An Open-label, Multi-center, Roll-over Study to Assess Long Term Safety in Patients With Endogenous Cushing's Syndrome Who Have Completed a Prior Novartis-sponsored Osilodrostat (LCI699) Study and Are Judged by the Investigator to Benefit From Continued Treatment With Osilodrostat
Phase: PHASE2
Conditions: Cushing's Syndrome
Sponsor: RECORDATI GROUP

 
Recordati Research and Development 
LCI699 (osilodrostat) 
Clinical Trial Protocol CLCI699C2X01B 
An open-label, multi-center, roll-over study to assess long 
term safety in patients with endogenous Cushing’s 
syndrome who have completed a prior Novartis-sponsored 
osilodrostat (LCI699) study and are judged by the 
investigator to benefit from continued treatment with 
osilodrostat 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2017-002840-34 
ClinicalTrials.gov 
Identifier: 
NCT03606408 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
II b 
Release date: 
06-May-2020 
Sponsor: 
RECORDATI AG - Lindenstrasse 8, 6340 Baar, Switzerland   
tel: + 41 (0) 61 205 61 00 
CRO: 
IQVIA 
Property of Recordati 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Recordati 
 
 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Amendment 01 (18-Mar-2019) ........................................................................................... 8 
Glossary of terms ............................................................................................................... 11 
Protocol summary .............................................................................................................. 11 
1 
Introduction ....................................................................................................................... 13 
1.1 
Background ............................................................................................................ 13 
1.1.1 
Epidemiology and pathogenesis of Cushing’s syndrome ..................... 13 
1.1.2 
Current treatment modalities ................................................................. 14 
1.1.3 
Unmet medical need .............................................................................. 15 
1.2 
Purpose .................................................................................................................. 15 
1.2.1 
Overview of osilodrostat ....................................................................... 15 
2 
Objectives and endpoints ................................................................................................... 19 
3 
Study design ...................................................................................................................... 20 
3.1 
Description of study design ................................................................................... 20 
4 
Rationale ............................................................................................................................ 21 
4.1 
Rationale for study design ..................................................................................... 21 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 21 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 21 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 22 
4.5 
Risks and benefits .................................................................................................. 22 
5 
Population .......................................................................................................................... 24 
5.1 
Inclusion criteria .................................................................................................... 24 
5.2 
Exclusion criteria ................................................................................................... 24 
6 
Treatment ........................................................................................................................... 25 
6.1 
Study treatment ...................................................................................................... 25 
6.1.1 
Investigational and control drugs .......................................................... 26 
6.1.2 
Additional study treatments .................................................................. 26 
6.1.3 
Treatment arms/group ........................................................................... 26 
6.1.4 
Guidelines for continuation of treatment .............................................. 27 
6.1.5 
Treatment duration ................................................................................ 27 
6.2 
Other treatment(s) .................................................................................................. 27 

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6.2.1 
Concomitant therapy ............................................................................. 27 
6.2.2 
Prohibited medication ........................................................................... 28 
6.3 
Subject numbering, treatment assignment, randomization .................................... 29 
6.3.1 
Subject numbering ................................................................................ 29 
6.3.2 
Treatment assignment, randomization .................................................. 29 
6.4 
Treatment blinding ................................................................................................ 29 
6.5 
Dose modification .................................................................................................. 29 
6.5.1 
Dose modifications ................................................................................ 29 
6.5.2 
Follow-up for toxicities ......................................................................... 34 
6.5.3 
Follow up for potential drug-induced liver injury (DILI) cases ........... 34 
6.6 
Additional treatment guidance ............................................................................... 35 
6.6.1 
Treatment compliance ........................................................................... 35 
6.6.2 
Emergency breaking of assigned treatment code .................................. 36 
6.7 
Preparation and dispensation ................................................................................. 36 
6.7.1 
Handling of study treatment .................................................................. 36 
7 
Informed consent procedures ............................................................................................ 36 
8 
Visit schedule and assessments ......................................................................................... 37 
8.1 
Screening ............................................................................................................... 40 
8.1.1 
Information to be collected on screening failures ................................. 40 
8.2 
Subject demographics/other baseline characteristics............................................. 40 
8.3 
Efficacy .................................................................................................................. 40 
8.3.1 
Efficacy assessments ............................................................................. 40 
8.3.2 
Appropriateness of efficacy assessments .............................................. 40 
8.4 
Safety ..................................................................................................................... 40 
8.4.1 
Physical Examination ............................................................................ 41 
8.4.2 
Body weight and blood pressure ........................................................... 41 
8.4.3 
Laboratory evaluations .......................................................................... 41 
8.4.4 
Electrocardiogram (ECG) ..................................................................... 41 
8.4.5 
Pregnancy and assessments of fertility ................................................. 42 
8.4.6 
Pituitary scan ......................................................................................... 42 
8.4.7 
Appropriateness of safety measurements .............................................. 42 
8.5 
Additional assessments .......................................................................................... 42 
9 
Study discontinuation and completion .............................................................................. 42 
9.1 
Discontinuation ...................................................................................................... 42 
9.1.1 
Discontinuation of study treatment ....................................................... 42 
9.1.2 
Withdrawal of informed consent ........................................................... 44 

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9.1.3 
Lost to follow-up ................................................................................... 44 
9.1.4 
Early study termination by the sponsor ................................................. 45 
9.2 
Study completion and post-study treatment .......................................................... 45 
10 Safety monitoring and reporting ........................................................................................ 45 
10.1 
Definition of adverse events and reporting requirements ...................................... 45 
10.1.1 
Adverse events ...................................................................................... 45 
10.1.2 
Serious adverse events .......................................................................... 47 
10.1.3 
SAE reporting........................................................................................ 48 
10.1.4 
Pregnancy reporting .............................................................................. 48 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 49 
10.2 
Additional Safety Monitoring ................................................................................ 49 
11 Data Collection and Database management ...................................................................... 50 
11.1 
Data collection ....................................................................................................... 50 
11.2 
Database management and quality control ............................................................ 50 
11.3 
Site monitoring ...................................................................................................... 50 
12 Data analysis and statistical methods ................................................................................ 51 
12.1 
Analysis sets .......................................................................................................... 51 
12.1.1 
Full Analysis Set ................................................................................... 51 
12.1.2 
Safety set ............................................................................................... 51 
12.1.3 
Per-Protocol set ..................................................................................... 51 
12.1.4 
Dose-determining analysis set ............................................................... 51 
12.1.5 
Pharmacokinetic analysis set ................................................................. 51 
12.1.6 
Other analysis sets ................................................................................. 52 
12.2 
Subject demographics and other baseline characteristics ...................................... 52 
12.3 
Treatments ............................................................................................................. 52 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 52 
12.4.1 
Definition of primary endpoint(s) ......................................................... 52 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 52 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 52 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 52 
12.5 
Analysis of secondary endpoints ........................................................................... 53 
12.5.1 
Safety endpoints .................................................................................... 53 
12.6 
Analysis of exploratory endpoints ......................................................................... 54 
12.7 
Interim analyses ..................................................................................................... 54 
12.8 
Sample size calculation.......................................................................................... 54 
13 Ethical considerations and administrative procedures ...................................................... 54 

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13.1 
Regulatory and ethical compliance ........................................................................ 54 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 54 
13.3 
Publication of study protocol and results............................................................... 55 
13.4 
Quality Control and Quality Assurance ................................................................. 55 
14 Protocol adherence ............................................................................................................ 55 
14.1 
Protocol Amendments ........................................................................................... 56 
15 References ......................................................................................................................... 57 
16 Appendices ........................................................................................................................ 59 
16.1 
Appendix 1: List of drugs to be used with caution with LCI699 .......................... 59 
16.2 
Appendix 2: Medications with a “Known risk to cause TdP” and with a 
“Possible risk to cause TdP” .................................................................................. 59 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 19 
Table 6-1 
Investigational and control drug ............................................................ 26 
Table 6-2 
Dose Modification Guidelines for osilodrostat-suspected toxicities .... 30 
Table 6-3 
Criteria for interruption and re-initiation of osilodrostat for 
abnormal liver function ......................................................................... 31 
Table 8-1 
Assessment Schedule ............................................................................ 38 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 49 
 
List of figures 
Figure 1-1 
Mechanism of action of osilodrostat in Cushing’s Syndrome .............. 16 
Figure 3-1 
Study Design ......................................................................................... 21 
Figure 6-1 
QT monitoring Flow Chart.................................................................... 34 
 

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List of abbreviations 
ACE 
Angiotensin-converting enzyme 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase/Glutamic Pyruvic Transaminase (GPT) 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase (GOT) 
b.i.d. 
bis in die/twice a day 
BP  
Blood Pressure 
BUN  
Blood Urea Nitrogen 
CD 
Cushing’s Disease 
CK 
Creatine Kinase 
CI 
Confidence Interval 
CS 
Cushing’s Syndrome 
CMV 
Cytomegalovirus 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CSR 
addendum 
An addendum to Clinical study report (CSR) that captures all the additional information that is 
not included in the CSR 
CT  
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DB  
Database 
DDI 
Drug Drug Interaction 
DILI 
Drug-Induced Liver Injury 
DLT 
Dose Limiting Toxicity 
CMO&PS 
Chief Medical Office and Patient Safety 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
EOT 
End Of Treatment 
FAS 
Full Analysis Set 
FPFV 
First Patient First Visit 
GGT 
Gamma-Glutamyl Transferase 
HbA1c 
Hemoglobin A1c 
hCG 
Human Chorionic Gonadotropin 
HSV 
Herpes Simplex Virus 
IUD 
Intrauterine Device 
IUS  
Intrauterine System 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System 
LFT 
Liver Function Test  
LLN 
Lower Limit Normal 
MRI  
Magnetic Resonance Imaging 

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MoA 
Mechanism of Action 
mUFC 
Mean Urinary Free Cortisol 
NCI CTC 
National Cancer Institute Common Terminology Criteria 
PHI 
Protected Health Information 
PK 
Pharmacokinetics) 
PT  
Prothrombin Time 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
s.c. 
subcutaneous 
SD 
Standard Deviation 
SMR 
Standardized Mortality Ratio 
SRS 
Stereotactic radiosurgery 
TBIL 
Total Bilirubin 
TdP 
Torsades des Pointes 
WOCBP 
Women of childbearing potential 
UFC 
Urinary Free Cortisol 
ULN 
Upper Limit Normal 
 
 

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Amendment 02 (06-May-2020) 
Amendment rationale  
As of 8 April 2020, 100 patients are enrolled in this trial. Within the framework of a worldwide 
purchase agreement between Novartis and Recordati (an international pharmaceutical group 
with a specialized business dedicated to treatments for rare diseases) on July 2019, the two 
Companies agreed to a sponsorship transfer of this study with LCI699 (osilodrostat).  
The purpose of this substantial amendment is to reflect the change in sponsorship, and to add 
IQVIA as the CRO in charge for performing some trial-related activities on behalf of Recordati.  
An update on the investigational medicinal product is also included, since osilodrostat 
(Isturisa®) has been granted an approval from the European Commission on 9th January 2020 
for the treatment of endogenous Cushing syndrome in adults, and from FDA on 6th March 2020 
for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have 
undergone the surgery but still have the disease. 
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 underline for insertions. 
• All sections: were updated to substitute the name of the current sponsor Novartis with the 
name of the new sponsor Recordati. 
• Activities performed by the CRO IQVIA on behalf of Recordati has been mentioned.  
• Section 1.1.4.2 (Clinical experience) was updated in line with EMA and FDA approval for 
use in the adult population. 
• Section 6.1.1 (Investigational and control drugs): IQVIA vendor has been inserted as a new 
site for packaging, and as responsible for labelling and drug supply at sites after sponsorship 
transfer  
• Section 13.3 (Publication of study protocol and results) mention to the Novartis publication 
policy has been deleted. 
 
