A Retrospective Observational Study to Evaluate the Safety and Effectiveness of Osilodrostat for the Treatment of Non-Cushing's Disease Cushing's Syndrome (LINC7)
Conditions: Cushing's Syndrome
Sponsor: RECORDATI GROUP

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TITLE PAGE 
RETROSPECTIVE OBSERVATIONAL STUDY PROTOCOL  
Protocol Title: 
A retrospective observational study to evaluate the 
safety and effectiveness of Osilodrostat for the 
treatment of non-Cushing’s disease Cushing’s 
syndrome (LINC7 Study) 
 
Protocol Number: 
LCI699-RECAG-NI-0596 
Protocol Version: 
2.0 
Protocol Date: 
18 April 2023 
 
 
 
This document contains confidential information of Recordati AG. 
Do not copy or distribute without written permission from Recordati AG. 
CONFIDENTIAL 

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Table of Contents 
TITLE PAGE ...................................................................................................................... 1 
1 
LIST OF ABBREVIATIONS ....................................................................................... 5 
2 
RESPONSIBLE PARTIES ........................................................................................... 7 
3 
PROTOCOL SIGNATURE PAGE (FOR SPONSOR) ................................................. 8 
4 
SYNOPSIS ................................................................................................................. 10 
5 
AMENDMENTS AND UPDATES ............................................................................ 12 
Section 4: Synopsis ........................................................................................................... 13 
Section 7: Table-1 Design elements (New Secondary Endpoint) ..................................... 13 
Section 7: Table-1 Design elements (Secondary End point) ............................................ 13 
Section 7: Table-1 Design elements (Secondary Endpoint) ............................................. 14 
Section 7: Table-1 Design elements (Exploratory Endpoint) ........................................... 14 
Section 7: Table 1: Design elements ................................................................................. 14 
Section 8.1: Figure 1: Study Schematic ............................................................................ 15 
Section 8.1: Study Design and .......................................................................................... 16 
Section 8.7.10: Analysis of Exploratory Endpoints .......................................................... 24 
Section 10: Management and reporting of adverse events/adverse drug reactions .......... 25 
6 
. BACKGROUND AND RATIONALE ..................................................................... 26 
7 
RESEARCH QUESTION AND OBJECTIVES, ENDPOINTS, AND VARIABLES
 
31 
8 
RESEARCH METHODS ........................................................................................... 33 
8.1 
Study Design .......................................................................................................... 33 
8.1.1 
Rationale for the Study Design ........................................................................... 41 
8.2 
Setting ..................................................................................................................... 41 
8.2.1 
Inclusion Criteria ................................................................................................ 41 
8.2.2 
Exclusion Criteria ............................................................................................... 42 
8.2.3 
Patient Enrolment ............................................................................................... 42 
8.2.4 
Patient Withdrawal and Replacement ................................................................. 42 
8.2.5 
Patient Identification Numbers ........................................................................... 42 

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8.3 
Variables ................................................................................................................. 43 
8.3.1 
Primary Variable ................................................................................................. 43 
8.3.2 
Secondary Variables ........................................................................................... 43 
8.4 
Data Sources ........................................................................................................... 44 
8.5 
Study Size ............................................................................................................... 45 
8.6 
Data Management ................................................................................................... 45 
8.6.1 
Data Collection ................................................................................................... 46 
8.6.2 
Data Processing .................................................................................................. 46 
8.6.3 
Archiving Study Records ................................................................................... 47 
8.7 
Data Analysis .......................................................................................................... 47 
8.7.1 
Statistical Hypothesis ......................................................................................... 48 
8.7.2 
General Considerations ...................................................................................... 48 
8.7.3 
Analysis Population(s) ........................................................................................ 48 
8.7.4 
Control of Bias and Confounding ....................................................................... 49 
8.7.5 
Patient Disposition .............................................................................................. 49 
8.7.6 
Protocol Deviation .............................................................................................. 49 
8.7.7 
Demographics and Baseline Disease Characteristics ......................................... 50 
8.7.8 
Analysis of Primary Endpoint ............................................................................ 50 
8.7.9 
Analysis of Secondary Endpoints ....................................................................... 50 
8.7.10 
Analysis of Exploratory Endpoint ...................................................................... 52 
8.7.11 
Interim Analyses ................................................................................................. 52 
8.7.12 
Stratified Analysis .............................................................................................. 52 
8.8 
Quality Control ....................................................................................................... 53 
8.8.1 
Data Quality Assurance ...................................................................................... 53 
8.8.2 
Electronic Data Capture/Electronic Case Report Forms and Source 
Documentation ................................................................................................... 53 
8.8.3 
Access to Source Data ........................................................................................ 54 
8.9 
Limitations of the Research Methods ..................................................................... 54 
8.10 Other Aspects .......................................................................................................... 55 
9 
PROTECTION OF HUMAN SUBJECTS ................................................................. 55 
9.1 
Ethical Considerations ............................................................................................ 55 
9.2 
Informed Consent ................................................................................................... 55 
9.3 
Protocol Approval and Amendment ....................................................................... 55 
9.4 
Confidentiality ........................................................................................................ 56 
9.5 
Duration of the Study ............................................................................................. 56 

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10 MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE DRUG 
REACTIONS .............................................................................................................. 56 
10.1 Definitions .............................................................................................................. 57 
10.1.1 
Categorisation of Adverse events ....................................................................... 58 
10.2 Collection and Reporting of Adverse Events/Adverse Reactions .......................... 59 
11 PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .. 60 
12 REFERENCES ........................................................................................................... 61 
13 APPENDICES ............................................................................................................ 63 
13.1 Appendix 1: List of Supplementary Documents .................................................... 63 
 
 
 
 
Figure 1. Study Schematic ................................................................................................ 35 
Table 1 Design Elements .................................................................................................. 31 
Table 2 Data Collection Schedule ..................................................................................... 37 
 
 
 

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1 LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse Event 
AESI 
Adverse events of special interest 
BL 
Baseline 
CD 
Cushing’s Disease 
CRF 
Case Report Form 
CRH 
Corticotropin-releasing hormone 
CRO 
Contract Research Organisation 
CS  
Cushing’s Syndrome  
CT 
computed tomography 
DCF  
Data Clarification Form 
DMP 
Data Management Plan 
DVS 
Data Validation Specification 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture  
EMA 
European Medicines Agency 
ENCePP 
European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance 
EU 
European Union 
FSH 
Follicle Stimulating Hormone 
GPP 
Good Pharmacoepidemiology Practices 
HbA1C 
Glycated Haemoglobin 
HCP 
Health Care Providers 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
LH 
Luteinizing Hormone 
LTF 
Loss to Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOL 
No Objection Letter 
PT 
Preferred Term 
QA 
Quality Assurance 
SAP 
Statistical Analysis Plan 
SD   
Standard Deviation 

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SMP 
Site Management Plan 
sNDA 
Supplemental New Drug Application 
SOC  
System Organ Class 
TEAE 
Treatment-emergent adverse events  
TFL 
Tables, Figures, Listings 
UFC  
Urinary free cortisol  
ULN 
Upper Limit Normal  
WK 
Week 
 

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2 RESPONSIBLE PARTIES 
  
Sponsor 
Recordati AG 
Rare Disease Branch 
Uferstrasse, 90                                                               
4057 Basel                                                                    
Ph. +41 61 205 61 00                                      
Fax +41 61 205 61 39 
 
Contract Research 
Organization (CRO)  
PAREXEL International (IRL) Limited 
70 Sir John Rogerson's Quay 
Dublin 2 
Ireland 
Principal or Coordinating 
Investigator(s) or 
Responsible Physician 
Dr Antoine Tabarin  
Hôpital Haut Lévèque 
1 Avenue De Magellan 
33604 Pessac  
France  

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3
PROTOCOL SIGNATURE PAGE (FOR SPONSOR)
PROTOCOL TITLE: A retrospective observational study to evaluate the safety 
and effectiveness of osilodrostat for the treatment of non-Cushing’s disease 
Cushing’s syndrome
PROTOCOL NUMBER: LCI699-RECAG-NI-0596
PROTOCOL VERSION: 2.0
Signature of Sponsor’s authorized representative(s):
Alberto M. PEDRONCELLI, MD, PhD
Clinical Development and Medical Affairs Head
33'

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STATEMENT OF COMPLIANCE – INVESTIGATOR SIGNATURE PAGE 
This study titled “A retrospective observational study to evaluate the safety and 
effectiveness of Osilodrostat for the treatment of non-Cushing’s disease 
Cushing’s syndrome” (Protocol Code: LCI699-RECAG-NI-0596)  
will be conducted in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), the ethical principles that 
have their origin in the Declaration of Helsinki and the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46). The 
Principal Investigator will assure that no deviation from, or changes to the 
protocol will take place without prior agreement from the sponsor. All 
personnel involved in the conduct of this study have completed Human 
Subjects Protection and ICH GCP Training. Also, the French data authority has 
been notified about this study documents and no-objection letter. 
I agree to ensure that all staff members involved in the conduct of this study 
are informed about their obligations in meeting the above commitments. 
 
Principal Investigator: ______________________ ___________________ 
Signature  
 
 
 
Date 
 
Name: ____________________________________________________ 
 
Address: __________________________________________________ 
__________________________________________________________ 
__________________________________________________________________ 
 
 
 

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4 SYNOPSIS  
 
Protocol Title: 
A retrospective observational study to evaluate the safety and 
effectiveness of osilodrostat for the treatment of non-Cushing’s 
disease Cushing’s syndrome (LINC7 Study) 
  
Protocol Number: 
LCI699-RECAG-NI-0596 
Protocol Version: 
2.0  
Protocol Date: 
18 April 2023 
Sponsor: 
Recordati AG  
Study Centre(s): 
13 sites in France  
Rationale and Background: 
Osilodrostat-an orphan medicine-was approved by the European 
Medicnes Agency (EMA) on 9 January 2020 for the treatment of 
endogenous Cushing’s Syndrome (CS) in adults, and by the 
United States (US) Food Drug Administration (FDA) on 6 March 
2020 for the treatment of adult patients with Cushing’s disease 
(CD) for whom pituitary surgery is not an option or has not been 
curative. Prior to approval and commercialization of osilodrostat 
in the european union (EU), patients with CS had already been 
initiated on osilodrostat under the French Autorisation Temporaire 
d’Utilisation (ATU) programme. 
 
Recordati proposes an FDA label expansion for osilodrostat to 
include all forms of CS. This study therefore intends to evaluate 
the safety and effectiveness of osilodrostat for the treatment of 
non-CD CS patients in support of an FDA supplemental New 
Drug Application (sNDA). 
 
