D 
7.2.2.4.6 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
Salivary cortisol (morning and late night) 
D 
7.2.2.4.6 
  
  
  
x 
  
  
x 
x 
x 
x 
x 
x 
Serum 11-Deoxycorticosterone 
D 
7.2.2.4.6 
  
  
  
x 
  
  
x 
x 
x 
x 
x 
x 
Fasting serum Insulin, plasma glucose and 
lipids 
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 


Novartis 
Confidential 
Page 80 
Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
  
Category 
Protocol 
Section 
Extension-Treatment 
Post-
Treatment 
Follow-up 
  
 
EOT 
Extension 
Day 
  
  
337 
365 
393 
421 
449 
477 
505 
589 
673 
757, 
then 
every 
168 
days 
 
Last dose 
+30d 
Week 
  
  
48 
52 
56 
60 
64 
68 
72 
84 
96 
108, 
then 
every 
24 
weeks  
 
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 
12-Lead 24-hour Holter ECG recording  
D 
7.2.2.6.1 
  
  
  
  
  
  
x 
  
 
 
x 
  
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hair Cortisol 
D 
7.2.4.2 
  
  
  
x 
  
  
  
  
x 
 
x 
 x 
Imaging 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
Pituitary MRI (or CT) 
D 
7.2.2.5 
  
  
  
  
  
  
x 
  
x 
 
x 
  
 
DXA scan 
D 
7.2.1.3 
  
  
  
  
  
  
  
  
x 
 
x 
  
Patient Reported Outcomes 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
CushingQoL 
D 
7.2.6 
  
  
  
  
  
  
x 
  
x 
 
x 
x 
 
Beck Depression Inventory 
D 
7.2.6 
  
  
  
  
  
  
x 
  
x 
 
x 
x 
 
EQ-5D-5L 
D 
7.2.6 
  
  
  
  
  
  
x 
  
 
 
x 
x 
 
Patient diary 
S 
7.1.3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Study Drug administration 
D 
6.1 
continuous b.i.d. dosing 
End of Phase disposition  
D 
 
  
  
  
  
  
  
  
  
 
 
x 
x 


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7.1.1 
Screening 
Written main informed consent must be obtained before any study specific assessments are 
performed. IRT will be contacted to register the patient at screening. 
The screening assessments must be performed within 56 days before the first study drug dose 
on Day 1. 
When applicable, patients must have undergone washout of any current drug therapy for CD 
according to washout periods described in the Inclusion criteria (Section 5.2).  During washout, 
some patients may have loss of control of co-morbidities such as hypertension and diabetes. 
Therefore the screening period should be viewed as a “run-in” period in which the treatment of 
co-morbidities is optimized. Patients should be closely monitored and treated accordingly, 
aiming ideally for normalization of blood pressure, fasting glucose and potassium. 
Information on the most recent prior medical therapy for CD will be collected including the 
drug name, dose, duration of therapy and outcome, provided such data are available. 
The three 24-hour urine samples for the mUFC value eligibility assessment should be collected. 
In addition, two late night salivary cortisol samples need to be collected to exclude pseudo-
cushing’s disease (Alwani et al 2014). These urine and saliva samples should be collected after 
the washout period is over, in order to avoid any interference with the washed out therapy. It is 
highly recommended to send them 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 
prior to Day 1. 
For laboratory evaluations used to determine eligibility, repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If laboratory 
results are pending at the end of the screening period, the screening period will be extended 
until the results become available to site. If the latest repeated laboratory result(s) meet the 
criteria, those results may be used to determine eligibility. If the latest repeated laboratory 
result(s) do not meet the criteria, the patient will be considered a screening failure. 
Patients who do not meet eligibility criteria are allowed to be rescreened up to a maximum of 
two times. The rescreening should be documented in the source files and re-registered in IRT. 
If a patient is re-screened the patient should retain their study Subject Number. 
If rescreening is within 60 days of the end of the original screening period, the following 
procedures do not have to be repeated: pituitary MRI (or CT) and DXA scan. All other 
assessments must be repeated. 
If rescreening is done more than 60 days after the end of original screening period, all 
assessments must be repeated. 
For details of assessments and day windows, refer to Table 7-1a. 
An additional biomarker informed consent will be proposed to the patient for optional 
participation. For details, refer to Section 7.2.4.2.  


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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 randomized. 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 the patient starting the 
treatment phase and receiving the first dose of study drug (osilodrostat/placebo). 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 to 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 Phase Disposition Page. 
The demographic information, informed consent and Inclusion/Exclusion pages must also be 
completed for Screen Failure subjects.  
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 be randomized, the IRT must be notified within 2 days of the screen fail 
that the patient was not randomized. 
7.1.1.3 
Patient demographics and other baseline characteristics 
The following patient demographics and baseline characteristics will be collected on the eCRF: 
• Demography including date of birth, sex, predominant race and ethnicity (where permitted). 
• Height, weight and 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 diseases which are 
recorded on the Medical History eCRF should include the toxicity grade when applicable. 
• Information on the most recent prior medical therapy for CD 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. 
All assessments to be completed and documented during screening and at baseline are detailed 
in Table 7-1a. 


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Day 1 assessments / samples should be taken before the patient receives study drug as these 
values will be considered the baseline values for the study. Where multiple values are available 
for a parameter prior to study drug, the last value prior to the start of study drug will be 
considered the baseline value.  
7.1.2 
Run-in period 
The screening period should be viewed as a “run-in” period in which the treatment of co-
morbidities is optimized (see rescue medication plan in Section 6.1.3). For details of 
assessments, refer to Section 7.1.1 and Table 7-1a. 
7.1.3 
Treatment phase 
Treatment phase is divided in 2 study periods plus an Extension phase as described in Section 
4.1. Patients must be seen for all visits on the designated day with a visit window of ± 3 days 
for all visits, except Week 1 (Day 1) where the window is +3 days. During Period 1 (Weeks 1 
to 12), patients will attend the site 2 weeks after starting study medication, and then at Weeks 
5, 8 and 12.  
During Period 2 (Weeks 12 to 48), patients will attend the site for the Week 14 visit, then every 
3 weeks until Week 32, and every 4 weeks from Week 32 to Week 48. 
At Week 48, patients have the option to enter a 48-week open-label extension phase. Patients 
not entering the optional Extension phase will complete the study with a 30 day follow-up. 
Patients currently enrolled in the optional Extension phase must end study participation within 
4 weeks after Protocol Amendment 02 is approved at the site, or by Week 96 whichever occurs 
first. Refer to Section 6.1.5 for details. If patients are benefitting from study treatment, they 
have the option to enter a separate long-term safety follow-up study or stop study treatment.  
Patients not entering the long-term safety follow-up study will complete the study with a 30 day 
follow-up. 
 
During study treatment phases, patients will be instructed to: 
• bring urine samples (collected as described in Section 7.2.1.1) to each study visit 
• complete a patient diary collecting information on study drug, and urine and salivary 
collections. The diary will be reviewed at each site visit by site staff.  
For details of assessments, please refer to Table 7-1a, Table 7-1b and Table 7-2 for the Core 
and Extension, respectively. 
7.1.4 
Discontinuation of Study drug  
Patients may voluntarily discontinue from the study drug for any reason at any time. If a 
patient decides to discontinue from the study drug, the investigator should make a reasonable 
effort (e.g. telephone, e-mail, letter) to understand the primary reason for this decision while 
respecting the subjects rights and record this information in the patient’s chart and on the 
appropriate eCRF pages.  Patients 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. 


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In order to help retain patients in the placebo-controlled phase (Period 1, Weeks 1 - 12), rescue 
therapy for co-morbid conditions should be optimized before a decision is made to discontinued 
patients from study drug or from the study.   
Patients who discontinue study drug should NOT be considered withdrawn from the study. 
For patients who discontinue treatment during Weeks 1 - 12, investigators should make 
reasonable efforts to follow patients and perform all assessments identified for all visits up to 
and including Week 12 as indicated in Table 7-1a (Post-treatment follow-up) and Section 7.1.6, 
even if study drug has been discontinued and alternative cortisol-lowering therapy has been 
initiated.  Patients discontinuing study drug at any time before Week 48 of the Core 
phase or  during the optional  Extension phase, should be scheduled for an End of Treatment 
(EOT) visit as soon as possible, at which time the assessments listed for the EOT visit will be 
performed (Table 7-1a, Table 7-1b and Table 7-2), with the following exceptions:  
• Patients discontinuing treatment prior to the Week 36 visit do not need to have an EOT 
DXA scan 
• Patients discontinuing prior to the Week 14 visit or between the Week 26 and Week 36 
visits do not need to have an EOT pituitary MRI (or CT) (i.e. scans are needed if patients 
discontinue within the 12 week period prior to the Week 26 and Week 48 visits).  
The date and reason for stopping the study drug should be recorded in the eCRF. If a patient 
fails to return for the assessments for unknown reasons, reasonable efforts (e.g. telephone, 
email, letter) should be made to contact them as specified in Section 7.1.7. 
The investigator must discontinue study drug for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being. The investigator must also contact 
the IRT to register the patient’s discontinuation from study drug. 
Patients must discontinue study drug if any of the following occur: 
• Emergence of the following adverse events: 
• hypertension defined as office mean supine systolic BP > 180 mmHg or mean supine 
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). 
• hyperglycemia (fasting plasma glucose ≥ 15.0 mmol/L).  
* Persistent is defined as unresolved with osilodrostat dose change or after adjustments to 
other concomitant medications targeting the co-morbidity in question.  
• Abnormal liver function as described in Table 6-2. 
• Mean QTcF > 500 msec, if the QTc value is confirmed by a cardiologist (see Section 
7.2.2.7). 


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• Mean 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). 
• Mean increase in QTcF > 30 msec from the mean baseline value at 1.5h post-first dose or 
the QTcF is > 480 msec at Day 1. 
• QTcF increase > 60 msec from the pre-dose measurement earlier during the same visit. 
• Pituitary tumor growth, if symptomatic or complicated by compression of the optic chiasm 
or other structures in and near the sella turcica (visual field loss, cranial nerve palsies, 
diplopia) and confirmed by MRI of the pituitary (see Section 7.2.2.5). 
• Pregnancy. 
• Use of prohibited treatment (refer to Section 6.4.3). 
• 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 drug should be 
discontinued for any patient whose treatment code has been broken inadvertently for any reason. 
The investigator must also contact the IRT to register the patient’s discontinuation from 
study drug within 2 days. 
7.1.4.1 
Replacement policy 
Not applicable. 
7.1.5 
Withdrawal of 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 any longer, and does not want any further visits or assessments, and does not want any 
further study related contact. 
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator should make reasonable effort (e.g. telephone, 
e-mail, letter) to determine the primary reason for this decision while respecting the subject’s 
rights and record this information. 
Study drug must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow-up. 
7.1.6 
Follow-up period  
All patients must have safety evaluations performed approximately 30 days after the last dose 
of study drug. Patients who discontinue study drug before the Week 12 visit must perform 
scheduled post-treatment follow-up visits through and including Week 12 (±3 days) as indicated 
in Table 7-1a and Section 7.1.4. If the 30 day follow-up evaluations should occur at the time of 
a scheduled visit; any assessments common to both visits only need to be performed once.  


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Data collected should be added to the Adverse Events eCRF and the Concomitant Medications 
eCRF. 
7.1.7 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow-up should be recorded as such on the appropriate 
Disposition eCRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Table 7-3 
Disease and Imaging Assessment collection plan 
Procedure 
Screening 
During Treatment/Follow-up 
24-hour urine samples to test for 
Urine Free Cortisol and 
creatinine 
Mandated at screening 
(post washout) 
Mandated for Periods 1 and 2, the optional 
Extension and the 30 day Post Treatment 
Follow-up, as detailed in Table 7-1a, Table 7-
1b and Table 7-2.  
*Every effort should be made to collect 
samples for patients discontinuing treatment 
prior to Week 12 during Period 1 per Table 7-
1a. 
Three 24-hour samples are to be collected at 
screening, Day 1, Week 12, Week 36, Week 
48 and Week 12 Post-Treatment follow-up 
visit. Two 24-hour samples are to be collected 
at all other study time points. 
Physical features of CD 
Mandated at screening 
Mandated for Periods 1 and 2, the optional 
Extension and the 30 day Post Treatment 
follow-up, as detailed in Table 7-1a, Table 7-
1b and Table 7-2. 
DXA scan  (lumbar spine and 
total hip) 
Mandated at screening 
Mandated at End of Treatment Core and End 
of Treatment Extension, unless EOT occurs 
less than 6 months before the scheduled 
Week 96 visit.  
* For patients who discontinued study drug during Period 1. 
All urine samples will be sent to the central laboratory designated by Novartis for assessment. 
During Period 1, once results are available, an alert (by email or fax) will be sent to the IE. The 
central laboratory and the IE will ensure that the sites and Novartis remain blinded to the results. 
Starting from Week 14 in Period 2, UFC results will be sent directly by the central laboratory 
to the investigators. 


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7.2.1.1 
Urinary Free Cortisol 
The primary efficacy parameter, Urinary Free Cortisol (UFC), will be assessed using a central 
laboratory. UFC will be measured in two or three 24-hour urine samples (Table 7-1a, Table 7-
1b, Table 7-2, and Table 7-3). Values from the individual samples for a visit will be averaged 
to obtain the mean UFC (mUFC) level. Urine creatinine levels will also be measured to ensure 
validity of the 24-hour collection.  
Throughout the study, patients will collect the 24-hour UFC samples preferably on consecutive 
days according to Table 7-1a, Table 7-1b, Table 7-2, and Table 7-3 and will complete the patient 
diary. Patients are to bring both the urine samples and the patient diary to each study visit.  
Screening (post washout): Three 24-hour UFC samples must be collected (preferably on 
consecutive days) 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: Three 24-hour UFC samples will be collected (preferably on consecutive days) within 
7 days prior to first day of treatment to serve as baseline value.  
Treatment period: Patients will collect two 24-hour UFC samples preferably over the 2 
consecutive days immediately prior to the each visit, i.e. the last urine sample should be 
collected the day prior to the site visit (collection may end on the morning of the visit) as defined 
in Table 7-1a and Table 7-1b for Periods 1 and 2 (Core phase), and Table 7-2 for the optional 
Extension phase. Patients will collect three 24-hour UFC samples preferably on consecutive 
days immediately prior to the Week 12, Week 36, Week 48 and Week 12 Post-treatment follow-
up visits.  If only one UFC value is available at a visit, this value will be used for dose decision 
making only and not for mUFC based analysis. 
7.2.1.2 
Physical features of Cushing’s disease 
The following clinical signs (physical findings) of Cushing’s disease will be assessed clinically 
for severity at time points defined in Table 7-1a, Table 7-1b, Table 7-2 and Table 7-3: facial 
rubor, hirsutism (female 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.  
Physical features of Cushing’s disease will also be documented by photography. A total of four 
photographs will be taken. 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 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. Photographs will be centrally collected and checked for 
quality by an imaging vendor. The quality checks will be detailed in the vendor manual. 


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If for cultural reasons, usual lifestyle, or other reasons, 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 (BMD) of the lumbar vertebrae (L1-L4) and left total hip are to be 
measured using Lunar or Hologic DXA (dual-energy X-ray absorptiometry; DXA) instruments. 
A patient should be scanned on the same DXA instrument throughout the study. If a scan of the 
left proximal femur is not possible, then the right proximal 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 manufacturer’s instructions and the imaging acquisition guidelines 
provided for this study. The image acquisition guidelines include detailed instructions on 
scanning methods, calibration of individual DXA machines and cross-calibration of DXA 
machines at different sites. The BMD results must be reported in actual density (gm/cm2) and 
standardized against the peak bone mass in a healthy young adult population (BMD T-score). 
Analysis and reporting of BMD results will be conducted centrally by the imaging vendor for 
this study. This assessment will be done as defined in Table 7-1a, Table 7-1b, Table 7-2 and 
Table 7-3. If EOT occurs less than 6 months before the scheduled Week 96 visit, MRI (or CT) 
and DXA is not mandatory at EOT. 
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 assessments, imaging 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. The 
risk of suicide will be also collected and assessed as part of safety monitoring. 
7.2.2.1 
Physical examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. This will be conducted at 
visits according to Table 7-1a, Table 7-1b and Table 7-2. 
Significant findings that were present prior to the signing of informed consent must be recorded 
in the Medical History page of the patient’s eCRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event eCRF. 
7.2.2.1.1 Signs and symptoms of adrenal insufficiency 
Signs and symptoms of adrenal insufficiency (AI) should be assessed at every study visit and / 
or contact according to Table 7-1a, Table 7-1b and Table 7-2. Signs and symptoms of AI are to 
be recorded on the Signs and symptoms of AI eCRF and in the AE eCRF during Period 1, and 
in the AE eCRF only during all other study periods. 
Definition of signs and symptoms of AI (Charmandari, et al 2014):   


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• Symptoms: Nausea, vomiting, diarrhea, fatigue, asthenia, dizziness, syncope, decreased 
appetite, myalgia, arthralgia, and pyrexia 
• Signs: hypotension, orthostatic hypotension, and tachycardia. 
7.2.2.2 
Vital Signs 
Vital signs include blood pressure and pulse measurements, and body temperature will be 
assessed according to Table 7-1a, Table 7-1b and Table 7-2. Pulse and systolic and diastolic 
blood pressure will be measured using an automated validated device with an appropriately 
sized cuff according to the following sequence and times at each visit:  
1. Supine: two separate recordings after the patient has been supine for a minimum of five 
minutes 
2. Standing: one recording after the patient has been standing for 1 minute and another 
recording after the patient has been standing for 3 minutes.  
 These measurements will be used to assess the presence of orthostatic hypotension.  
A drop in systolic blood pressure of ≥20 mmHg, or in diastolic blood pressure of ≥10 mmHg 
in the supine vs standing measurements, or presence of lightheadedness or dizziness is 
considered abnormal and should be recorded on the appropriate form (see section 7.2.2.1.1). 
Vital sign assessments at screening may be repeated, if necessary, up to a maximum of 3 times. 
7.2.2.3 
Height and 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 7-1a, Table 7-1b 
and Table 7-2. 
To measure waist circumference, patients should remove clothing from around the waist to 
ensure the measuring tape is correctly positioned. Using e.g. a cosmetic pencil, make a mark at 
the “natural waist” midway between the palpated iliac crest and the palpated lowest rib margin 
in the left and right mid-axillary lines. Place the non-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, coagulation, urinalysis, thyroid panel and 
additional tests mentioned in Table 7-4 below) are to be performed by the central laboratory.  
At any time during the study, abnormal laboratory parameters which are clinically significant 
and require an action to be taken with study drug (e.g., require dose modification and/or 
interruption of study drug, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the CTCAE version 4.03 if applicable.  


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Table 7-4 
Central Clinical laboratory parameters 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, RBC 
Morphology, Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils, Bands, Other (absolute value preferred , %s  are acceptable) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST , Bicarbonate, Glucose, Calcium, Chloride, 
Creatinine, Creatine phosphokinase (CPK), Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), inorganic phosphorus, lipase, amylase, magnesium, 
potassium, sodium, Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, Total Protein, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid 
Urinalysis  
Macroscopic Panel (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, pH, 
Protein, Specific Gravity) 
Coagulation 
International normalized ratio (INR), Activated partial thromboplastin time (APTT) 
Thyroid 
Free T4, Thyroid-Stimulating Hormone (TSH) 
Additional tests 
Pregnancy test: serum (central lab testing) / Urine dipstick pregnancy testing (local lab 
testing) 
Additional hormones: 
Serum testosterone, estradiol,  FSH 
Serum DHEAS, androstenedione and estrone 
Plasma renin 
Plasma ACTH 
Serum aldosterone, cortisol and 11-deoxycortisol 
Salivary cortisol (morning and late night)* 
Serum 11-deoxycorticosterone  
LH 
Other parameters:  
Fasting serum insulin, fasting plasma glucose and fasting lipid profile (including: Total 
Cholesterol, LDL, HDL, Triglycerides) 
HbA1c 
Hair cortisol 
* Salivary cortisol samples will be collected within the following intervals: Late night samples between 10:00 pm 
and 11:00 pm and morning samples between 8:00 am and 10:00 am. Late night salivary cortisol samples will 
be collected with each 24-hr UFC collection (or with the last two 24-hr UFC collections closest to the next visit if 
3 samples are being collected), and the morning salivary cortisol sample will be collected with the last 24-hr 
UFC collection. 
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 7-1a, Table 7-1b, Table 7-2, and 
Table 7-4.  
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 7-1a, Table 7-1b, Table 7-2, and 
Table 7-4. 