IRBs/IECs  
A copy of this amended protocol version 02 will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, as per local requirements. 
The changes described in this amended protocol are substantial and do require IRB/IEC 
approval prior to implementation.  

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Amendment 01 (18-Mar-2019) 
Amendment rationale  
As of 29th Jan 2019, 23 patients are enrolled in this trial. This amendment was required due to 
the request of Health Authorities to specify the safety monitoring in the study. Therefore, the 
following safety assessments have been defined at scheduled study visits: physical examination, 
body weight and blood pressure, laboratory evaluations, ECG and pituitary MRI. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. The 
changes being made to the protocol due to this amendment are incorporated in the following 
sections: 
• Cover page:  Authors were removed 
• Table of contents: The text was updated reflecting the changes in the amended protocol. 
• List of abbreviations: The list of abbreviations was updated. 
• Protocol Summary: the text for secondary objectives, safety assessment and data analysis 
was updated  
• Table 2-1 : Secondary safety objective and secondary safety objective endpoint added 
• Section 3-1: The word “reimbursed” was removed from the paragraph describing the 
duration of subject treatment. 
• Section 4.1: The text describing the duration of the study and subject treatment was 
deleted as it is a duplicate from section 3.1.  
• Section 4.2: Text was added as a guidance to the Investigator for dose modification. 
• Section 4.5: Procedures added to the existing ones to mitigate the potential risks related to 
the administration of osilodrostat. The following text is also added “Drug administration 
record for dosing of osilodrostat will be completed at each visit”. 
• Table 8-1 : Content is updated to reflect the additional safety assessments 
• Section 8.4 : Text added specifying that safety assessments must be maintained in source 
documentation for each patient  
• Section 8.4.1 : Physical examination is described 
• Section 8.4.2 : Body weight and blood pressure procedures are described  
• Section 8.4.3 : Laboratory evaluations are listed  
• Section 8.4.4 : Text for ECG is added 
• Section 8.4.5: Text is added specifying the frequencies of the pregnancy tests. 
• Section 8.4.6 : The section is added to describe the MRI process and assessment 
• Section 8.4.7 : This section was renumbered due to the insertion of sections 8.4.1, 8.4.2 
and 8.4.6 
• Section 9.1.1: Text was added for clarification. The word “reimbursed” was removed from 
the paragraph describing the circumstances for study treatment discontinuation. 

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• Section 12.5. The following paragraph was added “The secondary safety objective of the 
study is to evaluate long term safety, assessed using laboratory data, vital signs (blood 
pressure and body weight), ECG and pituitary MRI. Details of the specific analyses for 
each type of safety endpoint is given in Section 12.5.1.”  
• Section 12.5.1 Analysis methods for additional safety assessments added. 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg once a day, 
75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using data 
collection systems, such as Web-based applications, interactive voice response systems 
and clinical laboratory interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source forms used at the 
point of care. 
Enrollment 
Point/time of subject entry into the study at which informed consent must be obtained 
Medication 
number 
A unique identifier on the label of medication kits 
Patient 
An individual with the condition of interest for the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-coded 
data, such as paper or eSource. 
Subject 
A trial participant (can be a healthy volunteer or a patient) 
Study treatment 
Any single drug or combination of drugs or intervention administered to the subject as 
part of the required study procedures. 
Study treatment 
discontinuation 
When the subject permanently stops taking any of the study drug(s) prior to the defined 
study treatment completion date (if any) for any reason; may or may not also be the 
point/time of study discontinuation 
Subject number 
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, etc. 
Roll-over study 
A roll-over study allows patients from previous parent studies for similar or different 
indications to continue treatment with the same drug after completion of the parent study.  
Variable 
A measured value or assessed response that is determined from specific assessments 
and used in data analysis to evaluate the drug being tested in the study 
Protocol summary 
Full Title 
An open-label, multi-center, roll-over study to assess long term safety in patients with 
endogenous Cushing’s syndrome who have completed a prior Novartis-sponsored 
osilodrostat (LCI699) study and are judged by the investigator to benefit from continued 
treatment with osilodrostat 
Brief title 
Roll-over study in patients with endogenous Cushing’s syndrome 
Sponsor and 
Clinical Phase 
Recordati, IIb 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is the evaluation of long-term safety of osilodrostat in patients 
who have already received osilodrostat treatment in a previous Global Novartis-
sponsored trial and who, based on investigators’ judgement, will continue benefiting with 
its administration. 
Primary 
Objective(s)  
To evaluate the long term safety data with osilodrostat treatment i.e. adverse events 
(AEs) and serious adverse events (SAEs). 
Secondary 
Objectives 
To evaluate clinical benefit as assessed by the Investigator 
To evaluate the long term safety of osilodrostat treatment, as assessed by physical 
examination, laboratory data, vital signs, ECG and pituitary MRI. 
Study design 
This is a multi-center, open label study to evaluate the long term safety of osilodrostat in 
patients currently being treated in a Global Novartis-sponsored study and who are judged 

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by their parent study Investigator as benefiting from the current study treatment. The 
study is expected to remain open for approximately 5 years (or until 31-Dec-2023 in the 
UK) from First Patient First Visit (FPFV). Patients will continue to be treated in this study 
until they are no longer benefiting from their osilodrostat treatment as judged by the 
Investigator or until one of the protocol defined discontinuation criteria is met. 
Population 
Patients with endogenous Cushing’s syndrome who are currently enrolled in a Global 
Novartis-sponsored study and benefiting from treatment with osilodrostat, as determined 
by the Investigator. 
Key Inclusion 
criteria 
1. Patient is currently participating in a Global Novartis-sponsored study receiving 
osilodrostat for any type of endogenous CS and has fulfilled all the requirements in the 
parent study. 
2. Patient is currently benefiting from treatment with osilodrostat, as determined by the 
Investigator. 
3. Patient has demonstrated compliance, as assessed by the Investigator, with the parent 
study protocol requirements. 
4. Patient is willing and able to comply with scheduled visits and treatment plans. 
5. Written informed consent/adolescent assent obtained prior to enrolling into the roll-over 
study. 
Key Exclusion 
criteria 
1. Patient has been permanently discontinued from osilodrostat study treatment in a 
parent Novartis-sponsor study. 
2. Patients who are receiving osilodrostat in combination with unapproved or experimental 
treatments for any type of endogenous CS. 
3. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory evaluation. 
Study treatment 
Osilodrostat, film-coated tablets up to 30 mg b.i.d, oral use  
Efficacy 
assessments  
At every quarterly visit, the Investigator is required to confirm that the patient continues to 
have clinical benefit and may continue receiving study treatment. 
Safety 
assessments 
AEs/SAEs, physical examination, body weight and blood pressure, blood chemistry tests, 
hematology, hormones, ECG and pituitary MRI. 
Data analysis 
The assessment of safety will be based mainly on the frequency and severity of 
AEs/SAEs and on the number of laboratory values that fall outside of pre-determined 
ranges. Other safety data, such as physical examination, vital signs (blood pressure and 
body weight), ECG and Pituitary MRI or CT will also be presented. Proportions of patients 
with clinical benefit as assessed by the Investigator will be summarized at scheduled 
visits. 
Key words 
Osilodrostat, endogenous Cushing’s syndrome, roll over study, long term safety 
IRBs/IECs 
A copy of this amended protocol version 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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1 
Introduction 
1.1 
Background 
1.1.1 
Epidemiology and pathogenesis of Cushing’s syndrome 
Cushing’s syndrome (CS) is a rare disorder with a reported incidence of 0.7–2.4 per million 
population per year. In European countries and in the US, the prevalence rates have been 
reported to range from 19 to 79 cases per million inhabitants, with the highest prevalence (79 
cases per million) reported from New Zealand. In a survey conducted in Japan by the Ministry 
of Health, Labour and Welfare in 1997, the prevalence of CS has been reported to be 
approximately 1250 cases.   
CS is characterized by a chronic excess of cortisol secretion, which results in numerous clinical 
features that are associated with a higher mortality compared with the general population, if not 
appropriately treated (Pivonello et al, 2008). 
CS can be either exogenous or endogenous. The most common cause of exogenous CS is 
iatrogenic due to the external administration of excessive doses of glucocorticoids. 
Endogenous CS is classified as either adrenocorticotropic hormone (ACTH)-dependent or 
ACTH-independent. ACTH-dependent CS accounts for 80%–85% of cases. Of these, 75%–
80% are due to ACTH production from a pituitary adenoma (Cushing’s disease [CD]), 15%–
20% are due to ACTH production from non-pituitary tumors (ectopic ACTH syndrome) and 
<1% are caused by corticotrophin-releasing hormone (CRH)-producing tumors.  
ACTH-independent CS accounts for 15%–20% of endogenous CS in adults; 90% are unilateral 
adrenal tumors. Of these, adenomas are the cause in ~80% of the cases, while the others are 
adrenocortical carcinoma. 
Cushing’s disease (CD) is the most common cause of CS (70% of cases) in Western countries, 
while it makes up a smaller proportion of the CS population in Japan (35.8%). It is caused by 
excessive secretion of cortisol from the adrenal glands as a consequence of excessive ACTH 
secretion from a pituitary tumor, generally an adenoma (90%), whereas a carcinoma is a very 
rare cause of the disease (less than 10%). It affects adults aged 20-50 years-old more commonly 
with a marked female preponderance (Pivonello et al 2008; Newell-Price et al 2006).  
Endogenous CS is characterized by chronic hypercortisolism, which results in a variety of 
metabolic abnormalities and co-morbidities that collectively lead to an overall 4-fold higher 
mortality rate than age- and gender-matched subjects in the general population (Arnaldi et al, 
2003). 
The clinical manifestations are variable and include obesity affecting mainly the face, neck, 
trunk, and abdomen, thinned skin, purple striae, muscular weakness, fatigue, hypertension, 
diabetes mellitus (DM), neuropsychiatric disorders, acne, hirsutism, and menstrual irregularities 
(Arnaldi et al, 2012).  
There is an increased cardiovascular risk and it is mainly due to the metabolic syndrome, insulin 
resistance, weight gain, glucose intolerance, dyslipidemia and hypercoagulation.  

