Clinical trial NCT03606408
Conditions: Cushing's Syndrome
Keywords: Cushing's syndrome osilodrostat LCI699 endogenous Cushing's syndrome
Sponsor: RECORDATI GROUP
Start date: 2018-10-05; Completion date: 2023-11-16
Enrollment: 127 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is the evaluation of long-term safety of osilodrostat in patients who have already received osilodrostat treatment in a previous Global Novartis-sponsored trial and who, based on investigators' judgement, will continue benefiting with its administration.

Detailed description:
There will be no screening period for this study. Eligible subjects can start their treatment with osilodrostat as soon as they are enrolled in the study. The first study visit will be scheduled at the time of the last study visit for the parent study. Subjects must return to the study center at least on a quarterly basis (every 12 weeks ± 2 weeks) for safety and clinical benefit assessments, and resupply of study medication. Drug dispensing and administration information and adverse events will be collected. The subject may return to the clinic at any given time as per standard of care or treating physician recommendation; however, only the quarterly study visits will be recorded in the Case Report Form (CRF). Study medication dispensed will be recorded in the CRF dose administration page.

All adverse events and serious adverse events, including pregnancy, will be collected throughout the study. Subjects will continue to be treated in this roll-over study until they are no longer benefiting from their osilodrostat treatment as judged by the Investigator or until osilodrostat is commercially available or until one of other discontinuation criteria is met.

Arms: arm 1: open label, with patients receiving same dose as provided in the parent study
Interventions: intervention 1: osilodrostat
Intervention descriptions: intervention 1: osilodrostat, in the form of film coated tablets for oral administration, in the following tablet strengths: 1mg, 5mg, 10mg. Each strength has unique tablet size, colour and imprint.

Protocol documents:
ICF_002.pdf: 
Recordati Research and Development 
LCI699 
Protocol Title 
An open-label, multi-center, roll-over study to assess long 
term safety in patients with endogenous Cushing’s 
syndrome who have completed a prior Novartis-sponsored 
osilodrostat (LCI699) study and are judged by the 
investigator to benefit from continued treatment with 
osilodrostat
Global Model Informed Consent Form 
for Protocol No. CLCI699C2X01B 
Document type: 
Model Informed Consent (Clean) 
EUDRACT number: 
2017-002840-34 
ClinicalTrials.gov 
Identifier: 
NCT03606408 
Based on: 
Amended Protocol Version No. 02 dated 06-May-2020 
Release date: 
7-Mar-2022
Sponsor: 
RECORDATI AG - Lindenstrasse 8, 6340 Baar, Switzerland   
tel: + 41 (0) 61 205 61 00 
CRO: 
IQVIA 
Property of Recordati 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Recordati 


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Table of contents 
 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 3 
1 
Why have I been given this document to read? ................................................................... 5 
2 
What is the purpose of this study? ....................................................................................... 5 
3 
What do I need to know if I join this study? ....................................................................... 6 
3.1 
Can I decide to stop my participation in the study?................................................. 9 
3.2 
Can I withdraw my consent to collect and use my Personal Data? ......................... 9 
3.3 
Are there any reasons that my study treatment or participation may be 
stopped early? ........................................................................................................ 10 
3.4 
Who owns the data and results created during the study? ..................................... 10 
3.5 
Can my samples be used after the study? (Health Authority requests) ................. 10 
4 
What are the possible benefits if I join this study? ............................................................ 10 
5 
What are the possible risks if I join this study? ................................................................. 11 
6 
What do I need to know about birth control and pregnancy? ............................................ 14 
7 
What are my responsibilities and are there any costs for me if I agree to join this 
study? ................................................................................................................................. 15 
8 
What other choices are available if I choose not to join this study? ................................. 15 
9 
What if I become injured because of participation in this study? ..................................... 16 
10 What will happen to my Personal Data? ........................................................................... 16 
10.1 
What is Personal Data? .......................................................................................... 16 
10.2 
How will my Personal Data be used? .................................................................... 17 
10.3 
Where are Personal Data kept and secured? .......................................................... 17 
10.4 
Who can see my Personal Data? ............................................................................ 18 
10.5 
Your specific rights about your Personal Data ...................................................... 18 
10.6 
What are Anonymized Data and who can use them? ............................................ 19 
11 Where can I receive more information? ............................................................................ 20 
12 Signature pages .................................................................................................................. 21 
13 Optional Consent for additional research using your Personal Data ................................. 23 


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List of tables 
Table 3-1 
Study overview........................................................................................ 6 
Table 5-1  
Side effects ............................................................................................ 12 
Table 7-1 
Responsibilities related to study appointments/visits, study 
treatment, and costs ............................................................................... 15 
 
 
 
 
 
 


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Informed Consent Form Summary of Changes 
You may have signed a previous version of the informed consent for this study; however, new 
information has been made available that we need to share with you. 
This Summary of Changes includes the new information, and is only for patients who have been 
previously consented. It may not be applicable for new patients enrolled after the date the 
Summary of Changes has been approved. 
If you have questions please ask the study doctor and/or staff assigned to the trial to answer 
them. 
 
The following changes have been implemented throughout the document: 
 
Section 
Brief description of the change and/or new 
text  
4 
Sentence changed from: “Osilodrostat has 
recently been approved in USA and European 
Union as Isturisa® for the treatment of 
Cushing’s disease in adults”. To: “Osilodrostat 
has recently been approved in USA, European 
Union and Japan as Isturisa® for the treatment 
of Cushing’s disease in adults”. 
 
5 
Table 5-1: Side effects has been updated 
 
10.4 
Sentence changed from: “In those cases, the 
transfer will take place in the presence of the 
appropriate safeguards imposed by GDPR on 
the transfer of data outside the European 
Union”. To “In those cases, the transfer will 
take place in the presence of the appropriate 
safeguards imposed by General Data Protection 
Regulation (GDPR) on the transfer of data 
outside the European Union”. 
 


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1 
Why have I been given this document to read? 
You are being asked to give your voluntary consent to join in this research study to find out if 
the study treatment with osilodrostat is safe and can help others who have Endogenous Cushing 
Syndrome. 
Please read this document carefully. It tells you about the study, including possible benefits and 
risks.  This information is provided to you to help you make your decision on whether or not to 
join this study and is confidential. Do not share this information with anyone other than close 
family or friends or others who you need to help you make your decision.  
If you have any questions about this information at any time, please ask the study doctor or 
study staff. 
2 
What is the purpose of this study? 
 
This study is an extension of the previous study you participated in. The drug (osilodrostat) may 
still not be available in your country as it has been already approved as Isturisa® in USA and 
European Union only. The purpose of the study is to evaluate the clinical benefits and long-
term safety data of osilodrostat and allow continued use of osilodrostat to patients who suffer 
from a chronic excess of a hormone called “cortisol”. This is called “endogenous Cushing 
syndrome”. The most common causes are: a tumor of a gland located in the brain (Cushing 
disease), outside the brain, or in the adrenal glands. 
You should only take the study treatment as instructed and should not do anything else with it. 
You may discuss with a doctor or health care professional, who is not directly involved in the 
study, health issues or medical problems related to the study treatment or disclose information 
related to the study treatment. In this case you should tell your doctor or health care professional 
that the Recordati drug, which is part of the study treatment, and information relating to it is 
Recordati property and is confidential. 
 
You must always remember not to throw away your empty study drug containers. Instead keep 
them in a safe place and bring them back to the doctor’s office at every visit and whenever your 
study doctor or nurse ask you to. 
 
At the end of the study or if you stop study treatment you should return any study treatment, 
that you still have remaining to the study doctor. 
 
In this study, you will receive osilodrostat. Your starting dose of osilodrostat will be the same 
as that given to you in the previous study. During this study, your study doctor may change the 
dose depending on how you tolerate and respond to osilodrostat. It is very important that you 
take the medicine given to you just as the doctor tells you to do. Do not miss any tablets. Tell 
the study staff about any medications you are taking during the study. This includes prescription 
drugs, over-the-counter medicines, vitamins, herbal treatments and alternative treatments. 
 