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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 7-1a, Table 7-1b, Table 7-2, and Table 7-4. 
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 will be performed. 
7.2.2.4.4 Coagulation 
Coagulation factors specified in Table 7-4 will be assessed by the central laboratory according 
to Table 7-1a, Table 7-1b and Table 7-2. 
7.2.2.4.5 Thyroid Panel 
Thyroid Panel specified in Table 7-4 will be assessed by the central laboratory according to  
Table 7-1a, Table 7-1b and Table 7-2. 
7.2.2.4.6 Additional hormones 
Additional hormones as specified in Table 7-4 will be assessed by the central laboratory 
according to Table 7-1a, Table 7-1b and Table 7-2. 
7.2.2.4.7 Other laboratory parameters 
Other laboratory parameters as specified in Table 7-4 will be assessed by the central laboratory 
according to Table 7-1a, Table 7-1b and Table 7-2. 
7.2.2.4.8 Pregnancy and assessments of fertility 
Serum pregnancy tests will be performed at screening and End of Treatment, and analyzed by 
the central laboratory. Urine dipstick pregnancy testing will be performed on site as indicated 
in Table 7-1a, Table 7-1b and Table 7-2. 
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 
randomized. 
7.2.2.5 
Radiological examinations 
Table 7-5 
Imaging Assessment collection plan 
Procedure 
Screening 
During Treatment/Extension 
Pituitary MRI (or CT) 
Mandated at screening 
Mandated, approximately every 6 
months 
Pituitary MRI scanning with gadolinium enhancement will be performed at visits according to 
Table 7-1a, Table 7-1b, Table 7-2, and Table 7-5. These will be assessed centrally by the 
imaging vendor to screen for pituitary enlargement either by tumor volume or maximum 


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dimension of tumor. If MRI scan 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 
for consistency in the measurement of dimensions. The modality should remain consistent to 
that used at baseline unless there is a development of a contraindication. Please see the study 
imaging manual for further information. If EOT occurs less than 6 months before the scheduled 
Week 96 visit, MRI (or CT) and DXA is not mandatory at EOT.  
7.2.2.6 
Cardiac assessments 
Cardiac monitoring will include 12-lead Safety ECGs, which are the primary assessment of 
safety at study visits. The 24 hour Holter assessments are not intended to provide real-time 
assessment of cardiac intervals and cardiac rhythm.  
Table 7-6 
ECG collection plan 
Week 
Day 
Time point 
ECG 
Type 
Central or 
Local reading 
reading 
Post wash-out (up to Week -
3) 
up to -15 
Anytime 
12 Lead 
Local 
-2 to -1  
-14 to -1 
Anytime 
12 Lead 
Local 
-2 to -1 
-14 to -1 
24-hour 
Holter 
Central 
1 
1 
Pre-dose 
12 Lead 
Local 
1, 2, 5, 8, 12, 14, 17, 20, 23, 
26, 29, 32, 36, 40, 44  
1, 15, 36, 57, 85, 99, 
120, 141, 162, 183, 
204, 225, 253, 281, 
309 
1.5 hours Post-dose  
12 Lead 
Local 
48* 
337* 
Anytime for patients 
not continuing in 
extension 
12 Lead 
Local 
2, 12, 14, 36 
15, 85, 99, 253 
Start at Pre-dose  
24-hour 
Holter 
Central 
Post Treatment Follow-up 
week 2, 5, 8, 12** 
15, 36, 57, 85** 
Anytime 
12 Lead 
Local 
Post Treatment Follow-up 
week 2, 12** 
15, 85** 
Anytime 
24-hour 
Holter 
Central 
Optional Extension: 48*, 60, 
72, 84, 96 and every six 
month afterward *** 
337*, 421, 505, 589 
1.5 hours Post-dose  
12 Lead 
Local 
End of treatment extension 
visit 
 
Anytime 
12 Lead 
Local 
Optional Extension: 72 
505 
Start at Pre-dose  
24-hour 
Holter 
Central 
End of treatment extension 
visit**** 
 
 
24-hour 
Holter 
Central 
Post Treatment Follow-up 
Last dose + 30d  
Anytime 
12 Lead 
Local 
Unscheduled assessment 
Anytime 
12 Lead 
Local 


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Week 
Day 
Time point 
ECG 
Type 
Central or 
Local reading 
reading 
*Patients will have only one ECG at Week 48 (Day 337). For patients not continuing in optional extension, ECG 
will be performed anytime during the visit. For patients continuing in optional extension, ECG will be performed 
at 1.5 hours post-dose, except for EOT Ext., if applicable 
**For patients who discontinued study drug during Period 1. 
***The patients who have completed Week 96 prior to the completion of study will be followed every six months 
as per the schedule of assessments in Table 7-2 until transitioning either to a separate long-term safety follow-
up study, a local alternative treatment option, or the completion of the study, whichever occurs first. 
****End of treatment optional Extension visit assessment should be completed at the time the patients are 
transitioning either to a separate long-term safety follow-up study, a local alternative treatment option, or the 
completion of the study, whichever occurs first. Note: Patients end participation in the optional extension period 
study within 4 weeks after Protocol Amendment 02 approval at the site, or by Week 96, whichever occurs first. 
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 7-1a, Table 7-1b, Table 7-2, and Table 7-6. Patients should  
be instructed to return their 24-hour Holter flashcards to the site at their next study visit in order 
to facilitate timely central reading of the Holter data. 
7.2.2.6.2 Electrocardiogram (ECG) 
Twelve-lead safety ECGs are collected at the study sites according to Table 7-1a, Table 7-1b , 
Table 7-2, and Table 7-6. 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).  
Twelve-lead safety ECGs are collected at the study site using ECG equipment provided by or 
validated 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 eCRF.  
Each 12-lead Safety ECG tracing must 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 must be 
synchronized with the central clock on a daily basis. 
Record the following on the eCRF: 
• date and time of ECG 
• heart rate 
• PR interval 
• QT and QTcF interval 
• QRS duration 


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The Fridericia QT formula (QTcF) to correct for variations in heart rate must 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 must be reported on the ECG eCRF. 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. 
Notable ECG abnormalities must be recorded on the Adverse Events eCRF page. If there is a 
notable abnormality, then a cardiology consult should be obtained as soon as possible, 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 
assessment. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and then blood sampling for osilodrostat pharmacokinetic (PK) 
assessment (Figure 7-1). ECG procedure may also be performed 30 minutes after PK sampling. 
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:  


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• On the first day of the first administration of osilodrostat (Day 1), pre-dose baseline ECGs 
must be done in triplicate. The mean of the QTcF values from these three ECG tracings is 
used to determine the mean baseline QTcF. 
• On Day 1, if the safety ECG (1.5 hours post-first dose of osilodrostat) shows an increase 
in QTcF > 30 msec from the mean baseline value, or the QTcF is > 480 msec, then the 
patient must be discontinued from study. The ECG reading should be performed in 
triplicate (to determine a mean value) and reviewed promptly by a consulting cardiologist 
before discontinuing the patient from osilodrostat therapy. 
• If at any following visit, a QTcF > 480 msec is observed or an increase of the QTcF of > 
60 msec compared to baseline mean 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 drug while an urgent 
cardiology consultation is obtained to re-evaluate the ECG and perform a clinical 
consultation. If immediate treatment is required for patient safety, this should be initiated 
at the study site without delay and without waiting for confirmation by a cardiologist. 
Based on the cardiologist consultation, the following should occur: 
• If a mean QTcF > 480 msec is NOT confirmed, no further action needs to be taken. 
• If the cardiologist confirms a mean QTcF > 500 msec, the patient has to discontinue 
according to the discontinuation procedure described in Section 7.1.4. and an unscheduled 
PK sample is to be 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. 
• If the cardiologist confirms that QTcF > 480 msec, osilodrostat treatment is temporarily 
interrupted and a thorough evaluation is performed to assess the patient for acute 
cardiovascular risk, and for possible underlying heart disease that needs additional 
evaluation and management. In addition, an unscheduled PK sample will be collected. 
• If based upon the assessment by the cardiologist, the investigator considers that there 
is an acute cardiovascular safety risk and that the subject should not continue with 
study medication, the subject needs to be discontinued immediately (discontinuation 
criteria described in Section 7.1.4). 
• If based upon the assessment by the cardiologist, the investigator considers that there 
is not an acute cardiovascular safety risk; the subject can continue to receive study 
medication. 


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Figure 7-2 
QT Monitoring Flow Chart 
 
7.2.3 
Pharmacokinetics 
Blood samples for osilodrostat pharmacokinetic (PK) evaluation will be collected from all 
patients who receive at least one dose of study drug. Pharmacokinetic blood sampling will be 
performed in each study period as indicated in the Visit Evaluation Schedule (Table 7-1a, Table 
7-1b and Table 7-2). Time points of blood sample collection for PK analyses are outlined in 
Table 7-7.  
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 drug dose prior to the sampling (24-h 


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clock time), must be obtained on all sampling days and recorded on the PK eCRF and/or 
Contract Research Organization (CRO) requisition form(s). Sampling problems will be noted 
in the relevant field in the eCRF. 
An additional blood sample (unscheduled) should be collected in the event that a patient 
experiences an AE which requires premature termination from the study drug.  
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 7-7. 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. 
Table 7-7 
Pharmacokinetic blood collection log 
Week 
Day 
Scheduled time 
pointa 
Dose reference 
IDb 
PK Sample 
No. 
Sample volume [mL] 
1 
1 
Pre-dose / 0 h 
1 
 
1 
Approximately 3.0  
1 
1 
Post-dose 1 – 2 h 
1 
 
2 
Approximately 3.0 
2 
15 
Pre-dose / 0 h 
2 
201 
3 
Approximately 3.0 
2 
15 
Post-dose 1 – 2 h 
2 
 
4 
Approximately 3.0 
5 
36 
Pre-dose / 0 h 
3 
301 
5 
Approximately 3.0 
5 
36 
Post-dose 1 – 2 h 
3 
 
6 
Approximately 3.0 
8 
57 
Pre-dose / 0 h 
4 
401 
7 
Approximately 3.0 
8 
57 
Post-dose 1 – 2 h 
4 
 
8 
Approximately 3.0 
12 
85 
Pre-dose / 0 h 
5 
501 
9 
Approximately 3.0 
12 
85 
Post-dose 1 – 2 h 
5 
 
10 
Approximately 3.0 
14 
99 
Pre-dose / 0 h 
6 
601 
11 
Approximately 3.0 
14 
99 
Post-dose 1 – 2 h 
6 
 
12 
Approximately 3.0 
17 
120 
Pre-dose / 0 h 
7 
701 
13 
Approximately 3.0 
17 
120 
Post-dose 1 – 2 h 
7 
 
14 
Approximately 3.0 
20 
141 
Pre-dose / 0 h 
8 
801 
15 
Approximately 3.0 
20 
141 
Post-dose 1 – 2 h 
8 
 
16 
Approximately 3.0 
23 
162 
Pre-dose / 0 h 
9 
901 
17 
Approximately 3.0 


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Week 
Day 
Scheduled time 
pointa 
Dose reference 
IDb 
PK Sample 
No. 
Sample volume [mL] 
23 
162 
Post-dose 1 – 2 h 
9 
 
18 
Approximately 3.0 
26 
183 
Pre-dose / 0 h 
10 
1001 
19 
Approximately 3.0 
26 
183 
Post-dose 1 – 2 h 
10 
 
20 
Approximately 3.0 
29 
204 
Pre-dose / 0 h 
11 
1101 
21 
Approximately 3.0 
29 
204 
Post-dose 1 – 2 h 
11 
 
22 
Approximately 3.0 
32 
225 
Pre-dose / 0 h 
12 
1201 
23 
Approximately 3.0 
36 
253 
Pre-dose / 0 h 
13 
1301 
24 
Approximately 3.0 
40 
281 
Pre-dose / 0 h 
14 
1401 
25 
Approximately 3.0 
44 
309 
Pre-dose / 0 h 
15 
1501 
26 
Approximately 3.0 
48 
337 
12 h post dose 
9801 
98 
Approximately 3.0 
 
Unscheduled sample 
 
 
1001+ 
Approximately 3.0 
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 timepoint, and within 0.5h before the 12h post dose sampling.  If patient 
enters the extension phase of study, the 12 h post dose sampling should be taken prior to the first dose in the 
extension phase 
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 osilodrostat dose administered on study visit day, 
while PK collection number series “201, 301, 401…” is for the previous osilodrostat dose the subject received 
prior to the collection of the PK pre-dose (trough) sample 
7.2.3.2 
Analytical method 
The plasma samples from all subjects treated with osilodrostat will be assayed for osilodrostat 
concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-
MS/MS). The lower limit of quantitation (LLOQ) will be 0.10 ng/mL for osilodrostat; values 
below LLOQ will be reported as zero ng/mL, and missing samples will be labeled accordingly. 
Concentrations of osilodrostat will be expressed in mass per volume units (ng/mL). Placebo 
samples will not be analyzed.  


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r 
7.2.5 
Resource utilization 
Not applicable. 
7.2.6 
Patient reported outcomes 
Four patient reported outcome instruments will be used to assess the impact of treatment on 
patient quality of life and symptom burden. Patients must be asked to complete each 
questionnaire, including patients who discontinue from study drug, prior to clinical assessments 
being undertaken, and these must be completed in accordance with the schedules listed in Table 
7-1a, Table 7-1b, Table 7-2 and Table 7-11. 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 


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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 must be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs before any clinical study examinations. This assessment must be documented in study 
source records. If AEs or SAEs are confirmed, study investigators must 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. 
Table 7-11 
Patient reported outcomes (PROs) collection plan 
Patient 
Questionnaires1 
Week 
Day 
Time 
C-SSRS 
 
-5 to -1, 1, 2, 5, 8, 12, 
48, and at Core Post 
treatment follow-up. 
Post treatment follow-
up: Week 2**, 5**, 8**, 
12**.  
-35 to -1, 1, 15, 36, 57, 85, 
337, Last dose +30 days.   
Post treatment follow-up 
Day 15**, 36**, 57**,  85**. 
Prior to any clinical assessments, 
drug dosing (predose) or 
diagnostic testing. 
CushingQoL, 
Beck Depression 
Inventory-II 
1, 2, 5, 8, 12, 14, 17, 
20, 23, 26, 36, 48, and 
at Post treatment follow-
up. 
Post treatment follow-up 
Week 2**, 5**, 8**, 12**. 
1, 15, 36, 57, 85, 99, 120, 
141, 162, 253, 337, Last 
dose +30 days. 
Post treatment follow-up 
Day 15**, 36**, 57**, 85**. 
Prior to any clinical assessments, 
drug dosing (predose) or 
diagnostic testing. 
EQ-5D-5L 
1, 12, 14, 26, 36, 48, 
and at Post treatment 
follow-up. 
Post treatment follow-up 
Week 12**. 
1, 85, 99, 183, 253, 337, 
Last dose +30 days.   
 
Post treatment follow-up 
Day 85**. 
Prior to any clinical assessments, 
drug dosing (predose) or 
diagnostic testing. 
Cushing QoL 
Beck Depression 
Inventory-II 
EQ-5D-5L 
Optional Treatment 
Extension: 
72, 96, end of treatment 
Extension visit***, and 
at Post treatment follow-
up. 
 
505, 673, Last dose +30 
days.   
 
Prior to any clinical assessments, 
drug dosing (predose for Week 
72) 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 
** For patients  who discontinued study drug during Period 1 
*** End of treatment Extension visit assessment should be completed at the time the patients transitioning either to 
a separate long-term safety follow-up study, a local alternative treatment option, or the completion of the study, 
whichever occurs first. Note: Patients to end study participation within 4 weeks after  Protocol Amendment 02 is 
approved at the site, or by Week 96, whichever occurs first 


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Columbia Suicide Severity rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior using a semi-structured interview to probe 
patient responses.  
The eC-SSRS is a validated version of the C-SSRS that captures self-reported C-SSRS data via 
a web-based system. The eC-SSRS uses a detailed branched logic algorithm to perform the C-
SSRS subject answers in order to evaluate each subject’s suicidal ideation and behavior in a 
consistent manner. Data are handled as third party data. At the conclusion of each assessment, 
the investigator will receive a detailed eC-SSRS Findings Report via e-mail or fax. If the system 
assesses the patient as having positive suicidal signs, the investigator will be immediately 
notified by either fax, email and/or via telephone. 
The “baseline/screening” version of the C-SSRS will be provided to patient at the first visit by 
the clinician (see Table 7-1a). This version assesses Suicidal Ideation and Suicidal Behavior 
during the subject’s lifetime and during a predefined period. The predefined period currently 
used in Novartis trials is past six months for suicidal ideation and past two years for suicidal 
behavior. At subsequent visits, the “since last visit” version will be administered (see Table 7-
1a, Table 7-1b).  
If the score is “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS or “yes” 
on any item of the Suicidal Behavior section, the patient must be referred to a mental health 
care professional for further assessment and/or treatment. The decision on whether the study 
drug should be discontinued is to be taken by the investigator in consultation with the mental 
health professional to whom the patient is referred. 
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, during Study 
Periods 1 and 2 where it is believed that changes in Cushing’s disease symptoms will occur 
rapidly among patients 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. 


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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 
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). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study drug. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
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 


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not be used in this study but is collected as a seriousness criteria; rather, information about 
deaths will be collected though a Death form. 
Table 8-1 
CTCAE v4.03 - General grading guideline 
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 
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. 
Please refer to: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
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: 
• The severity grade (CTCAE Grade 1-4) 
• Its duration (Start and end dates) 
• Its relationship to the study drug (Reasonable possibility that AE is related: No, Yes) 
• Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
• Whether medication or therapy was given 
• Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
• Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met. 
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 eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 


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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 drug), should be recorded on the Adverse Events eCRF. 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 lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.1.3 
Adverse events of special interest 
Some AEs are predicted by the mechanism of action (MoA) of osilodrostat or by the underlying 
disease, specifically in subjects 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” are listed under the following mechanistic groups: 
• Adrenal Hormone Precursor Accumulation-related AEs 
• Hypocortisolism related AEs 
• Pituitary tumor enlargement-related AEs 
• QT-prolongation-related AEs 
• Arrythmogenic potential AEs 
Two of the AEs of special interest, the potential for QT prolongation and glucocorticoid 
withdrawal/adrenal insufficiency are described in greater detail below. 
8.1.3.1 
Risk of QT Prolongation 
Preclinical cardiac safety studies have revealed a signal of QT prolongation with osilodrostat 
that is consistent across in vitro and in vivo studies. Preliminary clinical data suggest that there 
is a risk for QT prolongation in patients, at doses above the therapeutic range, but this requires 
further investigation to quantify the effect of osilodrostat and preliminary clinical data indicate 
that QT prolongation is a risk associated with osilodrostat therapy. Relevant QTc data from 
study [LCI699C2201] is presented in this section on the risk of QT prolongation.  


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Study [LCI699C2201]. Although the PoC study was not designed to control adequately for 
changes in the QT interval, locally read 12-lead EKGs were performed. In the 10-week analysis, 
the mean (± SD) for QTcF at screening was 388.60 ± 62.80 msec, and at the end of study was 
412.31 ± 28.861msec [CLCI699C2201 PT-Listing 16.2.9-1.2.2]. No conclusion can be drawn 
because of the high variability of results, the absence of correlation with osilodrostat plasma 
concentration, and the potential for several concomitant risk factors for QT prolongation. In 
addition, the end of study ECGs were performed 2 weeks after the last dose of osilodrostat was 
administered. There were no patients with QTcB > 480 msec, and no reported QT-related AEs 
or cardiac arrhythmias in this POC study. 
Study [LCI699C2105]. This study was an ICH E-14 compliant thorough QT/QTc study 
conducted in healthy volunteers (see Section 1.2.1.2.4 for a summary of the results). The results 
support the use of osilodrostat in doses up to 30 mg.    
8.1.3.2 
Glucocorticoid withdrawal and adrenal insufficiency 
Important and closely related AEs of special interest are glucocorticoid withdrawal and 
hypocortisolism (adrenal insufficiency). These AEs are a consequence of the potent activity of 
osilodrostat to inhibit cortisol synthesis. In patients Cushing’s disease, the relatively rapid 
correction of hypercortisolism can result in symptoms of glucocorticoid withdrawal. If the 
inhibition of cortisol synthesis is excessive, hypocortisolism with or without symptoms of 
adrenal insufficiency may develop. 
Although symptoms of frank adrenal insufficiency were not reported in the 10-week analysis 
of study [LCI699C2201], four patients did reports symptoms suggestive of glucocorticoid 
withdrawal. These symptoms were managed successfully by reducing the dose of osilodrostat. 
8.1.3.3 
Definitions and reporting 
Designated events of special interest will be collected through routine AE collection. These 
events will be presented and discussed separately in the CSR. 