Research Question and 
Objective(s): 
What is the effectiveness and safety of osilodrostat in non-CD CS 
patients treated in a real-world setting? 
Study Design: 
Retrospective, observational single-cohort study with up to 
36 months of retrospective real-world data review period.  

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Population: 
Patients treated with osilodrostat for CS under  
1. The 2019 French Autorisation Temporaire d’Utilisation 
(ATU), or 
2. routine clinical practice after commercialization of 
osilodrostat in France in June 2020 
Data Sources: 
Patients’ medical records  
Data Collection Method 
Electronic Data Capture (EDC) 
Study Size: 
Approximately 100 patients 
Data Analysis: 
Descriptive  

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5 AMENDMENTS AND UPDATES 
Amendment 1 
Overall Rationale for the Amendment: This amendment was initiated in response to 
FDA Advice/Information Request letter dated 13 February 2023. In addition, other 
updates and clarifications have been made for consistency throughout the protocol and to 
ensure alignment with regulatory authority requirements. 
Summary of changes are presented below. All underlined and bold texts denote new texts 
while strikethrough text is the deleted text in this Protocol Amendment 1. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 4: 
Synopsis 
Study centre(s): 
Deleted text: 
Approximately 20 sites in France 
New text: 
13 sites in France 
 
Study size: 
Deleted text: 
A minimum of 40-50 patients 
New text: 
Approximately 100 patients 
Study centre(s) and study size 
are updated. 
Section 7: Table-1 
Design elements 
(New Secondary 
Endpoint) 
 
New text: 
Proportion of patients with mUFC ≤ 
ULN at weeks 24, 36 and every 12 
weeks thereafter. 
To include “the proportion of 
patients with mUFC ≤ ULN at 
Weeks 24, 36, and every 12 
weeks 
thereafter” 
as 
a 
secondary endpoint, to assess 
the 
long-term 
effects 
of 
osilodrostat in patients with 
non-Cushing's 
disease 
Cushing's syndrome. 
Section 7: Table-1 
Design elements 
(Secondary End 
point)  
 
Deleted text: 
Change from baseline for biochemical 
variables to Week 4, 8, 12, 20, 28, 36, 
and to every 12 weeks until the earlier of 
loss to follow-up, death, or the end of the 
retrospective follow-up period or 
treatment discontinuation 
 
New text: 
Change from baseline for biochemical 
variables to Week 4, 8, 12, 18, 24, 36, 
and to every 12 weeks until the earlier of 
loss to follow-up, death, or the end of the 
retrospective follow-up period or 
treatment discontinuation 
To amend the protocol to 
replace 
study 
assessment 
visits. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 7: Table-1 
Design elements 
(Secondary 
Endpoint)  
 
Deleted text: 
Actual and percent Change in BMI, 
ECG, blood pressure, metabolic, 
biochemical, and hormone levels from 
baseline for clinical outcomes to Week 
4, 8, 12, 20, 28, 36, and to every 12 
weeks until the earlier of loss to follow-
up, death, or the end of the retrospective 
follow-up period or treatment 
discontinuation 
 
New text: 
Actual and percent Change in BMI, 
ECG, blood pressure, metabolic, 
biochemical, and hormone levels from 
baseline for clinical outcomes to Week 
4, 8, 12, 18, 24, 36, and to every 12 
weeks until the earlier of loss to follow-
up, death, or the end of the retrospective 
follow-up period or treatment 
discontinuation 
To amend the protocol to 
replace 
study 
assessment 
visits. 
Section 7: Table-1 
Design elements 
(Exploratory 
Endpoint)  
 
Deleted text: 
Proportion of patients with normal late 
night salivary cortisol at Week 4, 8, 12, 
20, 28, 36, and at every 12 weeks until 
the earlier of loss to follow-up, death, or 
the end of the retrospective follow-up 
period or treatment discontinuation 
New text: 
Proportion of patients with normal late 
night salivary cortisol at Week 4, 8, 12, 
18, 24, 36, and at every 12 weeks until 
the earlier of loss to follow-up, death, or 
the end of the retrospective follow-up 
period or treatment discontinuation 
To amend the protocol to 
replace 
study 
assessment 
visits. 
Section 7: Table 1: 
Design elements 
New text: 
Comprehensive metabolic panel 
(CMP), Complete blood count (CBC) 
Study 
variables 
made 
consistent across protocol 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.1: Figure 
1: Study 
Schematic 
Updated with new figure 
Updated last patient 
treatment start date according 
to actual study start date, 
which is actual first study 
site initiation visit date and 
replaced study assessment 
visits. 
Section 8.1:  Study 
Design 
 
Deleted text: 
Clinical practice medical records will be 
reviewed for all eligible patients who 
received osilodrostat between April 2019 
and the study start date (approximately 
Q4 2022) at study sites in France.  
New text: 
Clinical practice medical records will be 
reviewed for all eligible patients who 
received osilodrostat between April 2019 
and the study start date (16 December 
2022) at study sites in France. The study 
start date was the date the first site 
was initiated in the study, which was 
on 16 December 2022. 
All patients treated with osilodrostat 
between April 2019 and the study start 
date (16 December 2022) will be 
enrolled in the study. A no-objection 
letter (NOL) will be requested from the 
patients at enrolment unless the patient 
has previously signed a general consent 
for research.  
Updated last patient 
treatment start date according 
to actual study start date, 
which is actual first study 
site initiation visit date. 
 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.1:  Study 
Design,  
 
New text: 
 
Patients who have previously signed a 
general consent for research, either 
alive or deceased, can be enrolled with 
immediate effect. If no general consent 
was signed, a signed no-objection 
letter (NOL) will be requested from 
patients who are still alive. Some 
patients might not send the NOL back 
to the investigator. In such instance, 
the investigator can document a tacit 
approval from the patient if there is 
no response after a month of the first 
shipment of the NOL and after 3 
documented contact attempts. For 
deceased patients since their past 
treatment with osilodrostat, they can 
also be enrolled after the investigator 
has checked that the deceased patient 
did not leave any written document 
stating refusal to participate in any 
scientific research.  
 
To clarify NOL/tacit 
approval process. 
 
Section 8.1: Study 
Design and  
 
New text: 
The only patients excluded from the 
primary efficacy analyses will be the 
ones who started treatment with 
osilodrostat less than 12 weeks prior 
to the end of the abstraction period, 
and are still treated with osilodrostat 
at the end of the abstraction period. 
These patients will be included only in 
the analyses of the secondary and 
exploratory endpoints including 
safety. The patients who discontinued 
treatment for any reason or were lost-
to-follow up prior to 12 weeks will be 
considered non-responders for the 
primary endpoint. 
To clarify patients who 
discontinued treatment prior 
to 12 weeks for any reason or 
were lost-to-follow up will 
be considered non-
responders for the primary 
endpoint. 
Section 8.1: Table 
2: Data collection 
schedule 
 
• 
Replaced Week 20 +/-4 weeks 
with Week 18+/- 2 weeks 
• 
Replaced Week 28 +/-4 weeks 
with Week 24 +/-4 weeks  
To amend the protocol to 
replace 
study 
assessment 
visits. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.1: Table 
2: Data collection 
schedule 
Deleted Assessment: 
Comorbidities 
 
Form 
to 
capture 
co-
morbidities no longer present. 
The information whether a 
Medical 
history 
(MH)/Adverse Event (AE) is 
related to CS is enabled. 
Section 8.1: Table 
2: Data collection 
schedule 
New Assessment: 
Prior medications 
Updated prior medication 
collection period 
 
Section 8.1: Table 
2: Data collection 
schedule 
(footnote) 
 
Deleted footnote-b text: 
Any assessments occurred out of the 
tolerated time window will be collected 
as Unscheduled visits. 
New foot note-b text: 
The assessments which occurred 
closest to each defined visit should be 
recorded in the CRF, even if these 
assessments occurred on different 
dates. 
To clarify that there is no 
requirement 
to 
collect 
assessments out of tolerated 
time-window as unscheduled 
since there are no planned 
analysis with this data. 
 
Section 8.1: Table 
2: Data collection 
schedule 
(footnote) 
 
Deleted footnote-c text: 
A no-objection letter (NOL) will be 
requested from the patients at enrolment 
unless the patient has previously signed 
a general consent for research. 
 
New foot note-c text:  
Either the patient has previously signed 
a general consent for research, or a 
signed no-objection letter (NOL) will 
be requested from the patient if still 
alive. If patient does not send the NOL 
back to the investigator, the 
investigator can document a tacit 
approval from the patient if there is 
no response after a month of the first 
shipment of the NOL and after 3 
documented contact attempts. For a 
deceased patient since his/her past 
treatment with osilodrostat, access 
after the investigator has checked that 
this deceased patient did not leave any 
written document stating his/her 
refusal to participate in any scientific 
research.  
To clarify conditions for 
getting access to patient’s 
medical 
data 
before 
enrollment 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.1: Table 
2: Data collection 
schedule 
(footnote) 
 
New foot note-e text:  
All prior medications taken within 6 
months prior to the first dose of 
Osilodrostat must be collected.  
Updated prior medication 
collection period 
 
Section 8.1: Table 
2: Data collection 
schedule 
(footnote) 
New foot note-f text: 
Baseline mean urinary free cortisol 
(mUFC) data can be collected within 1 
month prior to osilodrostat initiation. 
To clarify previous data 
collection period for mUFC 
Section 8.1: Table 
2: Data collection 
schedule 
(footnote) 
New foot note-g text: 
Footnote-a is not applicable to the 
following assessments: prior 
medications, concomitant medications, 
medical and surgical history, and 
mean urinary free cortisol. 
To clarify foot note-a is not 
applicable to a few 
assessments 
Section 8.1: Table 
2: Data collection 
schedule 
(footnote) 
New foot note-h text: 
All available medical history and 
surgical history related to CS must be 
collected. Medical and surgical history 
not related to CS that occurred within 
6 months prior to the first dose of 
Osilodrostat must be collected. 
To clarify collection period 
for medical and surgical 
history related or not to CS 
Section 8.1: Table 
2: Data collection 
schedule 
(footnote) 
New foot note-$ text: 
Lipid variables include Total 
Cholesterol, HDL, LDL, and 
Triglycerides 
To clarify the lipid variables 
that will be captured. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.2: 
Setting 
 
Deleted text: 
The study population will consist of 
patients with non-CD CS. They must be 
able to provide electronically or 
manually a signed NOL and meet all the 
inclusion criteria and none of the 
exclusion criteria. 
New text: 
The study population will consist of 
patients with non-CD CS who meet all 
the inclusion criteria and none of the 
exclusion criteria. The authorization 
for getting access to the medical data 
of the patients must also be ensured, 
through the existence of a signed 
general consent, or requesting a 
signed NOL, or fulfilling the 
conditions of a tacit approval or no 
written document stating they refused 
any participation to scientific 
research. 
To clarify conditions for 
getting access to patients 
medical data. 
 