Call your study doctor or study staff immediately if you have any unusual symptoms. Do not 
wait until your next visit to inform your study doctor of your symptoms. Your dose may need 


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to be changed. If necessary, you may also have to stop taking study drug temporarily and the 
side effect(s) will be closely monitored until resolution. 
All study medication must be kept out of the reach of children. 
This clinical study is sponsored (funded) by a company called Recordati and some of the study 
activities are managed on its behalf by the Contract Research Organization IQVIA.  
3 
What do I need to know if I join this study? 
If you agree to join this study, the following table lists what will happen during the study. You 
will be given new information as it becomes available that may affect your willingness to stay 
in the study. You can then decide whether to continue with the study. 
Table 3-1 
Study overview 
 
Details 
Total number of 
subjects  
About 180 subjects will join in this study.  
Duration of the 
study and number 
of visits 
If you join the study, you will be asked to come to the study doctor’s 
office/clinic/study site every three months for a maximum period of 5 years. 
Each study visit should take about 1 hour. Your study doctor will need to 
confirm that you continue to benefit from treatment during these visits. If 
necessary, your study doctor may ask you to come more often if he/she thinks 
you need more frequent visits. 
 
After signing the 
informed consent 
The study doctor will discuss if there is any need for you to stop taking any of 
your current treatments before starting the study treatment. If you are eligible, 
you can start the treatment with osilodrostat as soon as you enter the study. 
 
Study Treatment 
At the Baseline/Enrollment visit, the study doctor will ask you about your 
health, your medical history and any medication you are taking. All the 
assessment as listed in the section “Assessments during the study” will be 
performed. If you meet the “entry criteria” of the study, you will receive 
sufficient study drug at the end of this visit for the period until the next 12-
weeks (±2 weeks) follow-up visit. 
 
During the study, you will take study drug twice a day except if your disease 
worsens, you experience a side effect that you cannot tolerate, you leave the 
study, or the study is completed per protocol. You will return to your study 
doctor’s office at regular intervals (every 12 weeks ±2 weeks) so that your 
condition can be monitored. You will receive sufficient re-supply of study 
medication at the end of the visit for the period until the next follow-up visit. 
The study doctor will assess whether you are still benefiting from treatment 
with osilodrostat. 
 
Pay close attention to the dose of study drug on each pack, as you may 
receive more than one tablet strength at the same visit. You will be asked 
to take the medication twice a day with liquids, with or without food. Study 
drug should be taken at approximately the same time each day, with about 
12 hours between each dose administration. If vomiting occurs after you take 
your study drug, you should not take the study drug again before the next 


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scheduled dose. Please do not miss any dose. You will be asked to return all 
unused/used study drug to the study site at every visit. Female patients of 
childbearing potential will be required to perform monthly home urine 
pregnancy tests during the study and during the 30 day safety follow up 
period. The urine pregnancy test will be provided. In case your urine 
pregnancy test is positive, you should inform your study doctor immediately, 
who will conduct an additional pregnancy test based on the analysis of your 
blood (5 ml, 1 teaspoon). 
If you decide to stop study medication on this study or leave the study, you 
should tell the study doctor or the study staff. They will ensure that proper 
procedures are followed and that a final visit (Safety Follow-up/End of Study 
visit) is made for your safety. 
 
At End of Treatment visit, your study doctor will ask you some health related 
questions. All the assessments as listed in the section “Assessments during 
the study” will be performed. 
 
At a Safety Follow-up visit/End of Study visit (30 days after stopping 
treatment) all the assessment as listed in the section “Assessments during 
the study” will be performed except Pituitary MRI scan.  
 
  
Assessments 
during the study 
The following safety assessments will be performed for the enrolled subjects 
in this study: 
 
Physical Examination 
Typically, the doctor will use tools to look in your eyes, ears, nose, and throat. 
They will listen to your heart and lungs. This exam also includes: touching, or 
“palpating,” parts of your body (like your abdomen). This will be conducted at 
every visit (i.e. Baseline, week 12 and every 12 weeks (+/- 2 weeks) 
thereafter, End of Treatment and End of Study visits. 
 
Body weight and blood pressure 
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without 
shoes) will be measured.  
Blood pressure will be measured at every visit (i.e. Baseline, week 12 and 
every 12 weeks (+/- 2 weeks) thereafter, End of Treatment and End of Study 
visits. 
 
Laboratory evaluations 
All laboratory evaluations will be performed using central laboratory:  blood 
chemistry (Albumin, alkaline phosphatase, total bilirubin,  calcium, creatinine, 
CK, g‑GT, fasting plasma glucose, inorganic phosphorus, lipase, amylase, 
magnesium, potassium, total protein, AST, ALT, sodium, urea/BUN and uric 
acid, HbA1c), hematology (Hemoglobin, hematocrit, red blood cell count, 
white blood cell count with differential [monocytes, eosinophils, basophils, 
neutrophils, lymphocytes], and platelet count), testosterone, serum cortisol 


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as clinically indicated, urine free cortisol (two 24-hour urine specimens 
collected) plasma ACTH, 11-deoxycortisol and 11 deoxycorticosterone.  
You will be asked to collect the urine samples before each visit and bring to 
the study site. These urine samples should preferably be collected over 
consecutive days with the last sample being taken the day just before the 
visit. You have to bring the urine samples to the site at the visit.  
All laboratory evaluations will be performed at Baseline, week 12 and every 
12 weeks (+/- 2 weeks) thereafter, and at End of Treatment and End of Study 
visits. Only 11-deoxycortisol, 11 deoxycorticosterone, testosterone, blood 
chemistry and hematology will be analyzed at Baseline, week 24 and every 
24 weeks (+/- 2 weeks) thereafter, and at End of Treatment and End of Study 
visits. 
 
Electrocardiogram (ECG) 
Twelve-lead safety ECGs are collected at the study site using ECG 
equipment available at the sites. ECG procedure is as follows: electrodes are 
placed on the skin of the chest and connected in a specific order to a machine 
that, when turned on, measures electrical activity all over the heart.  
ECG will be collected at Baseline, week 24 and every 24 weeks (+/- 2 weeks) 
thereafter, End of Treatment and End of Study visits. 
 
Magnetic Resonance Imaging (MRI) 
Pituitary MRI scanning with gadolinium enhancement will be performed using 
the local site facility, to monitor any change in size. If you cannot have 
intravenous contrast (eg due to allergy or kidney problems), a non-contrast 
MRI scan may be performed. If MRI cannot be performed at all then a 
computer tomography (CT) (with i.v. contrast if not contraindicated) may be 
performed. MRI uses a magnetic field and radio waves to create detailed 
images of the organs and tissues within your body. 
Pituitary MRI scanning will be performed at Baseline, week 48 and every 48 
weeks thereafter and End of Treatment visits. 
 
Pregnancy and assessments of fertility 
If you are a female and of child-bearing potential you will be tested to see if 
you are pregnant with a urine pregnancy test. In case it is positive, a serum 
pregnancy test will be required and 5 ml (1 teaspoon) of blood will be taken. 
Urine pregnancy test will be performed monthly at home and at Baseline, 
week 12 and every 12 weeks (+/- 2 weeks) thereafter, End of Treatment and 
End of Study visits. 
 
 
Sample collection 
Blood and urine will be collected for the laboratory evaluations. Approximately 
1 to 2.5 tablespoons (up to 32 ml) will be taken for routine blood safety tests. 
The minimum required urine volume per sample will be 5 ml (1 teaspoon). 
Your biological samples will be coded with a unique number and stored 
under Recordati’ control for a maximum of 15 years. 
Access to study 
treatment after 
study completion 
Study completion is defined as when the last subject finishes their Study 
Completion visit, and any repeat assessments associated with this visit have 
been documented and followed-up appropriately by the study doctor, or in 
the event of an early study termination decision, the date of that decision.  


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All treated subjects should have a safety follow-up visit conducted 30 days 
after last administration of study treatment.  
 