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8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization,  
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event. 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 30 days after the patient has 
stopped study drug must be reported to Novartis within 24 hours of learning of its occurrence. 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes 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. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.  
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 drug (if there is more than one study drug), complete the SAE Report Form in 
English, and submit the completed form within 24 hours Novartis.  Detailed instructions 
regarding the submission process and requirements for signatures are to be found in the 
investigator folder provided to each site. 


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A copy of the SAE data submitted must be kept with the case report form documentation at the 
study site. 
Follow-up information is submitted in the same way as the original SAE Report.  Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study drug, 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 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 drug 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 in case of emergency. The investigator will inform the patient how to contact his/her 
backup in cases of emergency when he/she is unavailable. The protocol number, study drug 
name if available, subject number, and instructions for contacting the local Novartis CPO (or 
any entity to which it has delegated responsibility for emergency code breaks) will be provided 
to the patient in case emergency unblinding is required at a time when the investigator and 
backup are unavailable. However, if a mechanism is already in place to ensure that the 
investigator and/or back-up can always be reached in case of emergency then the procedure 
above is not required. 
Study drug must be discontinued 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 drug should be discontinued for 
a given patient and, if applicable, whether the patient can continue to receive study drug and be 
followed as described in the protocol. 


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8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study drug must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
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 drug any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form. 
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 
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 
This study will institute a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will be constituted prior to the randomization 
of the first patient. The DMC will be responsible to review safety data at a frequency to be 
decided jointly by the DMC and Novartis. This includes but does not limit the role of the DMC 
to evaluate these data and to provide recommendations to the sponsor to continue the study 
without change, modify the study, or stop the study early.  
It is expected that the DMC will consist of a minimum of two physicians with appropriate 
disease area qualifications, one cardiologist, and one statistician. There will be a meeting with 
the DMC describing their roles and responsibilities and discussing potential data format and 
process issues prior to the finalization of DMC charter. 
A DMC subcommittee consisting of a group of Independent Endocrinologists (IEs) will be 
responsible for dose titration during the double-blind, placebo-controlled period of the study.  
The DMC members who are not IEs have a responsibility to oversee the function of the IEs, 
specifically as it relates to reporting accurate and timely UFC information to the IEs, capturing 
and communicating the dose recommendation of the IE to the study sites, and showing that 
study drug information was actually received at the study sites.   
A charter will be prepared and approved by both Novartis and the DMC. This will occur prior 
to the enrollment of the first patient. The DMC charter will specify the format and conduct of 
the meetings, conference calls, the role and responsibilities of Core and extended members, the 
type of data to be reviewed, and the timing and frequency of meetings.  


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8.7 
Steering Committee 
A Steering Committee (SC) will be established prior to the enrollment of the first patient. Most 
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. 
The SC will 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 
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 eCRFs 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 eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study drug is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits. 


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The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs 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 eCRF 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 eCRFs 
are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs and, allow modification or verification of the entered 
data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
Pharmacokinetic (PK) 
 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 and Biomarker Sample Collection eCRFs, 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, subject ID, etc.) and 
one copy will be retained by the site. 
ECG tracings, and Imaging (MRI and DXA) will be transferred to central readers. Methods for 
data collection will be described in respective manuals. A [Laboratory Manual] will also be 
available for Central Laboratory. 
9.4 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 


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Laboratory samples for hematology, chemistry, coagulation, thyroid panel, serum pregnancy 
test, additional hormones and others laboratory parameters as specified in Table 7-4 will be 
performed by a Central Laboratory. Results of analysis tested centrally will be sent 
electronically to Novartis (or a designated CRO). 
Samples and/or data for 
PK sampling, imaging, ECG readings and IRT will 
be processed centrally and the results will be sent electronically to Novartis (or a designated 
CRO). 
Diary data will be entered into a paper diary by the patient and brought to site at every visit for 
consultation by investigator.  
Randomization codes and data about all study drugs 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 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 when all enrolled patients have completed the Core 
phase of study (Period 1 and 2) or have prematurely withdrawn from the study prior to the end 
of the Core phase. After the Core study phase, patients may continue in the optional extension 
phase. The additional data collected in the extension phase, will be further summarized in a 
final study report once these patients completed the study. 
Novartis or designated CRO will analyze all data using the SAS System for data analysis V9.3 
or higher. Any data analyses carried out independently by an investigator should be submitted 
to Novartis and approved 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. 


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10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all randomized patients who have received at least one 
dose of study drug (osilodrostat or placebo). According to the intent-to-treat (ITT) principle, 
patients will be analyzed according to the treatment and stratum they have been assigned to 
during the randomization. This is the default analysis set for efficacy.  
10.1.2 
Safety Set 
The Safety Set (SS) includes all patients who received at least one dose of study drug 
(osilodrostat or placebo). Patients will be analyzed according to the study drug 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 received if the randomized/assigned treatment 
was never received. 
10.1.3 
Per-Protocol Set 
Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant with 
the requirements of the Clinical Study Protocol and have no CSR-reportable protocol deviation.  
The criteria for CSR-reportable protocol deviation will be defined prior to database lock. 
10.1.4 
Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of osilodrostat and have at least one evaluable pharmacokinetic concentration (post-first-dose) 
at any visit. 
10.1.5 
Other analysis sets  
Not applicable 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data will be summarized descriptively for the FAS and the 
safety set (if not the same). 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented.  
Relevant medical histories and current medical at baseline will be summarized by system organ 
class and preferred term, by treatment group and all patients. 
10.3 
Treatments (study drug, concomitant therapies, compliance) 
When appropriate, patients in a given analysis set can be classified into mutually exclusive 
treatment arms as described below: 
For patients in FAS/PPS 


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Osilodrostat arm: patients randomized to osilodrostat for the placebo control period of the 
study 
Placebo arm: patients randomized to placebo for the placebo control period of the study 
For patients in SS 
Osilodrostat arm: patients receiving osilodrostat for the placebo control period of the study 
Placebo arm: patients receiving placebo for placebo control period of the study  
Exposure to study drug will be summarized descriptively using SS by treatment arm and study 
periods. The actual and planned doses administered and reason for dose change will be listed. 
The number of patients with dose adjustments will be 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 by ATC class, preferred term, treatment arms 
and study periods for the safety set.  The usage of concomitant medications for the treatment of 
hypertension, diabetes, and dyslipidemia will be separately summarized. 
10.4 
Primary objective 
The primary objective is to demonstrate the superiority of osilodrostat compared to placebo in 
achieving a complete response (mUFC ≤ ULN) at week 12. 
10.4.1 
Variable 
The primary efficacy variable is the proportion of randomized patients in each treatment arm 
who are complete responders at Week 12.  
10.4.2 
Statistical hypothesis, model, and method of analysis 
The primary analysis will be based on a Cochran–Mantel–Haenszel (CMH) exact test stratified 
by the history of pituitary irradiation (yes/no) using the FAS. Following the ITT principle, 
patients are analyzed according to the drug and stratum they were assigned to at randomization.  
The statistical null hypothesis states that the complete response rates at the end of the 12-week 
placebo-controlled period (i.e., at Week 12) are the same between the two randomized arms. To 
test this hypothesis, if the 1-sided p-value is ≤ 0.025, and the odds ratio (osilodrostat vs. 
Placebo) is > 1, the null hypothesis will be rejected and the complete response rate in the 
osilodrostat arm will be considered higher than that in the placebo arm.  
10.4.3 
Handling of missing values/censoring/discontinuations 
It is scheduled to collect three individual 24 hours Urine Free Cortisol (UFC) samples at visits 
Weeks 1, 12, 36, 48 and Week 12 Post-treatment Follow-up, and two UFC samples at all other 
visits. For a given visit, Mean Urine Free Cortisol (mUFC) is the mean of all available (need to 
be ≥2) individual UFC values determined at a central laboratory. In case only one or no 
individual UFC value is available, the mUFC will be considered missing for that visit. 
During the double blind period, early discontinued patients (prior to Week 12) will be followed 
at regular visits and have assessments performed as indicated in Table 7-1a (post-treatment 


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follow-up). Patients who discontinued prior to Week 12 or had a missing mUFC assessment at 
Week 12 will be considered as non-responder in the primary analysis. No imputation will be 
used. 
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 FAS. 
In addition, both stratified CMH exact test and un-stratified Fisher’s exact test of the primary 
endpoint will be performed using PPS. 
To deal with potential missing mUFC at Week 12, imputation methods such as multiple 
imputation will be used as sensitivity analysis. For patients who discontinued the study early, 
mUFC collected during the follow-up visit at Week 12 will also be used for sensitivity analysis. 
If mUFC during the follow up visit is missing at Week 12, patient will be considered as non-
responder.  
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) in both arms combined at Week 36 in patients receiving 
osilodrostat treatment.   
The statistical null hypothesis states that the proportion of complete response rate at Week 36 
is < 30%. The analysis of the key secondary objective will be based on the 2-sided 95% exact 
confidence interval (CI) constructed using the Clopper-Pearson method in FAS patients 
receiving osilodrostat treatment. Patients with missing mUFC at Week 36 will be counted as 
non-responders. 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% at Week 36. 
Patients randomized to placebo who do not switch to osilodrostat will not be included in this 
analysis. 
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%. 
As supportive analysis of the key secondary objective, analysis will be repeated using PPS 
patients receiving osilodrostat treatment. In addition, the same analysis will be performed in the 
patients randomized to osilodrostat arm only. For each supportive analysis, the 2-sided 95% 
exact confidence interval of the complete response rate at Week 36 will be provided.  
Patients with missing mUFC at Week 36 will be considered as non-responders for key 
secondary analysis. In order to evaluate the impact of missing mUFC, imputation method such 
as multiple imputations will be considered as sensitivity analyses.   


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10.5.2 
Other secondary efficacy objectives 
10.5.2.1 Assess the overall response rate at Week 12, Week 36, and Week 48 
Proportion of overall responders (enrolled patients with mUFC ≤ ULN or have at least 50% 
reduction in mUFC from baseline  and > ULN) at Week 12, Week 36 and Week 48 will be 
summarized using point estimates and Clopper-Pearson 95% Cis by treatment arms and for 
overall patients. For the osilodrostat arm, denominator will be the number of patient randomized 
to osilodrostat; whereas for placebo arm, denominator will be number of randomized patients 
switched to osilodrostat. 
10.5.2.2 Assess the change in mUFC during the Core and optional Extension 
periods of the study 
For the actual and percentage change in mUFC from baseline, descriptive summaries will be 
provided for every visit in Core and optional extension phase at which UFC is collected. 95% 
CIs for the percentage change from baseline will also be provided by treatment arms and for 
overall patients. 
10.5.2.3 Compare the time-to-first control of mUFC during the placebo-
controlled period between patients randomized to osilodrostat and 
placebo 
Time-to-first control of mUFC during the placebo control period will be analyzed using Kaplan-
Meier plots and the logrank test. Time-to-first control of mUFC is defined as the time (in days) 
from randomization to the time of the first post-baseline mUFC collection that was ≤ ULN 
(based on central lab result) before discontinuation or completion of placebo-controlled period, 
whichever is earlier. 
10.5.2.4 Assess the time-to-escape during treatment of osilodrostat up to 
Week 48  
For patients who attained normal mUFC (≤ ULN), time-to-escape will be analyzed using 
Kaplan-Meier plots. This will be performed by randomized treatment assignment and for the 
overall trial population. Time-to-escape is defined as the time (in weeks) from the first 
collection of post-baseline normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on  2 
consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose 
interruption or dose reduction due to safety reasons. Time-to-escape will not be assessed for 
patients during the first 26 weeks. 
Patients that have dose interruption or dose reduction for safety reasons will be censored at the 
time of the first dose interruption.   
10.5.2.5 Assess the change from baseline in cardiovascular and metabolic 
related parameters associated with Cushing’s disease during the core 
period of the study  
For cardiovascular and metabolic parameters associated with Cushing’s disease (e.g. fasting 
glucose, HbA1c, fasting lipid profile, SBP, DBP, weight and waist circumference): 


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For actual and percentage change from baseline to Week 12, Week 36 and Week 48, descriptive 
summaries will be provided by treatment arm and for overall patients. 
For the actual and percentage change from the baseline to the end or the last available 
measurement of the placebo control period, whichever occurs earlier, in addition to the 
descriptive summary, the mean difference between two randomized arm and associated 2-sided 
95% C.I. will be estimated with adjustment for corresponding baseline parameter value. In 
addition, shift tables using normal/abnormal categories for BP (SBP, DBP), FPG, HbA1c, 
fasting lipid profile, weight and waist circumference from baseline at Week 12, 36, and 48 by 
randomized arms and for overall patients will be assessed. Normal for these parameters is 
defined as shown in Appendix 3. 
10.5.2.6 Assess the change from baseline in physical features of Cushing’s 
disease 
For each of physical features of Cushing’s disease: facial rubor, hirsutism (female only), striae, 
supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) 
obesity, and ecchymoses (bruises), Likert scores will be measured.  The change from baseline 
at Weeks 12, 36 and 48 will be assessed using by randomized treatment arm and for overall 
patients.  
10.5.2.7 Assess the change from baseline in bone mineral density by DXA scan 
at Week 48 
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 will be provided by 
randomized treatment arm and for overall patients. 
10.5.2.8 Assess the change from baseline in serum, salivary and hair cortisol 
levels 
Change in the actual and percentage change from baseline to each post-baseline visit for serum 
cortisol, late night salivary cortisol, morning salivary cortisol and hair cortisol levels will be 
assessed. Descriptive summaries will be provided for every visit in the Core and Extension 
phases at which the biomarkers of hypercortisolism are collected. Salivary cortisol samples will 
only be included if they are collected within the correct time window. 95% CIs for the 
percentage change from baseline will also be provided by treatment and for overall patients. 
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
The assessment of safety will be based mainly on the frequency and severity of AEs and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
ECG, vital signs, and special tests) will also be presented. All safety outputs will use the SS, 
which consists of all patients that received at least one dose of osilodrostat or placebo. Safety 
data will be presented in two different periods as defined below. 
• Placebo-controlled period: patients randomized to osilodrostat, patients randomized to 
placebo, and overall patients  


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• Overall study period: patients randomized to osilodrostat, patients randomized to placebo, 
and overall patients  
• The overall observation period will be divided into three mutually exclusive segments: 
• pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
• on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
• post-treatment period: starting at day 30+1 after last dose of study medication. 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) have to 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 (on-treatment and post-treatment) will be summarized.  
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. 
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 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. 


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• 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 using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
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. 
Tumor volume and longest dimension  
Tumor volume and longest dimension will be evaluated as defined in Section 7.2.2.6 
The longest dimension (in mm) will be summarized as absolute values and actual and percent 
change from baseline in longest dimension. The tumor invasiveness is also evaluated, in terms 
of the prevalence of tumors with extension outside sella turcica and/or invasion into surrounding 
structures at baseline and during the study (new onset/disappearance). 
In addition, if the tumor volume is evaluated, a descriptive summary of actual tumor volumes 
as well as actual and percent change from baseline in tumor volumes will be provided.   
Columbia Suicide Severity Reporting Scale (C-SSRS) 
C-SSRS data will be mapped to Columbia Classification Algorithm for Suicide Assessment 
(C-CASA) as per FDA guidance on suicidality (Food and Drug Administration 2010). The 
proportion of patients who have completed suicide, suicide attempt, preparatory actions 
toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior without 
suicidal intent will be summarized by treatment arm. The number of patients with SAEs 
referring to a positive suicidal evaluation will be summarized by treatment arm. 
10.5.3.5 Supportive analyses for secondary objectives 
Not applicable 


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10.5.3.6 Tolerability 
Tolerability will be studied in terms of dose reductions or drug interruption due to an AE. 
10.5.4 
Pharmacokinetics 
The PAS will be used in all pharmacokinetic data analysis and summary statistics. 
As sparse pharmacokinetic sampling is performed in this study, traditional non-compartmental 
analysis will not be performed to calculate pharmacokinetic parameters. Plasma concentration 
data of osilodrostat will be listed by subject, visit, incident dose and nominal sampling times. 
Descriptive statistics of plasma concentrations will be provided by incident dose, visit and 
nominal sampling times, and will include arithmetic and geometric mean, median, SD, CV, 
geometric CV, minimum and maximum. Zero concentrations will not be included in the 
geometric mean calculation. Graphical depiction (mean and individual) for osilodrostat 
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 
statistical analysis plan. 
10.5.4.1 Data handling principles 
Plasma concentrations of osilodrostat will be expressed in ng/mL. Missing concentration values 
will be labeled as such in data listings. Concentrations below the limit of quantitation (LLOQ) 
will be treated as zero in summary statistics and reported as zero in data listings. 
10.5.6 
Resource utilization 
Not Applicable. 
10.5.7 
Patient-reported outcomes 
The CushingQoL 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 


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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 baseline in the CushingQoL score during Study Period 1 and 2 will be analyzed 
using a linear mixed effect model for longitudinal data to assess the treatment effect over time. 
The differences in least square means between osilodrostat and placebo arm, and the 
corresponding 2-sided 95% confidence interval (CI) at each time point will be presented. 
Descriptive statistics will be used to summarize the raw and absolute change from baseline for 
the scores at each scheduled assessment including critical time points such as from baseline to 
Week 12 and Week 48, from Week 12 to Week 36 and from Week 36 to Week 48 etc. during 
both Core phase (Study Period 1 and 2) and the optional extension phase. 
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 baseline 
and at least one non-missing post-baseline assessments during the Core phase will be included 
in the linear mixed effect model analysis. All available data until completion or early 
discontinuation during Core phase will be used in the linear mixed effect models analyses with 
missing scores at any time point are assumed to be missing-at-random (MAR).  


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10.7 
Interim analysis 
The study will have no planned interim analysis for efficacy. The DMC will conduct periodic 
safety data reviews as outlined in Section 8.6. 
10.8 
Sample size calculation 
Eligible patients will be stratified at randomization according to history of pituitary irradiation 
(yes/no). Based on the LCI699C2201 study, it is assumed that approximately 20% of 
randomized patients will have a history of pituitary radiation.  
With 2:1 randomization ratio, to detect a difference of 45% in complete response rate between 
60% in osilodrostat arm and 15% in placebo arm (equivalent odds ratio equals 8.5), a sample 
size of 42 patients in osilodrostat arm and 21 patients in placebo arm will provide 91% power 
based on a 1-sided CMH exact test at the 0.025 level. In order to adjust for drop-outs, an 
additional 10% patients will be enrolled. Thus a total of approximately 69 patients will be 
enrolled in 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% at Week 36 . Both the SOM230G2304 trial of Pasireotide 
LAR and the SOM230B2305 trial of Pasireotide s.c. were powered to show a response rate 


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where the lower bound of the 95% confidence interval was ≥15%. Therefore an increase in this 
lower bound of the 95% confidence interval to a threshold of ≥30% would provide a significant 
improvement in clinical benefit to this patient arm. 
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 60% complete response rate at Week 36, and less than 50% discontinuation rate of 
patients in placebo arm prior to Week 12. For the 69 patients in the pooled population, there is 
higher than 98% chance that the lower bound of 2-side 95% exact CI (based on Clopper-Pearson 
method) of the observed response rate is larger than 30%. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
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 eCRFs. 
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. 


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Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in  
Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis 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 


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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, 
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 (eCRF) 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 eCRFs and all other required reports. Data reported 
on the eCRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF must be 
recorded. Any missing data must be explained. For electronic CRFs an audit trail will be 
maintained by the system. The investigator should retain records of the changes and corrections 
to eCRFs. 
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. 