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Normalization of hypercortisolism is expected to improve or reverse the increased morbidity 
and mortality associated with the untreated disease. 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 CD (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 meta-analysis of published mortality studies (Clayton, et al 2011) showed that the 
standardized mortality ratio (SMR) is much higher in CD patients with persistent 
hypercortisolism (SMR=5.5) than those in remission (SMR=1.2). 
1.1.2 
Current treatment modalities 
Surgical resection of the source of glucocorticoid excess (pituitary adenoma, non-pituitary 
tumor-secreting ACTH or adrenal tumor[s]) remains the first-line treatment of all forms of 
endogenous CS. 
The first line-treatment of CD is mainly represented by the surgical removal of the pituitary 
tumor by TSS (Pivonello 2015). 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 a 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). 
In the International Consensus Statement on the treatment of ACTH-dependent CS (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. 
Medical therapy is an attractive option for patients with CD 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, and many other countries, for the treatment of CD.  
Mifepristone, a glucocorticoid receptor antagonist, is approved in the US for the treatment of 
hyperglycemia secondary to hypercortisolism in adult patients with endogenous CS who have 
type 2 diabetes mellitus or glucose intolerance. 
Several other drugs have been used with and without regulatory approval for the treatment of 
CD, including the steroidogenesis inhibitors ketoconazole and metyrapone (both approved in 
Europe), mitotane (adrenolytic agent), and cabergoline (dopamine agonist). 
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 

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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). 
Bilateral adrenalectomy in ACTH-dependent CS may be used when surgery and medical 
therapy are unsuccessful, or based on patient preference. It leads to rapid resolution of 
hypercortisolemia and related morbidity. However, after bilateral adrenalectomy, patients need 
lifelong glucocorticoid and mineralocorticoid replacement.  
Another concern with bilateral adrenalectomy in patients with CD is the development of 
Nelson’s syndrome (local tumor growth with mass effects and increased ACTH levels causing 
hyperpigmentation 
1.1.3 
Unmet medical need 
The treatment of patients with CS still represents a challenge, especially for patients with CD 
since the available treatments do not lead to biochemical control in quite a large number of 
patients and many of them lose biochemical control over time.  
Therefore, there is an unmet medical need to develop new drugs with improved safety, efficacy 
and a more patient-friendly profile.   
Osilodrostat, a novel adrenal-directed steroidogenic inhibitor, is under evaluation, due to its 
safety and efficacy profile, as demonstrated by preliminary data from the LINC 2 study, 
conducted in patients with Cushing’s disease.  
Based on these results osilodrostat shows promise in fulfilling an unmet medical need in all 
types of endogenous CS. 
1.2 
Purpose 
1.2.1 
Overview of osilodrostat 
Osilodrostat (company research code: LCI699) is a potent, oral inhibitor of 11β-hydroxylase 
(CYP11B1), the enzyme that catalyzes the last step in the biosynthesis of cortisol. This provides 
the rationale for investigating the use of osilodrostat in endogenous causes of CS.  
It is manufactured as a phosphate salt and available in film-coated tablets of 1 mg, 5 mg and 10 
mg. 
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 Syndrome 
 
1.2.1.1 
Non-clinical experience 
For detailed non-clinical pharmacokinetics and toxicity findings, please refer to the 
[Investigator Brochure]. 
1.2.1.2 
Clinical experience 
Currently, osilodrostat (Isturisa®) has been granted an approval: 
• from the European Commission on 9th January 2020 for the treatment of endogenous 
Cushing syndrome in adults and  
• from FDA on 6th March 2020 for adults with Cushing’s disease who either cannot 
undergo pituitary gland surgery or have undergone the surgery but still have the disease. 
1.2.1.2.1 Results of study LCI699C2201 
Results of LCI699C2201 study in CD. 
The purpose of the LCI699C2201 study was to determine whether the ability of osilodrostat to 
inhibit 11β-hydroxylase could safely reduce UFC (Urinary Free Cortisol) in patients with CD.  
This was initially studied over a 10-week treatment duration Proof-of Concept (Part I). Part II 
of the study aimed to further evaluate the observations from the Part I by enrolling a cohort of 
patients who participated in Part I and a new cohort (Expansion cohort) of patients and 
evaluating the long-term efficacy and safety of osilodrostat treatment. 
In Part I, osilodrostat was effective in controlling cortisol production in all 12 patients studied. 
At daily osilodrostat doses between 2 mg twice a day (b.i.d.) and 50 mg b.i.d., 24-hour cortisol 
decreased rapidly and normalized at least once in all patients studied. In general at 5 mg b.i.d. 

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patients showed cortisol reduction after 2 weeks (at first cortisol measurement after dose 
titration). 
The primary endpoint, defined as cortisol ≤ Upper Limit Normal (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 [± 
Standard Deviation (SD)] of osilodrostat required to reach the primary endpoint was 13.5±13.9 
mg b.i.d. with 75% of patients normalizing cortisol on ≤ 10 mg b.i.d. At Day 84, two weeks 
after osilodrostat was withdrawn, cortisol levels increased to a mean of 4-fold above upper limit 
of normal (ULN). 
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 cortisol 
levels at week 22 (79%). During treatment with osilodrostat, the mean cortisol levels decreased 
quickly and stabilized to a normal level (11 to 138 nmol/24h) at Week 4. After Week 4, normal 
mean cortisol 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. The study 
is ongoing. 
• Two phase III multi-center studies are ongoing:  
a. C2301: this is a double-blind, randomized, withdrawal study following a 24 week, 
single-arm, open-label, dose titration and treatment period to evaluate the safety and 
efficacy of osilodrostat in the treatment of patients with CD. Primary endpoint: 
proportion of randomized patients in each treatment group with mUFC ≤ ULN at 
week 34 who neither discontinued nor had dose increase above the week 24. This 
study has enrolled 137 subjects with CD. 
b. C2302: this is a randomized, double-blind, placebo-controlled 48-week study with an 
initial 12 week placebo-controlled period to evaluate the safety and efficacy of 
osilodrostat in patients with CD. Primary endpoint: proportion of randomized patients 
with a complete response at Week 12. The study plans to enroll 69 subjects with CD. 
• One phase II multi-center study is ongoing in Japan: 
a. C1201: this is an open label, dose titration, multi-center study to assess the safety, 
tolerability and efficacy of osilodrostat in patients with all types of endogenous CS, 
except CD. 
1.2.1.2.2 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 Serious Adverse 
Events (SAEs) and discontinuations due to AE were infrequent, and were reported at a rate 

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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.  
Overall, in patients with CD (study CLCI699C2201), safety data from the 10-week analysis has 
also showed that osilodrostat was well tolerated with similar common AEs to those in the 
hypertension trials, including: fatigue, nausea, vomiting, diarrhea, headache, dizziness, 
hypokalemia and muscle spasms. 
In Part I of the study, all 12 patients (100%) experienced adverse events but these were generally 
grade 1 or grade 2 (National Cancer Institute Common Terminology Criteria (NCI CTC)). 
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 I, SAEs of decreased hemoglobin, tachycardia, chest pain and reactivation of Takayasu’s 
arteritis were reported in one patient. The events were attributed to progression of the 
preexisting conditions and were not suspected to be related to study drug. 
In Part II, osilodrostat was also 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 
performed after the last patient had completed 22 weeks of treatment showed that except for 
one patient in the Expansion cohort, all patients experienced AEs, grade 1 and grade 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 Preferred Term ]. There were no new safety concerns during the Extension Period 
to Month 31. This study is ongoing. 
In Part II (31-month analysis), a total of 9 SAEs were reported in 4 patients, including (by 
preferred term) pituitary-dependent Cushing’s syndrome (in 2 patients), electrocardiogram QT 
prolonged, food poisoning, gastroenteritis, headache, non-cardiac chest pain, pituitary tumor 
and pituitary tumor benign.  
Of these, one event of QT prolongation was reported as related to study drug by the Investigator, 
however the event developed in the context of gastroenteritis with anorexia and dehydration. 
There were no reported cardiac symptoms or cardiac arrhythmia. QT prolongation resolved 
after osilodrostat was discontinued, and did not reoccur when osilodrostat was re-started at a 
lower dose.  
Other notable events included pituitary tumor enlargement and pituitary tumor reported in two 
patients. Both patients had elevated ACTH level. The study treatment was stopped in both 
patients because of pituitary surgery. The Investigators did not suspect a relationship between 
the events and treatment with osilodrostat. 