After the study is completed and all data examined, a summary of the study results will be 
shared with your study doctor. The study doctor and/or representatives may share these results 
with you.  
After the study is completed, a summary of the study results will be publically available at 
www.ClinicalTrials.gov, and/or at the European Clinical Trials Database (EudraCT, 
www.eudract.ema.europa.eu/).   
3.1 
Can I decide to stop my participation in the study? 
You are free to stop your participation in this study at any time. If you want to stop participation 
in the study, you should notify the study doctor (in writing or in any other form required 
locally). This could mean:  
1. Stopping study treatments and continuing visits. If you decide to stop study treatments you 
will be asked to return to the study center as soon as possible to have a physical check-up  
2. Or, stopping study treatments and all future visits. Your study doctor or staff may ask you 
to do regular phone calls until the end of the study. 
The information already collected during the study including your samples (defined as Personal 
Data in this consent) will still be used together with the data collected from other patients in the 
study according to this informed consent and local laws.  
In addition to stopping participation in the study, you could decide to withdraw your consent as 
explained in Section 3.2. If you decide to stop study treatment and/or other study-related 
activities you should tell the study doctor or study staff. They will make sure that proper 
procedures are followed. 
3.2 
Can I withdraw my consent to collect and use my Personal Data? 
You may decide to withdraw your consent from this study.  You should inform your study 
doctor at any time in writing, (or in any other form required locally). This means that you want 
to stop full participation in the study and any further collection of your Personal Data. 
You can discuss your ongoing medical care with the study doctor, and return to your regular 
medical care. 
Recordati will continue to keep and use your collected study information (including any data 
resulting from the analysis of your samples until your time of withdrawal) according to local 
laws.  This is done to guarantee the study results can be verified, to determine the effects of the 
study treatment, and to ensure complete study documentation. 
You also have the right to request that your samples be destroyed (or returned at any time) (only 
add if mandated by local laws and regulations).  


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ALWAYS USE THE FOLLOWING TEXT FOR TRIALS IN EU.  FOR ROW COUNTRIES ALSO 
USE THIS LANGUAGE, UNLESS SPECIFIC COUNTRY LAWS REQUIRE MORE 
MANDATORY CUSTOMIZATIONS. 
Your samples that have not yet been analyzed at the time of your withdrawal will no longer be 
used, unless permitted by local laws. They will be stored according to applicable legal 
requirements. 
(USE THE FOLLOWING TEXT FOR TRIALS IN THE US or JAPAN) 
Otherwise, your samples that have not yet been analyzed at the time of your withdrawal may 
still be used for further testing/analysis in accordance with the terms of the protocol and of this 
informed consent form. 
3.3 
Are there any reasons that my study treatment or participation 
may be stopped early? 
The study doctor may remove you from this study for any justified reason and will discuss your 
options. 
Examples why you may have to stop some or all study-related activities, including study 
treatment are: 
1. You need treatment that is not allowed in this study 
2. You do not follow instructions 
3. You become pregnant.  (If you or your partner becomes pregnant, an additional ICF for 
pregnancy follow-up will be required)  
4. You experience side effects from the study treatments that you find unacceptable 
5. The study doctor thinks keeping you in the study might be harmful and is not in your best 
interest  
6. Recordati decides to stop this study  
7. Your current therapy becomes locally available and reimbursed in this indication. 
3.4 
Who owns the data and results created during the study?  
Recordati will own all data and results created during this study. 
3.5 
Can my samples be used after the study? (Health Authority 
requests) 
Health Authorities may request more testing on your samples in order to generate more study 
data. In such a case, Recordati will perform the requested testing. 
4 
What are the possible benefits if I join this study? 
The study drug may help to manage signs and symptoms of Cushing’s disease but taking part 
in this research study may not benefit you directly, but we may learn new things that could help 
other patients with the same condition. 


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You will receive medical care during the study. Osilodrostat has recently been approved in 
USA, European Union and Japan as Isturisa® for the treatment of Cushing’s disease in adults. 
Information from this study may help you and/or other people with Cushing’s disease. 
If new scientific developments occur during the course of the study that may relate to your 
willingness to continue participation, information regarding these developments will be 
provided to you so that you can make the decision whether or not you wish to continue study 
participation. 
 
5 
What are the possible risks if I join this study? 
Risks are possible side effects from the study treatment and from tests done during the study. 
You should tell the study doctor if you have any unusual complaints, behaviors, or side 
effects, or had other doctor visits or hospitalizations outside of the study. 
The most common side effects include such events as fatigue/asthenia (weakness), nausea, 
vomiting, headache, oedema (swelling) and adrenal insufficiency (low cortisol levels). In some 
patients, these symptoms may be caused by lowering of the cortisol level. Such symptoms could 
happen even if the cortisol level is normal – this is called steroid withdrawal. In other cases, the 
symptoms are because the cortisol level is too low (below normal) – this is called 
hypocortisolism or adrenal insufficiency. If your doctor thinks you have adrenal insufficiency, 
you may be told to take a lower dose or stop taking the study medication for a short time until 
the symptoms improve. Your doctor may also give other medications such as hydrocortisone, 
which can help with these symptoms.  
In some women, hirsutism (hair growth in a pattern like men, such as on the face) and acne has 
been seen. The most common changes on blood testing were low potassium and increases in 
some hormones. 
Animal studies show that when very high doses of osilodrostat were used (many times higher  
than would be used in humans) changes in the conduction of electrical activity in the heart, 
called QT interval prolongation on the ECG (ECG; a tracing of electrical activity in the heart) 
were seen, and in one case there was a temporary irregular heartbeat. Increase (prolongation) in 
the QT interval may lead to an irregular heartbeat which in rare instances can develop into a 
sudden, life-threatening condition. Although the risk is small, these findings suggest a risk for 
prolonged QT interval and associated risk for irregular heart rate in patients with Cushing’s 
disease treated with osilodrostat. For safety reasons, you will have monitoring of your heart 
rhythm during this study. ECGs (tracings of the heart rhythm) will be done each time you attend 
your study visit. 
 
There have been cases of neutropenia observed with osilodrostat treatment. Neutropenia is an 
abnormally low concentration of neutrophils (a type of white blood cells) in the blood. 
Neutrophils serve as the primary defense against infections. Patients with neutropenia may be 
more susceptible to infections. A Complete Blood Count (CBC) will be regularly performed 
during the study to detect any changes of your white blood cells. 
 
Your study doctor is aware of these potential side effects, as well as methods for treating them, 
and will discuss the risks with you before you begin taking study medication. If you expect to 


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undergo surgery or have any new illness, you should inform your study doctor so that 
appropriate measures can be taken. 
 
Problems or side effects that are not currently known could also occur. You will be given any 
new information as it becomes available that can help you choose to continue in the study. 
Should you experience any possible side effects, or other health problems, you should report 
them to your Study Doctor. 
 
If you experience any of these serious side effects, tell your doctor immediately.  
• Report if you experience more than one of the following: nausea, vomiting, fatigue, 
abdominal pain, loss of appetite, and dizziness, as these may be symptoms suggestive of 
very low cortisol level, known as adrenal insufficiency.  
• Heart problem or a heart rhythm problem, such as an irregular heartbeat could be a sign of 
QT prolongation.  
 