Section 8.2.1: 
Inclusion Criteria 
 
New text:  
Patients treated with osilodrostat 
between April 2019 and the study start 
date (16 December 2022) as part of 
ATU programme or commercialisation.  
Updated last patient 
treatment start date according 
to actual study start date, 
which is actual first study 
site initiation visit date. 
Section 8.2.2: 
Exclusion Criteria 
1 
 
New text:  
Patients 
who 
participated 
in 
an 
interventional clinical trial anytime 
during the study period. 
To clarify that patients who 
participated in an 
interventional clinical trial 
cannot be enrolled. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.2.3: 
Patient Enrolment 
 
Deleted text: 
Site policies and local regulations 
regarding patient consent (NOL) will be 
followed.  
New text: 
Site policies and local regulations 
regarding the access to their medical 
records will be followed All eligible 
patients identified at a site between April 
2019 and study start date (16 December 
2022) and consenting to be part of the 
study will be included. 
Updated last patient 
treatment start date according 
to actual study start date, 
which is actual first study 
site initiation visit date. 
To clarify that the access to 
patient’s medical records will 
be as per local regulations. 
 
Section 8.3.2: 
secondary 
Variables,  
Section 8.7.7: 
Demographics and 
Baseline Disease 
Characteristics 
Table 2: Data 
collection schedule 
Deleted text: 
Removed race and ethnicity details. 
Race/ethnicity are not 
collected due to local 
regulations. 
 
Section 8.3.2: 
Secondary 
Variables 
Deleted text: 
Co-morbidities (obesity, hypertension, 
osteopenia/osteoporosis, diabetes, 
impaired glucose tolerance, 
dyslipidaemia, poor wound healing, 
recurrent infections, oligomenorrhea or 
infertility, thromboembolic disease, and 
cardiovascular, neurologic, and 
psychiatric manifestations). 
Form to capture co-
morbidities no longer 
present. The information 
whether a MH/AE is related 
to CS is enabled. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.3.2: 
Secondary 
Variables 
Deleted text: 
Late night salivary cortisol. Laboratory 
investigations (CMP, CBC, lipids, 
HBA1c). 
New text: 
Morning serum cortisol and mUFC. 
Laboratory abnormalities (sodium, 
potassium, calcium levels, CO2, 
glucose, Glycated hemoglobin 
(HBA1c) and lipids. 
Comprehensive metabolic panel 
(CMP) and Complete blood count 
(CBC). 
Study variables made 
consistent across protocol. 
Removed late night salivary 
cortisol as it is not a 
secondary endpoint but 
exploratory endpoint. 
Section 8.7.3: 
Analysis 
Population 
 
 
New text: 
The ITT population consists of all 
enrolled participants who have met all 
inclusion/exclusion criteria and have 
received osilodrostat treatment for non-
CD CS, with a potential follow-up of at 
least 12 weeks. The only patients 
excluded from the primary efficacy 
analyses will be the ones who started 
treatment with osilodrostat less than 
12 weeks prior to the end of the 
abstraction period, and are still 
treated with osilodrostat at the end of 
the abstraction period. These patients 
will be included only in the analyses of 
the secondary and exploratory 
endpoints including safety. 
To clarify all patients enrolled 
in the study are included in 
the Intention to Treat (ITT) 
population, instead of only 
patients who have received 
osilodrostat with at least 12 
weeks follow up.  

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.7.3: 
Analysis 
Population 
Deleted text: 
The ITT population consists of all 
participants who have signed a general 
consent or the No-objection letter, have 
met all inclusion/exclusion criteria and 
have received osilodrostat treatment for 
non-CD CS, with at least 12 week follow 
up. 
New text: 
The ITT population consists of all 
enrolled participants who have met all 
inclusion/exclusion criteria and have 
received osilodrostat treatment for non-
CD CS, with a potential follow-up of at 
least 12 weeks. 
To clarify about patients 
included in the ITT 
population. 
 
Section 8.7.4: 
Control of Bias 
and Confounding 
New text: 
Investigators will include all patients 
treated with osilodrostat between April 
2019 and the study start date (16 
December 2022); to avoid selection bias 
in participant recruitment, all eligible 
patients will be included in the study. 
Updated last patient 
treatment start date according 
to actual study start date, 
which is actual first study 
site initiation visit date. 
 
Section 8.7.8: 
Analysis of 
Primary Endpoint 
New text: 
The patients who discontinued 
treatment for any reason or were lost-
to-follow up prior to 12 weeks will be 
considered non-responders for the 
primary endpoint. The patients who 
started treatment with osilodrostat 
less than 12 weeks prior to the end of 
the abstraction period, and are still 
treated with osilodrostat at the end of 
the abstraction period will be excluded 
from the analysis. 
To 
clarify 
patients 
who 
discontinued treatment for 
any reason or were lost-to-
follow up prior to 12 weeks 
will 
be 
considered 
non-
responders for the primary 
endpoint and those treated for 
less than 12 weeks but were 
still under treatment at the 
time of the end of the 
abstraction period should be 
excluded from the primary 
analysis. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.7.9: 
Analysis of 
Secondary 
Endpoints, 
 
Deleted text: 
Changes from baseline for biochemical 
variables and clinical outcomes to 
Week 4, 8, 12, 20, 28, 36, and to every 
12 weeks until the earlier of loss to 
follow-up, death, or the end of the 
retrospective follow-up period or 
treatment discontinuation will be 
summarised descriptively and provided 
as listing. 
New text: 
Changes from baseline for biochemical 
variables and clinical outcomes to 
Week 4, 8, 12, 18, 24, 36, and to every 
12 weeks until the earlier of loss to 
follow-up, death, or the end of the 
retrospective follow-up period or 
treatment discontinuation will be 
summarised descriptively and provided 
as listing. 
To amend the protocol to 
replace 
study 
assessment 
visits. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.7.10: 
Analysis of 
Exploratory 
Endpoints 
Deleted text: 
Late night salivary cortisol observed 
values at baseline and changes from 
baseline to Week 4, 8, 12, 20, 28, 36 and 
to every 12 weeks until the earlier of loss 
to follow-up, death, or the end of the 
retrospective follow-up period or 
treatment discontinuation will be 
summarised descriptively and provided 
as listing. Where applicable, proportion 
of patients with normal and/abnormal 
late night salivary cortisol at Week 4, 8, 
12, 20, 28, 30, 36 and at every 12 weeks 
until the earlier of loss to follow-up, 
death, or the end of the retrospective 
follow-up period or treatment 
discontinuation. 
New text: 
Late night salivary cortisol observed 
values at baseline and changes from 
baseline to Week 4, 8, 12, 18, 24, 36 and 
to every 12 weeks until the earlier of loss 
to follow-up, death, or the end of the 
retrospective follow-up period or 
treatment discontinuation will be 
summarised descriptively and provided 
as listing. Where applicable, proportion 
of patients with normal and/abnormal 
late night salivary cortisol at Week 4, 8, 
12, 18, 24, 30, 36 and at every 12 weeks 
until the earlier of loss to follow-up, 
death, or the end of the retrospective 
follow-up period or treatment 
discontinuation. 
To amend the protocol to 
replace 
study 
assessment 
visits. 

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Section # and 
Title 
Description of Change 
Brief Rationale 
Section 8.7.12: 
Stratified Analysis 
New text: 
 
The number and proportion of 
patients with mean urinary free 
cortisol (mUFC) ≤ULN at 12 weeks 
will be stratified if they received or not 
other therapies for Cushing’s 
syndrome (regardless of the type of 
therapy) and will be summarised 
descriptively along with associated 
95% CI. Differences in the 
proportions and 95% CI of the 
different groups will be evaluated. 
Further details will be described in the 
final SAP. 
To specify how to handle 
those patients who are on 
other therapies for Cushing's 
syndrome and who may 
confound the interpretation of 
the osilodrostat-related safety 
and efficacy results of the 
study.  
Section 9.2: 
Informed Consent 
Deleted text: 
However, a NOL for study participation 
has to be signed from the potential 
patients 
 
New text: 
The authorization for getting access to 
the medical data of the patients must 
also be ensured, through the existence 
of a signed general consent, or 
requesting a signed NOL, or fulfilling 
the conditions of a tacit approval or no 
written document stating they refused 
any participation to scientific 
research.  
To clarify conditions for 
getting access to patients’ 
medical data. 
 
Section 9.4: 
Confidentiality 
Deleted text: 
Documents not to be submitted to 
Parexel that identify the patient (e.g., the 
signed NOL) must be maintained in 
confidence by the investigator. 
To clarify that documents 
that could identify the patient 
should not be submitted to 
Parexel.  
Section 10: 
Management and 
reporting of 
adverse 
events/adverse 
drug reactions 
New text: 
Being a retrospective chart review, it 
does not require active reporting of 
AEs/ADRs to regulatory authorities. 
To clarify that reporting of 
AEs/ADRs refers to 
regulatory authorities, and 
not to investigator reporting 
responsibilities. 