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


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13 
References (available upon request) 
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Fleseriu M, Loriaux DL, Ludlam WH (2007) Second-line treatment for Cushing's disease 
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Webb S, Badia X, Barahona M, et al (2008) Evaluation of health-related quality of life in 
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14 
Appendices 
Appendix 1: List of drugs to be used with caution with osilodrostat 
Table 14-1 
List of medications with potential drug-drug interactions with 
osilodrostat – to be used with caution 
CYP1A2 
substrates 
CYP2C19 
substrates 
CYP2D6 substrates 
CYP3A4/5 substrates 
CYP2E1 substrates 
Atypical 
antipsychotics: 
Clozapine 
Olanzapine 
Xanthines: 
Caffaine1 
Theophylline2 
Others: 
Nabumetone 
Riluzole 
Ropivacaine 
Zolmitriptan 
Alosetron1 
Duloxetine1 
Melatonin1 
Ramelteon1 
Tacrine1 
Tizanidine1,2 
 
Anti-epileptics: 
Diazepam 
Phenytoin 
Phenobarbitone 
S-mephenytoin1,2 
Benzodiazepines: 
Clobazam1 
Proton pump 
inhibitors: 
Lansoprazole1 
Omeprazole1 
Pantoprazole 
Rabeprazole 
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 
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:  
Enflurane 
Halothane 
Isoflurane 
Methoxyflurane 
Sevoflurane 
Acetaminophen 
Chlorzoxazone 
Ethanol 
N, N-
Dimethylformamide 
Theophylline 


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Amended Protocol Version 02 Clean 
 
Protocol No. CLCI699C2302 
 
 
CYP1A2 
substrates 
CYP2C19 
substrates 
CYP2D6 substrates 
CYP3A4/5 substrates 
CYP2E1 substrates 
Tricyclics/ 
tetracyclics: 
Desipramine1 
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 
Aripiprazole 
Haloperidol  
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 
Corticosteroids: 
Budesonide1 
Fluticasone1 
Erectile dysfunction 
agents: 
Sildenafil1 
Vardenafil1 
Antiemetics: 
Aprepitant1 
Casopitant1 
Others: 
Alpha-
dihydroergocryptine1 
Aplaviroc1 
Buspirone1 
Cisapride2 
Conivaptan1 
Darifenacin1 


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Protocol No. CLCI699C2302 
 
 
CYP1A2 
substrates 
CYP2C19 
substrates 
CYP2D6 substrates 
CYP3A4/5 substrates 
CYP2E1 substrates 
Eletriptan1 
Eplerenone1 
Lumefantrine1 
Maraviroc1 
Ridaforolimus1 
Ticagrelor1 
Tolvaptan1 
Vicriviroc1 
1 Sensitive substrates: drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor. 
2 Substrates with narrow therapeutic index: drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns. 
This database of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; from the FDA’s “Guidance for Industry, Drug Interaction Studies” and from the University of 
Washington’s Drug Interaction Database. 


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Protocol No. CLCI699C2302 
 
 
Appendix 2: Medications with a “Known risk to cause TdP” and with a 
“Possible risk to cause TdP” 
The following e-link provides a list of medications with a “Known risk to cause TdP” and with 
a “Possible risk to cause TdP”.  These medications are prohibited to be used concomitantly with 
osilodrostat: www.crediblemeds.org. 
Investigators are advised to utilize this website when considering the addition of a new 
concomitant medication, as the lists are periodically updated. If necessary, a discussion can be 
held with the Novartis Medical Monitor when considering the use of medications with a 
“Known risk to cause TdP” and with a “Possible risk to cause TdP”. 


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Protocol No. CLCI699C2302 
 
 
Appendix 3: 
Normal ranges for cardiovascular risk factors  
Parameter 
Conventional Units 
SI Units 
Comment 
Systolic blood 
pressure (SBP) 
90-139 mmHg 
90-139 mmHg 
Conventional and SI units   
are the same 
Diastolic blood 
pressure (DBP) 
60-90 mmHg 
60-90 mmHg 
Conventional and SI units   
are the same  
Fasting plasma 
glucose (FPG) 
70-115 mg/dL                     
70-125 mg/dL 
3.9-6.4 mmol/L 
3.9-6.9 mmol/L 
Age 13-49 years 
Age ≥ 50 years 
HbA1c 
< 6.5 % 
< 6.5 % 
Percent of total hemoglobin 
Total cholesterol 
< 170 mg/dL 
< 200 mg/dL 
0.00-4.35 mmol/L                    
0.00-5.15 mmol/L 
Age 3-19 years 
Age ≥ 20 years  
HDL cholesterol 
> 34 mg/dL 
> 0.89 mmol/L 
All adult ages 
LDL cholesterol 
0-110 mg/dL 
0-130 mg/dL 
0.00-2.85 mmol/L                    
0.00-3.35 mmol/L 
Age 3-19 years 
Age ≥ 20 years  
Triglycerides 
< 200 mg/dL 
2.24 mmol/L 
All adult ages 
SI: Age13-64 years  
SI: Age ≥ 65 years 
Source: Chobanian A, et al JNC 7 (2003).  FPG, HbA1c :  ADA Diabetes Standards 2015   . 
Lipids: Central Laboratory Reference Ranges as of writing of original version of this protocol 
(consult Laboratory Manual for most current information). 

SAP_001.pdf: 
Clinical Development
LCI699/Osilodrostat
CLCI699C2302 / NCT02697734
A Phase III, multi-center, randomized, double-blind, 48 
week study with an initial 12 week placebo-controlled 
period to evaluate the safety and efficacy of osilodrostat in 
patients with Cushing’s disease 
Statistical Analysis Plan (SAP)
Author:
Trial statistician,
Document type:
SAP Documentation
Document status:
Final v1.0 - Amendment 1
Release date:
01-Apr-2019
Number of pages:
35
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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CLCI699C2302
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason 
for 
update
Outcome for update
Section and title 
impacted (Current)
22-
Jun-
2016
Prior to 
FPFV
Creation of 
final 
version
Creation of first version
All
01-
Apr-
2019
Prior to 
DBL & 
unblinding
Creation of 
amendment 
1
Change from baseline analysis of 
serum, salivary and hair cortisol added 
as a trial objective.
Updated description of the extension 
period to allow for patients remaining 
beyond week 96
Removal of longidutinal model of 
change in mUFC for the core and 
extension period.
Removal of visit window requirement
Removal of section 2.4.1.3
 Removal of 
sections 2.10.1 and 2.10.2, and update 
of 2.10.3
Update of PK collection windows
Removal of PRO longitudinal models
Language and grammer updates
1.2 Study objectives and 
endpoints
2.7.8 Assess the change 
from baseline in serum, 
salivary and hair cortisol 
levels
1.1.4 Extnesion phase
2.7.2 Assess the change in 
mUFC during the Core and 
Extension periods of the 
study  
2.1.1 General definitions
2.4.1.3 Dose level of 
osilodrostat
 
2.2.4 Pharmacokinetic 
analysis set
2.9 Pharmacokinetic 
endpoints
2.11 Patient reported 
outcomes
Multiple sections


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CLCI699C2302
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.1.1
Screening period......................................................................................9
1.1.2
Period 1 (Weeks 1-12): double-blind, placebo-controlled period...........9
1.1.3
Period 2 (Weeks 13-48): single arm, open-label treatment period .........9
1.1.4
Extension phase:....................................................................................10
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................15
2.2.1
Full Analysis Set ...................................................................................15
2.2.2
Safety Set ..............................................................................................15
2.2.3
Per-Protocol Set ....................................................................................15
2.2.4
Pharmacokinetic analysis set.................................................................16
2.2.5
Withdrawal of informed concent ..........................................................17
2.3
Patient disposition, demographics and other baseline characteristics ...................17
2.3.1
Demographics and baseline characteristics...........................................17
2.3.2
Patient disposition.................................................................................17
2.3.3
Medical history......................................................................................18
2.3.4
Protocol deviations................................................................................18
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................19
2.4.1
Study treatment / compliance................................................................19
2.4.2
Prior, concomitant and post therapies...................................................19
2.5
Analysis of the primary objective..........................................................................20
2.5.1
Primary endpoint...................................................................................20
2.5.2
Statistical hypothesis, model, and method of analysis..........................20
2.5.3
Handling of missing values/censoring/discontinuations.......................20
2.5.4
Supportive analyses...............................................................................21
2.6
Analysis of the key secondary objective ...............................................................21
2.6.1
Key secondary endpoint........................................................................21
2.6.2
Statistical hypothesis, model, and method of analysis..........................21
2.6.3
Handling of missing values/censoring/discontinuations.......................22


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CLCI699C2302
2.7
Analysis of secondary efficacy objectives.............................................................22
2.7.1
Assess the overall response rate at Week 12, Week 36, and Week 
48...........................................................................................................22
2.7.2
Assess the change in mUFC during the Core and Extension periods
of the study............................................................................................22
2.7.3
For the actual value and change in mUFC from baseline during 
placebo-control period, descriptive summaries will be provided. 
Compare the time-to-first control of mUFC during the placebo-
controlled period between patients randomized to osilodrostat and 
placebo ..................................................................................................22
2.7.4
Assess the time-to-escape during treatment of osilodrostat up to 
Week 48 ................................................................................................23
2.7.5
Assess the change from baseline in cardiovascular and metabolic 
related parameters associated with Cushing’s disease during the 
core period of the study.........................................................................23
2.7.6
Assess the change from baseline in physical features of Cushing’s 
disease ...................................................................................................24
2.7.7
Assess the change from baseline in bone mineral density by DXA 
scan at Week 48 ....................................................................................24
2.7.8
Assess the change from baseline in serum, salivary andor hair 
cortisol levels ........................................................................................24
2.8
Safety analyses.......................................................................................................24
2.8.1
Adverse events (AEs)............................................................................25
2.8.2
Deaths....................................................................................................26
2.8.3
Laboratory data .....................................................................................26
2.8.4
Other safety data ...................................................................................27
2.9
Pharmacokinetic endpoints....................................................................................28
29
.29
2.11
Patient-reported outcomes .....................................................................................29
29
.30
 
30
30
30
30
2.14
Interim analysis......................................................................................................31
3
Sample size calculation .....................................................................................................31


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CLCI699C2302
4
Change to protocol specified analyses ..............................................................................31
5
Appendix ...........................................................................................................................32
5.1
Imputation rules.....................................................................................................32
5.1.1
Study drug.............................................................................................32
5.1.2
AE date imputation ...............................................................................32
5.1.3
Concomitant medication date imputation .............................................33
5.2
AEs coding/grading ...............................................................................................35
5.3
Laboratory parameters derivations ........................................................................35
6
Reference...........................................................................................................................35


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CLCI699C2302
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
AR
Auto regression
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Classification
BDI-II
Beck Depression Inventory-II
bid
bis in diem/twice a day
BMI
Body mass index
BMD
Bone mineral density
BP
Blood pressure
CD
Cushing’s Disease
CI
Confidence interval
CMH
Cochran-Mentel-Haenszel
CRO
Contract research organization
CSR
Clinical Study report
C-SSRS
Columbia Suicide Severity Reporting Scale
CT
Computed tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee 
DRL
Drug Reference Listing
DXA
Dual-energy X-ray absorptiometry
ECG
Electrocardiogram
FAS
Full Analysis Set
FPG
Fasting plasma glucose
eCRF
Electronic Case Report Form
HbA1c
Hemoglobin A1c
ITT
Intent to treat
IRT 
Interactive response technology
LLOQ
The limit of quantitation
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI
Magnetic resonance imaging
mUFC
Mean Urine Free Cortisol
NCI
National Cancer Institute
q.d.
Once Daily
PD
Pharmacodynamics
PK
Pharmacokinetics


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PAS
Pharmacokinetics analysis set
PD
Protocol deviations
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
PT
Preferred term
qd
Qua’que di’e / once a day
QoL
Quality of Life
QTcF
QT corrected (Fridericia QT formula)
SAE
Serious adverse events
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SOC
System Organ Class
SS
Safety Set
SSD
Study specific document
TBIL
Total bilirubin
TDM
Trial Design Model
TV
Trial Visit
UFC
Urine Free Cortisol 
ULN
Upper Limit of Normal
WHO
World Health Organization


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CLCI699C2302
1
Introduction
This statistical analysis plan (SAP) describes the planned statistical analysis for the primary 
clinical study report (CSR) of study LCI699C2302. The analysis will be performed after all 
patients have completed 48 weeks treatment (the core phase of the study) or discontinued earlier. 
Data from extension phase will be included in the analysis if prior to data cut-off.
This SAP is formulated according to the information provided in the  study protocol. All 
decisions regarding to the analysis described here,  have been made prior to database lock and 
unblinding of study data.
1.1
Study design
This is a Phase III, global, multi-center, randomized, double-blind, placebo-controlled study.  
The study design is placebo-controlled during the first 12 weeks, followed by open-label 
treatment with osilodrostat until week 48, and an optional 48 week Extension phase. A 
schematic diagram of the Core study design is shown below in Figure 1-1. After the screening 
period, eligible patients are randomized in a 2:1 ratio to osilodrostat or placebo in a 12-week 
double-blind placebo-control period. At Week12, all patients will enter an open-label
osilodrostat treatment period until Week 48, which concludes the core phase of the study. At 
the end of the core phase, the patients can enter an optional 48-week extension phase. 
It is planned to enroll 69 patients in this study, 46 on osilodrostat arm, and 23 in placebo arm. 
The primary efficacy variable is to assess response rate at Week 12 in the 2 randomized arms. 
There is no interim analysis planned for this study. The analysis of the primary endpoint will 
occur after all patients completed the core phase of the study.
A detail description of the study design is presented in the following sections.
Figure 1-1
Schematic of Core study design


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1.1.1
Screening period
The screening period will have a maximum duration of 8 weeks to enable patients to washout 
their current treatment for Cushing’s disease. Patients will be evaluated for trial eligibility after 
the washout period is completed.
1.1.2
Period 1 (Weeks 1-12): double-blind, placebo-controlled period
This is the randomized, double-blind, placebo-controlled period (Weeks 1-12).  Eligible 
patients are randomized in a 2:1 ratio to treatment with study drug (osilodrostat or placebo, 
respectively). Patients are stratified at randomization according to history of pituitary irradiation 
(yes/no). Study visits occur at Weeks 2, 5, 8, and 12 (Figure 1-2).  Study drug is started on Day 
1 at a dose of 2 mg b.i.d., and titrated according to the regimen described in protocol Section 
6.2, to a dose which lowers mUFC to within the normal range. 
Figure 1-2
Schematic of Period 1
Three 24-hour urine samples will be collected by patients, preferably on consecutive days at 
screening, immediately prior to Day 1 and the Week 12 visit (primary endpoint) during this 
study period. Two 24-hour urine samples will be collected, preferably on consecutive days,
immediately prior to each of the other visits (i.e. at Weeks 2, 5, and 8). 
In order to maintain the treatment blind during Period 1, all laboratory results that may disclose 
the randomized treatment assignment are blinded to patients, investigators and the Novartis 
Clinical Trial Team. A group of independent endocrinologists (IEs) is responsible for managing 
dose titrations during Period 1 between visits. Titrations for patients assigned to placebo will 
aim to simulate the active arm. 
If patients discontinue study drug treatment before the Week 12 visit, Investigators should make 
reasonable efforts to follow patients and perform assessments for all scheduled visits up to and 
including the Week 12 visit, even if alternative cortisol lowering therapy has been initiated. 
During Period 1, the investigator may temporarily interrupt study drug in the event of an AE of 
suspected adrenal insufficiency, or any AE that requires replacement or stress doses of 
glucocorticoid therapy.
1.1.3
Period 2 (Weeks 13-48): single arm, open-label treatment period
Period 2 starts immediately after the Week 12 visit, when the trial becomes open-label with all 
patients receiving the active drug, osilodrostat. During Period 2 patients randomized to placebo 


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SAP
CLCI699C2302
switch to osilodrostat and undergo their first dose titration with active drug, while patients 
randomized to osilodrostat continue this treatment and undergo a “second” dose titration.  
During Period 2, the investigator is responsible for dose titration. Osilodrostat can be titrated 
up to a maximum dose of 30 mg b.i.d. during this period. The investigator has access to all 
laboratory results from the Week 14 assessments onward. The IE does not participate in dose 
decisions beyond Week 12. 
Three 24-hour urine samples will be collected by patients, preferably on consecutive days 
immediately prior to the Week 36 visit (key secondary endpoint) and Week 48 (end of Core 
phase), two 24-hour samples will be collected prior to all other visits in Period 2.  A patient is 
considered to have reached a stable efficacious dose when mUFC remains ≤ULN. This dose is 
continued, unless a change is needed.
1.1.4
Extension phase:
At Week 48, patients have the option to enter a 48 week open-label Extension phase.  Patients 
who do not enter the extension discontinue osilodrostat at Week 48 and conclude with a Post-
Treatment (End of Study) visit after 30 days off study drug.  Patients who enter the extension 
phase will continue therapy with osilodrostat for another 48 weeks without interruption. At the 
end of this extension phase (Week 96), patients will conclude the study with a Post-Treatment 
(End of Study) visit after 30 days off study drug. During the extension phase the dose of 
osilodrostat will be maintained at the established effective dose unless a change is required 
based on mUFC results collected at Weeks 48, 60, 72, and 84. Some patients may remain in the 
extension phase beyond Week 96, if they are not able to immediately transistion to either the 
long-term follow up study, or to an alternative treatment.
1.2
Study objectives and endpoints
Table 1-1
Study objectives and endpoints 
Objective
Endpoint
Primary
To demonstrate the superiority of osilodrostat 
compared to placebo in achieving a complete 
response (mUFC ≤ ULN) at Week 12.  
The proportion of randomized patients with a 
complete response, i.e. mUFC ≤ ULN at Week 12.  
Key secondary
To assess the complete response rate in both arms 
combined at Week 36 in patients receiving 
osilodrostat treatment. 
The proportion of patients with mUFC ≤ ULN at Week 
36 for  combined randomized patients who receive 
osilodrostat treatment.
Other secondary
To assess the proportion of patients with a complete 
response (mUFC ≤ ULN) or a partial response 
(mUFC decrease ≥ 50% from baseline and > ULN) at 
Week 12, Week 36, and Week 48. 
The overall response rate defined as proportion of 
complete responders (mUFC ≤ ULN) plus partial 
responders (≥ 50% reduction in mUFC from baseline 
and > ULN) will be provided at Week 12, Week 36, 
and Week 48 by treatment arm. Response rate will 
also be provided for all patients in open-label period.
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 at which UFC is collected will be 
provided by treatment arm. Change will also be 
provided for all patients in open-label period.


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Objective
Endpoint
To compare the time-to-first control of mUFC during 
the placebo-controlled period (Weeks 1-12) between 
the randomized treatment arms.
Time-to-first control of mUFC, which is defined as the 
time (in days) from randomization to the first mUFC 
collection that was ≤ ULN before completion or 
discontinuation of placebo-controlled period, 
whichever is earlier.
To assess the time-to-escape during osilodrostat 
treatment up to Week 48. 
Time-to-escape is defined as the time (in weeks) 
from the first collection of normal mUFC (≤ ULN) to 
the first mUFC > 1.3 x ULN on two consecutive visits 
on the highest tolerated dose of osilodrostat and not 
related to a dose interruption or dose reduction due 
to safety reasons. Escape will not be assessed for 
patients during the first 26 weeks.
To assess cardiovascular and metabolic related 
parameters associated with CD (fasting plasma 
glucose, HbA1c, fasting lipid profile, blood pressure, 
weight and waist circumference) by assessing actual 
and percent change from baseline and shift table at 
Weeks 12, 36, and 48.
The actual and percent change from baseline in 
fasting plasma glucose (FPG), HbA1c, fasting lipid 
profile, blood pressure (BP), weight and waist 
circumference at Week12, Week 36, and Week 48 by 
treatment arm and for the overall patient population
in the open-label period.
To assess the change from baseline at Weeks 12, 
36, and 48 in physical features of CD.
Mean change from baseline to Week 12, Week 36, 
and Week 48 in each of the following clinical signs of 
Cushing’s disease, captured by: a semi-quantitative 
Likert scale for facial rubor, striae, supraclavicular fat 
pad, dorsal fat pad, proximal muscle wasting 
(atrophy), central (abdominal) obesity, and 
ecchymoses (bruises) by randomized treatment arm 
and for overall population in the open-label period.  
To assess the change from baseline in bone mineral 
density (BMD) by DXA scan at the lumbar spine and 
total hip at Week 48.  
The change from baseline in bone mineral density, 
and BMD T-score, at the lumbar spine (L1-L4) and 
total hip at Week 48 by treatment arm and for overall 
patient population. 
To determine the safety and tolerability of osilodrostat 
in the study population.
Adverse events and laboratory abnormalities.  
Assessed events include: AEs of special interest, 
laboratory evaluation, ECG, vital signs, and pituitary 
MRI, etc..
To assess the change from baseline in Health Related 
Quality of Life, as measured by the CD-specific QoL 
questionnaire (CushingQoL); by the Beck Depression 
Inventory (BDI-II); and by the general health-related 
QoL instrument EQ-5D-5L, by randomized treatment 
arm and overall.
Change in standardized score of CushingQoL, Beck 
Depression Inventory-II, and EQ-5D-5L, from 
baseline to Week 12 and Week 48, from Week 12 to 
Week 36, and from Week 36 to Week 48, or the last 
measurement prior to early discontinuation, 
whichever occurs earlier, by treatment arms. The 
change will also be provided for overall population 
during the open-label period.
To evaluate pharmacokinetic exposure of osilodrostat 
in the study population.
Plasma concentrations (pre-dose, 1-2 h post-dose) of 
osilodrostat.
To assess the change from baseline in serum, 
salivary and hair cortisol levels
The actual and percentage change from baseline in 
serum cortisol, late night salivary cortisol, morning 
salivary cortisol and hair cortisol levels for every visit 
in the Core and extension phases at which the 
cortisol markers are collected, by treatment arms and 
for all patients.