Other possible side effects  
Other side effects include the following listed below. If these side effects become severe, 
please tell your doctor.  
Table 5-1 Side effects 
Very common: may 
affect more than 1 in 
10 people 
• 
fast heartbeat (tachycardia)  
• 
very low cortisol levels (adrenal insufficiency)  
• 
nausea 
• 
vomiting 
• 
tiredness (fatigue)  
• 
swelling of the legs, ankles or other signs of fluid retention 
(oedema)  
• 
increased level of a hormone called corticotrophin in the 
blood (increased ACTH)  
• 
increased level of testosterone in the blood  
• 
abnormal results of liver function test  
• 
decreased appetite  
• 
pain in joint (arthralgia) 
• 
muscular pain (myalgia) 
• 
headache  
• 
dizziness 
• 
low blood pressure (hypotension)  


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Common: may affect 
up to 1 in every 10 
people 
• 
diarrhoea 
• 
abdominal pain 
• 
feeling of general discomfort, illness (malaise) 
• 
abnormal electrical signal in the heart (electrocardiogram QT 
prolongation)  
• 
low level of potassium in the blood (hypokalaemia) 
• 
fainting (syncope)  
• 
acne  
• 
excessive facial and/or body hair growth (hirsutism)  
• 
rash 
 
As part of this study, you will have a sample of your blood collected. The risks of collecting 
blood may include fainting, pain, and/or bruising. Rarely, there may be a small blood clot or 
infection at the site of the needle puncture or central line. 
The blood pressure cuff may also cause discomfort or bruising to the upper arm. Physical 
examinations and electrocardiograms (ECGs) are routine procedures in clinical practice and 
present practically no risk for you. 
In rare instances, a nurse, study doctor, or laboratory technician, may be exposed to your blood, 
tissue or body fluids by needle stick, cut, or damaged skin. If this happens, it may be necessary 
to test your sample for certain viral infections including Hepatitis B and C and HIV and, if 
possible, will be done on a sample already available. This will make it possible for that person 
to receive appropriate monitoring and treatment as needed. The study doctor will provide results 
of your tests and advise on the next steps. Confidentiality of the results of your tests will be 
respected at all times.  
 
Imaging risks: 
You may not have an MRI done if you have metal in your body, for example, some hip 
replacements, hearing aids, pacemakers, bullets, or jewelry that cannot be removed. You should 
inform the technologist or physician if you have any metal in your body. During the MRI exam, 
you may feel some heat and hear banging noises but have no reason to worry. Some people may 
have a ‘closed in’ (claustrophobic) feeling while inside the machine. The injection may make 
you sick to your stomach or have pain, warmth, swelling, bruising, a small blood clot or 
infection at the injection site. Rarely, you may get a rash or other signs of allergy from the 
injection or get a rare disease where some of your body parts get scarred. If you have a history 
of kidney problems you must inform the technologist or physician as you may not be able to 
receive an injection during the MRI exam. You should inform the physician or technologist 
if you are pregnant, or suspect to be, as this exam may cause harm to unborn babies. Your 
physician or technologist can explain the procedure and risks in greater detail and clarify any 
concerns or questions. 
If you are not able to have the MRI exam as advised by your Study Doctor you will do instead 
a CT scan. You will receive radiation when CT is done. The radiation received during one CT 
exam is the same as 2 - 10 years of normal radiation received in everyday life, depending on 


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the body parts included. Although repeated radiation exposure may damage your body tissues 
and slightly increase your chances of having cancer, you should not expect an increased risk 
from the imaging being done for this study. Some people may have a ‘closed in’ 
(claustrophobic) feeling while inside the machine. The injection may make you sick to your 
stomach, pass-out, or have pain, warmth, swelling, bruising, a small blood clot or infection at 
the injection site. You may get a rash or other signs of allergy from the injection. You should 
inform the physician or technologist if you have any history of allergies, for example, to seafood 
or medications, asthma, high blood sugar (or diabetes), heart problems, kidney problems, or 
thyroid problems, as all of these may increase your chances of having problems with the CT 
injection. You should inform the physician or technologist if you are pregnant, or suspect 
to be, as this exam may cause harm to unborn babies. Your physician or technologist can 
explain the procedure and risks in greater detail and clarify any concerns or questions. 
6 
What do I need to know about birth control and pregnancy?  
Women who are pregnant or nursing (breastfeeding) a child cannot participate in this study. 
You must confirm, to the best of your knowledge, that you are not now pregnant, and that you 
do not intend to become pregnant during the study. 
Studies in pregnant animals have shown that the medication you are required to take in this 
study can potentially harm an unborn or nursing baby. 
The risks to an unborn human fetus or a nursing child from the medications you are required to 
take in this study are not presently known. 
As a female participant in the study it is therefore important that you use a highly effective form 
of birth control method (contraception) if you are sexually active and may become pregnant. 
Highly effective methods of birth control have a less than 1% chance of unwanted pregnancy 
during one year, if used appropriately according to the instructions of the manufacturer.  Please 
discuss with your Study Doctor the most appropriate birth control method for you that also 
respects your cultural and religious situation. Examples of highly effective birth control 
methods are: 
• Total abstinence, when this is in line with your preferred and usual lifestyle. Periodic 
abstinence like calendar, ovulation, symptothermal, post-ovulation methods, and 
withdrawal are not acceptable methods of contraception.  
• Female sterilization, when you have been already surgically sterilized prior to the study 
by surgical bilateral removal of ovaries (woman's reproductive system that stores and 
releases eggs for fertilization and produces female sex hormones), or tubal ligation 
(getting your “tubes tied”) at least six weeks prior to starting the study treatment. 
• Your male partner has already been sterilized with the appropriate documentation. The 
sterilized male partner should be your sole partner.  
Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception 
that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception (in case of oral contraception you should have been using 
the same pill on a stable dose for a minimum of 3 months before taking study treatment). 


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If you become pregnant or suspect being pregnant during study treatment or within 1 week 
after completing study treatment, you must inform the Study Doctor immediately, and you have 
to stop ongoing study treatment immediately. You will not be allowed to continue study 
treatment if you are pregnant. Your Study Doctor will medically follow your pregnancy until 
delivery to monitor you and your child`s safety. 
7 
What are my responsibilities and are there any costs for me 
if I agree to join this study? 
If you agree to join this study, you have the following responsibilities: 
Table 7-1 
Responsibilities related to study appointments/visits, study treatment, 
and costs 
Study appointments/visits 
and procedures 
• 
Follow the instructions given by the study doctor and staff 
• 
Attend all of the study appointments. If you have to miss an 
appointment, you must reschedule with the study doctor or staff 
• 
Complete and return required study documents such as surveys, 
or diaries, as instructed. 
 
Study treatment 
It is very important to; 
• 
 take the study treatment as you have been instructed   
• 
 ensure that the study treatment is stored in a safe place 
You may discuss with a doctor or health care professional (who is 
not directly involved in the study) any health issues or your medical 
problems related to the study treatment or disclose information 
related to the study treatment. You should tell your doctor or health 
care professional that the Recordati treatment, and any information 
relating to it, is Recordati’ property and is confidential. 
Other treatments you may be taking: 
You must tell the study doctor about any treatments you are currently 
taking or may take during the course of the study (e.g. prescription, 
vitamins, over the counter, herbal supplements etc.) some of these 
may need to be stopped/reduced. 
Returning study treatment after stopping study treatment: 
When the study ends or if you decide to stop study treatment early, 
return all of extra osilodrostat and empty pill bottles as instructed.  
Costs 
You will not have to pay for your study treatment(s) or any of the 
tests and procedures done for study purposes. 
8 
What other choices are available if I choose not to join this 
study? 
 
You do not need to participate in this study to receive treatment for your condition. Treatment 
alternatives for Cushing’s disease depend on your disease history and on locally available 
therapy. They may include surgical removal of the pituitary tumor (where feasible), 


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radiotherapy and, other locally available medications (depending on your country, this may 
include drugs called metyrapone and ketoconazole), other experimental therapies (in a clinical 
trial), or in very rare and severe cases, a removal of the adrenal glands. These alternatives may 
be discussed with your study doctor about their potential benefits and risks. 
 