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In reviewing the clinical trial experience with osilodrostat to date, AEs have been identified that 
are consistent with the mechanism of action of the drug as an inhibitor of both cortisol and 
aldosterone synthesis. These can be summarized as follows: 
• Changes in adrenal hormones: cortisol decreased, aldosterone decreased, and their 
precursors (11-deoxycortisol, 11-deoxycorticosterone) increased  
• Change in pituitary hormone: ACTH increased 
• 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) 
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 CD, 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 CD 
trials and has included cases of neutropenia which were associated with cortisol levels that were 
either below normal or have had a rapid and substantial decline from baseline. In the cases 
observed to date, neutropenia has rapidly reversed with discontinuation of osilodrostat, and has 
also reversed when osilodrostat was continued, typically with decreasing doses.  
For a comprehensive review of clinical safety data with osilodrostat, see the [Investigator’s 
Brochure]. 
1.2.1.2.3 Osilodrostat: QT/QTc in healthy volunteers 
The potential impact of osilodrostat on cardiac repolarization potential was assessed in the 
definitive ICH E14 compliant thorough QT Study (TQT) study LCI699C2105 in 86 healthy 
male and female subjects. 
Based on the predicted exposure levels, 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 LCI699 doses up to 30 mg b.i.d. 
2 
Objectives and endpoints 
Objectives and related endpoints are described in Table 2-1 below.  
Table 2-1 
Objectives and related endpoints  
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
● To evaluate long term safety data 
Endpoint(s) for primary objective(s)  
● Frequency and severity of AEs/SAEs;  
Secondary Objective(s) 
● To evaluate clinical benefit as assessed 
Endpoint(s) for secondary objective(s) 
● Proportion of patients with clinical benefit as assessed by the 
Investigator at scheduled visits 

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Objective(s) 
Endpoint(s) 
by the investigator.  
● To evaluate long term safety data 
● Frequency, severity and summaries of relevant safety 
assessments. Safety assessments include: laboratory 
evaluations, vital signs (blood pressure and body weight), ECG 
and pituitary MRI. 
3 
Study design 
3.1 
Description of study design 
This is a multi-center, open label phase IIb study to evaluate the long-term safety of osilodrostat 
in subjects receiving osilodrostat in a Global Novartis-sponsored study which has fulfilled its 
requirements for the primary objective, and who are judged by their parent study Investigator 
as benefiting from continued treatment with osilodrostat. 
There will be no screening period for this study. Eligible subjects can start their treatment with 
osilodrostat as soon as they are enrolled in the study. The first study visit will be scheduled at 
the time of the last study visit for the parent study. At that time, sufficient supply of osilodrostat 
to cover a period of approximately 3 months may be dispensed to the subject/caregiver or as 
per local practice.   
Subjects must return to the study center at least on a quarterly basis (every 12 weeks ± 2 weeks) 
for safety and clinical benefit assessments, and resupply of study medication. Drug dispensing 
and administration information and adverse events will be collected. The subject may return to 
the clinic at any given time as per standard of care or treating physician recommendation; 
however, only the quarterly study visits will be recorded in the Case Report Form (CRF). Study 
medication dispensed will be recorded in the CRF dose administration page.  
All adverse events and serious adverse events, including pregnancy, will be collected 
throughout the study. 
The study is expected to remain open for approximately 5 years (or until 31-December-2023 in 
the UK) from First Patient First Visit (FPFV). Subjects will continue to be treated in this roll-
over study until they are no longer benefiting from their osilodrostat treatment as judged by the 
Investigator or until osilodrostat is commercially available or until one of other discontinuation 
criteria is met (please refer to Section 9.1.1). At every quarterly visit (every 12 weeks ± 2 weeks), 
the Investigator is required to confirm that the subject continues to have clinical benefit and 
may continue receiving study treatment. 
A subject will reach the end of study when osilodrostat treatment is permanently discontinued. 

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Figure 3-1 
Study Design  
 
4 
Rationale  
The purpose of this study is to evaluate the long-term safety of osilodrostat and to allow its 
continued supply to subjects who are currently receiving osilodrostat treatment in a Global 
Novartis- sponsored study that has reached its study objectives.  
These subjects are judged by the parent study Investigator as benefiting from continued 
treatment with osilodrostat and by the fact that, they would not be able to access osilodrostat 
outside a clinical trial. 
4.1 
Rationale for study design 
This is a multi-center, open-label, phase IIb roll-over study to evaluate the long-term safety of 
osilodrostat in subjects who have completed the parent studies and are judged by the parent 
study Investigator as benefiting from treatment. 
This roll-over study will not include a screening phase, at the completion of the parent study, 
as subjects will directly transfer from the parent studies. When their participation in the parent 
study has finished, eligible patients will start receiving osilodrostat only after they have signed 
the Informed Consent and have met the selection criteria for this roll-over study. 
 
4.2 
Rationale for dose/regimen and duration of treatment 
At the time of transition to this roll-over study, the starting dose should be the same as the last 
dose that was given at the last visit in the parent study. During the roll-over study, dose 
modification may be done at the discretion of the Investigator following the guidelines in 
Section 6.5. 
The maximum dose may not exceed 30 mg bid, which is the same maximum dose also applied 
in the parent studies.    
Osilodrostat (LCI699) will be given in form of film-coated tablets for oral administration, and 
available in the following dose strengths: 1 mg, 5 mg and 10 mg. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs  
Not applicable. 
 
Parent Novartis
Study 
 
   
 
Osilodrostat 
 
  
 
 
 
 
 
 
Osilodrostat is 
permanently discontinued 
 
Roll-over 
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End of Roll-over
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4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
4.5 
Risks and benefits 
There is still an unmet need in the treatment of CD: despite available therapies, a substantial 
number of subjects do not achieve normalization of cortisol, lose biochemical control over time 
or present medication-related adverse reactions and may stop treatment because of this.  
In order to mitigate the potential risks related to the administration of osilodrostat, some 
procedures will be taking place: 
• The starting dose should be the same as the dose provided in the parent osilodrostat study 
at the time of transition to the roll-over study. However, the investigator can change the 
dose based on the subject’s response; the maximal dose should not exceed 30 mg b.i.d. 
• Subjects will be evaluated by the treating investigator for clinical benefit and safety  based 
on the following assessments:  
• Physical examination (every 12 weeks) 
• Body weight / blood pressure (every 12 weeks), 12-lead safety ECG (every 24 
weeks), blood chemistry and hematology (every 24 weeks), 11-deoxycortisol and 11 
deoxycorticosterone (every 24 weeks), testosterone (every 24 weeks), Urinary Free 
Cortisol (UFC) (every 12 weeks), serum cortisol as clinically indicated, plasma 
ACTH (every 12 weeks) and pituitary MRI (every 48 weeks or more frequently if 
clinically needed). 
• AEs and SAEs will be reported continuously and evaluated by the investigator at each 
visit. 
• Drug administration record for dosing of osilodrostat will be completed at baseline and 
during treatment visits. 
• For females, urinary pregnancy test will be performed at each visit (every 12 weeks) and 
monthly, at home.   
• Upon administration of the last drug dose, discontinuation from the study or study end, the 
patient will have a follow-up visit 30 days later.  
• The protocol provides specific guidance for dose modifications and/or stopping rules, due 
to osilodrostat-related toxicities. In addition, a safety follow-up for liver toxicity and 
management of QT prolongation have also been included.  
Potential subject benefits 
There is an unmet medical need in subjects with CS since this is a rare and serious disease but 
with limited medical treatment options. 
An open label, proof-of-concept, single-arm study (CLCI699C2201, LINC 2) has been 
conducted to assess the safety and tolerability of osilodrostat in patients with CD after 10 weeks 
of treatment.  
In this study, 12 CD patients received osilodrostat orally for 10 weeks. The drug was given at 
the starting dose of 2 mg b.i.d., and was progressively increased on the basis of the urinary 

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cortisol levels till their normalization or a maximum dose of 50 mg b.i.d. was achieved. After 
10 weeks of treatment, all 12 patients normalized urinary cortisol levels or achieved a > 50% 
reduction in urinary cortisol levels. The reduction of urinary cortisol levels was accompanied 
by a trend towards a decrease in BP. Osilodrostat was generally well tolerated, with the most 
frequently reported adverse events being fatigue (58.3%), nausea (41.7%), diarrhea (25%), 
headache (25%), hypokalemia (25%), muscle spasms (25%) and vomiting (25%).  
Recently, an amended extension of the phase II study (CLCI699C2201, LINC 2) is currently 
ongoing with the overall objective of evaluating the efficacy and safety of osilodrostat for a 
longer period of time. After 22 weeks of treatment, 15 out of 19 patients (78.9%) had 
normalized UFC. The decrease in urinary cortisol levels was associated with improvements in 
the glucose and lipid profiles. Adverse events during this extension of the study included GI 
disturbances (nausea and diarrhea in 31.6%), asthenia (31.6%) and adrenal insufficiency 
(31.6%), together with an increase in ACTH, cortisol and aldosterone precursors, and an 
increase in testosterone, which, in some women was associated with onset or worsening of acne 
and hirsutism.  
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.  
After the initial 22 weeks (core study), patients were invited to enter the extension study up to 
month 31. Safety and efficacy results have shown that the drug’s profile will fulfill the unmet 
need in the medical management of endogenous hypercortisolism because: 
• Normal UFC was maintained for >2.5 years in a majority of patients. 
• None of the patients with normalization of cortisol experienced escape from response 
• Clinical  measures improved, particularly body weight and BMI 
• Occurrences of the most commonly reported AEs decreased over time 
Therefore, osilodrostat seems to be a promising drug for the treatment of CD, with a satisfactory 
safety and tolerability profile. 
Risks of osilodrostat treatment in study population 
Known risks of treatment with LCI699 in patients with CS include: QT prolongation, 
hypocortisolism/adrenal insufficiency, AEs related to the accumulation of precursor molecules, 
including: increased or decreased blood pressure, hypokalemia or hyperkalemia, hyponatremia, 
weight gain, edema, and increase in the synthesis of sex steroids (primarily adrenal androgens 
in women) that may lead to menstrual changes and hirsutism in women and acne in either men 
or women. Skin rash has been observed. Corticotroph tumor progression, with or without 
compressive symptoms, is a potential risk. 
Neutropenia has been observed in a small number of patients with CD receiving 
osilodrostat. Preliminary assessment suggests that these events might be associated with 
cortisol levels that are either below normal or have had a rapid and substantial decline from 
baseline. In the observed cases, neutropenia rapidly reverses either spontaneously (typically 
after dose decrease) or with discontinuation of osilodrostat. 