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2
Statistical methods
2.1
Data analysis general information
The primary analysis will be performed when all enrolled patients have completed the Core 
phase of study (Period 1 and 2) or have prematurely withdrawn from the study prior to the end 
of the Core phase at Week 48. The results and outcomes of this analysis will be presented in a 
CSR. After the Core study phase, patients receiving clinical benefit from osilodrostat treatment
have the option to enter a 48-week extension phase. The additional data collected in the 
extension phase, will be further summarized in a final study report once these patients 
completed the study. There is no interim analysis planned for this study.
Novartis or designated CRO will analyze all data using the SAS System for data analysis V9.4
or higher. Any data analyses carried out independently by an investigator should be submitted 
to Novartis and approved 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.
All data with an assessment date or event start date (e.g. vital sign assessment date or start date 
of an adverse event) prior to or on the cut-off date will be included in the analysis. Any data 
collected beyond the cut-off date will not be included in the analysis and will not be used for 
any derivations.
The randomization will be stratified by history of  pituitary irradiation. To take stratification 
into account, the primary efficacy endpoint will be analyzed using Cochran-Mantel-Haenszel 
(CMH) exact test.
Categorical data or qualitative characteristics of a subject (e.g., gender, race, subject disposition, 
etc.) will be summarized by frequency count (number of subjects) and percentages. Percentages 
will be calculated using the number of subjects in the relevant population or subgroup as the 
denominator.
Continuous data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive
statistics (mean, standard deviation, median, minimum, and maximum).


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2.1.1
General definitions
Study drug
Through out the SAP, investigational drug refers to osilodrostat, and study treatment/ study 
drug refers to osilodrostat or placebo.
Date of study treatment
The start date of study treatment is defined as the first date when a nonzero dose of study 
treatment was administered and recorded on DAR eCRF. The date of first administration of 
study treatment in period 1 will be referred as the start date of study treatment.
The last date of study treatment is defined as the last date when a nonzero dose of study drug 
was administered and recorded on DAR eCRF.
Study day
Study day is used to represent an evaluation, a measurement or an event (e.g. AE onset, 
laboratory abnormality occurrence, disease progression, etc). The study day is calculated as 
Study day = date of assessment –start date of study treatment + 1 (if date of assessment is after 
start date of study treatment)
Study day = date of assessment –start date of study treatment (if date of assessment is before 
start date of study treatment)
For any assessment or events such as baseline characteristics or medical history that is supposed 
to occur prior to start date of the study treatment, study day will be negative. There is no Day 0 
defined.
Study day associated with a UFC assessment
The study day associated with a UFC assessment at any particular visit is defined as the study 
day of the last UFC sample collection for that visit.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25.
Baseline
Baseline values for efficacy and safety evaluations are defined as the last assessment available 
before or on the start date of study treatment. If patients have no assessments as defined above, 
the baseline result will be missing.
Follow up
Regular safety follow-up is scheduled at 30 days after the last date of study treatment. In 
addition, for patients who discontinued study treatment during Period 1 (Weeks 1 to 12),  
reasonable efforts should be made to follow the patients and perform the assessments as 
indicated in protocol visit evaluation schedule table (protocol Table 7-1a) up to and including 
Week 12. The data collected during the follow up visits in Period 1 will be used as sensitivity 
analysis for efficacy, and will be used for safety.


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Visit number and time window
The following visit schedule tables are generated from TDM/TV domain.
Table 2-1
Scheduled visits in core phase 
Core study Visit 
Day/Week
Clarifying Notes
Visit 10
Day -56 to day -1
Screening 
Visit 101
Day 1/Week 1
Baseline / Week 1
Visit 102
Day 15/Week 2
Period 1/ Double blind period
Visit 103
Day 36/Week 5
Period 1/ Double blind period
Visit 104
Day 57/Week 8
Period 1/ Double blind period
Visit 105
Day 85/Week 12
Period 1/ Double blind period
Visit 301
Day 15/Week 2 FUP
Period 1/ Double blind period
Visit 302
Day 36/Week 5 FUP
Period 1/ Double blind period
Visit 303
Day 57/Week 8 FUP
Period 1/ Double blind period
Visit 304
Day 85/Week 12 FUP
Period 1/ Double blind period
Visit 106
Day 99/Week 14
Period 2/ Open-label treatment period
Visit 107
Day 120/Week 17
Period 2/ Open-label treatment period
Visit 108
Day 141/Week 20
Period 2/ Open-label treatment period
Visit 109
Day 162/Week 23
Period 2/ Open-label treatment period
Visit 110
Day 183/Week 26
Period 2/ Open-label treatment period
Visit 111
Day 204/Week 29
Period 2/ Open-label treatment period
Visit 112
Day 225/Week 32
Period 2/ Open-label treatment period
Visit 113
Day 253/Week 36
Period 2/ Open-label treatment period
Visit 114
Day 281/Week 40
Period 2/ Open-label treatment period
Visit 115
Day 309/Week 44
Period 2/ Open-label treatment period
Visit 199
Day 337/EOT core
End of treatment core phase
Visit 399
POST TRT FU
Post treatment follow-up
Visit 499
END POST TRT FU
End of post treatment follow-up


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Table 2-2
Scheduled visits in extension phase 
Extension study Visit 
Day/Week
Clarifying Notes
Visit 201
Day 365/Week 52
Extension
Visit 202
Day 393/Week 56
Extension
Visit 203
Day 421/Week 60
Extension
Visit 204
Day 449/Week 64
Extension
Visit 205
Day 477/Week 68
Extension
Visit 206
Day 505/Week 72
Extension
Visit 207
Day 589/Week 84
Extension
Visit 299
Day 673/EOT EXTN
End of treatment extension phase
Visit 399
POST TRT FU
Post treatment follow-up
Visit 499
END POST TRT FU
End of post treatment follow-up
2.2
Analysis sets
2.2.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all randomized patients who have received at least one 
dose of study drug (osilodrostat or placebo). According to the intent-to-treat (ITT) principle, 
patients will be analyzed according to the treatment and stratum they have been assigned to 
during the randomization. This is the default analysis set for efficacy. The randomization is 
stratified by history of pituitarory irradiation yes/no.
2.2.2
Safety Set
The Safety Set (SS) includes all patients who received at least one dose of study drug 
(osilodrostat or placebo). Patients will be analyzed according to the study drug 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 received if the randomized/assigned treatment 
was never received.
2.2.3
Per-Protocol Set
Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant with 
the requirements of the Clinical Study Protocol. The following protocol deviations will lead to 
exclusion from PPS.

Informed consent for core phase not documented

mUFC or ACTH related inclusion criteria not met

Pituitary source of excess ACTH is not confirmed


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
Cushing's disease confirmation is missing

Pituitary surgery related inclusion criteria not met

Pituitary irradiation related inclusion criteria not met

Washout period related inclusion criteria not met

Participation in another trial with an investigational drug does meet the exclusion 
criteria

Subject pregnant or lactating at study entry does mee the exclusion criteria

Subject's history of inherited syndrome as cause for hormone over secretion does meet 
the exclusion criteria

Subject's medical history of Cushing's syndrome due to ectopic ACTH secretion or 
ACTH-independent (adrenal) Cushing’s syndrome does meet the exclusion criteria

Subject's moderate or severe renal impairment does meet the exclusion criteria

Subject met the discontinuation criteria, but was not discontinued from the trial *

Subject took a prohibited concomitant medication **

*if PD occurs before Week 12, exclude from PPS, if occurs between Week 12 and Week 
36, exclude from PPS for key secondary analysis

**if PD occurs between Week 12 and Week 36, exclude from PPS for key secondary 
analysis. Not applicable for primary analysis.
2.2.4
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of osilodrostat and have at least one evaluable pharmacokinetic concentration (post-first-dose) 
at any visit.
A PK concentration is considered as non evaluable if: 
-
The patient didn’t receive the incident dose (last dose administered prior to PK 
collection) as planned per protocol, or 
-
If the elapsed time between PK sample and prior dose didn’t fall within acceptable 
window: 
o
pre-dose samples within 0.5 h before dose administration, and within 9h to 
15h after the previous dose 
o
post-dose samples with elapsed time within nominal time range (i.e. within 
1h to 2h),
o
12h PK sample with elapsed time within 9h to 15h after previous dose. 
-
Or if vomiting occurs within 4 hours after the last intake prior to the PK sample draw. 
Additionally, a PK concentration or parameter can be considered non-evaluable as per scientific 
judgment of the clinical pharmacology expert; reasons will be documented. Such PK 
concentration and parameter will be excluded from PK 
 tables/figures, but will be 
included in listings with flags and reasons for exclusion.


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2.2.5
Withdrawal of informed concent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis datasets. The date on which 
a patient withdraws full consent will be recorded in the eCRF.
Third party data e.g. PK, biomarker etc. collected in the clinical database without having 
obtained consent for collection will not be included in the analysis datasets. These data will be 
excluded by the presence of the appropriate protocol deviation criterion.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Demographics and baseline characteristics
Demographic and other baseline data will be summarized descriptively for the FAS and the 
safety set (if not the same).
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
Demographic variables include Age (in year), Age category (< 65/≥ 65), gender, race, and 
ethnicity.
Baseline disease characteristics include time to first LCI699 dose since diagnosis of Cushing’s 
disease, Cushing’s disease status (de novo or persistent/recurrent), use of previous treatment, 
or surgery, mean UFC at baseline. 
2.3.2
Patient disposition
The number of screened patients and number of patients randomized will be tabulated. The 
summary will be produced for all pre-screened patients. Reasons for screening failure will be 
summarized and listed.
Patient disposition will be tabulated for FAS. The summary will include the number of patients 
who were randomized, treated, ongoing, permanently discontinued from study treatment.
The following summaries will be presented: % is based on total number of FAS patients:

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated (based on eCRF DAR 
page not completed for any study treatment component)

Primary reason for not being treated (based on eCRF End of Treatment Phase 
Completion page)

Number (%) of patients who were treated (based on eCRF DAR page of each study 
treatment component completed with non-zero dose admistered)

Number (%) of patients who are still on treatment (based on eCRF End of Treatment 
Phase page not completed)


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
Number (%) of patients who discontinued the study treatment phase (based on eCRF 
End of Treatment Phase page)

Primary reason for study treatment phase discontinuation (based on eCRF End 
of Treatment Phase Completion page)

Number (%) of patients who entered post-treatment follow up

Number (%) of patients who discontinued from post-treatment follow-up

Primary reason for discontinuation from post-treatment follow-up

Number (%) of patients who discontinued in Period 1(prior to Week 12)

Primary reason for discontinuation in Period 1

Number (%) of patients who discontinued in Period 2 (Weeks 13 to 48)

Primary reason for discontinuation in Period 2

Number (%) of patients who completed core phase (week 48)

Completed Week 48 and did not enter Extension phase

Completed Week 48 and entered Extension phase

Number (%) of patients who are ongoing in Extension 

Number (%) of patients who discontinued in the Extension

Primary reason for discontinuation in the Extension

Number (%) of patients who completed extension 
* Patients who completed Week 48 and did not enter extension phase are not counted as 
discontinuations.
2.3.3
Medical history
Relevant medical history and ongoing medical conditions at baseline will be summarized and 
listed. The summary will be presented using FAS by primary system organ class (SOC), 
preferred term (PT), by treatment group and all patients.
2.3.4
Protocol deviations
The number (%) of patients in FAS with any PDs wil be tabulated by deviation category (as 
specified in the study specification document (SSD) by treatment group. Major PDs leading to 
exclusion from PPS will be tabulated separately by treatment group. All PDs will be listed.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
2.4.1.1
Duration of exposure 
The exposure to the study drug will be summarized based on study periods, i.e., period 1 and 
period 2, and overall period by treatment group.
Period 1 (Week 1 to Week 12)
Duration of exposure (weeks) = (min (date of Week 12 visit 1, date of last date of study 
treatment, date of data cut-off, date of death) – date of first date of study treatment + 1)/7
Period 2 (Week 13 to Week 48)
Duration of exposure (weeks) = (min (date of Week 48 visit, date of last date of study treatment, 
date of data cut-off, date of death) – date of first date of study treatment in period 2 (Week 12 
visit) + 1)/7
Overall Period
Duration of exposure (weeks) = (min (date of last date of study treatment, date of data cut-off, 
date of death) – date of first date of study treatment + 1)/7
In the overall period, the total duration of exposure to study treatment is considered by taking 
account of the duration of exposure in both Period 1, Period 2, as well as extension. Patients in 
osilodrostat arm will have exposure only to osilodrostat, and patients in placebo arm will have 
exposure to both osilodrostat and placebo presented separately.
The above duration calculation includes the periods of temporary interruptions.
Summary of duration of exposure to study treatment will include categorical summaries and 
continuous summaries using appropriate unit of time.
2.4.1.2
Dose reduction/interuption
The number of patients who have at least one dose reduction or interruption, and the 
corresponding reasons will be summarized by study period. Although patients may have 
multiple dose reductions or interruptions with the same reason, patients will be counted only 
once for each distinct reason.
The total daily dose administered and reason for dose change will be listed with UFC 
information by date.
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.


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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 and summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded
using MedDRA and summarized by SOC and preferred term. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior to 
the start of study treatment or starting more than 30 days after the last date of study treatment 
or safety follow-up whichever is later will be flagged in the listing. The safety set will be used 
for all concomitant medication tables and listings.
Concomitant medications and significant non-drug therapies will be summarized using 
frequency counts and percentages by ATC class, preferred term and treatment group within 
each of three study periods: Period 1 (Week 1 to Week 12), Period 2 (Week 13 to Week 48), 
and overall study period. If a patient discontinued from study in Period 1, the concomitant 
medications taken during the follow-up period will be summarized in Period 1 and overall 
period.
2.5
Analysis of the primary objective
The primary objective is to demonstrate the superiority of osilodrostat compared to placebo in 
achieving a complete response (mUFC ≤ ULN) at week 12.
2.5.1
Primary endpoint
The primary efficacy variable is the proportion of randomized patients in each treatment arm 
who are complete responders at Week 12. A complete responder is defined as a patient who has 
mUFC ≤ ULN (based on central lab result) at Week 12. Patients who discontinued the study 
during the placebo-control period will be counted as non-responders for the primary endpoint. 
Dose reductions and temporary dose interuptions for safety reason during the placebo-control 
period do not preclude patients from being counted as a complete responder for the primary 
endpoint.
2.5.2
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 the 12-week placebo-controlled period (i.e., at Week 12) are the same between the 
two randomized arms. To test this hypothesis, a Cochran–Mantel–Haenszel (CMH) exact test 
stratified by the history of pituitary irradiation (yes/no) will be performed using the FAS.
Following the ITT principle, patients are analyzed according to the drug and stratum they were
assigned to at randomization. 
If the 1-sided p-value is ≤ 0.025, and the odds ratio (osilodrostat vs. Placebo) is > 1, the null 
hypothesis will be rejected and the complete response rate in the osilodrostat arm will be 
considered higher than that in the placebo arm. 
2.5.3
Handling of missing values/censoring/discontinuations
It is scheduled to collect three individual 24 hours Urine Free Cortisol (UFC) samples at visits 
Week 1, 12, 36, and 48, and two UFC samples at all other visits. For a given visit, Mean Urine 


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Free Cortisol (mUFC) is the mean of all available (with a minimum of 2) individual UFC values 
determined at a central laboratory. In the case that only one or no UFC value is available, the 
mUFC will be considered missing for that visit.
During the double blind period, early discontinued patients (prior to Week 12) will be followed 
at regular visits and have assessments performed as indicated in protocol visit evaluation 
schedule table (Table 7-1a). Patients who discontinued prior to Week 12 or had a missing mUFC 
assessment at Week 12 will be considered as non-responder in the primary analysis. No 
imputation will be used.
2.5.4
Supportive analyses
As a supportive analysis to the primary analysis, an un-stratified Fisher’s exact test of the 
primary endpoint will be performed using FAS.
In addition, both stratified CMH exact test and un-stratified Fisher’s exact test of the primary 
endpoint will be performed using PPS.
To deal with potential missing mUFC at Week 12, , multiple imputation assuming missing at 
random will be performed as a sensitivity analysis. For patients who discontinued the study 
early, mUFC collected during the follow-up visit at Week 12 will also be used for sensitivity 
analysis. If mUFC during the follow up visit is missing at Week 12, the patient will be 
considered as a non-responder. 
2.6
Analysis of the key secondary objective
The key secondary objective is to assess the complete response rate (proportion of enrolled 
patients with mUFC ≤ ULN) in both arms combined at Week 36 in patients receiving 
osilodrostat treatment.  
2.6.1
Key secondary endpoint
The key secondary efficacy variable is the proportion of complete responders at Week 36 in 
FAS patients receiving osilodrostat treatment. A complete responder is defined as an enrolled 
patient who has mUFC ≤ ULN at Week 36. Dose reductions and temporary dose interruptions 
for safety reasons do not preclude patients from being counted as a complete responder for the 
key secondary endpoint.
2.6.2
Statistical hypothesis, model, and method of analysis
For the key secondary endpoint, the statistical null hypothesis states that the proportion of 
complete response rate at Week 36 is < 30%. The analysis of the key secondary objective will 
be based on the 2-sided 95% exact confidence interval (CI) constructed using the Clopper-
Pearson method in FAS patients receiving osilodrostat treatment. Patients with missing mUFC 
at Week 36 will be counted as non-responders. 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% at Week 36. Patients randomized to placebo who do not switch to 
osilodrostat will not be included in this analysis.


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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%.
As supportive analysis of the key secondary objective, analysis will be repeated using  PPS 
patients receiving osilodrostat treatment. In addition, the same analysis will be performed in the 
patients randomized to osilodrostat arm only. For each supportive analysis, the 2-sided 95% 
exact confidence interval of the complete response rate at Week 36 will be provided.
2.6.3
Handling of missing values/censoring/discontinuations
Placebo patients who discontinued during Period 1 and not received osiltrostat treatment in this 
study will not be included in the analysis. Patients who received osilodrstat treatment with 
missing mUFC at Week 36 will be considered as non-responders for key secondary analysis. In 
order to evaluate the impact of missing mUFC, multiple imputations assuming missing at 
random will be considered as sensitivity analyses.  
2.7
Analysis of secondary efficacy objectives
2.7.1
Assess the overall response rate at Week 12, Week 36, and Week 48
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 in mUFC from 
baseline  and > ULN) will be summarized using point estimates for every scheduled visit in the 
core and extension phase at which UFC is collected by treatment arm. Response rate will also 
be provided for all patients in the open-label period. 95% 2-sided CIs will be provided at Week 
12, Week 36 and Week 48. To calculate the response rate during the open label treatment period, 
for the osilodrostat arm, the denominator will be the number of patients randomized to 
osilodrostat in Period 1; whereas for the placebo arm, the denominator will be the number of 
patients randomized to placebo in Period 1 who switched to osilodrostat. The FAS will be used 
for this analysis.
2.7.2
Assess the change in mUFC during the Core and Extension periods of 
the study

Change in mUFC from baseline during the placebo-control period only
2.7.3
For the actual value and change in mUFC from baseline during 
placebo-control period, descriptive summaries will be provided. 
Compare the time-to-first control of mUFC during the placebo-
controlled period between patients randomized to osilodrostat and 
placebo
Time-to-first control of mUFC is defined as the time (in days) from first study treatment date
to the time of the first post-baseline mUFC collection that was ≤ ULN (based on central lab 
result) before discontinuation or completion of placebo-controlled period, whichever is earlier.
It will be defined as censored at the last mUFC collection date if the mUFC was not controlled 
during the placebo-controlled period.