Participation in this study is not a substitute for your usual medical care by your regular doctor 
or specialist. You are strongly encouraged to ask the study doctor or a member of the study staff 
if you have questions about study treatment or any other possible therapies. 
During your participation in this study, you may not participate in any other clinical study. 
9 
What if I become injured because of participation in this 
study? 
If you are injured as a result of this study, please contact the study doctor immediately 
(investigator’s name and contact information); he/she will arrange treatment. 
Recordati will cover the reasonable costs of treatment for study-related injuries beyond what is 
reimbursed by your health insurance under the following conditions and in accordance with 
local laws: 
• If you received medical care and followed instructions, 
• If the injury is related to the study treatment or to study procedures (not usual medical care), 
and if such procedures are properly performed, 
• If the injury is not the result of the natural course of any disease existing before proper 
administration of the study treatment. 
(Remove for US) If you become injured as a result of the clinical study, Recordati has taken out 
an insurance policy for this purpose.  
By signing this consent, you do not give up any legal rights.   
10 
What will happen to my Personal Data? 
10.1 
What is Personal Data? 
The study doctor will collect your Personal Data meaning your name, initials, address, gender, 
age/date of birth, health information, study samples and medical images.  
If you have a primary doctor, the study doctor may let him/her know that you are participating 
in this clinical trial. If you do not want your primary doctor to be informed, please discuss this 
with your study doctor. 
Your study doctor may collect more information from your other doctors.  
The study doctor will replace your name and other general information about you, excluding 
age/date of birth and gender, with a special code that identifies you.  The study doctor will 
associate this code with the study information and any biological samples to make it unlikely 
that anyone will be able to identify you. 


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Recordati, which has appointed as its data processing representative in the European Union 
Recordati Rare Diseases Italy s.r.l., with registered office in Via Civitali 1, 20148 Milan (Italy), 
will receive some of the Personal Data below from your study doctor for the purpose of the 
study: 
• Your assigned code and age/date of birth, gender  
• Study information 
• Biological samples. 
The Sponsor is the data controller for the processing of personal data you provided in the past 
to Novartis, and of personal data which you may provide in the future to Recordati. The 
Sponsor has contracted a Clinical Research Organization IQVIA for the data processing 
activities for the purpose of this study. 
10.2 
How will my Personal Data be used? 
Your Personal Data will be examined to see whether the study is done accurately and to see if 
the study treatment is safe and effective. It will be examined with the Personal Data from all of 
the other participants in this study to learn more about the effects of the treatment.  
Your Personal Data may also be combined with data from other studies. This is to analyze and 
better understand the safety and efficacy of the study treatment. Personal Data may be used to 
check that the study is accurate and conducted correctly. Some of the processing of your 
Personal Data may be automated, meaning that Recordati may use computers and other 
technologies to process the Personal Data. 
Although you already consented to the processing by Novartis of the personal data you had 
provided, Recordati wishes to obtain your renewed consent to the processing of your personal 
data already collected by Novartis and of the additional data that Recordati may collect directly 
from you during the study. Your decision to provide your consent is completely free. However, 
if you decide not to renew your consent to the processing of your personal data by Recordati, 
you will no longer be able to take part in this study, and therefore the staff and the doctors of 
the study will not be able to collect the necessary information. If you give your consent, you 
allow such access to your Personal Data including your original medical records. 
Your coded medical images (for example X-ray, MRI, CT, ultrasound, etc.) will be studied.  
They may also be used to develop new ways to look at this type of information. 
(USE THE FOLLOWING TEXT FOR TRIALS IN THE US) 
The individuals mentioned in bullets 2 and 3 of the Section ‘Who Can see my Personal Data’ 
(Section 10.4) may use your Personal Data, including any of your remaining coded biological 
samples, for additional medical and/or scientific research  outside of the current study purpose 
and objectives. 
10.3 
Where are Personal Data kept and secured? 
Upon the renewal of your consent to the processing of past and future data, Recordati will keep 
your personal data for a period of 25 years from the last follow-up relating to this clinical study. 
This retention period may be extended if this should prove necessary for Recordati in relation 
to any dispute, investigation or proceedings or if this should be required by new legislation. In 


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the absence of the renewal of your consent, Recordati will store the data collected by Novartis 
for the period of time prescribed by the law.  
The Personal Data collected in this study by Novartis and Recordati will be entered in 
Recordati’ secure electronic systems, and the companies who work with Recordati (such as the 
Contract Research Organization IQVIA) may operate these systems.  Your Personal Data at the 
investigational site will be stored for the period requested by local regulations after the end of 
the study. 
A description of this study will be available in registries in countries where the study is 
conducted, and will not include information that can directly identify you. For example, a 
description of this clinical study will be available on ClinicalTrials.gov.   
A summary of the results may also be published at conferences or in journals. If the results of 
the study are presented to the public, you will not be named. Some authorities may ask that 
Recordati disclose study data for transparency reasons. However, the data shared will not 
identify you. 
10.4 
Who can see my Personal Data? 
Your Personal Data will be kept secure and will only be available to the people listed below: 
• The study doctor and study staff, 
• Recordati, companies of  Recordati’ group, Recordati study/research staff (e.g., monitors, 
auditors, and authorized agents such as contract research organizations (CROs),  
• In the future a new company acquiring or licensing rights from Recordati or part of its 
business, 
• Review boards checking ethics of the study, 
• Health Authorities or other authorities, as applicable, 
• Other third parties (which may include third parties in other jurisdictions) (Be as 
specific as possible), 
However, these people must keep the Personal Data confidential. They may be located in 
Switzerland, in countries of the European Economic Area (EEA), or other countries like the 
United States. The data protection laws in these countries may not be as strict as in your own 
country. In those cases, the transfer will take place in the presence of the appropriate safeguards 
imposed by General Data Protection Regulation (GDPR) on the transfer of data outside the 
European Union (such as, for example, the adoption of standard contractual clauses, pursuant 
to articles 46 and following of the GDPR).   
10.5 
Your specific rights about your Personal Data 
You have the right to review your Personal Data. However, during the study, access to the 
Personal Data may be limited to protect the integrity of the study. You may have access to your 
Personal Data at the end of the study. 
You should ask the study doctor if you have any questions about the collection and use of 
information.  You should also inform him/her if you wish to exercise your rights about this 
information; such as if you decide to have some Personal Data corrected or to withdraw consent 


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(add additional contact information as required by local law).   
You can at any time contact (enter contact details of the Data Privacy Officer at the site or of 
other responsible person) if you have any questions about this Informed Consent Form or the 
collection, processing, or use of your Personal Data as described above. You are also entitled 
by law to lodge complaints in front of the relevant data privacy authority. 
 
10.6 
What are Anonymized Data and who can use them? 
Recordati may anonymize your Personal Data, which means that your Personal Data cannot be 
traced back to identify you. Therefore, it is no longer considered Personal Data. This 
Anonymized Data may be shared by Recordati with external parties, which include health 
authorities and authorized external researchers to help predict how people might respond to a 
treatment in a future, unrelated study, or to learn more about this or other diseases.   


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11 
Where can I receive more information? 
If you have questions about the study, please contact: (insert name and the phone number; 
usually the Investigator and/or study nurse/study coordinator) at any time. 
 
Role 
 
Name 
 
Telephone Number 
Principal Investigator 
 
 
 
 
Study Nurse/ Coordinator 
 
 
 
 
 
If you have questions related to your rights, please contact: (insert name of the IRB/EC and the 
phone number). 
 
Role 
 
Name 
 
Telephone Number 
IRB/EC 
 
 
 
 
 
In the event of a research-related injury, please contact (insert name and phone number). 
 