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In addition, the protocol provides specific guidance for safety follow-up for liver toxicity 
(increased transaminases, increased total bilirubin) and an algorithm for monitoring and 
management of QT prolongation.   
Conclusion 
The treatment of patients with CS still represents a challenge: the available treatments do not 
lead to biochemical control in quite a large number of patients and many of them lose 
biochemical control over time.  
Therefore there is an unmet medical need to develop new drugs with improved safety, efficacy 
and a more patient-friendly profile.  
Based on current safety and efficacy data of osilodrostat, the overall benefit-risk of trial 
participation is expected to be positive for all subjects to be enrolled in this study. 
5 
Population 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Patient is currently participating in a Global Novartis-sponsored study receiving 
osilodrostat for any type of endogenous CS and has fulfilled all their requirements in the 
parent study. 
2. Patient is currently benefiting from treatment with osilodrostat, as determined by the 
Investigator.  
3. Patient has demonstrated compliance, as assessed by the Investigator, with the parent 
study protocol requirements. 
4. Willingness and ability to comply with scheduled visits and treatment plans. 
5. Written informed consent obtained prior to enrolling into the roll-over study before 
evaluating the applicability of the subject’s participating in the study. 
• If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness. 
5.2 
Exclusion criteria 
Patients meeting any of the following criteria are not eligible for inclusion in this study. 
1. Patient has been permanently discontinued from osilodrostat study treatment in a parent 
Novartis-sponsor study. 
2. Patients who are receiving osilodrostat in combination with unapproved or experimental 
treatments for any type of endogenous CS. 
3. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory evaluation. 

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Pregnant or nursing (lactating) women 
4. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 1 week of study after stopping medication. Highly effective 
contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation. at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to baseline). The vasectomized male partner 
should be the sole partner for that subject 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment, and must be used in combination with a 
barrier method (male condom). 
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) or 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, it will be considered not of child bearing 
potential. 
6 
Treatment 
Study treatment and investigational treatment refer to osilodrostat. 
6.1 
Study treatment 
The study treatment consists of osilodrostat (LCI699), in the form of film-coated tablets for oral 
administration, in the following tablet strengths: 1 mg, 5 mg and 10 mg. Each strength has a 
unique size, color and imprint (Y1, Y2 and Y3) on each tablet which can be used for specific 
identification. 

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6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply type 
Sponsor (global 
or local) 
Osilodrostat 
Film-coated tablet up to 
30 mg 
Oral use 
Open label 
bulk supply 
Bulk product 
supplied by 
Novartis  
Finished product: 
supplied by IQVIA 
Vendor* or 
Novartis 
∗ 
Upon sponsorship approval status 
The starting dose of study treatment for patients in this study should be the same as the dose 
provided in the parent osilodrostat study at the time of transition to the roll-over study.  
However, the investigator can change the dose and frequency of osilodrostat administration 
based upon the subject’s response but should not exceed 30 mg b.i.d.  
Study drug should be taken twice a day (b.i.d.). For example a subject 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. If vomiting occurs 
during the course of treatment, patients should not take the study drug again before the next 
scheduled dose. Subjects 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.  
At every quarterly visit (every 12 weeks ± 2 weeks) patients will receive sufficient supply of 
osilodrostat to cover a period of at least 3 months until the next scheduled visit.  
Subjects should be requested to bring their unused study drug, including the empty packs, to 
the clinic at each visit. Compliance should be verified and documented by the Investigator’s 
staff by counting the number of dispersible tablets consumed between visits. The Investigator 
(or his/her designee) will document dosage administration and all dose changes during the study 
in the eCRF. The site must maintain an overall drug accountability log for the study, as well as 
individual accountability records for each patient. The dose, amount dispensed, amount 
received, and amount remaining unused must be recorded in the source document. Drug 
accountability will be noted by the field monitor during site visits and at the completion of the 
study. The patient will return all unused study drug at each dispensing visit and at the end of 
the study. 
6.1.2 
Additional study treatments  
Not applicable. 
6.1.3 
Treatment arms/group  
Subjects will receive the same dose as the dose provided in the parent osilodrostat study at the 
time of transition to the roll-over study. 

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6.1.4 
Guidelines for continuation of treatment  
Osilodrostat therapy is continued unless it must be interrupted or discontinued for safety or 
other reasons. See Section 6.5  for details. 
6.1.5 
Treatment duration 
The study is expected to remain open for approximately 5 years (or until 31-December-2023 in 
the UK) from FPFV. Subjects will continue to be treated in the roll-over study until they are no 
longer benefiting from their osilodrostat treatment as judged by the Investigator or until 
osilodrostat is commercially available or until one of other discontinuation criteria is met 
(please refer to Section 9.1.1). At every quarterly visit (every 12 weeks ± 2 weeks), the 
Investigator is required to confirm that the subject continues to have clinical benefit and can 
continue receiving study treatment. A subject will reach the end of the roll-over study when 
osilodrostat treatment is permanently discontinued. 
6.2 
Other treatment(s)  
6.2.1 
Concomitant therapy 
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 subject 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 subject signs the informed 
consent must be documented at the study site. 
6.2.1.1 
Permitted concomitant therapy 
The subject must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be documented at the study site. 
6.2.1.2 
Permitted concomitant therapy requiring caution and/or action  
Spironolactone and eplerenone are permitted for the treatment or prevention of study drug-
related edema or hypokalemia. The use of these drugs should be done with close monitoring for 
the potential risk of severe hyperkalemia, which is further increased if renal insufficiency is 
present. 
Spironolactone, cyproterone acetate or finasteride for treatment of hirsutism are approved in 
some countries and are not prohibited. 
Medications that are metabolized by CYP450 enzymes 
In vitro drug metabolism studies show that LCI699 is a potential inhibitor of CYP1A2, 
CYP2C19, CYP2D6, CYP3A4/5 and CYP2E1, and may consequently increase exposure to 
drugs metabolized by this enzyme. 

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In a clinical DDI study, LCI699 was found to be a moderate inhibitor of CYP1A2 (2.5-fold 
increase in substrate exposure), a weak to moderate inhibitor of CYP2C19 (1.9-fold increase in 
substrate exposure), and a weak inhibitor of CYP2D6 and CYP3A4/5 (1.5-fold increase in 
substrate exposure). Therefore concomitant medications that are known substrates of these 
enzymes (see Appendix 1) and which have a narrow therapeutic index should be used with 
caution. 
The subject and the Investigator should be aware of potential signs of overdose of the 
concomitant medication and in the event of suspected toxicities; administration of either the 
substrate or LCI699 should be discontinued according to Investigator’s judgment. 
6.2.2 
Prohibited medication 
Use of the following concomitant medication is prohibited during the study: 
• Other drug treatments for CD or CS; 
• Medications with a “known risk to cause Torsades des Pointes (TdP)” and “possible risk 
to cause TdP”; 
• Eplerenone and glucocorticoids, except under certain conditions: 
• Eplerenone may be used if necessary in acute post-myocardial infarction management, 
and in the event of refractory hypokalemia in patients with hypertension or edema; 
glucocorticoids may be used as required for the short-term treatment of hypocortisolism 
or adrenal insufficiency. 
• Glucocorticoids (e.g., prednisone, prednisolone, and dexamethasone) may be used as 
required for the short-term treatment of hypocortisolism or adrenal insufficiency. If 
glucocorticoids are used in stress doses, or as replacement therapy, for > 4 weeks, then 
the investigator should consider temporary interruption of LCI699, weaning and 
discontinuation of glucocorticoid therapy, or early discontinuation from the study. 
6.2.2.1 
Concomitant medications with a “Known risk to cause TdP” and with 
a “Possible risk to cause TdP”. 
Preclinical and clinical data indicate that there is a risk of QTc prolongation in humans (see 
Section 6.5.1.2). Therefore, the use of medications with a “known risk to cause TdP” and 
with a “possible risk to cause TdP” concomitantly with LCI699 is prohibited. If a subject 
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 subject requires such a drug for short-term therapy, e.g., antibiotics for active 
infection, then the LCI699 treatment may be interrupted temporarily while this drug is 
administered after a thorough risk-benefit assessment. This does not require the subject to 
discontinue from the study prematurely. Washout periods for LCI699 and the short-term 
prohibited drug in many cases may not be possible; this is acceptable if the benefit of the drug 
outweighs the risk of withholding LCI699 therapy in the investigator’s judgment. In such 
cases, a discussion with the Recordati Medical Monitor is recommended. 
Please refer to Section 14.2 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 

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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 Recordati Medical 
Monitor when considering the use of medications with a “known risk to cause TdP” and with 
a “possible risk to cause TdP”A list of drugs with a “known risk to cause TdP” and with a 
“possible risk to cause TdP” can be found at crediblemeds.org\ 
6.3 
Subject numbering, treatment assignment, randomization  
6.3.1 
Subject numbering 
Each subject 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 subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Recordati to the investigative site) with a sequential 
subject 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. 
6.3.2 
Treatment assignment, randomization 
All consented subjects who satisfy all the inclusion and exclusion criteria, are eligible to receive 
osilodrostat. 
6.4 
Treatment blinding  
Not applicable. 
6.5 
Dose modification 
6.5.1 
Dose modifications 
6.5.1.1 
Dose modification and dose delay 
The osilodrostat dose should be adjusted until normalization of cortisol. The treating physician 
can increase the dose as needed, up to 30 mg b.i.d.  
For subjects who are unable to tolerate the current dose, dose adjustments can be done at 
investigator’s discretion. The guidelines below may be followed: 
• If the subject has not reached normalization of cortisol, but does not tolerate the current 
dose, administration of an intermediate dose (between the current and preceding dose) or 
repeated administration of the preceding, tolerated dose should be considered. 
• If the subject has reached normalization of cortisol, but the current dose is no longer 
tolerated, an intermediate dose between the current dose and previous dose should be 
considered. 
• If the subject had reached normalization of cortisol, but the current dose is no longer 
efficacious based on cortisol measurements, dose escalation should resume. 