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Time-to-first control of mUFC during the placebo control period will be analyzed using Kaplan-
Meier plots and the logrank test. The quantiles of time-to-first control and corresponding two-
sided 95% CI will be calculated using Kaplan-Meier methodology. FAS will be used for this 
analysis.
2.7.4
Assess the time-to-escape during treatment of osilodrostat up to 
Week 48 
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)

patient reached highest tolerated dose of osilodrostat

2 consecutive mUFC (collected at scheduled visits) were above 1.3x ULN

the loss of control of UFC is not related to a dose interruption or dose reduction due to 
safety reasons

happens beyond Week 26 when the patients have a chance to be treated with doses as 
high as 30 mg bid 
Time-to-escape is defined as the time (in weeks) from the first collection of post-baseline 
normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on  2 consecutive scheduled visits on 
the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction 
due to safety reasons after Week 26.
The highest tolerated dose is defined as

30 mg bid if reached, or

being on a reduced dose due to safety reasonse such as AEs, or 

being on the same dose for at least 3 scheduled visits if the previous two criteria are not 
met.
For patients who attained normal mUFC (≤ ULN), time-to-escape will be analyzed using 
Kaplan-Meier plots. This will be performed by randomized treatment assignment and for the 
overall trial population using FAS. 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. Time-to-
escape will not be assessed for patients during the first 26 weeks.
Patients that have dose interruption or dose reduction for safety reasons will be censored at the 
time of the first dose interruption. Patients who discontinued the study are considered as 
censored. Patients who were controlled until the end of the study will be censored at the last 
mUFC collection date. FAS will be used for this analysis.
2.7.5
Assess the change from baseline in cardiovascular and metabolic 
related parameters associated with Cushing’s disease during the core 
period of the study 
For cardiovascular and metabolic parameters associated with Cushing’s disease (e.g. fasting 
glucose, HbA1c, fasting lipid profile, SBP, DBP, weight and waist circumference):


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For actual value and  change from baseline to Week 12, Week 36 and Week 48, descriptive 
summaries will be provided by treatment arm and for overall patients in open-label period.
For the actual value and change from the baseline to Week 12 or the last available measurement 
of the placebo control period, whichever occurs earlier, in addition to the descriptive summary, 
the mean difference between two randomized arms and associated 2-sided 95% C.I. will be 
estimated with adjustment for corresponding baseline parameter value. In addition, shift tables 
using normal/abnormal categories for BP (SBP, DBP), FPG, HbA1c, fasting lipid profile, 
weight and waist circumference from baseline to Week 12, 36, and 48 by randomized arms and 
for overall patients during the open-label period will be assessed. Normal for these parameters 
is shown in protocol Appendix 4. FAS will be used for this analysis.
2.7.6
Assess the change from baseline in physical features of Cushing’s 
disease
For each of physical features of Cushing’s disease: facial rubor, striae, supraclavicular fat pad, 
dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses 
(bruises), Likert scores will be measured. The change from baseline at Weeks 12, 36 and 48 
will be assessed by shift tables in each of the randomized treatment arms. The change will also 
be provided for overall patients in open-label period. In addition, the proportions of patients 
having a favourable shift from baseline to post-baseline time points will be tabulated. FAS will 
be used for this analysis.
2.7.7
Assess the change from baseline in bone mineral density by DXA 
scan at Week 48
For bone mineral density measured by DXA scan at the lumbar spine and total hip, descriptive 
summaries of actual and percentage change from baseline to Week 48 will be provided by 
randomized treatment arm and for overall patients. FAS will be used for this analysis.
2.7.8
Assess the change from baseline in serum, salivary andor hair cortisol 
levels
The actual and percentage change from baseline to each post-baseline visit for serum cortisol, 
late night salivary cortisol, morning salivary cortisol and hair cortisol levels will be assessed. 
Descriptive summaries will be provided for every visit in the Core and Extension phases at 
which the cortisol markers are collected. Salivary cortisol samples will only be included if they 
are collected within the correct time window. 95% CIs for the percentage change from baseline 
will also be provided by treatment arms and for all patients.
2.8
Safety analyses
The assessment of safety will be based mainly on the frequency and severity of AEs and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
ECG, vital signs, and special tests) will also be presented. All safety outputs will use the SS, 
which consists of all patients who received at least one dose of osilodrostat or placebo. Safety 
data will be presented by two different periods in different treatment groups as descrbied below.

Placebo-control period: osilodrstat arm, placebo arm


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
Overall study period: osilodrstat arm, placebo arm excluding placebo-control period, and 
overall patients (excluding safety data of placebo arm collected during placebo-control 
period)
* Safety summarized during overall study period focuses on safety of osilodrostat 
treatment, safety of placebo arm is summarized during placebo-control period.
The overall observation period will be divided into three mutually exclusive segments:

pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication

on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication

post-treatment period: starting at 31 days after last dose of study medication.
2.8.1
Adverse events (AEs)
Summary tables for adverse events (AEs) have to 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 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.
AEs will be summarized by number and percentage of subjects having at least one AE, having
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only
once in the respective AE category. A subject with multiple CTCAE grades for the same
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
In AE summaries the primary system organ class will be presented alphabetically and the
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the osilodrostat arm.
The following adverse event summaries will be produced by treatment; overview of adverse
events and deaths (number and % of subjects who died, with any AE, any SAE, any drug 
reductions/interuptions), AEs by SOC and PT, summarized by relationship (all AEs and AEs
related to study treatment), seriousness (SAEs and non-SAEs), leading to treatment
discontinuation, leading to dose interruption/adjustment, requiring additional therapy and
leading to fatal outcome. In addition, for the summary of serious and non-serious adverse events 
the number of occurrences will be produced (an occurrence is defined as >1 day between start 
and prior end date of record of same preferred term).


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2.8.1.1
Adverse events of special interest / grouping of AEs
Groupings of AEs of special interest consist of adverse events for which there is a specific 
clinical interest in connection with osilodrostat treatment (i.e. where osilodrostat may influence 
a common mechanism of action responsible for triggering them) or adverse events which are 
similar in nature (although not identical). 
An Excel file with the exact composition of the adverse events groupings is available in the 
CREDI folder “/CREDI Projects/L/LCI699C/Administrative files/CIS (Clinical Information 
Sciences)/Biostatistics” which is to be used to map reported adverse events to the adverse events 
groupings. This file is updated periodically after MedDRA update and/or review of 
accumulating trial data. Prior to database lock, the file will be copied to proper CREDI study 
specific folder such as RAP folder.
2.8.2
Deaths
All deaths (on-treatment and post-treatment) will be produced by treatment arm, system organ 
class and preferred term. Post treatment deaths will be flagged
2.8.3
Laboratory data
Laboratory data summaries will include all assessments available for the lab parameter 
collected no later than 30 days or safety follow-up whichever is laterafter the last study 
treatment admistration date using data from all sources. All laboratory assessments will be listed 
and those collected later than 30 days after the last study treatment date will be flagged in the 
listings.
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 that are graded for both low and high values, summaries 
will be done separately and labeled by direction, e.g., sodium will be summarizedas 
hyponatremia and hypernatremia.
For laboratory tests where grades are not defined by CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges.
For laboratory tests where grades are defined by CTCAE 

Summary table for AEs of grades 3 or 4

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 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE ,

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value
In addition, the following laboratory results will be summarized.


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
Selected laboratory data will also be displayed by presenting summary statistics of change 
from baseline value

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), e-dish 
plot may be provided as well
The following listings will be produced for the laboratory data:

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
the classifications relative to the laboratory reference ranges  

Listing of notable laboratory abnormalities (i.e. CTC grade 3 or 4 laboratory toxicities).
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
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.
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
2.8.4.2
Vital signs
All vital signs data (height (cm), weight (kg), body temperature (0C), supine pulse rate (beats 
per minute), and supine systolic/diastolic blood pressure (mmHg)) will be listed by patient and 
visit/time, and abnormalities will be flagged on listing. For blood pressure, two measuments are 
planned to be taken and the average will be used for analysis purpose. Shift table based on 
notable value will be provided for vital signs. Change over time from baseline will be 
summarized.
The criteria for clinically notable abnormalities are defined as follows:
Clinically notable elevated values


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• Systolic BP: 180 mmHg and an increase 20 mmHg from baseline
• Diastolic BP: 105 mmHg and an increase 15 mmHg from baseline.
• Supine pulse: 120 bpm with increase from baseline 15 bpm
• Weight: Increase from baseline of 10%
Clinically notable below normal values
• Systolic BP: 90 mmHg and a decrease 20 mmHg from baseline
• Diastolic BP: 50 mmHg and a decrease 15 mmHg from baseline
• Supine pulse: 50 bpm with decrease from baseline 15 bpm
• Weight: Decrease from baseline of 5%
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.
2.8.4.3
Tumor volume and longest dimension 
For tumor volume evaluated by MRI (or CT) scanning, descriptive summary of actual tumor 
volumes as well as its change from baseline will be provided at visits where evaluation is 
scheduled (Week 26, 48, 72, and 96). For MRI (or CT) images that are not interpretable for 
tumor volume, the longest dimension (in mm) will be summarized instead. Due to evaluation 
schedule, this analysis will only be performed for the overall study period.
2.8.4.4
Columbia Suicide Severity Reporting Scale (C-SSRS)
C-SSRS data will be mapped to Columbia Classification Algorithm for Suicide Assessment (C-
CASA) as per FDA guidance on suicidality (Food and Drug Administration 2010). The 
proportion of patients who have committed suicide, attempted suicide, done preparatory actions 
toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior without 
suicidal intent will be summarized by treatment arm. The number of patients with SAEs 
referring to a positive suicidal evaluation will be summarized by treatment arm.
2.9
Pharmacokinetic endpoints
The PAS will be used in all pharmacokinetic data analysis and summary statistics.
As sparse pharmacokinetic sampling is performed in this study, traditional non-compartmental 
analysis will not be performed to calculate pharmacokinetic parameters. Plasma concentration 
data of osilodrostat will be listed by subject, visit, incident dose and nominal sampling times. 
Descriptive statistics of plasma concentrations will be provided by incident dose, visit and 
nominal sampling times, and will include arithmetic and geometric mean, median, SD, CV%, 
geometric CV%, minimum and maximum. Zero concentrations will not be included in the 
geometric mean calculation.
Listing of all PK parameters will be provided by patient and visit:


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-
Ctrough as defined by pre-dose concentration collected within 0.5h prior to dosing  and 
within 9h to 15h after the previous dose and
-
and Cmax, defined as concentration collection within 1-2hr post-dose.
Plasma concentrations of osilodrostat 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.
 
 
 
2.11
Patient-reported outcomes
The CushingQoL 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.
Descriptive statistics will be used to summarize the actual and change from baseline for the 
scores at each scheduled assessment including critical time points such as from baseline to 
Week 12 and Week 48, from Week 12 to Week 36 and from Week 36 to Week 48 etc.


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2.14
Interim analysis
The study will have no planned interim analysis for efficacy. The DMC will conduct periodic 
safety data reviews and dosing review as outlined in DMC charter.
3
Sample size calculation
Eligible patients will be stratified at randomization according to history of pituitary irradiation 
(yes/no). Based on the LCI699C2201 study, it is assumed that approximately 20% of 
randomized patients will have a history of pituitary radiation. 
With 2:1 randomization ratio, to detect a difference of 45% in complete response rate between 
60% in osilodrostat arm and 15% in placebo arm (equivalent odds ratio equals 8.5), a sample 
size of 42 patients in osilodrostat arm and 21 patients in placebo arm will provide 91% power 
based on a 1-sided CMH exact test at the 0.025 level. In order to adjust for drop-outs, an 
additional 10% patients will be enrolled. Thus a total of approximately 69 patients will be 
enrolled in the study.
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% at Week 36 . Both the SOM230G2304 trial of Pasireotide 
LAR and the SOM230B2305 trial of Pasireotide s.c. were powered to show a response rate 
where the lower bound of the 95% confidence interval was ≥15%. Therefore an increase in this 
lower bound of the 95% confidence interval to a threshold of ≥30% would provide a significant 
improvement in clinical benefit to this patient arm.
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 60% complete response rate at Week 36, and less than 50% discontinuation rate of 
patients in placebo arm prior to Week 12. For the 69 patients in the pooled population, there is 
higher than 98% chance that the lower bound of 2-side 95% exact CI (based on Clopper-Pearson 
method) of the observed response rate is larger than 30%.
4
Change to protocol specified analyses
In the SAP, clarification is made that efficacy will be summarized by randomized treatment 
arms during the placebo-control period. The same analysis will be performed by randomized 
treatment arms and for overall patients during the open-label period.


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Safety will be summarized by randomized treatment arms during the placebo-control period. 
For the overall study period, only safety data associated with osilodrostat treatment will be 
summarized, which means safety data in placebo-arm collected during placebo-control period 
will be excluded from the analysis.
5
Appendix
5.1
Imputation rules
Parital dates will remain partial in the data listings. For the purpose of analysis, the following 
imputation rules will be used to impute the partial dates.
5.1.1
Study drug
Any partial dates or gaps between dates should be resolved for analysis purpose. The end date 
of study drug is derived by using the last non-zero dose end date from the dose administration 
record CRF page. If after DBL the partial dates still exist for end date, the imputation rule is as 
below:
If month and year is present, but day is missing, set the end date to be the first day of the month.
If after imputation of day, study medication end date is earlier then study medication start date 
set study medication end date to study medication start date.
5.1.2
AE date imputation
Summary tables for adverse events (AEs) have to include only AEs that started or worsened
during the on-treatment period, the treatment-emergent AEs. However, all safety data
(including those from the post-treatment period) will be listed and those collected during the
pre-treatment and after 30 days of post- treatment period or safety follow-up whichever is later
are to be flagged.
Any missing onset date, causality, or severity must be queried for resolution. Unsolved  missing 
values will be imputed according to the following:
AE end date imputation:
1. If the AE end date month is missing, the imputed end date should be set to the earliest 
of the (treatment follow up period date, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
AE start date imputation:
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date.  Therefore, if the AE year value is missing, the imputed AE start date is set to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment.  Therefore:


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a.
If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to  the mid-month 
point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:
a.
If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day.
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
c.
Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.
5.1.3
Concomitant medication date imputation
The start/stop dates recorded in the electronic case report form (eCRF) will be used to identify
when a concomitant medication or a significant non-drug therapy was taken during the study.
Concomitant medications and significant non-drug therapies after the start of the study
treatment will be listed and summarized by ATC class and standardized medication term for
the Safety Set. These summaries will include medications starting on or after the start of study
treatment or medications starting prior to the start of study treatment and continuing after the
start of study treatment. Any prior medications and significant non-drug therapies starting and
ending prior to the start of study treatment will be listed. These analyses will be based on Safety 
Set.
Any missing date will be queried for resolution. For any unsolved missing dates, the
following rules in the following order will be applied to decide if a concomitant medication or
a significant non-drug therapy was taken after the start of the study treatment and to decide if
the data should be included in the summary table. Originally collected date will be listed
in listings.
CM end date imputation:
1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the minimum of  treatment end date and the last day of the month.
2. If CM end day/month are missing and CM year is non-missing then impute CM day as 
the minimum of  treatment end date and the end of the year (31DECYYYY).


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3. If CM day/month/year is missing then use the treatment end date + 1 day as the imputed 
CM end date. 
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date.
1. CM start date imputation:If the CM start date year value is missing, the imputed CM
start date is set to one day prior to treatment start date.
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment.  Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a.
And the CM month is missing or the CM month is equal to the treatment start 
date month, then the imputed CM start date is set to one day prior treatment start 
date.
b. Else if the CM month is less than the treatment start date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY).
c.
Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.
5.1.3.1
Prior events date imputation
Partial  date of prior events (other than AE and CM) date imputation rules are as below:
If only day is missing then impute to be 15th of month. If both day and month are missing, then 
impute to June 30th. If entire date is missing then leave as missing. If after imputation, the date 
is after the first dosing date, then use the first dosing date.
5.1.3.2
Post events and therapies date imputation
Partial  date of post events/therapies (other than AE and CM) date imputation rules are as below:
Start date:

If Day is missing, then impute to the max (reference start date, first day of the month).


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
Day and month are missing then impute to the max(reference start date, Jan 1)

Reference start date will be last date of study treatment administration + 1.
End date: No imputation
5.2
AEs coding/grading
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA)
terminology. AEs are graded according to the Common Terminology Criteria for Adverse
Events (CTCAE) version 4.03.
CTCAE grading is by definition a 5-point scale generally corresponding to 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). The CTCAE grade of 5 (death) is not used; rather, 
‘fatal’ is collected as AE outcome and death information is also collected on a separate eCRF 
page.
5.3
Laboratory parameters derivations
All laboratory values except FPG and HbA1c, will be converted into SI units and the severity 
grade calculated using appropriate common toxicity criteria (CTC).
As CTC only grades lab values as grade 1-4, grade 0 will be used when lab value is normal. A
severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher.
Grade 5 will not be used. For laboratory tests that are graded for both low and high values,
summaries will be done separately and labelled by direction, e.g., sodium will be summarized
as hyponatremia and hypernatremia.
If sites report WBC differential counts in percentage (%) with corresponding lab normal ranges 
in terms of %, the % differentials will be converted to absolute differentials as Absolute value 
= [Value (%)/100] x WBC.
6
Reference
American Diabetes Association, (2010), ‘Diagnosis and Classification of Diabetes Mellitus’, 
Diabetes Care, 33, Supplement 1, S62-S69.
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.
Smith B, Vandenhende F, DeSante K, et al (2000),  ‘Confidence interval criteria for assessment 
of dose proportionality’, Pharmaceutical research, 17, No 10


Clinical Development
LCI699/osilodrostat
CLCI699C2302 / NCT02697734
A Phase III, multi-center, randomized, double-blind, 48 
week study with an initial 12 week placebo-controlled 
period to evaluate the safety and efficacy of osilodrostat in 
patients with Cushing’s disease 
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation
Document status:
Final
Release date:
01-Dec-2020
Number of pages:
34
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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SAP Final Analysis 
CLCI699C2302
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
01-Dec-
2020
Prior to 
Final 
DBL
Creation of 
SAP for final 
analysis
N/A – First version


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.1.1
Screening period......................................................................................8
1.1.2
Period 1 (Weeks 1-12): double-blind, placebo-controlled period...........8
1.1.3
Period 2 (Weeks 12-48, open-label period) ............................................9
1.1.4
Optional Extension phase........................................................................9
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................11
2.1
Data analysis general information .........................................................................11
2.1.1
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................15
2.2.1
Full Analysis Set ...................................................................................15
2.2.2
Safety Set ..............................................................................................15
2.2.3
Withdrawal of informed consent...........................................................15
2.3
Patient disposition, demographics and other baseline characteristics ...................16
2.3.1
Demographics and baseline characteristics...........................................16
2.3.2
Patient disposition.................................................................................16
2.3.3
Medical history......................................................................................17
2.3.4
Protocol deviations................................................................................17
2.3.5
COVID-19 impact.................................................................................17
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................17
2.4.1
Study treatment / compliance................................................................17
2.4.2
Prior, concomitant and post therapies...................................................18
2.5
Analysis of the primary objective..........................................................................18
2.6
Analysis of the key secondary objective ...............................................................18
2.7
Analysis of secondary efficacy objectives.............................................................19
2.7.1
Assess the overall response rate............................................................19
2.7.2
Assess the change in mUFC during the Core and Extension periods 
of the study............................................................................................19
2.7.3
Compare the time-to-first control of mUFC during the placebo-
controlled period between patients randomized to osilodrostat and 
placebo ..................................................................................................19
2.7.4
Assess the time-to-escape during treatment of osilodrostat..................19


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2.7.5
Assess the change from baseline in cardiovascular and metabolic 
related parameters associated with Cushing’s disease during the 
core period of the study.........................................................................20
2.7.6
Assess the change from baseline in physical features of Cushing’s 
disease ...................................................................................................20
2.7.7
Assess the change from baseline in bone mineral density by DXA 
scan........................................................................................................21
2.7.8
Assess the change from baseline in serum, salivary and hair 
cortisol levels ........................................................................................21
2.8
Safety analyses.......................................................................................................21
2.8.1
Adverse events (AEs)............................................................................21
2.8.2
Deaths....................................................................................................23
2.8.3
Laboratory data .....................................................................................23
2.8.4
Other safety data ...................................................................................24
2.9
Patient-reported outcomes .....................................................................................26
26
 
26
26
26
3
Sample size calculation .....................................................................................................27
4
Change to protocol specified analyses ..............................................................................27
5
Appendix ...........................................................................................................................27
5.1
Imputation rules.....................................................................................................27
5.1.1
Study drug.............................................................................................28
5.1.2
AE date imputation ...............................................................................28
5.1.3
Concomitant medication date imputation .............................................29
5.2
AEs coding/grading ...............................................................................................30
5.3
Laboratory parameters derivations ........................................................................31
5.4
Patient-reported outcomes scores ..........................................................................31
5.4.1
CushingQoL..........................................................................................31
5.4.2
BDI-II....................................................................................................32
5.4.3
EQ-5D-5L .............................................................................................32
6
Reference...........................................................................................................................34


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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
AR
Auto regression
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Classification
BDI-II
Beck Depression Inventory-II
bid
bis in diem/twice a day
BMI
Body mass index
BMD
Bone mineral density
BP
Blood pressure
CD
Cushing’s Disease
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CRO
Contract research organization
CSR
Clinical Study report
C-SSRS
Columbia Suicide Severity Reporting Scale
CT
Computed tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee 
DRL
Drug Reference Listing
DXA
Dual-energy X-ray absorptiometry
ECG
Electrocardiogram
FAS
Full Analysis Set
FPG
Fasting plasma glucose
eCRF
Electronic Case Report Form
HbA1c
Hemoglobin A1c
ITT
Intent to treat
IRT 
Interactive response technology
LLOQ
The limit of quantitation
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI
Magnetic resonance imaging
mUFC
Mean Urine Free Cortisol
NCI
National Cancer Institute
q.d.
Once Daily
PD
Pharmacodynamics
PK
Pharmacokinetics


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PAS
Pharmacokinetics analysis set
PD
Protocol deviations
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
PT
Preferred term
qd
Qua’que di’e / once a day
QoL
Quality of Life
QTcF
QT corrected (Fridericia QT formula)
SAE
Serious adverse events
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SOC
System Organ Class
SS
Safety Set
SSD
Study specific document
TBIL
Total bilirubin
TDM
Trial Design Model
TV
Trial Visit
UFC
Urine Free Cortisol 
ULN
Upper Limit of Normal
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes the planned statistical analysis for the final clinical 
study report (CSR) of study LCI699C2302. 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 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 Week 48 CSR written following the DBL which 
occurred once all patients had completed the core phase or discontinued earlier. Details of these 
analyses can be found in the corresponding SAP, with cover date 01-Apr-2019.
The content of this SAP is based on the LCI699C2302 protocol v02 released on 20-Dec- 2019.
1.1
Study design
This is a Phase III, global, multi-center, randomized, double-blind, placebo-controlled study.  
The study design is placebo-controlled during the first 12 weeks, followed by open-label 
treatment with osilodrostat until week 48, and an optional 48-week Extension phase. A 
schematic diagram of the Core study design is shown below in Figure 1-1. After the screening 
period, eligible patients were randomized in a 2:1 ratio to osilodrostat or placebo in a 12-week
double-blind placebo-controlled period. At Week12, the patients entered an open-label
osilodrostat treatment period until Week 48, which concludes the core phase of the study. At 
the end of the core phase, the patients had the option to enter a 48-week extension phase. 
It was planned to enroll 69 patients in this study, 46 on osilodrostat arm, and 23 in placebo arm. 
The primary objective is to demonstrate the superiority of osilodrostat compared to placebo in 
achieving a complete response (mUFC ≤ ULN) at Week 12. There was no interim analysis 
planned for this study. The analysis of the primary endpoint occurred after all patients 
completed the core phase of the study.
A detailed description of the study design is presented in the following sections.