Role 
 
Name 
 
Telephone Number 
Principal Investigator 
 
 
 
 
 


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12 
Signature pages 
Use for US Sites: Please use/modify the following signature page with the currently approved 
HIPAA wording for the signature page. 
Use for non-US sites: Use/modify the following signature page; add or delete signature lines 
according to local laws 
Protocol number and version: CLCI699C2X01B, Version 02 dated 06-May-2020 
Protocol title: An open-label, multi-center, roll-over study to assess long term safety in patients 
with endogenous Cushing’s syndrome who have completed a prior Novartis-sponsored 
osilodrostat (LCI699) study and are judged by the investigator to benefit from continued 
treatment with osilodrostat 
I have read this document/had its contents explained to me. I understand the purpose and what 
will happen to me in this study. I do freely give my consent to join this study, as described to 
me in this document. I understand that I will receive a copy of this signed document. 
By signing this consent form, I authorize the use, access, and sharing of my Personal Data as 
described in this document.  
This consent is valid unless and until I revoke it. 
 
type/print name 
 
 
 
 
Subject name 
 
Signature  
 
Date 
(The execution by witness must be authorized under local laws. The witness cannot be a 
healthcare professional in charge of the subject. A copy of their ID must be obtained and 
archived with the executed consent form. Please check with local legal regulations) 
 
type/print name 
 
 
 
 
Witness 
(If subject gives oral consent but 
cannot sign the consent form) 
 
Signature 
 
Date 
(The execution by a legal representative, when the subject cannot provide consent, must be 
governed by local laws. Please check with local legal about local requirements) 
 
 
type/print name 
 
 
 
 
Legal representative (if required) 
(Legally authorized to act as 
personal representative to sign for 
(name of subject)) 
 
Signature 
 
Date 
 
 
type/print name 
 
 
 
 
Investigator 
 
Signature 
 
Date 


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type/print name 
 
 
 
 
Name of presenter 
(Who presented/explained the 
document) 
 
Signature 
 
Date 


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13 
Optional Consent for additional research using your 
Personal Data 
During or after the study, Recordati may want to use your Personal Data for additional research 
projects. Personal Data includes your year of birth, gender, a special code that identifies you, 
study information, as explained in the section ‘What will happen to my Personal Data?’ 
Wherever permitted by law or requested by the authorities, this additional research may include 
studies to get more information on Cushing’s Disease. It may be used to design or improve 
methods for analyzing, comparing, or combining your study data with data from subjects given 
other treatments. It may involve new approaches or biological markers of Cushing’s Disease 
and other aspects of the disease. Researchers may study the benefits and risks effects of 
osilodrostat and compare the data from osilodrostat with other treatments. This will allow 
Recordati and other researchers to better understand Cushing’s Disease, how osilodrostat works 
and to be able to find the best way to treat patients with Cushing’s Disease or other diseases in 
the same therapeutic area. 
 
The information under the ‘What will happen to my Personal Data?’ section is applicable 
to this optional consent.  
 
You will not own any data and discoveries generated from the additional research studies. The 
data will not become part of your medical record. 
If you choose to give consent for additional research, you can change your mind at any time. If 
you decide you no longer want Recordati to use your Personal Data for additional research this 
is possible. You can continue to be in the main study. Please notify the study doctor if this is 
the case.  
 
 
By signing below, I agree to the use of my Personal Data for additional research as described 
above.  
This consent is valid unless and until I revoke it 
 
type/print name 
 
 
 
 
Subject Name 
 
Signature 
 
Date 
 
type/print name 
 
 
 
 
Legal representative name 
(legally authorized to act as personal 
representative to sign for) 
 
Signature 
 
Date 
 


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type/print name 
 
 
 
 
Name of presenter 
(who presented/explained the 
document) 
 
Signature 
 
Date 
 

Prot_000.pdf: 
 
Recordati Research and Development 
LCI699 (osilodrostat) 
Clinical Trial Protocol CLCI699C2X01B 
An open-label, multi-center, roll-over study to assess long 
term safety in patients with endogenous Cushing’s 
syndrome who have completed a prior Novartis-sponsored 
osilodrostat (LCI699) study and are judged by the 
investigator to benefit from continued treatment with 
osilodrostat 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2017-002840-34 
ClinicalTrials.gov 
Identifier: 
NCT03606408 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
II b 
Release date: 
06-May-2020 
Sponsor: 
RECORDATI AG - Lindenstrasse 8, 6340 Baar, Switzerland   
tel: + 41 (0) 61 205 61 00 
CRO: 
IQVIA 
Property of Recordati 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Recordati 
 
 


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


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


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


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


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


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


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


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


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


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


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by their parent study Investigator as benefiting from the current study treatment. The 
study is expected to remain open for approximately 5 years (or until 31-Dec-2023 in the 
UK) from First Patient First Visit (FPFV). Patients will continue to be treated in this study 
until they are no longer benefiting from their osilodrostat treatment as judged by the 
Investigator or until one of the protocol defined discontinuation criteria is met. 
Population 
Patients with endogenous Cushing’s syndrome who are currently enrolled in a Global 
Novartis-sponsored study and benefiting from treatment with osilodrostat, as determined 
by the Investigator. 
Key Inclusion 
criteria 
1. Patient is currently participating in a Global Novartis-sponsored study receiving 
osilodrostat for any type of endogenous CS and has fulfilled all the requirements in the 
parent study. 
2. Patient is currently benefiting from treatment with osilodrostat, as determined by the 
Investigator. 
3. Patient has demonstrated compliance, as assessed by the Investigator, with the parent 
study protocol requirements. 
4. Patient is willing and able to comply with scheduled visits and treatment plans. 
5. Written informed consent/adolescent assent obtained prior to enrolling into the roll-over 
study. 
Key Exclusion 
criteria 
1. Patient has been permanently discontinued from osilodrostat study treatment in a 
parent Novartis-sponsor study. 
2. Patients who are receiving osilodrostat in combination with unapproved or experimental 
treatments for any type of endogenous CS. 
3. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory evaluation. 
Study treatment 
Osilodrostat, film-coated tablets up to 30 mg b.i.d, oral use  
Efficacy 
assessments  
At every quarterly visit, the Investigator is required to confirm that the patient continues to 
have clinical benefit and may continue receiving study treatment. 
Safety 
assessments 
AEs/SAEs, physical examination, body weight and blood pressure, blood chemistry tests, 
hematology, hormones, ECG and pituitary MRI. 
Data analysis 
The assessment of safety will be based mainly on the frequency and severity of 
AEs/SAEs and on the number of laboratory values that fall outside of pre-determined 
ranges. Other safety data, such as physical examination, vital signs (blood pressure and 
body weight), ECG and Pituitary MRI or CT will also be presented. Proportions of patients 
with clinical benefit as assessed by the Investigator will be summarized at scheduled 
visits. 
Key words 
Osilodrostat, endogenous Cushing’s syndrome, roll over study, long term safety 
IRBs/IECs 
A copy of this amended protocol version will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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1 
Introduction 
1.1 
Background 
1.1.1 
Epidemiology and pathogenesis of Cushing’s syndrome 
Cushing’s syndrome (CS) is a rare disorder with a reported incidence of 0.7–2.4 per million 
population per year. In European countries and in the US, the prevalence rates have been 
reported to range from 19 to 79 cases per million inhabitants, with the highest prevalence (79 
cases per million) reported from New Zealand. In a survey conducted in Japan by the Ministry 
of Health, Labour and Welfare in 1997, the prevalence of CS has been reported to be 
approximately 1250 cases.   
CS is characterized by a chronic excess of cortisol secretion, which results in numerous clinical 
features that are associated with a higher mortality compared with the general population, if not 
appropriately treated (Pivonello et al, 2008). 
CS can be either exogenous or endogenous. The most common cause of exogenous CS is 
iatrogenic due to the external administration of excessive doses of glucocorticoids. 
Endogenous CS is classified as either adrenocorticotropic hormone (ACTH)-dependent or 
ACTH-independent. ACTH-dependent CS accounts for 80%–85% of cases. Of these, 75%–
80% are due to ACTH production from a pituitary adenoma (Cushing’s disease [CD]), 15%–
20% are due to ACTH production from non-pituitary tumors (ectopic ACTH syndrome) and 
<1% are caused by corticotrophin-releasing hormone (CRH)-producing tumors.  
ACTH-independent CS accounts for 15%–20% of endogenous CS in adults; 90% are unilateral 
adrenal tumors. Of these, adenomas are the cause in ~80% of the cases, while the others are 
adrenocortical carcinoma. 
Cushing’s disease (CD) is the most common cause of CS (70% of cases) in Western countries, 
while it makes up a smaller proportion of the CS population in Japan (35.8%). It is caused by 
excessive secretion of cortisol from the adrenal glands as a consequence of excessive ACTH 
secretion from a pituitary tumor, generally an adenoma (90%), whereas a carcinoma is a very 
rare cause of the disease (less than 10%). It affects adults aged 20-50 years-old more commonly 
with a marked female preponderance (Pivonello et al 2008; Newell-Price et al 2006).  
Endogenous CS is characterized by chronic hypercortisolism, which results in a variety of 
metabolic abnormalities and co-morbidities that collectively lead to an overall 4-fold higher 
mortality rate than age- and gender-matched subjects in the general population (Arnaldi et al, 
2003). 
The clinical manifestations are variable and include obesity affecting mainly the face, neck, 
trunk, and abdomen, thinned skin, purple striae, muscular weakness, fatigue, hypertension, 
diabetes mellitus (DM), neuropsychiatric disorders, acne, hirsutism, and menstrual irregularities 
(Arnaldi et al, 2012).  
There is an increased cardiovascular risk and it is mainly due to the metabolic syndrome, insulin 
resistance, weight gain, glucose intolerance, dyslipidemia and hypercoagulation.  