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6 . BACKGROUND AND RATIONALE 
Endogenous Cushing Syndrome (CS) is a rare endocrine disorder characterised by 
sustained elevated cortisol levels, posing risk of multiple comorbidities leading to 
cardiovascular diseases and mortality. Cushing’s disease (CD) represents the most 
frequent cause of CS in 65-80% of cases. Ectopic Adrenocorticotropic hormone 
(ACTH)-secreting tumours (including neuroendocrine tumours) correspond to 10-15% of 
CS cases but may be underdiagnosed.  Adrenal adenomas and carcinomas are the cause 
of ~20% of CS cases, and the <10% remaining cases are caused by rarer diseases such as 
bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenocortical 
disease, or ectopic Corticotropin-releasing hormone (CRH) production.  
Endogenous CS is characterised by chronic hypercortisolism, resulting in metabolic 
dysregulation and comorbidities. Manifestations may be overt or subtle depending on 
severity of hypercortisolism. Comorbidities include menstrual irregularities and hirsutism 
in women, dermatological problems with striae, bruising, atrophy, hyperpigmentation, 
and fungal infections, obesity with moon facies, enlarged supraclavicular fat pads, and 
dorsal fat pad, glucose intolerance and diabetes, sleep apnoea, cardiovascular disease, 
venous thromboembolic events, bone loss, neuropsychiatric disease, and potentially 
severe infections. Whereas untreated Cushing’s syndrome had a 50% five-year mortality 
rate, treatment to control cortisol production should substantially mitigate the risk of 
death due to hypercortisolism (Nieman et al. 2015). 
Endogenous CS is a rare disease. Estimates of regional incidence have been limited and 
vary by aetiology and possibly methodology. CD is the most common cause of 
endogenous CS, with an estimated incidence in Europe of up to 2.4 per million and in the 
US of up to 7.6 per million depending on the series (Etxabe and Vazquez 1994; Broder et 
al. 2015; Tabarin et al. 2022). Adrenal tumours represent ~20% of CS cases (but may be 
higher in some countries such as Japan (Tanaka et al. 2020) and Italy (Invitti et al. 1999). 
Ectopic ACTH secretion from neuroendocrine tumours represent 10-15% of known CS 
cases. Different diseases causing CS manifest at different ages, i.e., smoking-related non-
small lung cancer increases after the age of 50 years, neuroendocrine (carcinoid) tumours 

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occur earlier in adulthood, and adrenal tumours have bimodal age peaks (1st decade and 
40-50 years old), whereas the peak incidence for CD is in women 25-45 years old 
(Bertagna and Orth 1981; Luton et al. 1990). CD occurs approximately 3 times than in 
men, women have a 4-5 times greater incidence of adrenal tumour causing CS, and 
neuroendocrine tumours causing CS are similar in incidence between the sexes 
(Carpenter 1988; Nieman et al. 2015). Heterogeneity in the cause and populations 
affected by non-CS CS, support the need of a dedicated efficacy and safety study 
focusing on non-CD CS population. Patients with CS have increased mortality, which 
applies both to patients with pituitary-dependent CS and adrenal-dependent CS, as well 
as patients with ectopic CS who have the worst prognosis (Ragnarsson et al. 2019).  
The Endocrine Society guidelines (Nieman et al. 2015) recommend normalisation of 
cortisol in patients with overt Cushing’s syndrome to mitigate signs, symptoms and 
comorbidities. Although first line of treatment for endogenous CS is often surgery or 
other disease-specific treatment (such as chemotherapy for a neuroendocrine tumour), 
patients often demonstrate the need for secondary treatments such pharmacotherapy 
because of persistence or recurrence, lack of surgical candidacy, and poor success rates of 
surgery other than bilateral adrenalectomy. Bilateral adrenalectomy ultimately may be 
required for control of unremittent disease in surgical candidates, resulting in permanent 
adrenal insufficiency.  
Pasireotide is a second-generation somatostatin receptor ligand indicated for the medical 
treatment of Cushing’s disease, suppresses corticotroph ACTH secretion that ultimately 
decreases cortisol production in the adrenals.  Cabergoline has also historically been used 
without regulatory approval to treat Cushing’s disease by inhibiting ACTH secretion at 
the pituitary level. 
Mifepristone is a glucocorticoid receptor antagonist approved in the US for the treatment 
of hyperglycaemia secondary to hypercortisolism in adult patients with endogenous 
Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance. 
Steroidogenesis inhibitors are often preferred, but use may be limited by availability, 
efficacy, compliance, or toxicity. Ketoconazole and metyrapone are not licenced in the 
United States: they tend to have a short onset of action and half-lives; metyrapone is 

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often a preferred class agent in Europe. Etomidate is also a steroidogenesis inhibitor with 
a rapid onset of action indicated for induction of general anaesthesia, requiring intensive 
monitoring by trained personnel. Mitotane is approved as an adrenolytic agent for 
adrenal cancer and has a relatively slow onset and long half-life. 
Osilodrostat is a potent oral 11β-hydroxylase inhibitor, blocking the cortisol synthesis 
process. The LINC-3 (Pivonello et al. 2020) demonstrated its rapid efficacy and 
sustained control of mean 24-hour urinary free cortisol (UFC) alongside improvements in 
clinical signs of hypercortisolism. Also, it was well-tolerated by patients.  
LINC 3 was a 4-period prospective, multicentre, open-label, phase III study with a 
double-blind randomised withdrawal period, which studied osilodrostat in 137 adults 
with confirmed persistent or de novo CD. Participants were initiated and treated to target 
mean UFC (mUFC) with open-label osilodrostat during Weeks 1 to 12, continued on a 
therapeutic dose of osilodrostat during weeks 13-24; eligible patients were randomised to 
either continue osilodrostat or switch to matching-placebo at Week 26 until Week 34, 
and then given open-label osilodrostat from Week 34 until study end at Week 48 whereas 
non—eligible patients continued open-label osilodrostat until the end of the core phase. 
At Week 34, maintenance of complete response was found in more patients in the 
osilodrostat group compared with the placebo group (31 [86%] vs 10 [29%]; odds ratio 
13·7 [95% CI 3·7–53·4]; p<0·0001). At Week 24, The proportion of patients with 
normal mUFC at week 24 is 93/137 (67.9) (CI (59.37, 75.60). Nausea (57/137 [42%]), 
headache (46/137 [34%]), fatigue (39/137 [28%]), and adrenal insufficiency (38/137 
[28%]) were the most common adverse events (AEs) (i.e., occurred in >25% of 
participants). Hypocortisolism-related AE were observed in (51%; n=70) and adrenal 
hormone precursors-related AE in (42%; n=58) of study patients. Also, other adverse 
events included anemia (8%), hypokalaemia (18 [13%]) and hypertension (17 [12%]). 
Non-serious cardiac adverse events included QT interval prolongation in five (4%) 
patients and pituitary adverse events included pituitary tumour enlargement, pituitary 
tumour volume increase, increased adenoma size, or pituitary tumour growth in four 
(3%) patients. This trial demonstrated adequate safety and efficacy of osilodrostat in 
patients with CD (Pivonello et al. 2020).  

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LINC-4 was a multinational phase III study of osilodrostat which assessed 73 adults with 
CD, with an upfront 12-week randomised, double-blind, placebo-controlled period 
followed by 36 weeks of open-label treatment. The LINC-4 study demonstrated that 
about 9 times more patients treated with osilodrostat (77%) compared with placebo (8%) 
achieved mUFC ≤ upper limit of normal (ULN) at Week 12 (OR 43.4; 95% CI 7.1-343.2; 
P<0.0001). The study showed that 80.8% of patients – including both patients initially 
randomised to osilodrostat or to placebo and then switched to active osilodrostat at 
Week 12 - had normal mUFC at week 36 with a maintained benefit at the end of 
treatment. During the overall study period, the most common AEs reported were 
consistent with the ones reported in LINC3 with the exception of adrenal insufficiency 
that was less frequently observed in LINC4 than in LINC3. The most common AEs were 
arthralgia, decreased appetite, nausea, and fatigue (Gadelha et al. 2022).  
Additionally, a phase II, single-arm, open-label, dose-titration, multicentre study (Tanaka 
et al. 2020) evaluating osilodrostat in Japanese patients with non-CD CS, demonstrated a 
reduction in mUFC in all patients with endogenous CS other than CD, regardless of 
disease type with a safety profile that was consistent with that reported previously in CD 
patients. Of the nine patients enrolled in the study, seven completed the 12-week core 
treatment period and two discontinued at or prior to Week 12 due to AEs. Of the seven 
patients who completed 12 weeks of study treatment, two completed 48 weeks of study 
treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose 
including dose interruption (0 mg/day) was 2.143 (1.16–7.54) mg/day. Median (range, 
population) percentage change in mUFC was –94.47% (–99.0% to –52.6%, n=7) at 
Week 12. At Week 12, 6/9 patients were complete responders (mUFC ≤ULN) and 
1/9 was a partial responder (mUFC >ULN but decreased by ≥50% from baseline). Most 
frequent AEs were adrenal insufficiency (n=7), gamma-glutamyl transferase increase, 
malaise, and nasopharyngitis (n=3 each). Serious AEs were seen in four patients. No 
deaths occurred in this study.  
Proven clinical evidence from such previous studies (Pivonello et al. 2020; Gadelha et al. 
2022) have made osilodrostat an effective orphan medicine with regulatory approval of 
its use in Europe and Japan for the treatment of endogenous CS and in the US for CD. 

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Prior to approval and commercialization of osilodrostat in the EU, patients with CS had 
already been initiated on osilodrostat within the French Autorisation Temporaire 
d’Utilisation (ATU) scheme as of April 2019.  
Recordati proposes an FDA label expansion for osilodrostat to include all forms of 
endogenous CS. This study therefore intends to evaluate the safety and effectiveness of 
osilodrostat for the treatment of non-CD CS patients in support of an FDA supplemental 
New Drug Application (sNDA). 

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7 RESEARCH QUESTION AND OBJECTIVES, ENDPOINTS, AND 
VARIABLES  
The proposed study will address the following questions:  
The overall objectives of this study are to retrospectively evaluate the safety and 
effectiveness of osilodrostat in the treatment of non-CD CS in France and to characterise 
clinical parameters of CS patients treated with osilodrostat. 
The proposed study will address the following research questions:  
• What are the safety and effectiveness of osilodrostat in the management of non-
CD CS patients in a real-world setting?  
• What is the cohort demography, and how do clinical characteristics change with 
osilodrostat treatment?  
• How is osilodrostat dosed and titrated in this patient cohort?  
• What are the outcomes in these patients, including long term?  
• How are these patients monitored (i.e., biochemically, and follow up 
characteristics)? 
• What is the incidence of overall treatment-emergent adverse events (TEAEs) and 
adverse events of special interest (AESI)? 
 