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Figure 1-1
Schematic of Core study design
1.1.1
Screening period
The screening period enabled patients to washout their current treatment for Cushing’s disease.
Patients were evaluated for trial eligibility after the washout period was completed.
1.1.2
Period 1 (Weeks 1-12): double-blind, placebo-controlled period
This is the randomized, double-blind, placebo-controlled period (Weeks 1-12).  Eligible 
patients were randomized in a 2:1 ratio to treatment with study drug (osilodrostat or placebo, 
respectively). Patients are stratified at randomization according to history of pituitary irradiation 
(yes/no). Study visits occur at Weeks 2, 5, 8, and 12 (Figure 1-2).  Study drug started on Day 1 
at a dose of 2 mg b.i.d., and titrated according to the regimen described in protocol Section 6.2, 
to a dose which lowers mUFC to within the normal range. 
Figure 1-2
Schematic of Period 1
Three urine samples drawn at 24-hour intervals were collected by patients at screening, within 
7 days prior to Day 1 and immediately prior to Week 12 visit (primary endpoint). Two 24-hour 
urine samples were collected immediately prior to each of the other visits (i.e. at Weeks 2, 5, 
and 8). The dose was increased if mUFC was above normal (>ULN). The dose was reduced if 
mUFC <LLN, or if the patient was symptomatic and mUFC was in the lower part of the normal 


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range. The dose was maintained if mUFC was within the normal range and the patient had no 
signs or symptoms of adrenal insufficiency.
In order to maintain the treatment blind during Period 1, all laboratory results that may disclose 
the randomized treatment assignment were blinded to patients, investigators and the Novartis 
Clinical Trial Team. A group of independent endocrinologists (IEs) was responsible for 
managing dose titrations during Period 1 between visits. Titrations for patients assigned to 
placebo aimed to simulate the active arm. 
1.1.3
Period 2 (Weeks 12-48, open-label period)
Period 2 started immediately after the Week 12 visit, when the trial became open-label with all 
patients receiving the active drug, osilodrostat. During Period 2 patients randomized to placebo 
switched to osilodrostat and underwent their first dose titration with active drug, while patients 
randomized to osilodrostat continued this treatment and underwent another dose titration.  
During Period 2, the investigator was responsible for dose titration. Osilodrostat was titrated up 
to a maximum dose of 30 mg b.i.d. during this period. Dose titration decisions were made by 
the investigator based on mean urinary free cortisol (mUFC) results and other relevant patient 
data. 
Three 24-hour urine samples were collected by patients immediately prior to the Week 36 visit 
(key secondary endpoint) and Week 48 (end of Core phase), two 24-hour samples were
collected prior to all other visits in Period 2.  A patient was considered to have reached a stable 
efficacious dose when mUFC remains ≤ULN. This dose was continued, unless a change was
needed.
1.1.4
Optional Extension phase
At Week 48, patients had the option to enter an open-label Extension phase.  Patients who did
not enter the optional extension discontinued osilodrostat at Week 48 and concluded with a 
Post-Treatment (End of Study) visit after 30 days off study drug.  Prior to Protocol Amendment 
02, the optional extension ended at Week 96 for all patients, and patients still deriving benefit 
from osilodrostat treatment had the option to continue treatment on study until other treatment 
options became available. After Protocol Amendment 02, patients enrolled in the optional 
extension phase had to end study participation within 4 weeks after Protocol Amendment 02 
was approved at their site, or by Week 96, whichever occurred first. Patients who are benefitting 
from study treatment, have the option to enter a separate long-term safety follow-up study or 
stop study treatment. Patients who do not enter the long-term safety follow-up study will 
discontinue osilodrostat and  conclude the study with a Post-Treatment (End of Study) visit 
after 30 days off study drug.
During the extension phase the dose of osilodrostat is maintained at the established effective 
dose unless a change is required based on mUFC results collected at Weeks 48, 60, 72, and 84. 
1.2
Study objectives and endpoints
The following table displays the study objectives/endpoints. For the final CSR, not all study 
objectives will be reported. This is documented in the corresponding SAP section for each 
objective.


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Table 1-1
Study objectives and endpoints 
Objective
Endpoint
Primary
To demonstrate the superiority of osilodrostat 
compared to placebo in achieving a complete 
response (mUFC ≤ ULN) at Week 12.  
The proportion of randomized patients with a 
complete response, i.e. mUFC ≤ ULN at Week 12.  
Key secondary
To assess the complete response rate in both arms 
combined at Week 36 in patients receiving 
osilodrostat treatment. 
The proportion of patients with mUFC ≤ ULN at Week 
36 for combined randomized patients who receive 
osilodrostat treatment.
Other secondary
To assess the proportion of patients with a complete 
response (mUFC ≤ ULN) or a partial response 
(mUFC decrease ≥ 50% from baseline and > ULN) at 
Week 12, Week 36, and Week 48. 
The overall response rate defined as proportion of 
complete responders (mUFC ≤ ULN) plus partial 
responders (≥ 50% reduction in mUFC from baseline 
and > ULN) at Week 12, Week 36, and Week 48 by 
treatment arms and for all patients.
To assess the change in mUFC during the Core and 
optional Extension periods of the study. 
Actual and percentage change in mUFC from 
baseline to each post-baseline visit during the Core 
and Extension at which UFC is collected by treatment 
arms and for all patients.
To compare the time-to-first control of mUFC during 
the placebo-controlled period (Weeks 1-12) between 
the randomized treatment arms.
Time-to-first control of mUFC, which is defined as the 
time (in days) from randomization to the first mUFC 
collection that was ≤ ULN before completion or 
discontinuation of placebo-controlled period, 
whichever is earlier.
To assess the time-to-escape during osilodrostat 
treatment up to Week 48. 
Time-to-escape is defined as the time (in weeks) 
from the first collection of normal mUFC (≤ ULN) to 
the first mUFC > 1.3 x ULN on two consecutive visits 
on the highest tolerated dose of osilodrostat and not 
related to a dose interruption or dose reduction due 
to safety reasons. Escape will not be assessed for 
patients during the first 26 weeks.
To assess cardiovascular and metabolic related 
parameters associated with CD (fasting plasma 
glucose, HbA1c, fasting lipid profile, blood pressure, 
weight and waist circumference) by assessing actual 
and percent change from baseline and shift table at 
Weeks 12, 36, and 48.
The actual and percent change from baseline in 
fasting plasma glucose (FPG), HbA1c, fasting lipid 
profile, blood pressure (BP), weight and waist 
circumference at Week12, Week 36, and Week 48 by 
treatment arms and for the overall patient population.
To assess the change from baseline at Weeks 12, 
36, and 48 in physical features of CD.
Mean change from baseline to Week 12, Week 36, 
and Week 48 in each of the following clinical signs of 
Cushing’s disease, captured by: a semi-quantitative 
Likert scale for facial rubor, striae, supraclavicular fat 
pad, dorsal fat pad, proximal muscle wasting 
(atrophy), central (abdominal) obesity, and 
ecchymoses (bruises) by randomized treatment arm 
and overall population.  
To assess the change from baseline in bone mineral 
density (BMD) by DXA scan at the lumbar spine and 
total hip at Week 48.  
The change from baseline in bone mineral density, 
and BMD T-score, at the lumbar spine (L1-L4) and 
total hip at Week 48 by treatment arm and for overall 
patient population. 
To determine the safety and tolerability of osilodrostat 
in the study population.
Adverse events and laboratory abnormalities.  
Assessed events include: AEs of special interest, 
laboratory evaluation, ECG, Holter recording, and
pituitary MRI.


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Objective
Endpoint
To assess the change from baseline in Health Related 
Quality of Life, as measured by the CD-specific QoL 
questionnaire (CushingQoL); by the Beck Depression 
Inventory (BDI-II); and by the general health-related 
QoL instrument EQ-5D-5L, by randomized treatment 
arm and overall.
Change in standardized score of CushingQoL, Beck 
Depression Inventory-II, and EQ-5D-5L, from 
baseline to Week 12 and Week 48, from Week 12 to 
Week 36, and from Week 36 to Week 48, or the last 
measurement prior to early discontinuation,
whichever occurs earlier. 
To evaluate pharmacokinetic exposure of osilodrostat 
in the study population.
Plasma concentrations (pre-dose, 1-2 h post-dose) of 
osilodrostat.
To assess the change from baseline in serum, 
salivary and hair cortisol levels
The actual and percentage change from baseline in 
serum cortisol, late night salivary cortisol, morning 
salivary cortisol and hair cortisol levels for every visit 
in the Core and extension phases at which the 
biomarkers of hypercortisolism are collected, by 
treatment arms and for all patients. 
2
Statistical methods
2.1
Data analysis general information
The primary analysis was performed when all enrolled patients completed the Core phase of 
study (Period 1 and 2) or have prematurely withdrawn from the study prior to the end of the 
Core phase at Week 48. The results and outcomes of this analysis were presented in an interim
CSR. Analysis for the final CSR will be performed once all patients have either completed the 
extension period or discontinued earlier.
Novartis will analyze all data using the SAS System for data analysis V9.4 or higher. 
The data from all centers participating in the trial will be combined, so that an adequate number 
of patients will be available for analysis.


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2.1.1
General definitions
Study drug
Throughout the SAP, investigational drug refers to osilodrostat, and study treatment/ study drug 
refers to osilodrostat or placebo.
Overall study period
The overall study period refers to the complete study duration (including core and extension 
period) with data presented by the osilodrostat arm, placebo arm excluding placebo-control 
period, and overall patients (excluding data of placebo arm collected during placebo-control 
period).
Date of study treatment
The start date of study treatment is defined as the first date when a nonzero dose of study 
treatment was administered and recorded on DAR eCRF. The date of first administration of 
study treatment in period 1 will be referred as the start date of study treatment.
The last date of study treatment is defined as the last date when a nonzero dose of study drug 
was administered and recorded on DAR eCRF.
Study day
Study day is used to represent an evaluation, a measurement or an event (e.g. AE onset, 
laboratory abnormality occurrence, disease progression, etc.). The study day is calculated as 
Study day = date of assessment –start date of study treatment + 1 (if date of assessment is after 
start date of study treatment)
Study day = date of assessment –start date of study treatment (if date of assessment is before 
start date of study treatment)
For any assessment or events such as baseline characteristics or medical history that is supposed 
to occur prior to start date of the study treatment, study day will be negative. There is no Day 0 
defined.
Study day associated with a UFC assessment
The study day associated with a UFC assessment at any particular visit is defined as the study 
day of the last UFC sample collection for that visit.
Calculating mean UFC
It is scheduled to collect three individual 24 hours Urine Free Cortisol (UFC) samples at visits 
Week 1, 12, 36, and 48, and two UFC samples at all other visits. For a given visit, Mean Urine 
Free Cortisol (mUFC) is the mean of all available (with a minimum of 2) individual UFC values 
determined at a central laboratory. In the case that only one or no UFC value is available, the 
mUFC will be considered missing for that visit.
Calculation of proportions of responders
All randomized patients will be included in the analysis for calculating the proportion of 
responders at time points up to Week 48 based on the FAS.


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For calculation of proportion of responders beyond Week 48 (e.g. a time point in extension 
phase), the following rules will be applied to determine whether patients are included in the 
analysis.
1) patients who declined to enter optional extension phase after completion of the core phase 
will be excluded. 
2) patients who completed the extension phase will be included until their individual end of 
study dates (EOT EXT visit, as per   Protocol Amendment 02)
3) patients who discontinued prior to the data cutoff date for the Final DBL will be included for 
visits they could have completed if they had continued until week 96 or data cut off for the 
analysis (whatever occurs earlier), but excluded for further visits. For example, if the last 
completed scheduled visit for an early discontinued patient is Week 84, and the time between 
data cutoff and last completed scheduled visit is 20 weeks, he/she will be included in the 
analyses up to Week 96.
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.
Criteria of adequate follow-up for time points in the extension phase
For a given time point in the extension phase, 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.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25.
Baseline
Baseline values for efficacy and safety evaluations are defined as the last assessment available 
before or on the start date of study treatment. If patients have no assessments as defined above, 
the baseline result will be missing.
Follow up
Regular safety follow-up is scheduled at 30 days after the last date of study treatment. In 
addition, for patients who discontinued study treatment during Period 1 (Weeks 1 to 12), 
reasonable efforts should be made to follow the patients and perform the assessments as 
indicated in protocol visit evaluation schedule table (protocol Table 7-1a) up to and including 
Week 12. 
Visit number and time window
The following visit schedule tables are generated from TDM/TV domain.


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Table 2-1
Scheduled visits in core phase 
Core study Visit 
Day/Week
Clarifying Notes
Visit 10
Day -56 to day -1
Screening 
Visit 101
Day 1/Week 1
Baseline / Week 1
Visit 102
Day 15/Week 2
Period 1/ Double blind period
Visit 103
Day 36/Week 5
Period 1/ Double blind period
Visit 104
Day 57/Week 8
Period 1/ Double blind period
Visit 105
Day 85/Week 12
Period 1/ Double blind period
Visit 301
Day 15/Week 2 FUP
Period 1/ Double blind period
Visit 302
Day 36/Week 5 FUP
Period 1/ Double blind period
Visit 303
Day 57/Week 8 FUP
Period 1/ Double blind period
Visit 304
Day 85/Week 12 FUP
Period 1/ Double blind period
Visit 106
Day 99/Week 14
Period 2/ Open-label treatment period
Visit 107
Day 120/Week 17
Period 2/ Open-label treatment period
Visit 108
Day 141/Week 20
Period 2/ Open-label treatment period
Visit 109
Day 162/Week 23
Period 2/ Open-label treatment period
Visit 110
Day 183/Week 26
Period 2/ Open-label treatment period
Visit 111
Day 204/Week 29
Period 2/ Open-label treatment period
Visit 112
Day 225/Week 32
Period 2/ Open-label treatment period
Visit 113
Day 253/Week 36
Period 2/ Open-label treatment period
Visit 114
Day 281/Week 40
Period 2/ Open-label treatment period
Visit 115
Day 309/Week 44
Period 2/ Open-label treatment period
Visit 199
Day 337/EOT core
End of treatment core phase
Visit 399
POST TRT FU
Post treatment follow-up
Visit 499
END POST TRT FU
End of post treatment follow-up
Table 2-2
Scheduled visits in extension phase 
Extension study Visit 
Day/Week
Clarifying Notes
Visit 201
Day 365/Week 52
Extension
Visit 202
Day 393/Week 56
Extension
Visit 203
Day 421/Week 60
Extension


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Extension study Visit 
Day/Week
Clarifying Notes
Visit 201
Day 365/Week 52
Extension
Visit 204
Day 449/Week 64
Extension
Visit 205
Day 477/Week 68
Extension
Visit 206
Day 505/Week 72
Extension
Visit 207
Day 589/Week 84
Extension
Visit 299
Day 673/EOT EXTN
End of treatment extension phase
Visit 399
POST TRT FU
Post treatment follow-up
Visit 499
END POST TRT FU
End of post treatment follow-up
2.2
Analysis sets
Analysis sets used for the final CSR are described below. Further analysis sets as defined in the 
protocol and reported in the core CSR will not be repeated.
2.2.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all randomized patients who have received at least one 
dose of study drug (osilodrostat or placebo). According to the intent-to-treat (ITT) principle, 
patients will be analyzed according to the treatment and stratum they have been assigned to 
during the randomization. This is the default analysis set for efficacy. The randomization is 
stratified by history of pituitary irradiation yes/no.
2.2.2
Safety Set
The Safety Set (SS) includes all patients who received at least one dose of study drug 
(osilodrostat or placebo). Patients will be analyzed according to the study drug 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 received if the randomized/assigned treatment 
was never received.
2.2.3
Withdrawal of informed consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis datasets. The date on which 
a patient withdraws full consent will be recorded in the eCRF.
Third party data e.g. PK, biomarker etc. collected in the clinical database without having 
obtained consent for collection will not be included in the analysis datasets. These data will be 
excluded by the presence of the appropriate protocol deviation criterion.