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• If the subject has low serum cortisol < LLN, and the patient has signs/symptoms of 
cortisol-withdrawal syndrome or adrenal insufficiency, a dose reduction of LCI699 should 
be considered. 
Any dose changes must be recorded on the Dosage Administration Record eCRF. 
At the time of the next study visit, the patient must:  
• Return all unused tablets to the site for drug accountability. 
• The IRT system specifies which study drug packs are to be dispensed to the patient. It is 
very important for the site personnel and the subject to be aware that it is possible that 
more than one tablet strength may be dispensed at the same visit. 
• Receive instructions on how to administer the dose and dosing schedule.   
Additional dose modifications guidance is summarized in Table 6-2. Deviations to mandatory 
dose interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-2 or listed in Section Section 9.1.1. 
Table 6-2 
Dose Modification Guidelines for osilodrostat-suspected toxicities 
Toxicity 
Suggested Actions 
Symptomatic hypocortisolism 
or adrenal insufficiency 
If the investigator at any time suspects hypocortisolism or adrenal insufficiency, 
they can immediately interrupt study drug and initiate replacement with 
glucocorticoids.  
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 cortisol 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 cortisol is 
normal or > ULN. 
Persistent asymptomatic 
hypocortisolism (cortisol < 
LLN) at the lowest dose of 
LCI699 (1 mg every other 
day) 
The investigator can interrupt study drug and restart at the same dose as 
clinically indicated. 
Glucocorticoid withdrawal 
syndrome 
Reduce or withhold dose until improved 
*Hypotension (mild, 
reversible) 
Reduce or withhold dose until improved 
*Hypertension 
Reduce or withhold dose until improved; consider angiotensin-converting-
enzyme (ACE) inhibitors if appropriate for treatment of hypertension, or 
spironolactone as a second line treatment, particularly if hypokalemia is 
present. ACE inhibitors and spironolactone should not be used in combination. 
*Weight gain, edema 
Reduce or withhold dose until improved; consider spironolactone for treatment 
of edema. 
*Hypokalemia 
Consider reducing or withholding dose until improved; replace potassium; 
consider spironolactone or eplerenone for prevention and treatment of 
hypokalemia 
*Hyperkalemia 
Consider reducing or withholding dose until improved; if on spironolactone or 
eplerenone, reduce or withhold; treat with kayexalate and other potassium 
lowering therapies as needed. 

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Toxicity 
Suggested Actions 
*Hirsutism (women only) 
Reduce or withhold dose until improved; review testosterone level; consider 
spironolactone, cyproterone acetate or finasteride per local guidelines. 
*Acne (women or men) 
Reduce or withhold dose until improved; review testosterone level; consider 
spironolactone, cyproterone acetate or finasteride per local guidelines. 
 * Abbreviations: ULN, upper limit of the normal reference range; LLN, lower limit of the normal reference 
range; ACE, angiotensin-converting-enzyme. 
It is expected that subjects will be seen urgently in an unscheduled visit at the site in the event 
of signs/symptoms of suspected hypocortisolism or adrenal insufficiency or any other AE that 
requires study drug interruption with or without glucocorticoid therapy. 
However, there may be occasions in which the subject has been seen at another health care 
facility, or has called in to report symptoms; in these cases, subjects should be advised to come 
to the site as soon as possible if it is safe, or go to the nearest hospital emergency room. 
In addition, any AE, regardless of suspected drug causality, may require interruption of 
osilodrostat and replacement or stress doses of glucocorticoid therapy until resolution of the 
event. 
• Upon recovery from the AE, the investigator may consider re-starting osilodrostat if the 
dose interruption has been ≤ 14 days. 
• If the dose interruption has been > 14 days, then the subject should be observed. If cortisol 
rises to above the ULN, and has been off glucocorticoid therapy for at least one week, 
osilodrostat may be re-started. 
Table 6-3 
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  
Withhold study drug. Monitor liver function tests (LFT)a weekly , or 
more frequently if clinically indicated, until resolved to ≤ 1.5 x ULN: 
If resolved in ≤ 14 days, then maintain dose level  
If resolved in > 14 days, then decrease by one dose level. 
> 3.0 - 10.0 x ULN*  
Withhold study drug. Monitor LFTsa weekly, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 x ULN: 
If resolved in ≤ 14 days, then decrease by one dose level. 
If resolved in > 14 days, then discontinue patient from study drug 
treatment. The patient should be monitored weekly (including LFTsa), 
or more frequently if clinically indicated, until total bilirubin has 
returned to baseline or stabilized over 4 weeks.  
> 10.0 x ULN* 
Discontinue patient from study drug treatment 
The patient should be monitored weekly (including LFTsa), or more 
frequently if clinically indicated, until total bilirubin has returned to 
baseline or stabilized over 4 weeks. 
Isolated AST or ALT elevation  
> ULN - 3.0 x ULN 
Maintain dose level 
> 3.0 - 5.0 x ULN  
 
 
 
Maintain dose level. Repeat LFTsa as soon as possible, preferably 
within 48-72 hours from awareness of the abnormal results; if 
abnormal lab values are confirmed upon the repeat test, then monitor 
LFTsa weekly, or more frequently if clinically indicated, until resolved 
to ≤ 3.0 x ULN 

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> 5.0 - 10.0 x ULN 
Withhold study drug. Repeat LFTsa as soon as possible, preferably 
within 48-72 hours from awareness of the abnormal results; monitor 
LFTsa weekly, or more frequently if clinically indicated, until resolved 
to ≤ 3.0 x ULN. Then: 
If resolved in ≤ 14 days, restart study drug and maintain dose level 
If resolved in > 14 days, restart study drug and decrease dose by one 
level 
If not resolved after 4 weeks, discontinue patient from study treatment 
> 10.0 x ULN  
Permanently discontinue study drug. Repeat LFTsa as soon as 
possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsa weekly, or more frequently if clinically 
indicated, until resolved to ≤3 x ULN. 
Combined b, c elevations of AST or ALT and total bilirubin 
For patients with normal baseline ALT 
and AST and total bilirubin value: 
AST or ALT >3.0 x ULN combined with 
total bilirubin >2.0 x ULN without 
evidence of cholestasisc  
OR   
For patients with elevated baseline AST 
or ALT or total bilirubin value: 
[AST or ALT>2x baseline AND > 3.0 
xULN] OR [AST or ALT > 8.0 xULN], 
combined with [total bilirubin >2x 
baseline AND >2.0 xULN 
Permanently discontinue patient from study drug treatment.  
 
Repeat as soon as possible, preferably within 48 hours from 
awareness of the abnormal results, then with weekly monitoring of 
LFTsa, or more frequently if clinically indicated, until AST, ALT, or 
bilirubin have returned to baseline or stabilized over 4 weeks.   
Refer to Section 6.5.3 for additional follow-up evaluations as 
applicable. 
All dose modifications should be based on the worst preceding toxicity. 
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.) 
“Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold. 
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose 
or at one dose lower if meeting a criterion for dose reduction 
“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. 
If the subject has interruption of osilodrostat for more than 4 weeks, the investigator should 
consider early discontinuation from the study. 
6.5.1.2 
Follow-up for QT prolongation  
In the event that QT prolongation is detected during routine investigation, the following 
guidance is provided to be followed by the investigator: 
• If a QTcF > 480 msec is observed or an increase of the QTcF of >60 msec compared to 
baseline QTcF assessment of the roll-over, then two additional ECGs, each 2-3 minutes 
apart, need to be taken after the initial ECG. The mean QTcF from the triplicate ECGs will 
be determined. If the mean QTcF is > 480 msec or the mean QTcF increase is >60 msec 
compared to baseline, the patient has to interrupt study treatment while an urgent cardiology 

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consultation is obtained to re-evaluate the ECG and perform a clinical consultation. If 
immediate treatment is required for subject 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 subject has to discontinue 
according to the discontinuation procedure described in Section 9.1.1. The subject 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.  
a. If based upon the assessment by the cardiologist, the investigator considers that there 
is an acute cardiovascular safety risk and that the patient should not continue with:study 
medication, the patient needs to be discontinued immediately (discontinuation criteria 
described in Section 9.1.1). 
b. If based upon the assessment by the cardiologist, the investigator considers that there 
is not an acute cardiovascular safety risk; the patient can continue to receive study 
medication. 

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Figure 6-1 
QT monitoring Flow Chart 
 
* Please refer to Section 9.1.1, study treatment must be discontinued under this circumstance. 
6.5.2 
Follow-up for toxicities  
Please refer to Section 6.5.1. 
6.5.3 
Follow up for potential drug-induced liver injury (DILI) cases 
In the event that concomitant aminotransferase and bilirubin elevations are detected during 
routine investigation, the following guidance is provided to be followed by the investigator. 
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 

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The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis. 
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 evaluations, 
detailed history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory evaluations should include ALT, AST, albumin, creatine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2 .  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. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is performed 
in the study. 
5. 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 10.1.2) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
 The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit using pill counts (if applicable) and 
information provided by the subject. This information should be captured in the source 

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document at each visit. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log. 
6.6.2 
Emergency breaking of assigned treatment code  
Not applicable. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document. 
6.7.1 
Handling of study treatment 
Study treatment must be received by a designated person 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, all study treatment must be stored according to the 
instructions specified on the labels and in the [Investigator’s Brochure]. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
Recordati Quality Assurance. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the CRO monitor or to the address provided by Recordati or the CRO in 
the investigator folder at each site. 
7 
Informed consent procedures  
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 

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Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
CRO on behalf of Recordati will provide to investigators in a separate document a proposed 
informed consent form that complies with the ICH GCP guidelines and regulatory requirements 
and is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed by Recordati before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB. This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 
Women of child bearing potential must be informed that taking the study treatment 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 requirements. 
A copy of the approved version of all consent forms must be provided to the sponsor after 
IRB/IEC approval. 
8 
Visit schedule and assessments 
Assessment schedule lists all of the assessments when they are performed. All data obtained 
from these assessments must be supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event recorded on the CRF. 