Table 1 Design Elements  
  
Objective 
Endpoint 
Variable  
Primary  
To estimate the 
effectiveness of 
osilodrostat in 
the treatment of 
non-CD 
Cushing’s 
Syndrome (CS) 
Number and Proportion of 
patients with mean urinary 
free cortisol (mUFC) 
≤upper limit of normal 
(ULN) at 12 weeks 
Mean Urinary free 
cortisol (mUFC) 

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Objective 
Endpoint 
Variable  
Secondary 
To assess the 
long-term 
effects of 
osilodrostat in 
the treatment of 
non-CD 
Cushing’s 
Syndrome (CS) 
Proportion of patients with 
mUFC ≤ ULN at weeks 24, 
36 and every 12 weeks 
thereafter. 
mUFC  
 
Secondary 
To assess the 
change in 
biochemical 
variables 
associated with 
osilodrostat 
treatment in 
non-CD CS 
patients  
Change from baseline for 
biochemical variables to 
Week 4, 8, 12, 18, 24, 36, 
and to every 12 weeks until 
the earlier of loss to 
follow-up, death, or the 
end of the retrospective 
follow-up period or 
treatment discontinuation 
mUFC; morning serum 
cortisol (normal and 
abnormal values as per 
standard definition) 
Secondary  
   
To assess actual 
and change in 
clinical 
outcomes 
associated with 
osilodrostat 
treatment in 
non-CD CS 
patients  
Actual and percent Change 
in BMI, ECG, blood 
pressure, metabolic, 
biochemical, and hormone 
levels from baseline for 
clinical outcomes to Week 
4, 8, 12, 18, 24, 36, and to 
every 12 weeks until the 
earlier of loss to follow-up, 
death, or the end of the 
retrospective follow-up 
period or treatment 
discontinuation 
Body Mass Index 
(BMI), 
electrocardiogram 
(ECG), Co-morbidities, 
Blood pressure, CS-
specific physical exam 
findings Laboratory 
abnormalities (sodium, 
potassium, calcium 
levels, CO2, glucose, 
Glycated haemoglobin 
(HBA1c), lipids), and 
hormones including: 
 Plasma ACTH 
 Serum 11-
Deoxycortisol 
 Plasma 11-
Deoxycorticosterone 
 Plasma Aldosterone, 
 Plasma Renin  
 Total Serum 
Testosterone or 
oestradiol per patient 
sex 
 Serum LH 
 Serum FSH 

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Objective 
Endpoint 
Variable  
To characterise 
initiating doses, 
up- and 
down--titration 
regimens for 
non-CD CS 
patients treated 
with osilodrostat 
Change from initial dose 
Dose 
To estimate the 
incidence of 
overall 
treatment-
emergent 
adverse events 
(TEAEs) and 
adverse events 
of special 
interest (AESI) 
for non-CD CS 
patients treated 
with osilodrostat 
Proportion of patients who 
experienced TEAE and 
AESI 
TEAE overall; TEAE 
specific to CS; AESI, 
Comprehensive 
metabolic panel (CMP), 
Complete blood count 
(CBC)  
Exploratory 
To assess 
change in late 
night salivary 
cortisol level 
from baseline to 
various 
timepoints for 
non-CD CS 
patients treated 
with osilodrostat  
Proportion of patients with 
normal late night salivary 
cortisol at Week 4, 8, 12, 
18, 24, 36, and at every 12 
weeks until the earlier of 
loss to follow-up, death, or 
the end of the retrospective 
follow-up period or 
treatment discontinuation  
Late night salivary 
cortisol 
 
8 RESEARCH METHODS 
8.1 Study Design  
This is a multi-centre, observational, non-comparative, retrospective cohort study 
designed to evaluate the long-term safety and effectiveness of osilodrostat in non-CD CS 
patients. Patients treated with oral osilodrostat regardless of the duration of their 
treatment will be followed retrospectively for up to 36 months after initiating 
osilodrostat. Follow-up for each patient will be variable, rather than fixed. Using a 
variable follow-up, rather than a fixed follow-up period for each patient, maximises the 

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person-time of patient follow-up in the study. This methodological approach allows for 
increased precision of findings compared to a fixed follow-up period because the unit of 
observation in analyses is person-time accrued aggregately across all eligible patients, 
rather than a count denominator of patients exposed to osilodrostat. Robust statistical 
properties are also associated with this study design feature.  
Participating institutions will be where the past treatment of patients took place using 
osilodrostat under ATU and/or as a part of routine clinical practice. Data will be 
abstracted from patients’ existing electronic, or paper institutional medical records 
collected during the French ATU and/or routine clinical care. Importantly, the historical 
decisions of health care providers (HCPs) to treat patients with osilodrostat were made 
purely at the discretion of the treating physicians as discussed with their patients. Thus, 
there is no relationship between the decision to treat patients with osilodrostat and 
inclusion in this study.  
The study schematic is presented in Figure 1 below and illustrates the dates 
corresponding to the study’s retrospective follow-up period, the French ATU, the latest 
date an osilodrostat-treated patient is eligible for inclusion in the cohort study, and 
general timelines.  
  

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Figure 1. Study Schematic 
Abbreviations : ATU : Autorisation Temporaire d’Utilisation. ; F/U : Follow Up ; LTFU : Lost to Follow 
Up. 
Clinical practice medical records will be reviewed for all eligible patients who received 
osilodrostat between April 2019 and the study start date at study sites in France. The 
study start date was the date the first site was initiated in the study, which was on 16 
December 2022. The study will screen all patients at each site who were treated with 
osilodrostat in France within the frame of the ATU programme prior to commercial 
availability along with the patients who were treated with commercially available 
osilodrostat. All patients treated with osilodrostat between April 2019 and the study start 
date (16 December 2022) will be enrolled in the study.  
Patients who have previously signed a general consent for research, either alive or 
deceased, can be enrolled with immediate effect. If no general consent was signed, a 
signed no-objection letter (NOL) will be requested from patients who are still alive. 
Some patients might not send the NOL back to the investigator. In such instance, the 
investigator can document a tacit approval from the patient if there is no response after a 
month of the first shipment of the NOL and after 3 documented contact attempts. For 
deceased patients since their past treatment with osilodrostat, they can also be enrolled 
after the investigator has checked that the deceased patient did not leave any written 
document stating refusal to participate in any scientific research.  

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Investigators will manually review and abstract clinical information from selected 
patients’ medical records and will enter information into the electronic case report form 
(eCRF) from the date of initiating Osilodrostat through the follow-up period. All data are 
safeguarded using industry-best security practices to prevent unlawful disclosure and 
practices are compliant with Title 21 Part 11 policies of the Code of Federal Regulations. 
The HIMS software used for EDC purposes include password protection and encryption 
for all transmitted data. The platform will be approved by Recordati prior to study data 
abstraction or during site selection procedure. 
The follow-up period will be variable, from the start of their osilodrostat onset period 
until the earlier of loss to follow-up, death, the end of the retrospective follow-up period 
or treatment discontinuation occurs. The patients with a potential follow-up of at least 
12 weeks will be part of the primary analysis. The only patients excluded from the 
primary efficacy analyses will be the ones who started treatment with osilodrostat less 
than 12 weeks prior to the end of the abstraction period, and are still treated with 
osilodrostat at the end of the abstraction period. These patients will be included only in 
the analyses of the secondary and exploratory endpoints including safety. The patients 
who discontinued treatment for any reason or were lost-to-follow up prior to 12 weeks 
will be considered non-responders for the primary endpoint. The end of study is defined 
as the last available assessment after treatment initiation for the last patient. 
The timing of data collection is summarised in the Figure 1/Table 2 

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Table 2 Data Collection Schedule 
 
Data Collection Points 
Assessment 
BLa  Wk 
4b  
Wk 
8b  
Wk  
12b  
 
Wk 
18b  
Wk 
24b 
Wk 36  
and every 
12 wks 
until 
death, loss 
to F/U or 
end of 
patient 
data 
collection* 
Window period 
 
± 2 
wks 
± 2 
wks 
± 4  
wks 
± 2 
wks 
± 4 
wks 
± 4 wks 
Authorisation of 
access to patient’s 
data for enrollmentc 
X 
 
 
 
 
 
 
Inclusion-Exclusion 
Criteria  
X 
 
 
 
 
 
 
Demographics (age 
at diagnosis of CS, 
gender) 
X 
 
 
 
 
 
 
BMI 
X 
X 
X 
X 
X 
X 
X 
Clinical (disease) 
characteristics 
including date of 
diagnosis 
X 
 
 
 
 
 
 
Medical and surgical 
historyh 
Xg 
 
 
 
 
 
 
CS-Specific Physical 
Exam Findings (after 
BMI per every 
visit)@  
X 
X 
X 
X 
X 
X 
X 

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Data Collection Points 
Assessment 
BLa  Wk 
4b  
Wk 
8b  
Wk  
12b  
 
Wk 
18b  
Wk 
24b 
Wk 36  
and every 
12 wks 
until 
death, loss 
to F/U or 
end of 
patient 
data 
collection* 
Window period 
 
± 2 
wks 
± 2 
wks 
± 4  
wks 
± 2 
wks 
± 4 
wks 
± 4 wks 
Vital signs (blood 
pressure) 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
X 
X 
X 
X 
X 
X 
Prior CS 
treatment(s)  
X 
 
 
 
 
 
 
Prior medicationse 
Xg 
 
 
 
 
 
 
Concomitant 
medications 
Xg 
X 
X 
X 
X 
X 
X 
Osilodrostat 
initiating dose 
(date)d 
X 
X 
X 
X 
X 
X 
X 
Up /or down-
titration regimen for 
Osilodrostat (date)d  
 
X 
X 
X 
X 
X 
X 
Comprehensive 
Metabolic Panel 
(CMP&), Complete 
Blood Count 
(CBC#), lipids$ 
X 
X 
X 
X 
X 
X 
X 
 HBA1c 
X 
X 
X 
X 
X 
X 
X 

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Data Collection Points 
Assessment 
BLa  Wk 
4b  
Wk 
8b  
Wk  
12b  
 
Wk 
18b  
Wk 
24b 
Wk 36  
and every 
12 wks 
until 
death, loss 
to F/U or 
end of 
patient 
data 
collection* 
Window period 
 
± 2 
wks 
± 2 
wks 
± 4  
wks 
± 2 
wks 
± 4 
wks 
± 4 wks 
Mean urinary free 
cortisolf 
Xg 
X 
X 
X 
X 
X 
X 
Morning serum 
cortisol 
X 
X 
X 
X 
X 
X 
X 
Plasma 
Adrenocorticotropic 
hormone (ACTH), 
Serum 11-
Deoxycortisol, 
Plasma 11-
Deoxycorticosterone
,Plasma Aldosterone, 
Plasma Renin,  
Total Serum 
Testosterone or 
oestradiol (per 
patient sex), Serum 
LH, Serum FSH 
 
X 
X 
X 
X  
X 
X  
X 
Late night salivary 
cortisol 
 
X 
X 
X 
X 
X 
X 
X 

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Data Collection Points 
Assessment 
BLa  Wk 
4b  
Wk 
8b  
Wk  
12b  
 
Wk 
18b  
Wk 
24b 
Wk 36  
and every 
12 wks 
until 
death, loss 
to F/U or 
end of 
patient 
data 
collection* 
Window period 
 