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2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Demographics and baseline characteristics
All demographic and baseline disease characteristics were summarized in the interim CSR. 
They will not be reported in the final CSR.
2.3.2
Patient disposition
Patient disposition will be tabulated for FAS. The summary will include the number of patients 
who were randomized, treated, permanently discontinued from study treatment.
The following summaries will be presented: % is based on total number of FAS patients:

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated (based on eCRF DAR 
page not completed for any study treatment component)

Primary reason for not being treated (based on eCRF End of Treatment Phase 
Completion page)

Number (%) of patients who were treated (based on eCRF DAR page of each study 
treatment completed with non-zero dose administered)

Number (%) of patients who discontinued the study treatment phase (based on eCRF 
End of Treatment Phase page)

Primary reason for study treatment phase discontinuation (based on eCRF End 
of Treatment Phase Completion page)

Number (%) of patients who discontinued in Period 1 (prior to Week 12)

Primary reason for discontinuation in Period 1

Number (%) of patients who discontinued in Period 2 (Weeks 13 to 48)

Primary reason for discontinuation in Period 2

Number (%) of patients who completed core phase (week 48)

Completed Week 48 and did not enter Extension phase

Completed Week 48 and entered Extension phase

Number (%) of patients who discontinued 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

Number (%) of patients who completed extension 


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* Patients who completed Week 48 and did not enter extension phase are not counted as 
discontinuations.
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 (%) of patients in FAS with any PDs will be tabulated by deviation category (as 
specified in the study specification document (SSD)) by treatment group. All PDs will be listed.
In addition, the number (%) of patients in the FAS with any COVID-19 related protocol 
deviation will be tabulated by deviation category (as specified in the Study Specification 
Document) overall and by treatment group.
2.3.5
COVID-19 impact 
As per Novartis guidance, the start date, in a given country or region, is being defined as the 
approximate time point at which, according to the WHO situation reports and the Johns Hopkins 
database, the number of confirmed COVID-19 infections started to increase significantly 
(around 100 confirmed cases) and/or governments started to take measures (such as stay-at-
home orders) to contain the epidemic, whichever occurred first (China: January 1, 2020; Other 
countries with study sites: March 1, 2020).
The pandemic impact will be assessed based on two subsets:

Before pandemic set: Patients who completed (or discontinued) the trial before the 
pandemic start date in their region/country

During pandemic set: Patients with at least one on-treatment assessment or treatment-
emergent event during the pandemic dates as defined for their region/country
A summary of the number of patients in the pandemic sets within each country will be provided. 
The number of patients who completed or discontinued during the core phase, Week 48-72 and
after Week 72 will be tabulated by pandemic set.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The exposure for study period 1 (week 1-12) and 2 (week 13-48) was summarized in the interim 
CSR. In the final CSR the exposure to the study drug (osilodrostat) will be summarized for the 
overall study period including the extension period after week 48.
2.4.1.1
Duration of exposure 
Duration of exposure (weeks) = (min (date of last date of study treatment, date of data cut-off, 
date of death) – date of first date of study treatment + 1)/7


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In the overall period, the total duration of exposure to osilodrostat is considered by taking 
account of the duration of exposure in both Period 1, Period 2, as well as extension. For patients 
in the placebo arm, exposure to placebo is excluded. The duration calculation includes the 
periods of temporary interruptions.
Summary of duration of exposure to study treatment will include categorical summaries and 
continuous summaries using appropriate unit of time.
2.4.1.2
Dose reduction/interruption
The number of patients who have at least one dose reduction or interruption, and the 
corresponding reasons will be summarized for the overall study period. Although patients may 
have multiple dose reductions or interruptions with the same reason, patients will be counted 
only once for each distinct reason.
The total daily dose administered and reason for dose change will be listed with UFC 
information by date.
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 and summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior to 
the start of study treatment or starting more than 30 days after the last date of study treatment 
or safety follow-up whichever is later will be flagged in the listing. The safety set will be used 
for all concomitant medication tables and listings.
Concomitant medications and significant non-drug therapies will be summarized using 
frequency counts and percentages by ATC class, preferred term and treatment group within the
overall study period.
2.5
Analysis of the primary objective
The primary objective is to demonstrate the superiority of osilodrostat compared to placebo in 
achieving a complete response (mUFC ≤ ULN) at week 12. The results were reported in the 
interim CSR, and will not be performed for the final analysis.  
2.6
Analysis of the key secondary objective
The key secondary objective is to assess the complete response rate (proportion of enrolled 
patients with mUFC ≤ ULN) in both arms combined at Week 36 in patients receiving 


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osilodrostat treatment. The results were reported in the interim CSR, and will not be repeated 
for the final CSR.    
2.7
Analysis of secondary efficacy objectives
2.7.1
Assess the overall response rate 
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 in mUFC from 
baseline and > ULN) will be summarized using point estimates for all scheduled visits in the 
core and extension phase at which UFC is collected (provided adequate follow-up, as defined 
in section 2.1.1, Criteria of adequate follow-up for time points in the extension phase). 
Due to the COVID-19 (Coronavirus) pandemic, planned visits may have been cancelled, 
potentially resulting in missing UFC evaluations. Patients with insufficient information due to 
any reason at a visit will be considered as non-responder for that visit. The number of patients
with non-response due to missing visits linked to the pandemic (recorded as COVID-19 related 
PD) will be summarized. 
To explore the impact of the COVID19 pandemic in the extension phase, individual patient’s 
doses and overall response status over time will be graphically displayed together with 
pandemic start date.
The FAS will be used for this analysis.
2.7.2
Assess the change in mUFC during the Core and Extension periods of 
the study
For the actual value and change in mUFC from baseline, descriptive summaries will be provided 
for every scheduled visit in the core and extension (provided adequate follow-up, as defined in 
section 2.1.1, Criteria of adequate follow-up for time points in the extension phase) at which 
UFC is collected. The FAS will be used for the analysis.
2.7.3
Compare the time-to-first control of mUFC during the placebo-
controlled period between patients randomized to osilodrostat and 
placebo
The results were reported in the interim CSR, and will not be repeated for the final CSR.
2.7.4
Assess the time-to-escape during treatment of osilodrostat  
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)

patient reached highest tolerated dose of osilodrostat

2 consecutive mUFC (collected at scheduled visits) were above 1.3x ULN

the loss of control of UFC is not related to a dose interruption or dose reduction due to 
safety reasons


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
happens beyond Week 26 when the patients have a chance to be treated with doses as 
high as 30 mg bid 
Time-to-escape is defined as the time (in weeks) from the first collection of post-baseline 
normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on  2 consecutive scheduled visits on 
the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction 
due to safety reasons after Week 26.
The highest tolerated dose is defined as

30 mg bid if reached, or 

being on a reduced dose due to safety reasons such as AEs, or 

being on the same dose for at least 3 scheduled visits if the previous two criteria are not 
met.
For patients who attained normal mUFC (≤ ULN), time-to-escape will be analyzed using 
Kaplan-Meier plots. This will be performed by randomized treatment assignment and for the 
overall trial population using FAS. 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. Time-to-
escape will not be assessed for patients during the first 26 weeks.
Patients that have dose interruption or dose reduction for safety reasons will be censored at the 
time of the first dose interruption. Patients who discontinued the study are considered as 
censored. Patients who were controlled until the end of the study will be censored at the last 
mUFC collection date. FAS will be used for this analysis.
The results of time-to-escape during treatment of osilodrostat up to Week 48 (secondary 
objective) were reported in the interim CSR, and will not be repeated for the final CSR. Time-
to-escape up to end of study will be presented.
2.7.5
Assess the change from baseline in cardiovascular and metabolic 
related parameters associated with Cushing’s disease during the core 
period of the study 
For cardiovascular and metabolic parameters associated with Cushing’s disease (e.g. fasting 
glucose, HbA1c, fasting lipid profile, SBP, DBP, weight and waist circumference):
For actual value and change from baseline to Week 12, Week 36 and Week 48, descriptive 
summaries were reported in the core CSR. Additional information from further visits including 
the extension period will be provided.
FAS will be used for this analysis.
2.7.6
Assess the change from baseline in physical features of Cushing’s 
disease
For each of physical features of Cushing’s disease: facial rubor, striae, supraclavicular fat pad, 
dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses 
(bruises), Likert scores will be measured. The change from baseline at scheduled visits will be 


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summarized. This includes the proportions of patients having a favorable shift from baseline to 
post-baseline time points. FAS will be used for this analysis.
2.7.7
Assess the change from baseline in bone mineral density by DXA 
scan 
For bone mineral density measured by DXA scan at the lumbar spine and total hip, descriptive 
summaries of actual and percentage change from baseline to Week 48, Week 96 and EOT
Extension will be provided by randomized treatment arm and for overall patients. FAS will be 
used for this analysis.
2.7.8
Assess the change from baseline in serum, salivary and hair cortisol 
levels
The actual and percentage change from baseline to each post-baseline visit for serum cortisol, 
late night salivary cortisol, morning salivary cortisol and hair cortisol levels will be assessed. 
Descriptive summaries will be provided for every visit in the Core and Extension phases at 
which the cortisol markers are collected. Salivary cortisol samples will only be included if they 
are collected within the correct time window. 95% CIs for the percentage change from baseline 
will also be provided by treatment arms and for all patients.
2.8
Safety analyses
The assessment of safety will be based mainly on the frequency and severity of AEs and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
ECG, findings from Holter recordings, vital signs, and special tests) will also be presented. 
In the Final CSR results for the overall study period will be analyzed using the SS. Safety 
analyses presented for the placebo-control period in the interim CSR will not be repeated. Safety 
analyses for overall study period will focus solely on the safety of osilodrostat treatment. The 
analyses include the osilodrostat arm besides the placebo arm excluding placebo-control period, 
and overall patients (excluding safety data of placebo arm collected during placebo-control 
period).
The overall observation period will be divided into three mutually exclusive segments:

pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication

on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication

post-treatment period: starting at 31 days after last dose of study medication.
2.8.1
Adverse events (AEs)
Summary tables for adverse events (AEs) have to 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.


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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 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. A separate listing including any suspected or confirmed SARS-Cov-2 infections 
will be provided.
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the osilodrostat arm.
The following adverse event summaries will be produced by treatment; overview of adverse 
events and deaths (number and % of subjects who died, with any AE, any SAE, any drug 
reductions/interruptions), AEs by SOC and PT, summarized by relationship (all AEs and AEs 
related to study treatment), seriousness (SAEs and non-SAEs), leading to treatment 
discontinuation, leading to dose interruption/adjustment, requiring additional therapy and 
leading to fatal outcome. In addition, for the summary of serious and non-serious adverse events 
the number of occurrences will be produced (an occurrence is defined as >1 day between start 
and prior end date of record of same preferred term).
Additional exploratory analyses may be done to assess the impact of COVID-19 pandemic on 
adverse event reporting.
2.8.1.1
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 
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 defined in the eCRS (electronic 
Case Retrieval Strategy) in the DMS (Document Management System). The most up-to-date 
version of the CRS will be used at the time of analysis.
For each specified AESI, number (%) of participants with at least one event of the AESI 
occurring during on treatment period will be summarized together with the individual preferred 
terms in that grouping. In addition, number (%) of participants with at least one AESIs by 
maximum CTC grade, related AESIs, serious AESIs as well as action taken and outcome of the 
respective AESI will be summarized. 
All adverse events of special interest will be listed.


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2.8.1.2
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 12

Week 12 to Week 24

Week 24 to Week 36

Week 36 to Week 48

Week 48 to Week 60

Week 60 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
All deaths (on-treatment and post-treatment) will be listed, post treatment deaths will be flagged.
2.8.3
Laboratory data
Laboratory data summaries will include all assessments available for the lab parameter 
collected no later than 30 days or safety follow-up whichever is later after the last study 
treatment administration date using data from all sources. All laboratory assessments will be 
listed and those collected later than 30 days after the last study treatment date will be flagged 
in the listings.
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 that are graded for both low and high values, summaries 
will be done separately and labeled by direction, e.g., sodium will be summarized as 
hyponatremia and hypernatremia.
For laboratory tests where grades are not defined by CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, biochemistry and 
urinary tests:


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For laboratory tests where grades are defined by CTCAE 

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 grades to compare baseline to the worst and from baseline to 
the last post-baseline on-treatment value
For laboratory tests where grades are not defined by CTCAE ,

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst and from baseline to the last post-baseline on-treatment value
In addition, the following laboratory results will be summarized.

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), eDISH
plot may be provided as well
The following listings will be produced for the laboratory data:

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
the classifications relative to the laboratory reference ranges  

Listing of notable laboratory abnormalities (i.e. CTC grade 3 or 4 laboratory toxicities).
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
ECG data will be presented as follows:

Number and percentage of patients with clinically notable ECG values will be 
summarized.

ECG evaluations for all patients with at least one abnormality will be listed.
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
For 24hr Holter assessment, all findings will be listed and notable finding will be summarized 
based on clinical review of the Holter ECG data using the following criteria


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
Potentially related to QT (Ventricular extra beats ≥200/24h, Ventricular tachycardia, 
Non-sustained VT, Sustained VT, Ventricular fibrillation, Ventricular flutter, 
Syncope, Torsades de Pointes, Bradycardia < 40/min)

Potentially related to conduction (New Left Bundle Branch Block, New Right Bundle 
Branch Block, Mobitz II AV block, Complete heart block Grade III)

Other relevant arrhythmias (Atrial fibrillation, Atrial flutter)
2.8.4.2
Vital signs
All vital signs data (height (cm), weight (kg), body temperature (0C), supine pulse rate (beats 
per minute), and supine systolic/diastolic blood pressure (mmHg)) will be listed by patient and 
visit/time, and abnormalities will be flagged on listing. For blood pressure, two measurements
are planned to be taken and the average will be used for analysis purpose. Shift table based on 
notable value will be provided for vital signs. 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.
• Supine pulse: 120 bpm with increase from baseline 15 bpm
• Weight: Increase from baseline of 10%
Clinically notable below normal values
• Systolic BP: 90 mmHg and a decrease 20 mmHg from baseline
• Diastolic BP: 50 mmHg and a decrease 15 mmHg from baseline
• Supine pulse: 50 bpm with decrease from baseline 15 bpm
• Weight: Decrease from baseline of 5%
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.
2.8.4.3
Tumor volume and longest dimension 
For tumor volume evaluated by MRI (or CT) by central assessment of an independent 
neuroradiologist, descriptive summary of actual tumor volumes as well as its change from 
baseline will be provided at visits where evaluation is scheduled (Week 26, 48, 72, and 96). The 
independent neuroradiologist measured the tumor volume, when it cannot be easily 
distinguished, the whole pituitary gland was measured. For the analysis, only measurements of 
the tumor volume are used.


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Patients with pituitary volume assessments at baseline will be monitored and measured at the 
pre-specified timepoints. Patients with no visibile or measurable pituitary tumour at baseline 
will be assessed at all timepoints whether a tumour becomes visible and it can be measured 
accordingly. Patients will be assessed whether the pituitary tumour is within or goes beyond the 
sella turcica at each time points of MRI assessmenst. Measurements and available information 
about new lesions of patients with only pituitary gland dimensions at baseline will be listed.
2.8.4.4
Columbia Suicide Severity Reporting Scale (C-SSRS)
C-SSRS data will be mapped to Columbia Classification Algorithm for Suicide Assessment (C-
CASA) as per FDA guidance on suicidality (Food and Drug Administration 2010). The 
proportion of patients who have committed suicide, attempted suicide, done preparatory actions 
toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior without 
suicidal intent will be summarized by treatment arm.
2.9
Patient-reported outcomes
The CushingQoL 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 (see Section 5.4 for the score 
derivations). The FAS will be used for analyzing PRO data. No multiplicity adjustment will be 
applied.
Descriptive statistics will be used to summarize the actual and change from baseline for the 
scores at each scheduled assessment including critical time points such as from baseline to 
Week 12 and Week 48, from Week 12 to Week 36 and from Week 36 to Week 48 etc.


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3
Sample size calculation
Eligible patients will be stratified at randomization according to history of pituitary irradiation 
(yes/no). Based on the LCI699C2201 study, it is assumed that approximately 20% of 
randomized patients will have a history of pituitary radiation. 
With 2:1 randomization ratio, to detect a difference of 45% in complete response rate between 
60% in osilodrostat arm and 15% in placebo arm (equivalent odds ratio equals 8.5), a sample 
size of 42 patients in osilodrostat arm and 21 patients in placebo arm will provide 91% power 
based on a 1-sided CMH exact test at the 0.025 level. In order to adjust for drop-outs, an 
additional 10% patients will be enrolled. Thus a total of approximately 69 patients will be 
enrolled in the study.
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% at Week 36. Both the SOM230G2304 trial of Pasireotide 
LAR and the SOM230B2305 trial of Pasireotide s.c. were powered to show a response rate 
where the lower bound of the 95% confidence interval was ≥15%. Therefore an increase in this 
lower bound of the 95% confidence interval to a threshold of ≥30% would provide a significant 
improvement in clinical benefit to this patient arm.
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 60% complete response rate at Week 36, and less than 50% discontinuation rate of 
patients in placebo arm prior to Week 12. For the 69 patients in the pooled population, there is 
higher than 98% chance that the lower bound of 2-side 95% exact CI (based on Clopper-Pearson 
method) of the observed response rate is larger than 30%.
4
Change to protocol specified analyses
In the SAP for the core CSR, clarification is made that efficacy was summarized by randomized 
treatment arms during the placebo-control period and by randomized treatment arms and for 
overall patients during the open-label period. Safety was summarized by randomized treatment 
arms during the placebo-control period. 
For the overall study period, only safety data associated with osilodrostat treatment was
summarized, which means safety data in placebo-arm collected during placebo-control period 
was excluded from the analysis. The same approach will be followed for the final CSR.
5
Appendix
5.1
Imputation rules
Partial dates will remain partial in the data listings. For the purpose of analysis, the following 
imputation rules will be used to impute the partial dates.


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5.1.1
Study drug
Any partial dates or gaps between dates should be resolved for analysis purpose. The end date 
of study drug is derived by using the last non-zero dose end date from the dose administration 
record CRF page. If after DBL the partial dates still exist for end date, the imputation rule is as 
below:
If month and year is present, but day is missing, set the end date to be the first day of the month.
If after imputation of day, study medication end date is earlier then study medication start date 
set study medication end date to study medication start date.
5.1.2
AE date imputation
Summary tables for adverse events (AEs) have to include only AEs that started or worsened
during the on-treatment period, the treatment-emergent AEs. However, all safety data
(including those from the post-treatment period) will be listed and those collected during the
pre-treatment and after 30 days of post- treatment period or safety follow-up whichever is later
are to be flagged.
Any missing onset date, causality, or severity must be queried for resolution. Unsolved missing 
values will be imputed according to the following:
AE end date imputation:
1. If the AE end date month is missing, the imputed end date should be set to the earliest 
of the (treatment follow up period date, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
AE start date imputation:
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date.  Therefore, if the AE year value is missing, the imputed AE start date is set to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment.  Therefore:
a.
If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:
a.
If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).


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4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day.
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
c.
Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.
5.1.3
Concomitant medication date imputation
The start/stop dates recorded in the electronic case report form (eCRF) will be used to identify
when a concomitant medication or a significant non-drug therapy was taken during the study.
Concomitant medications and significant non-drug therapies after the start of the study
treatment will be listed and summarized by ATC class and standardized medication term for
the Safety Set. These summaries will include medications starting on or after the start of study
treatment or medications starting prior to the start of study treatment and continuing after the
start of study treatment. Any prior medications and significant non-drug therapies starting and
ending prior to the start of study treatment will be listed. These analyses will be based on Safety 
Set.
Any missing date will be queried for resolution. For any unsolved missing dates, the following 
rules in the following order will be applied to decide if a concomitant medication or a significant 
non-drug therapy was taken after the start of the study treatment and to decide if the data should 
be included in the summary table. Originally collected date will be listed in listings.
CM end date imputation:
1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the minimum of treatment end date and the last day of the month.
2. If CM end day/month are missing and CM year is non-missing then impute CM day as 
the minimum of  treatment end date and the end of the year (31DECYYYY).
3. If CM day/month/year is missing then use the treatment end date + 1 day as the imputed 
CM end date. 
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date.
1. CM start date imputation: If the CM start date year value is missing, the imputed CM
start date is set to one day prior to treatment start date.
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment.  Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY).


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b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a.
And the CM month is missing or the CM month is equal to the treatment start 
date month, then the imputed CM start date is set to one day prior treatment start 
date.
b. Else if the CM month is less than the treatment start date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY).
c.
Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.
5.1.3.1
Prior events date imputation
Partial date of prior events (other than AE and CM) date imputation rules are as below:
If only day is missing then impute to be 15th of month. If both day and month are missing, then 
impute to June 30th. If entire date is missing then leave as missing. If after imputation, the date 
is after the first dosing date, then use the first dosing date.
5.1.3.2
Post events and therapies date imputation
Partial  date of post events/therapies (other than AE and CM) date imputation rules are as below:
Start date:

If Day is missing, then impute to the max (reference start date, first day of the month).

Day and month are missing then impute to the max(reference start date, Jan 1)

Reference start date will be last date of study treatment administration + 1.
End date: No imputation
5.2
AEs coding/grading
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA)
terminology. AEs are graded according to the Common Terminology Criteria for Adverse
Events (CTCAE) version 4.03.
CTCAE grading is by definition a 5-point scale generally corresponding to 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). The CTCAE grade of 5 (death) is not used; rather, 


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‘fatal’ is collected as AE outcome and death information is also collected on a separate eCRF 
page.
5.3
Laboratory parameters derivations
All laboratory values except FPG and HbA1c, will be converted into SI units and the severity 
grade calculated using appropriate common toxicity criteria (CTC).
As CTC only grades lab values as grade 1-4, grade 0 will be used when lab value is normal. A
severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher.
Grade 5 will not be used. For laboratory tests that are graded for both low and high values,
summaries will be done separately and labelled by direction, e.g., sodium will be summarized
as hyponatremia and hypernatremia.
If sites report WBC differential counts in percentage (%) with corresponding lab normal ranges 
in terms of %, the % differentials will be converted to absolute differentials as Absolute value 
= [Value (%)/100] x WBC.
5.4
Patient-reported outcomes scores
5.4.1
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’). 
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
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.  


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(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 Table 5-1 below:
Table 5-1
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
5.4.2
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.  
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)
5.4.3
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 


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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:
Table 5-2
Illustration of calculating the utility index from raw score on the EQ-
5D-5L 


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6
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