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Table 8-1 
Assessment Schedule 
Visit Name 
Category 
Protocol 
Section 
Baseline / 
Enrollment 
Visits during Treatment 
(Week 12 and every 12 weeks (+/- 2 weeks) thereafter) 
End of study 
treatment (EoT) 
30 day safety 
follow-up post last 
dose of study drug 
/ End of Study 
 
 
W1D1 
W12D1 
W24D1 
W36D1 
W48D1 
W60D1 
Onwards 
EOT 
N/A 
Visit Number 
 
 
1 
110 
120 
130 
140 
150 
1999 
FU 
Obtain informed consent 
D 
7  
x 
 
 
 
 
 
 
 
Study History 
D 
8.2 
x  
 
 
 
 
 
 
 
Demography 
D 
8.2 
x  
 
 
 
 
 
 
 
Medical History 
D 
8.2 
x  
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
D 
5.1 
x 
 
 
 
 
 
 
 
Blood chemistry 
D 
8.4.3 
x  
 
x 
 
x 
 
x 
x 
Hematology 
D 
8.4.3 
x  
 
x 
 
x 
 
x 
x 
Physical examination  
S 
8.4.1 
x  
x 
x 
x 
x 
x 
x 
x 
Body weight / blood pressure  
D 
8.4.2 
x  
x 
x 
x 
x 
x 
x 
x 
UFC (two 24-h specimens)  
D 
8.4.3 
x  
x 
x 
x 
x 
x 
x 
x 
Plasma ACTH  
D 
8.4.3 
x  
x 
x 
x 
x 
x 
x 
x 
11-deoxycortisol and 11 
deoxycorticosterone, testosterone 
D 
8.4.3 
x  
 
x 
 
x 
 
x 
x 
12 Lead safety ECG assessment 
D 
8.4.4 
x  
 
x 
 
x 
 
x 
x 
Pituitary MRI  
D 
8.4.6 
x  
 
 
 
x 
 
x 
 
Urine pregnancy testing 
(if positive, serum pregnancy test 
required) – WOCBP only 
S 
8.4.5 
x  
At every visit and monthly (at home) 
x 
x 
Adverse events and Serious 
adverse events 
D 
10.1 
x  
continuous 
Osilodrostat drug administration 
record 
D 
6.1 
x  
continuous 
 
 

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Visit Name 
Category 
Protocol 
Section 
Baseline / 
Enrollment 
Visits during Treatment 
(Week 12 and every 12 weeks (+/- 2 weeks) thereafter) 
End of study 
treatment (EoT) 
30 day safety 
follow-up post last 
dose of study drug 
/ End of Study 
 
 
W1D1 
W12D1 
W24D1 
W36D1 
W48D1 
W60D1 
Onwards 
EOT 
N/A 
Confirmation of Clinical Benefit 
from Study Treatment 
D 
6.1.5 
x 
x 
x 
x 
x 
x 
x 
 
End of phase disposition 
D 
9.1.1 
 
 
 
 
 
 
x 
 
 
 

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8.1 
Screening 
Molecular pre-screening 
Not applicable. 
Screening 
At the enrollment visit the patient will complete a written informed consent. There will be no 
screening period for this study, this will be referred to as Baseline. Once consented, patients 
will be evaluated for eligibility via the inclusion and exclusion criteria. 
8.1.1 
Information to be collected on screening failures 
Not applicable. 
8.2 
Subject demographics/other baseline characteristics 
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF 
8.3 
Efficacy  
8.3.1 
Efficacy assessments 
At every 12 week-visit (± 2 weeks), the Investigator is required to confirm that the patient 
continues to have clinical benefit and may continue receiving study treatment. 
8.3.2 
Appropriateness of efficacy assessments 
Due to the nature of the roll over, only clinical benefit will be assessed. 
8.4 
Safety 
Safety assessments are specified in the assessment schedule, Table 8-1. 
For details on AE collection and reporting, refer to AE section.  
Safety assessments as specified below must be maintained in source documentation for each 
patient in the study consisting of case and visit notes (hospital or clinical medical records) as 
well in the clinical DB according to table 8.1. Letter “D” indicates which safety assessments 
should be recorded in eCRF and/or vendor DB and letter “S” indicates that the assessments 
should be recorded in site source patient data. 
At baseline visit, the data for all assessments (except Obtain inform consent, Confirmation of 
Clinical Benefit from Study Treatment, and End of phase disposition) will be taken from the 
parent study.  

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8.4.1 
Physical Examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities, vascular and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and/or pelvic exams may be performed. This will 
be conducted at visits according to the Assessment schedules. 
 Significant findings that are present prior to joining this study must be included in the Relevant 
Medical History/Current Medical Conditions screen on the patient’s eCRF. Significant findings 
made after the start of study drug which meet the definition of an Adverse Event must be 
recorded on the Adverse Event screen of the patients eCRF. 
8.4.2 
Body weight and blood pressure 
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured. Body weight will be measured at visits according to the Assessment schedules. 
After the patient has been sitting for 3 minutes, with back supported and both feet placed on the 
floor, systolic and diastolic blood pressure will be measured three times using an automated 
validated device, with an appropriately sized cuff. In case the cuff sizes available are not large 
enough for the patient's arm circumference, a sphygmomanometer with an appropriately sized 
cuff may be used. 
Blood pressure will be measured at visits according to the Assessment schedules.  
Body weight and blood pressure should be recorded in eCRF. 
8.4.3 
Laboratory evaluations 
All laboratory evaluations will be performed using central laboratory according to the 
Assessment schedule: blood chemistry (Albumin, alkaline phosphatase, total bilirubin,  calcium, 
creatinine, CK, GGT, inorganic phosphorus, lipase, amylase, magnesium, potassium, total 
protein, AST, ALT, sodium, urea/BUN and uric acid, HbA1c), hematology (Hemoglobin, 
hematocrit, red blood cell count, white blood cell count with differential, (monocytes, 
eosinophils, basophils, neutrophils, lymphocytes), and platelet count), testosterone, serum 
cortisol as clinically indicated, urine free cortisol (two 24-hour urine specimens collected), 
plasma ACTH, 11-deoxycortisol and 11 deoxycorticosterone. 
8.4.4 
Electrocardiogram (ECG) 
Twelve-lead safety ECGs are collected at the study site using ECG equipment available at the 
sites. This ECG must be read on site by a qualified physician (e.g., the investigator, or another 
qualified physician such as a consulting cardiologist) on the day they are collected and recorded 
in eCRF for each patient.  
Only ECGs with clinically significant (“notable”) abnormalities should be reported as AE. 
A “notable abnormality” is defined as: 
• QTcF > 480msec with acute cardiovascular risk, as assessed by a consulting cardiologist 
• Any QTcF > 500msec, confirmed by a consulting cardiologist 

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• QTcF increase > 60 msec from baseline. 
The frequency of the ECG assessment is provided in Table 8-1.  
8.4.5 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Pregnancy test will be performed as detailed in the assessment schedule Table 8-1. 
Assessments of Fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases: 
1. surgical bilateral oophorectomy without a hysterectomy 
2. reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at screening/baseline. 
8.4.6 
Pituitary scan 
Pituitary MRI scanning with gadolinium enhancement will be performed every 48 weeks or 
more frequently if clinically needed at visits according to the assessment schedule provided in 
Table 8-1 using the local site facility. These will be assessed locally to determine the longest 
diameter and the tumor volume. For MRI (or CT) images that are not interpretable for tumor 
volume, the longest dimension (in mm) will be summarized instead. If MRI intravenous contrast 
is contraindicated for a patient, a non-contrast MRI scan should be performed. If MRI cannot 
be performed at all then a CT (with i.v. contrast if not contraindicated) may be performed. 
Digital images are to be kept at the site in the event Recordati requests transfer of the files at a 
later date. The Pituitary MRI scanning should be recorded in eCRF. 
8.4.7 
Appropriateness of safety measurements 
The safety assessments are standard for this indication/subject population. 
8.5 
Additional assessments  
No additional tests will be performed on subjects entered into this study. 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment  
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator. 

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The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. Study treatment must be 
discontinued under the following circumstances: 
• Emergence of the following adverse events: 
 
• Hypertension defined as office mean sitting systolic BP> 180 mmHg or mean sitting 
diastolic BP> 110 mmHg ( confirmed and persistent, persistent is defined as 
unresolved with osilodrostat dose and/or other concomitant medication changes) 
• Any of the following laboratory abnormalities (confirmed): 
• Hyperkalemia (serum potassium > 6.0 mmol/L). 
• Hypokalemia (serum potassium <2.8 mmol/L). 
• Any of the following laboratory abnormalities (confirmed and persistent): 
• Hyperkalemia (serum potassium > 5.5 mmol/L). 
• Hypokalemia (serum potassium <3.0 mmol/L). 
• Hyponatremia (serum potassium <130 mmol/L). 
• AST or ALT >3.0 x ULN combined with total bilirubin >2.0 1 ULN without evidence 
of cholestasis. 
• QTcF > 500 msec, if confirmed by a cardiologist (see Section 6.5.1.2),  
• QTcF > 480 msec or QTcF increase is >60 msec compared to baseline 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. 
• 
 Pituitary tumor growth, if the tumor is < 2mm from the optic chiasm, or symptoms of 
actual compression of the optic chiasm emerge (visual field loss, cranial nerve palsies, 
diplopia) confirmed by MRI of the pituitary. 
• Protocol deviations 
• Lost to follow-up 
• Study terminated by the sponsor 
• Administrative problems 
• Physician decision 
• Subject/guardian withdraw consent 
• Subject has completed treatment based on study duration 
When current treatment becomes commercially available in the applicable country, the 
patient will be withdrawn from the study.  
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the subject 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 

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Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the subject/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the subject’s discontinuation from 
study treatment. 
9.1.2 
Withdrawal of informed consent  
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Recordati will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
9.1.3 
Lost to follow-up  
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed. 

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9.1.4 
Early study termination by the sponsor  
The study can be terminated by Recordati at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Recordati will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final visit) 
and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment  
Study completion is defined as when the last subject finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.  
All treated subjects should have a safety follow-up call conducted 30 days after last 
administration of study treatment. The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation. 
10 
Safety monitoring and reporting  
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Recordati qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory 
evaluation findings, or other assessments. 

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Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The [severity grade OR the Common Toxicity Criteria (CTC) AE grade (version 4.3 or 
higher)] 
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. its outcome i.e., its recovery status or whether it was fatal 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 

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• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.  
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.  
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met 

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Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.  
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the patient has stopped study treatment must 
be reported to IQVIA within 24 hours of learning of its occurrence. IQVIA, in its turn, will 
promptly inform Recordati. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. 
The date of the informed consent signed for this roll-over study (the roll-over date) is important 
to determine how SAEs should be reported: 
• Any SAEs occurred prior to that date should be reported for the parent protocol, including 
all the follow up information relevant to such SAEs. 
• New SAEs with an onset date on or after the roll-over date will be reported for this 
protocol. 
It is important to use the right SAE form with the correct protocol number for these two 
scenarios, to avoid confusion in SAE processing. For a patient already on the roll-over protocol 
but follow up information is reported for the previous SAEs in the parent protocol, it must be 
clearly labeled that this is for the parent protocol number. 
All follow-up information for the SAE including information on 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 must be reported separately as a new event. 
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 study treatment, IQVIA (in agreement with 
Recordati) may urgently require further information from the investigator for health authority 
reporting. IQVIA (on behalf of Recordati) may need to issue an Investigator Notification (IN) 
to inform all investigators involved in any study with the same study treatment 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 EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period after end of treatment should only be reported 
to IQVIA Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 

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To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to IQVIA (which in turn will promptly inform Recordati) 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 and reported by the investigator to IQVIA (which in turn will 
promptly inform Recordati). Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the study treatment any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported. 
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. Newborn of a patient who 
becomes pregnant during the study should be followed for 12 months post-delivery (from Day 
0 to Month 12 of life). 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
 
Table 10-1 
Guidance for capturing the study treatment errors including misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated 
with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
10.2 
Additional Safety Monitoring  
Not applicable. 