± 2 
wks 
± 2 
wks 
± 4  
wks 
± 2 
wks 
± 4 
wks 
± 4 wks 
Adverse event  
X 
X 
X 
X 
X 
X 
X 
Osilodrostat 
discontinuation with 
reason for 
discontinuation 
 
X 
X 
X 
X 
X 
X 
BL=Baseline 
a. At the time of osilodrostat initiation or the closest value within 2 weeks prior to osilodrostat initiation. 
b. Assessments at 4, 8, 12, 18, 24, 36 weeks will be collected, as well as all subsequent follow-up visits (at 
every 12 weeks until the earlier of loss to follow-up, death, or the end of the retrospective follow-up period 
or treatment discontinuation) under routine clinical practice, if available. The assessments which occurred 
closest to each defined visit should be recorded in the CRF, even if these assessments occurred on different 
dates. 
c. Either the patient has previously signed a general consent for research, or a signed no-objection letter 
(NOL) will be requested from the patient if still alive. If patient does not send the NOL back to the 
investigator, the investigator can document a tacit approval from the patient if there is no response after a 
month of the first shipment of the NOL and after 3 documented contact attempts. For a deceased patient 
since his/her past treatment with osilodrostat, access after the investigator has checked that this deceased 
patient did not leave any written document stating his/her refusal to participate in any scientific research. 
 
d. Osilodrostat initiation dose and up- and/or down-titration regimens (including dates) and reasons for 
titration will be recorded in the database during the study 
 
e. All prior medications taken within 6 months prior to the first dose of Osilodrostat must be collected. 
 
f. Baseline mean urinary free cortisol data can be collected within 1 month prior to osilodrostat initiation. 
 

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g. Footnote-a is not applicable to the following assessments: prior medications, concomitant medications, 
medical and surgical history, and mean urinary free cortisol. 
 
h. All available medical history and surgical history related to CS must be collected. Medical and surgical 
history not related to CS that occurred within 6 months prior to the first dose of Osilodrostat must be 
collected. 
 
*End of data collection may be due to earlier of loss-to-follow-up, death, end of retrospective follow-up 
period or treatment discontinuation 
#CBC includes WBC, RBC, Haemoglobin, Haematocrit, MCV, MCH, MCHC, RDW, Platelet Count, MPV 
and Differential (Absolute and Percent - Neutrophils, Lymphocytes, Monocytes, Eosinophils, and 
Basophils) 
&CMP includes Albumin, Alkaline Phosphatase, ALT, AST, Calcium, Carbon Dioxide, Chloride, 
Creatinine with GFR Estimated, Glucose, Potassium, Sodium, Total Bilirubin, Total Protein, (Blood) Urea 
Nitrogen 
 
$Lipid variables include Total Cholesterol, HDL, LDL, and Triglycerides 
@For list of CS-specific examination findings, please refer to 8.3.2. 
8.1.1 
Rationale for the Study Design 
The observational aspect of this study provides an approach to document the clinical 
course, treatment, and outcome in a real-world setting. Given that this information is 
readily available in the clinical setting, a retrospective review of patient data will enable 
efficient use of accessible information. 
8.2 Setting 
The study population will consist of patients with non-CD CS who meet all the inclusion 
criteria and none of the exclusion criteria. The authorisation for getting access to the 
medical data of the patients must also be ensured, through the existence of a signed 
general consent, or requesting a signed NOL, or fulfilling the conditions of a tacit 
approval or no written document stating refusal for any participation to scientific 
research. 
8.2.1 
Inclusion Criteria 
Patients will be entered into this study only if they meet all of the following criteria: 
1. Male and female patients ≥18 years old with diagnosis of CS, except for CD (i.e., 
an aetiology of adrenal adenoma, adrenocortical carcinoma, adrenal hyperplasia, 

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or ectopic adrenocorticotropic hormone secretion). Patients should have a 
contemporaneously documented diagnosis of CS as per effective guidelines.  
2. Patients treated with osilodrostat between April 2019 and study start date 
(16 December 2022) as part of ATU programme or commercialisation.  
8.2.2 
Exclusion Criteria 
Patients’ data will be considered for inclusion in this study only if they meet none of the 
following criteria: 
1. Patients who participated in an interventional clinical trial anytime during the study 
period. 
2. Patients with Pseudo-Cushing's syndrome, cyclic CS, or iatrogenic CS. 
8.2.3 
Patient Enrolment 
Patients meeting eligibility criteria will be retrospectively identified and included in the 
study by site investigators based on a review of medical records at site. Site policies and 
local regulations regarding the access to their medical records will be followed. All 
eligible patients identified at a site between April 2019 and study start date (16 December 
2022) and consenting to be part of the study will be included. 
8.2.4 
Patient Withdrawal and Replacement 
Not applicable  
8.2.5 
Patient Identification Numbers 
Each patient included in the study will be identified by a number assigned by the 
electronic database. The number will include a site identifier and a unique patient number 
that will be based solely on the order in which patients are entered into the database by 
the investigative site according to Recordati’s nomenclature practices. For example, 
Patient 1010001 will be the first patient entered into the database at site 101. 
Investigative sites will retain a record of the patient numbers and corresponding 
identifying patient information.  

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The participating investigator will agree to complete a participant/patient identification 
and enrolment log to permit easy identification of each patient during and after the study. 
This document will be reviewed by the sponsor or the designated CRO and participating 
site contact for completeness. The patient identification and enrolment log will be treated 
as confidential and will be filed by the participating investigator in the study file. To 
ensure patient confidentiality, no copy will be made. All reports and communications 
relating to the study will identify patients by patient identification and age (if allowed) at 
initial informed consent. In cases where the patient is not enrolled for data collection in 
the study, the date seen and age at initial informed consent will be used. Where 
applicable, the participating investigator should also complete a patient screening log, 
which documents all patients who were seen to determine eligibility for data collection in 
the study. 
8.3 Variables 
8.3.1 
Primary Variable 
• 
Mean urinary free cortisol (mUFC). 
8.3.2 
Secondary Variables 
• Demographics (age, gender). 
• Clinical (disease) characteristics (adrenal adenoma, adrenocortical carcinoma, 
ectopic adrenocorticotropic hormone secretion, adrenal hyperplasia) including 
date of diagnosis. 
• BMI. 
• Concomitant medications. 
• Medical and surgical history. 
• CS-specific physical exam findings, such as: 
o Plethora (facial rubor) 
o  Round face (moon faces) 
o  Centripetal (abdominal) obesity 
o  Female hirsutism 

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o  Ecchymoses (bruising) 
o  Dorsal/supraclavicular fat pad 
o  Purplish striae 
o  Proximal muscle weakness 
o  Acne 
o  Oedema 
o  Female balding 
• Vital signs (blood pressure) and ECG. 
• Morning serum cortisol and mUFC. 
• Laboratory abnormalities (sodium, potassium, calcium levels, CO2, glucose, 
Glycated haemoglobin (HBA1c), and lipids) . 
• Hormone levels  
 Plasma ACTH 
 Serum 11-Deoxycortisol 
 Serum or plasma 11-Deoxycorticosterone 
 Plasma Aldosterone  
 Plasma Renin  
 Total Serum Testosterone or oestradiol per patient sex 
 Serum LH  
 Serum FSH. 
• AEs, including treatment-emergent adverse events (TEAEs) and adverse events 
of special interest (AESI). 
• Comprehensive metabolic panel (CMP) and Complete blood count (CBC) 
• The exposure of interest (defined as osilodrostat treatment and is the basis of the 
start of follow-up for the retrospective cohort study to assess for the defined 
outcomes of interest). This will include initiating osilodrostat doses along with 
any dose titrations.  
8.4 Data Sources 
The primary data source for this study will be the existing electronic medical records 
stored in the hospital information management systems (HIMS) and laboratory 
information management systems (LIMS) at the investigative sites. Also, where 
applicable, data will be captured from paper medical records.  

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8.5 Study Size 
There is no statistical hypothesis testing for this study; therefore, power was not formally 
calculated, and no formal sample size calculations were performed. The sample size is 
based on practical considerations.  
Historical data will be collected from approximately 100 patients with a diagnosis of 
non-CD CS with an aetiology of adrenal adenoma, adrenocortical carcinoma, adrenal 
hyperplasia, or ectopic adrenocorticotropic hormone secretion treated with osilodrostat as 
follows:  
a) Under the April 2019 French ATU (5th Apr 2019) or  
b) Under conditions of routine clinical practice after commercialization of osilodrostat in 
France since June 2020. 
8.6 Data Management 
Standardised and validated procedures and systems will be utilized to collect, process 
and file the clinical data of this study. Any system used will be compliant with FDA 21 
CFR Part 11 requirements. 
A data management plan (DMP) will be prepared to describe the processes and dataflow 
within the clinical study timelines, versions for the computer systems and the coding will 
be defined in the DMP, and if applicable, sponsor specific requests will also be 
documented within. 
A Data Validation Specification (DVS) will be created to outline the validation checks to 
be performed during the study. The DVS must be finalised before data validation. The 
eCRFs will include programmable edits to obtain immediate feedback if critical data are 
missing, out-of-range, illogical or potentially erroneous. High data quality standards will 
be maintained, and processes and procedures utilised to repeatedly ensure that the data 
are as clean and accurate as possible when presented for analysis. Data quality will be 
enhanced through a series of programmed data quality checks that automatically detect 
out-of-range or anomalous data. 