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Normalization of hypercortisolism is expected to improve or reverse the increased morbidity 
and mortality associated with the untreated disease. Published data have suggested that recovery 
from the co-morbidities does occur, but may be delayed or incomplete (Valassi, et al 2012; 
Arnaldi, et al 2012). The duration and severity of chronic hypercortisolism may impact the 
reversibility of the co-morbidities associated with CD (Feelders, et al 2012). 
However, mortality studies have consistently shown that the mortality rate is significantly 
impacted by the biochemical status of the disease, i.e., persistent/recurrent hypercortisolism 
compared to biochemical remission of the disease.  
A meta-analysis of published mortality studies (Clayton, et al 2011) showed that the 
standardized mortality ratio (SMR) is much higher in CD patients with persistent 
hypercortisolism (SMR=5.5) than those in remission (SMR=1.2). 
1.1.2 
Current treatment modalities 
Surgical resection of the source of glucocorticoid excess (pituitary adenoma, non-pituitary 
tumor-secreting ACTH or adrenal tumor[s]) remains the first-line treatment of all forms of 
endogenous CS. 
The first line-treatment of CD is mainly represented by the surgical removal of the pituitary 
tumor by TSS (Pivonello 2015). Post-surgical remission rates of 70-80% have been reported. 
However, a 25% incidence of recurrent hypercortisolism has been reported at 10 years of 
follow-up (Bochicchio et al 1995; Sonino et al 1996). With a second pituitary surgery (re-
operation), success rates are lower and complications are higher than with primary pituitary 
surgery; therefore patients should be carefully selected (Fleseriu, et al 2007; Friedman, et al 
1989). 
In the International Consensus Statement on the treatment of ACTH-dependent CS (Biller, et 
al 2008), the goals of treatment are stated as: reversal of clinical features; normalization of 
biochemical changes with minimum morbidity; and long-term control without recurrence. 
Medical therapy is an attractive option for patients with CD who have persistent or recurrent 
hypercortisolism after primary pituitary surgery with or without radiation, and patients with de 
novo CD who are not surgical candidates for medical reasons, refuse to undergo surgery, or do 
not have access to a specialized center with experience in pituitary surgery. 
Pasireotide (Signifor®), a second generation somatostatin analogue, is currently approved in the 
US and in EU, and many other countries, for the treatment of CD.  
Mifepristone, a glucocorticoid receptor antagonist, is approved in the US for the treatment of 
hyperglycemia secondary to hypercortisolism in adult patients with endogenous CS who have 
type 2 diabetes mellitus or glucose intolerance. 
Several other drugs have been used with and without regulatory approval for the treatment of 
CD, including the steroidogenesis inhibitors ketoconazole and metyrapone (both approved in 
Europe), mitotane (adrenolytic agent), and cabergoline (dopamine agonist). 
Pituitary irradiation is an option for patients who are not surgical candidates or have persistent 
or recurrent hypercortisolism following primary pituitary surgery. However, the response to 
pituitary irradiation is slow and is related to the type of radiation administered. The two most 


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commonly used radiation modalities are stereotactic radiosurgery (SRS), which consists of a 
single high-dose treatment (e.g. proton beam, gamma knife or cyber knife), and conventional, 
fractionated radiation (linear accelerator). SRS is not only more convenient to the patient; it 
also has a faster onset of biochemical remission median of 17 months (Sheehan, et al 2013), 
than with conventional fractionated radiation, with an onset of 2-3 years (Loeffler and Shih, 
2011). In some cases of conventional fractionated radiation, remission may be delayed until 10 
years or longer (Losa, et al 2010; Minniti, et al 2007). The long term complications include 
hypopituitarism (Newell-Price, et al 2006), secondary malignant tumors (Sedney, et al 2012), 
and possibly an increased risk of death from cerebrovascular disease post-radiation (Ayuk 
2012). 
Bilateral adrenalectomy in ACTH-dependent CS may be used when surgery and medical 
therapy are unsuccessful, or based on patient preference. It leads to rapid resolution of 
hypercortisolemia and related morbidity. However, after bilateral adrenalectomy, patients need 
lifelong glucocorticoid and mineralocorticoid replacement.  
Another concern with bilateral adrenalectomy in patients with CD is the development of 
Nelson’s syndrome (local tumor growth with mass effects and increased ACTH levels causing 
hyperpigmentation 
1.1.3 
Unmet medical need 
The treatment of patients with CS still represents a challenge, especially for patients with CD 
since the available treatments do not lead to biochemical control in quite a large number of 
patients and many of them lose biochemical control over time.  
Therefore, there is an unmet medical need to develop new drugs with improved safety, efficacy 
and a more patient-friendly profile.   
Osilodrostat, a novel adrenal-directed steroidogenic inhibitor, is under evaluation, due to its 
safety and efficacy profile, as demonstrated by preliminary data from the LINC 2 study, 
conducted in patients with Cushing’s disease.  
Based on these results osilodrostat shows promise in fulfilling an unmet medical need in all 
types of endogenous CS. 
1.2 
Purpose 
1.2.1 
Overview of osilodrostat 
Osilodrostat (company research code: LCI699) is a potent, oral inhibitor of 11β-hydroxylase 
(CYP11B1), the enzyme that catalyzes the last step in the biosynthesis of cortisol. This provides 
the rationale for investigating the use of osilodrostat in endogenous causes of CS.  
It is manufactured as a phosphate salt and available in film-coated tablets of 1 mg, 5 mg and 10 
mg. 
The mechanism of action of osilodrostat is depicted in Figure 1-1 below. 


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Figure 1-1 
Mechanism of action of osilodrostat in Cushing’s Syndrome 
 
1.2.1.1 
Non-clinical experience 
For detailed non-clinical pharmacokinetics and toxicity findings, please refer to the 
[Investigator Brochure]. 
1.2.1.2 
Clinical experience 
Currently, osilodrostat (Isturisa®) has been granted an approval: 
• from the European Commission on 9th January 2020 for the treatment of endogenous 
Cushing syndrome in adults and  
• from FDA on 6th March 2020 for adults with Cushing’s disease who either cannot 
undergo pituitary gland surgery or have undergone the surgery but still have the disease. 
1.2.1.2.1 Results of study LCI699C2201 
Results of LCI699C2201 study in CD. 
The purpose of the LCI699C2201 study was to determine whether the ability of osilodrostat to 
inhibit 11β-hydroxylase could safely reduce UFC (Urinary Free Cortisol) in patients with CD.  
This was initially studied over a 10-week treatment duration Proof-of Concept (Part I). Part II 
of the study aimed to further evaluate the observations from the Part I by enrolling a cohort of 
patients who participated in Part I and a new cohort (Expansion cohort) of patients and 
evaluating the long-term efficacy and safety of osilodrostat treatment. 
In Part I, osilodrostat was effective in controlling cortisol production in all 12 patients studied. 
At daily osilodrostat doses between 2 mg twice a day (b.i.d.) and 50 mg b.i.d., 24-hour cortisol 
decreased rapidly and normalized at least once in all patients studied. In general at 5 mg b.i.d. 