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11 
Data Collection and Database management  
11.1 
Data collection 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
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, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control 
Recordati personnel (or designated CRO, IQVIA) will review the data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology. 
Data about all study treatment (s) dispensed to the subject and all dosage changes will be tracked 
using an Interactive Response Technology (IRT). 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Recordati development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, an IQVIA 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, IQVIA employs several methods 
of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The field 
monitor will visit the site to check the completeness of subject records, the accuracy of data 
capture / data entry, the adherence to the protocol and to Good Clinical Practice, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 

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according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized IQVIA/CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
IQVIA clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. IQVIA monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
12.1 
Analysis sets 
The following sets will be used for statistical analysis and data reporting. 
12.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who receive at least one dose of study 
medication after enrolling into the roll-over study.  
12.1.2 
Safety set 
The Safety Set includes all patients who received at least one dose of study medication after 
enrolling into the roll-over study. For this study, the definition of FAS is the same as the safety 
set. 
12.1.3 
Per-Protocol set 
Not applicable. 
12.1.4 
Dose-determining analysis set 
Not applicable.  
12.1.5 
Pharmacokinetic analysis set 
Not applicable. 

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12.1.6 
Other analysis sets  
Not applicable. 
12.1.6.1 Efficacy/evaluable set  
Not applicable. 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively. 
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. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure (week) to osilodrostat, the highest dose/average dose/dose with 
longest duration (from each individual patients) during the study and the dose level by visit 
(summary statistics of dose level among existing patients at a given visit) will be summarized 
by means of descriptive statistics. Boxplots for dose level by visit will be provided. 
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed. 
12.4 
Analysis of the primary endpoint(s)  
12.4.1 
Definition of primary endpoint(s)  
The primary objective is to evaluate long term safety as assessed by the occurrence of 
AEs/SAEs. 
12.4.2 
Statistical model, hypothesis, and method of analysis  
No hypothesis will be tested. 
12.4.3 
Handling of missing values/censoring/discontinuations  
Not applicable. 
12.4.4 
Sensitivity and Supportive analyses  
Not applicable. 

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12.5 
Analysis of secondary endpoints 
The secondary efficacy objective of the study is to evaluate clinical benefit as assessed by the 
Investigator. Proportions of patients with clinical benefit as assessed by the Investigator will be 
summarized at scheduled visits. Categorical data will be presented as frequencies and 
percentages. 
The secondary safety objective of the study is to evaluate long term safety, assessed using 
laboratory data, vital signs (blood pressure and body weight), ECG and pituitary MRI. Details 
of the specific analyses for each type of safety endpoint is given in Section 12.5.1. 
12.5.1 
Safety endpoints  
12.5.1.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used.  
The overall observation period will be divided into two mutually exclusive segments: 
1. on-treatment period: from day of first dose of study medication in this study to 30 days 
after last dose of study medication 
2. post-treatment period: starting at day 31 after last dose of study medication. 
12.5.1.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events 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 post-treatment periods) will 
be listed and those collected during post-treatment period will be flagged. 
12.5.1.3 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 evaluations where grades are not defined by CTCAE v4.03, results will be 
categorized as low/normal/high based on laboratory normal ranges. 

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Laboratory data will be listed and summarized as appropriate. Details of specific analyses will 
be given in the Statistical Analysis Plan. 
12.5.1.4 Other safety data 
Vital signs 
Vital signs (BP and body weight) will be listed and summarized as appropriate. Details of 
specific analyses will be given in the Statistical Analysis Plan. 
Pituitary MRI 
Tumor volume and longest dimension will be evaluated as defined in Section 8.4.6  
The longest dimension (in mm) and tumor volume (if evaluated) will be will be listed and 
summarized as appropriate. Details of specific analyses will be given in the Statistical Analysis 
Plan. 
12.6 
Analysis of exploratory endpoints 
Not applicable. 
12.7 
Interim analyses  
No formal interim analysis is planned for this study. Interim analysis may be performed for 
regulatory purposes if deemed necessary. 
12.8 
Sample size calculation  
Not applicable. 
13 
Ethical considerations and administrative procedures  
13.1 
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. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. 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 IQVIA 
monitors, auditors, Recordati/ Quality Assurance representatives, designated agents of 

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Recordati, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform IQVIA (and in turn 
Recordati) immediately that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be disclosed to Competent 
Authorities, Ethics Committees and Investigators, submitted for publication and posted in a 
publicly accessible database of clinical trial results, such as Health Authority websites (e.g. 
Clinicaltrials.gov, EudraCT etc.). 
In accordance with Recordati publication policy, multicenter studies should be submitted for 
publication in peer-reviewed journals before, or in parallel with, any secondary publication (e.g. 
subgroups analyses or results from individual centers). A coordinating investigator will be 
designated by mutual agreement. Authorship will be determined by mutual agreement and in 
line with International Committee of Medical Journal Editors authorship requirements.  
In order to protect proprietary information and to provide comments, Recordati reserves the 
right to review all manuscripts and abstracts before their submission for publication or 
presentation at scientific meetings.  
13.4 
Quality Control and Quality Assurance 
Recordati maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and CRO systems are performed by auditors, independent 
from those involved in conducting, monitoring or performing quality control of the clinical trial. 
The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Recordati processes. 
Recordati will ensure that the CRO has in place its own Quality Management System to ensure 
compliance with written Standard Operating Procedures as well as applicable global/local GCP 
regulations and ICH Guidelines. 
14 
Protocol adherence  
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 

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Recordati and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
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 Recordati 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
14.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Recordati, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, IQVIA (and in 
turn Recordati) should be notified of this action and the IRB/IEC at the study site should be 
informed according to local regulations. 

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15 
References  
Arnaldi G, Angeli A, Atkinson AB, et al (2003). Diagnosis and Complications of Cushing’s 
Syndrome: A Consensus Statement. J Clin Endocrinol Metab; 88(12):5593-5602. 
Arnaldi G, Mancini T, et al (2012). Advances in the epidemiology, pathogenesis, and 
management of Cushing's syndrome complications. J Endocrinol Invest. 35: 434-448. 
Ayuk J (2012). Does Pituitary Radiotherapy Increase the Risk of Stroke and, if so, What 
Preventative Actions Should be Taken? Clin Endocrinol. 76(3):328-331. 
Biller BMK, Grossman AB, Stewart PM, et al (2008). Treatment of adrenocorticotrop 
independent Cushing’s Syndrome: a consensus statement. J Clin Endocrinol Metab; 
93(7):2454-62. 
Bochicchio D, Losa M, Buchfelder M, et al (1995). Factors influencing the immediate and 
late outcome of Cushing's disease treated by transsphenoidal surgery: a retrospective study by 
the European Cushing's Disease Survey Group. Journal of Clinical Endocrinology and 
Metabolism; 80, 3114-3120. 
Clayton R, et al (2011). Mortality and Morbidity in Cushing’s Disease over 50 Years in 
Stoke-on-Trent, UK: Audit and Meta-Analysis of Literature. J Clin Endocrinol Metab. 96(3): 
632-642. 
Feelders R, Pulgar S, Kempel A, et al (2012). The burden of Cushing’s disease: clinical and 
health-related quality of life aspects. Eur J Endocrinol 167: 311–326. 
Fleseriu M, Loriaux DL, Ludlam WH (2007). Second-line treatment for Cushing's disease 
when initial pituitary surgery is unsuccessful. Curr Opin Endocrinol Diabetes Obes 2007 Aug; 
14(4):323-8. 
Friedman R, et al (1989). Repeat transsphenoidal surgery for Cushing’s disease. J 
Neurosurgery 71(4):520–527.Issa B, Page M, Read G, et al (1999). Undetectable urinary free 
cortisol concentrations in a case of Cushing’s disease. European Journal of Endocrinology 
140: 148–151. 
Loeffler J, Shih H (2011). Radiation Therapy in the Management of Pituitary Adenomas. J 
Clin Endocrinol Metab: 96(7):1992–2003. 
Losa M, et al (2010). Pituitary Radiotherapy for Cushing’s Disease. Neuroendocrinology 92 
(suppl 1):107–110. 
Masri-Iraqui H, Robenshtok E, et al (2014). Elevated white blood cell counts in Cushing’s 
disease: association with hypercortisolim. Pituitary 2014 Oct; 17(5):436-40. 
Minniti G, et al (2007). Long-term follow-up results of postoperative radiation therapy for 
Cushing’s disease. J Neurooncol 84(1):79–84. 
Newell-Price J, Bertagna X, Grossman AB, et al (2006). Cushing’s syndrome. Lancet 2006; 
367(9522): 1605–17. 
Pivonello R, De Martino MC, De Leo M, et al (2008) Cushing’s Syndrome. Endocrinol Metab 
Clin N Am; 37:135-49. 
Pivonello R, et al (2015) Neuropsychiatric disorders in Cushing's syndrome. Front. Neurosci. 
9:129. doi: 10.3389/fnins.2015.00129 

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Sedney C, Morris J, Giannini C, et al (2012). Radiation-associated sarcoma of the skull base 
after irradiation for pituitary adenoma. Rare Tumors 4(1): e7. 
Sheehan J, Xu Z, Salvetti D, et al (2013). Results of Gamma Knife surgery for Cushing’s 
disease. J Neurosurg 119:1486–1492. 
Sonino N, Zielezny M, Fava G, et al (1996). Risk factors and long-term outcome in pituitary- 
dependent Cushing’s disease. Journal of Clinical Endocrinology and Metabolism; 81(7), 
2647-2652. 
Valassi E, et al (2012). Clinical consequences of Cushing’s syndrome. Pituitary. 15: 319-329. 

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16 
Appendices  
16.1 
Appendix 1: List of drugs to be used with caution with LCI699 
Osilodrostat should be used with caution when co-administered with CYP1A2 and CYP2C19 
substrates with a narrow therapeutic index such as theophylline, tizanidine and mephenytoin.  
Please refer to Section 5.1.5 of the current IB for further information”.  
16.2 
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 
LCI699: 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 Recordati Medical Monitor when considering the use of medications with a 
“known risk to cause TdP” and “possible risk to cause TdP”.