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The study centre will allow the study monitor and sponsor representative direct access to 
all study documents, medical files, and source documents to enable verification of the 
study data, while maintaining the anonymity of the subject and confidentiality of the 
data. The responsible study monitor will check data during the monitoring visits either on 
site or remotely. The investigator will ensure that the data collected are accurate and 
complete. Data will be monitored within the EDC by the study monitor and any changes 
made during monitoring will be documented with a full audit trail within the EDC. 
The raw data intended for further processing will be checked by standard routines or 
according to the DVS and queries will be generated and sent to the investigator for 
review and resolution. Corrections resulting from these queries will be confirmed on the 
Data Clarification Forms (DCFs). This process will be repeated until no further 
discrepancies are found. The data will then be declared as clean. Applicable 
documentation will be stored in the study files. 
Only trained study staff will have access to the clinical database and every change in data 
will have a full audit trail. 
8.6.1 
Data Collection 
Data collected from the medical records will be incorporated into an eCRF, that will have 
restricted password-protected access and an audit trail for all data access and entry. All 
data entered within the EDC can be viewed by appropriate study team members. The 
system is 21 CFR Part 11 compliant. 
All data collection will be performed by appropriately trained site personnel in 
accordance with site privacy policies.  
8.6.2 
Data Processing 
All data will be entered by site personnel.  
The data-review and data-handling document, to be developed during the initiation phase 
of the study, will include specifications for consistency and plausibility checks on data 

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and will also include data-handling rules for obvious data errors. Query/correction sheets 
for unresolved queries will be sent to the study monitors for resolution with the 
investigator. The database will be updated based on signed corrections.  
A historical file of these procedures shall be maintained, including all revisions and the 
dates of such revisions. Any changes in data entries shall be documented. 
8.6.3 
Archiving Study Records 
According to International Society for Pharmacoepidemiology Guidelines on Good 
Pharmacoepidemiology Practices (GPP), the study archive should be maintained for at 
least 5 years after final report or first publication of study results, whichever comes later. 
The archive should include all source data and, where feasible, any biologic specimens.  
8.7 Data Analysis 
Statistical analysis of this study will be the responsibility of the sponsor’s designee. 
Any change to the data analysis methods described in the protocol will require an 
amendment only if it changes a principal feature of the protocol. Any other change to the 
data analysis methods described in the protocol, and justification for making the change, 
will be described in the final statistical analysis plan (SAP). The SAP will be developed 
as a separate document and approved prior to database lock, containing a description of 
the planned statistical analysis in detail with Tables, Figures and Listings (TFLs) 
templates.  
Any deviations from the planned analyses will be described and justified in the final 
study report. 
The overview of statistical analysis is detailed in the below section. 

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8.7.1 
Statistical Hypothesis  
The study plans to summarize only descriptive outputs and there is no inferential 
endpoint associated with the study. Hence no formal statistical hypothesis will be tested 
for this study. 
8.7.2 
General Considerations 
An SAP describing the planned statistical analysis in detail with TLF templates will be 
developed as a separate document. All statistical analyses will be performed using 
Statistical Analysis System® (version 9.4 or higher) unless otherwise stated. 
No formal statistical hypothesis testing will be performed, and all the analyses will be 
primarily descriptive in nature. When appropriate, and unless otherwise specified, 95% 
confidence intervals (CIs) will be displayed. 
Descriptive statistics will include the number of available data, number of missing data 
and the following: 
• Mean and associated standard error of mean (SE) standard deviation (SD), 
minimum, median, maximum, first and third quartiles and 95% CIs for 
means/medians, minimum (Min), maximum (Max). 
• Counts and percentages of each category for categorical variables with 95% CIs. 
Percentages will be based on the number of patients in safety or ITT population. 
8.7.3 
Analysis Population(s) 
The ITT population consists of all enrolled participants who , have met all 
inclusion/exclusion criteria and have received osilodrostat treatment for non-CD CS, 
with a potential follow-up of at least 12 weeks. The only patients excluded from the 
primary efficacy analyses will be the ones who started treatment with osilodrostat less 
than 12 weeks prior to the end of the abstraction period, and are still treated with 
osilodrostat at the end of the abstraction period. These patients will be included only in 
the analyses of the secondary and exploratory endpoints including safety. 

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The Safety population consists of all participants who receive at least one dose of 
osilodrostat. 
All effectiveness analysis will be performed on ITT population. Safety analysis will be 
performed on the safety population. 
8.7.4 
Control of Bias and Confounding 
The study will be conducted in France through the ATU prior to commercial availability 
along with the patients who were treated with commercially available osilodrostat in 
France. Investigators will include all patients treated with osilodrostat between April 
2019 and the study start date (16 December 2022); to avoid selection bias in participant 
recruitment, all eligible patients will be included in the study. Patients with CD should be 
strictly avoided by sites as a potential confounder and excluded from analysis if enrolled. 
Also, this will be the same for patients with Pseudo-Cushing’s syndrome, cyclic CS, or 
iatrogenic CS, who have been treated with osilodrostat: they should be strictly avoided 
and if enrolled, they will be excluded from analysis. 
Investigators will manually review and abstract clinical information from selected 
patients’ medical records and will enter information into the eCRF developed for the 
study. 
8.7.5 
Patient Disposition  
The numbers and percentages of participants in each population will be tabulated. The 
reasons for participant exclusions from data analysis sets for each of the populations will 
also be tabulated. In addition, the number of participants who were treated, who died will 
be tabulated. Primary reasons for osilodrostat treatment discontinuation will be tabulated. 
8.7.6 
Protocol Deviation 
In this context of a retrospective observational study with no additional ancillary 
activities or protocol-specific procedures, protocol deviations are defined as those 
functional changes from the protocol that are likely to have an impact on the patient’s 

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rights and/or the validity of the data for analysis. All protocol deviations will be reported 
in the clinical study report (CSR).  
The number of patients with protocol deviations will be summarised. 
Protocol deviations will be listed with date and study day of occurrence, description and 
analysis populations from which patient is excluded. 
8.7.7 
Demographics and Baseline Disease Characteristics 
The demographics and baseline clinical characteristic will be summarised descriptively 
and using descriptive statistics such as n, mean, 95% CI of the mean, SD, median, 
minimum, maximum or frequency of counts will be provided.  
• Demographics will include age, gender. 
• Clinical (disease) characteristics will include putative causation (i.e., adrenal 
adenoma, adrenocortical carcinoma, ectopic adrenocorticotropic hormone 
secretion, adrenal hyperplasia) and date of Cushing’s syndrome diagnosis. 
8.7.8 
Analysis of Primary Endpoint 
The number and proportion of patients with mean urinary free cortisol (mUFC) ≤ULN at 
12 weeks will be summarised descriptively along with associated 95% CI. It is a fixed 
value, which is upper limit of normal range. The patients who discontinued treatment 
prior to 12 weeks for any reason or were lost-to-follow up will be considered non-
responders for the primary endpoint. The patients who started treatment with osilodrostat 
less than 12 weeks prior to the end of the abstraction period, and are still treated with 
osilodrostat at the end of the abstraction period will be excluded from the analysis. 
8.7.9 
Analysis of Secondary Endpoints 
Changes from baseline for biochemical variables and clinical outcomes to Week 4, 8, 12, 
18, 24, 36, and to every 12 weeks until the earlier of loss to follow-up, death, or the end 
of the retrospective follow-up period or treatment discontinuation will be summarised 
descriptively and provided as listing. 

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Baseline is defined as the available value at the time of osilodrostat initiation or the 
closest value within 2 weeks prior to osilodrostat initiation. Change from baseline will be 
calculated as the visit value of interest minus the baseline value.  
For secondary variables, refer to Table 1. 
Change from initial dose 
The extent of exposure will be provided by summarising the description of initiating dose 
(and date) of osilodrostat, and up- and/or down-titration regimen (dose 
increases/decreases, date). 
Proportion of patients who experienced TEAEs and AESIs 
An overall summary table of all treatment-emergent adverse events (TEAEs) will be 
presented with the number and proportion of participants and the number of events. 
Summary incidence tables of all TEAEs (through Week 12 and follow-up at every 
12 weeks until the earlier of loss to follow-up, death, or the end of the retrospective 
follow-up period, or treatment discontinuation), SAEs and TEAEs by severity grade and 
relationship to study drug will be provided, classified by primary System Organ Class 
(SOC) and Preferred term (PT). 
All AEs will be coded according to the latest version of the Medical Dictionary for 
Regulatory Activities and will be classified by MedDRA PT and SOC. 
All safety data will be included in the participant data listings, such as listings of all 
TEAEs, SAEs, TEAEs leading to study drug withdrawal and listings of deaths. 
Summary incidence tables of select AEs specific to CS (AEs of fatigue, nausea, 
vomiting, headache, backache, oedema, clinical features including acne, hirsutism, 
laboratory abnormalities including hypokalaemia or hyperkalaemia, and hypertension) by 
severity grade and relationship to study drug will be provided, classified by primary SOC 
and PT. 
Adverse Events of Special Interest (AESI) will be defined as following AEs: 

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o Adrenal hormone precursor accumulation-related AEs 
o Hypocortisolism-related AEs 
o Pituitary tumour enlargement-related AEs 
o Arrhythmogenic potential and QT prolongation AEs 
The frequency and percentage of patients experiencing treatment emergent AESI will be 
summarised by severity grade and relationship to study drug and will be provided, 
classified by primary SOC and PT. 
8.7.10 Analysis of Exploratory Endpoint 
Late night salivary cortisol observed values at baseline and changes from baseline to 
Week 4, 8, 12, 18, 24, 36 and to every 12 weeks until the earlier of loss to follow-up, 
death, or the end of the retrospective follow-up period or treatment discontinuation will 
be summarised descriptively and provided as listing. Where applicable, proportion of 
patients with normal and/abnormal late night salivary cortisol at Week 4, 8, 12, 18, 24, 
36 and at every 12 weeks until the earlier of loss to follow-up, death, or the end of the 
retrospective follow-up period or treatment discontinuation. 
8.7.11 Interim Analyses  
Not applicable. 
8.7.12 Stratified Analysis 
The number and proportion of patients with mean urinary free cortisol (mUFC) ≤ULN at 
12 weeks will be stratified if they received or not other therapies for Cushing’s syndrome 
(regardless of the type of therapy) and will be summarised descriptively along with 
associated 95% CI. Differences in the proportions and 95% CI of the different groups 
will be evaluated. Further details will be described in the final SAP. 

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8.8 Quality Control 
8.8.1 
Data Quality Assurance 
Recordati or delegate will conduct a site visit to verify the qualifications of each 
investigator, inspect the site facilities, and inform the investigator of responsibilities and 
the procedures for ensuring adequate and correct documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded on the eCRFs for this study must be consistent with 
the patients’ source documentation (i.e., medical records). 
8.8.2 
Electronic Data Capture/Electronic Case Report Forms and 
Source Documentation 
All data obtained during this study should be entered in the eCRFs promptly using CISIV 
EDC tool. All source documents from which eCRF entries are derived should be placed 
in the patient’s medical records (electronic or paper). Measurements for which source 
documents are usually available include laboratory assessments, electrocardiogram 
(ECG) recordings, computed tomography (CT) scans, and X-rays.  
Once the eCRF clinical data have been submitted to the central server at the independent 
data centre, corrections to the data fields will be captured in an audit trail. The reason for 
change, the name of the person who performed the change, together with the time and 
date will be logged to provide an audit trail. 
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the EDC application. The appropriate staff at the study site will answer queries 
sent to the investigator. The name of the staff member responding to the query, and time 
and date stamp will be captured to provide an audit trail. Once all source data verification 
is complete and all queries are closed, the monitor will freeze the eCRF page. 

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The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site 
personnel will receive training on the EDC system/eCRF. 
8.8.3 
Access to Source Data 
During the study, a site monitor will perform remote monitoring and may also make site 
visits when required to review protocol compliance, compare eCRFs and individual 
patient’s medical records to ensure that the study is being conducted according to 
pertinent regulatory requirements. Electronic CRF entries will be verified against source 
documentation. The review of medical records will be performed in a manner to ensure 
that patient confidentiality is maintained. 
Checking of the eCRFs for completeness and clarity, and cross-checking with source 
documents, may be required to monitor the progress of the study. Moreover, regulatory 
authorities of certain countries, IRBs, IECs, and/or Recordati’ s Clinical Quality 
Assurance Group may wish to carry out such source data checks and/or on-site audit 
inspections. Direct access to source data will be required for these inspections and audits; 
they will be carried out giving due consideration to data protection and medical 
confidentiality. The investigator assures Parexel and Recordati teams of the necessary 
support at all times. It is to be noted that Recordati’ s visits or site audits covers their 
oversight responsibilities as a sponsor. 
8.9 Limitations of the Research Methods 
Due to the observational nature of this retrospective cohort study, conducted under 
conditions of routine clinical practice, bias is more prone to occur. Consequently, study 
findings may be subject to limitations in generalizability to the target population in 
availability of data, and variability in local treatment practices and guidelines. 
This study is an observational study and relies on patients’ existing medical records 
available at the time of notification of the protocol to the French Data Hub. Therefore, 
although all patients will be followed longitudinally using historical medical records, 
some data points may be missing. However, it is expected that any missing data will be 

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minimal and would not affect the study outcome, or that statistical methods of imputation 
and/or missingness will mitigate its effect. 
Many factors can lead to biased study results. The possible sources of bias are selection 
bias, inconsistent data collection, measurement error with continuous variables, 
misclassification with categorical variables, confounding factors, methodical errors, and 
other errors. A good study plan, a good risk management plan, and the good quality 
control procedures are the key to reducing, avoiding, correcting predictable problems. 
8.10 Other Aspects 
Not applicable. 
9 PROTECTION OF HUMAN SUBJECTS 
9.1 Ethical Considerations 
The procedures set out in this study protocol are designed to ensure that Recordati and 
investigator abide by the principles of the International Society for 
Pharmacoepidemiology GPP guidelines (Ispe 2008). The study will also be carried out in 
compliance with local legal requirements MR-004.  
9.2 Informed Consent 
Informed consent is not required for this study, because this study is a secondary data 
collection study using anonymised patient data. The authorisation for getting access to 
the medical data of the patients must also be ensured, through the existence of a signed 
general consent, or requesting a signed NOL, or fulfilling the conditions of a tacit 
approval or no written document stating they refused any participation to scientific 
research. 
9.3 Protocol Approval and Amendment 
Before the start of the study, the French health data hub will be notified with the study 
protocol and/or other relevant documents, in accordance with local legal requirements. 

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Recordati must ensure that all ethical and legal requirements have been met before the 
first patient is enrolled in the study. 
To alter the protocol, amendments must be sent to Competent Authority as notification 
prior to implementation. 
Administrative changes (not affecting patient risk) may be made without the need for a 
formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
9.4 Confidentiality 
All study findings and documents will be regarded as confidential. The investigator and 
members of his/her research team must not disclose such information without prior 
written approval from Recordati.  
The anonymity of participating patients must be maintained. Investigators shall ensure 
that personal identifiers will be removed from any study files that are accessible to non-
study personnel in accordance with applicable laws and regulations. Patients will be 
identified on eCRFs, and other documents submitted to Parexel by their patient number, 
initials and/or birth date (if allowed), not by name. Documents not to be submitted to 
Parexel that identify the patient must be maintained in confidence by the investigator.  
9.5 Duration of the Study 
The study duration will be approximately up to 3 years. It will be retrospective follow-up 
period at every 12 weeks until the earlier of loss to follow-up (LTF), death, or the end of 
the retrospective follow-up period or treatment discontinuation.  
10 MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE DRUG REACTIONS 
Being retrospective chart review, it does not require active reporting of AEs/ADRs to 
regulatory authorities. 

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10.1 Definitions  
Adverse events (AEs) 
An AE is any untoward medical occurrence in a patient or clinical study participant 
administered a pharmaceutical product, whether or not considered related to the product. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease (new or exacerbated) temporally 
associated with the use of a product.  
Treatment-emergent adverse events (TEAEs) 
Any AE with an onset date on or after the study drug start date and no later than 30 days 
after last dose of study drug, or any worsening of any AE on or after the study drug start 
date. 
Serious adverse events (SAEs) 
An SAE is any AE that: 
• Results in death. 
• Is life-threatening. (Note: The term ‘life-threatening’ in the definition of ‘serious’ 
refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe). 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
• Results in persistent or significant disability/incapacity.  
• Is a congenital anomaly/birth defect.  

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• Is an important medical event. Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
Adverse drug reaction (ADR) 
An ADR is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out.  
10.1.1 Categorisation of Adverse events 
10.1.1.1 Severity Assessment 
All AEs will be classified using the current version of the Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0, developed, and maintained by the Cancer 
Therapy Evaluation Program at the National Cancer Institute. 
Grade 1: Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; The AE is easily tolerated and does not interfere with 
daily activities.  
Grade 2: Moderate: minimal, local, or non-invasive intervention indicated; The AE 
interferes with daily activities, but the subject is still able to function.  
Grade 3. Severe: not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; The AE is incapacitating and requires medical 
intervention. Every effort will be made to obtain an adequate evaluation of the severity. 
Grade 4. Life threatening: consequences; urgent or emergent intervention needed. 
Grade 5. Death related to or due to AE. 

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10.1.1.2 Causality Assessment 
The following definitions of relationship to the study drug should be used to characterise 
the suspected causality of each AE, based on the investigator's consideration of all 
available information about the AE, including temporal relationship to drug 
administration, recognised association with drug product/class, pharmacological 
plausibility, and alternative aetiology (e.g., underlying illness, concurrent conditions, 
concomitant treatments): 
• Related - An AE that follows a reasonable possibility of a causal relationship to study 
drug i.e., reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug 
cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs, and concurrent treatments, may also be responsible 
• Not Related - An AE that does not follow a reasonable possibility of a causal 
relationship to the study drug i.e., no reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as underlying 
diseases, complications, concomitant drugs, and concurrent treatments. 
10.2 Collection and Reporting of Adverse Events/Adverse Reactions 
This study uses data from electronic and paper healthcare records. Consistent with 
regulatory requirements for a non-interventional study based on secondary use of data 
(EU Good Pharmacovigilance Practices VI.C.1.2.1), no reporting of AEs is required. It is 
assumed that any AEs identified in existing healthcare records have already been 
reported at the time it occurred in the past, therefore, no additional AE/SAE reporting 
will be made to regulatory authorities to avoid duplicate reports. 
All adverse events/reactions collected for the study will be recorded and summarised in 
the final study report.  

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11 PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS 
The results of the study will be communicated after the end of the study to the 
investigator and to Competent Authorities/Ethics Committee, as appropriate. They can be 
submitted to Regulatory Authorities and can be either submitted for publications and/or 
posted in a publicly available database. The Sponsor reserves the right to review all 
manuscripts and abstracts before their submission for publication or presentation. This is 
not intended to restrict or hinder publication or presentation but to allow the sponsor to 
protect the confidentiality of information and to provide comments that may not yet be 
available to the investigator. Publications will comply with internal Recordati standards 
and the International Committee of Medical Journal Editors (ICMJE). 
Ownership of all data will remain with the sponsor. 

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12 REFERENCES 
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patients with adrenocortical tumors admitted to a single medical center (1951 to 
1978). Am J Med. 1981 Nov;71(5):855–75.  
Broder MS, Neary MP, Chang E, Cherepanov D, Ludlam WH. Incidence of Cushing’s 
syndrome and Cushing’s disease in commercially-insured patients <65 years old 
in the United States. Pituitary. 2015 Jun;18(3):283–9.  
Carpenter PC. Diagnostic evaluation of Cushing’s syndrome. Endocrinol Metab Clin 
North Am. 1988 Sep;17(3):445–72.  
Etxabe J, Vazquez JA. Morbidity and mortality in Cushing’s disease: an epidemiological 
approach. Clin Endocrinol (Oxf). 1994 Apr;40(4):479–84.  
Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, et al. 
Randomized Trial of Osilodrostat for the Treatment of Cushing Disease. J Clin 
Endocrinol Metab. 2022 Jun 16;107(7):e2882–95.  
Invitti C, Pecori Giraldi F, de Martin M, Cavagnini F. Diagnosis and management of 
Cushing’s syndrome: results of an Italian multicentre study. Study Group of the 
Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-
Pituitary-Adrenal Axis. J Clin Endocrinol Metab. 1999 Feb;84(2):440–8.  
Ispe. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol 
Drug Saf. 2008;17(2):200–8.  
Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, et al. Clinical 
features of adrenocortical carcinoma, prognostic factors, and the effect of 
mitotane therapy. N Engl J Med. 1990 Apr 26;322(17):1195–201.  
Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, et al. 
Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice 
Guideline. J Clin Endocrinol Metab. 2015 Aug;100(8):2807–31.  
Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, et al. 
Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a 
multicentre phase III study with a double-blind, randomised withdrawal phase. 
Lancet Diabetes Endocrinol. 2020 Sep 1;8(9):748–61.  
Ragnarsson O, Olsson DS, Papakokkinou E, Chantzichristos D, Dahlqvist P, Segerstedt 
E, et al. Overall and Disease-Specific Mortality in Patients With Cushing Disease: 
A Swedish Nationwide Study. J Clin Endocrinol Metab. 2019 Jun 1;104(6):2375–
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Tabarin A, Assié G, Barat P, Bonnet F, Bonneville JF, Borson-Chazot F, et al. Consensus 
statement by the French Society of Endocrinology (SFE) and French Society of 

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Pediatric Endocrinology & Diabetology (SFEDP) on diagnosis of Cushing’s 
syndrome. Ann Endocrinol. 2022 Apr 1;83(2):119–41.  
Tanaka T, Satoh F, Ujihara M, Midorikawa S, Kaneko T, Takeda T, et al. A multicenter, 
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13 APPENDICES 
13.1 Appendix 1: List of Supplementary Documents 
 
Number 
Title 
1 
No Objection Letter  
2 
Sample Case Report Form