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patients showed cortisol reduction after 2 weeks (at first cortisol measurement after dose 
titration). 
The primary endpoint, defined as cortisol ≤ Upper Limit Normal (ULN) or ≥ 50% decrease 
from baseline at Day 70, was achieved by all patients. Overall, the mean time to response (UFC 
normalization or ≥ 50% reduction from baseline) was 34.3±14.1 days. The mean daily dose [± 
Standard Deviation (SD)] of osilodrostat required to reach the primary endpoint was 13.5±13.9 
mg b.i.d. with 75% of patients normalizing cortisol on ≤ 10 mg b.i.d. At Day 84, two weeks 
after osilodrostat was withdrawn, cortisol levels increased to a mean of 4-fold above upper limit 
of normal (ULN). 
Significant decreases in mean plasma cortisol and aldosterone from baseline (-60% and -70%, 
respectively) and marked increases in their precursors from baseline (11-deoxycortisol [13-
fold] and 11-deoxycorticosterone [42-fold], respectively) and ACTH [2.4-fold] were observed 
at Day 70. These biochemical changes were as expected based on the mechanism of action of 
the drug, i.e., primarily related to hypocortisolism, hypoaldosteronism, accumulation of their 
precursors, and increase in ACTH from baseline. 
In Part II, 17 out of 19 patients completed 22 weeks of treatment and 15 had normal cortisol 
levels at week 22 (79%). During treatment with osilodrostat, the mean cortisol levels decreased 
quickly and stabilized to a normal level (11 to 138 nmol/24h) at Week 4. After Week 4, normal 
mean cortisol levels were observed through the study up to Week 22. All patients attained UFC 
normalization at least once during the study, and no patient “escaped” UFC control. The study 
is ongoing. 
• Two phase III multi-center studies are ongoing:  
a. C2301: this is a double-blind, randomized, withdrawal study following a 24 week, 
single-arm, open-label, dose titration and treatment period to evaluate the safety and 
efficacy of osilodrostat in the treatment of patients with CD. Primary endpoint: 
proportion of randomized patients in each treatment group with mUFC ≤ ULN at 
week 34 who neither discontinued nor had dose increase above the week 24. This 
study has enrolled 137 subjects with CD. 
b. C2302: this is a randomized, double-blind, placebo-controlled 48-week study with an 
initial 12 week placebo-controlled period to evaluate the safety and efficacy of 
osilodrostat in patients with CD. Primary endpoint: proportion of randomized patients 
with a complete response at Week 12. The study plans to enroll 69 subjects with CD. 
• One phase II multi-center study is ongoing in Japan: 
a. C1201: this is an open label, dose titration, multi-center study to assess the safety, 
tolerability and efficacy of osilodrostat in patients with all types of endogenous CS, 
except CD. 
1.2.1.2.2 Overview of safety 
In the clinical trials for the treatment of hypertension or primary hyperaldosteronism, 
osilodrostat was tolerated with the overall incidence of adverse events being similar to placebo.  
Adverse events (AEs) were generally of mild to moderate intensity. Both Serious Adverse 
Events (SAEs) and discontinuations due to AE were infrequent, and were reported at a rate 


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similar to placebo in the hypertension studies. The most common AEs across these studies were: 
headache, dizziness (including postural dizziness), nausea, diarrhea and fatigue. There were 
also AEs of hyperkalemia and impaired ACTH-stimulated cortisol response in these trials, 
which are consistent with the potential for hypocortisolism and hypoaldosteronism.  
Overall, in patients with CD (study CLCI699C2201), safety data from the 10-week analysis has 
also showed that osilodrostat was well tolerated with similar common AEs to those in the 
hypertension trials, including: fatigue, nausea, vomiting, diarrhea, headache, dizziness, 
hypokalemia and muscle spasms. 
In Part I of the study, all 12 patients (100%) experienced adverse events but these were generally 
grade 1 or grade 2 (National Cancer Institute Common Terminology Criteria (NCI CTC)). 
Fatigue, muscle cramps, dizziness and gastrointestinal events were the most common events 
suspected to be drug related. Four patients reported AEs consistent with cortisol and/or 
aldosterone withdrawal; dose reductions or temporary dose interruption in these patients 
improved the symptoms. There were no discontinuations related to study drug and no serious 
adverse events of suspected drug relationship. 
In Part I, SAEs of decreased hemoglobin, tachycardia, chest pain and reactivation of Takayasu’s 
arteritis were reported in one patient. The events were attributed to progression of the 
preexisting conditions and were not suspected to be related to study drug. 
In Part II, osilodrostat was also generally well tolerated throughout the study. Of the 19 enrolled 
patients, 17 patients completed the 22 weeks treatment period with a median duration of 
exposure of 25.1 and 38.9 weeks in the Expansion cohort and Follow-up cohort, respectively. 
The safety findings identified in the interim analysis (data cut-off date: 23-Dec-2013) that was 
performed after the last patient had completed 22 weeks of treatment showed that except for 
one patient in the Expansion cohort, all patients experienced AEs, grade 1 and grade 2 in most 
of the cases. Adrenal insufficiency, nausea, fatigue and increase levels of oxycorticosteroids, 
blood corticotrophin, and blood testosterone were the most common AEs suspected to be drug 
related [by Preferred Term ]. There were no new safety concerns during the Extension Period 
to Month 31. This study is ongoing. 
In Part II (31-month analysis), a total of 9 SAEs were reported in 4 patients, including (by 
preferred term) pituitary-dependent Cushing’s syndrome (in 2 patients), electrocardiogram QT 
prolonged, food poisoning, gastroenteritis, headache, non-cardiac chest pain, pituitary tumor 
and pituitary tumor benign.  
Of these, one event of QT prolongation was reported as related to study drug by the Investigator, 
however the event developed in the context of gastroenteritis with anorexia and dehydration. 
There were no reported cardiac symptoms or cardiac arrhythmia. QT prolongation resolved 
after osilodrostat was discontinued, and did not reoccur when osilodrostat was re-started at a 
lower dose.  
Other notable events included pituitary tumor enlargement and pituitary tumor reported in two 
patients. Both patients had elevated ACTH level. The study treatment was stopped in both 
patients because of pituitary surgery. The Investigators did not suspect a relationship between 
the events and treatment with osilodrostat. 


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In reviewing the clinical trial experience with osilodrostat to date, AEs have been identified that 
are consistent with the mechanism of action of the drug as an inhibitor of both cortisol and 
aldosterone synthesis. These can be summarized as follows: 
• Changes in adrenal hormones: cortisol decreased, aldosterone decreased, and their 
precursors (11-deoxycortisol, 11-deoxycorticosterone) increased  
• Change in pituitary hormone: ACTH increased 
• Changes in electrolytes: potassium increased or decreased 
• Changes in body weight and blood pressure: potentially increased by mineralocorticoid 
effect of the aldosterone precursor 11-deoxycorticosterone 
• Changes in sex hormones: testosterone and estradiol increased (testosterone more than 
estradiol) 
In addition, treatment with osilodrostat can potentially result in neutropenia, which is 
considered to be an indirect effect of cortisol reduction, as reported in the literature. During 
hormonal control, a significant decrease of neutrophil count, which is commonly elevated in 
patients with CD, has been reported demonstrating the effect of glucocorticoids on these blood 
cells (Masri-Iraqi et al 2014). This effect has also been observed with osilodrostat in the CD 
trials and has included cases of neutropenia which were associated with cortisol levels that were 
either below normal or have had a rapid and substantial decline from baseline. In the cases 
observed to date, neutropenia has rapidly reversed with discontinuation of osilodrostat, and has 
also reversed when osilodrostat was continued, typically with decreasing doses.  
For a comprehensive review of clinical safety data with osilodrostat, see the [Investigator’s 
Brochure]. 
1.2.1.2.3 Osilodrostat: QT/QTc in healthy volunteers 
The potential impact of osilodrostat on cardiac repolarization potential was assessed in the 
definitive ICH E14 compliant thorough QT Study (TQT) study LCI699C2105 in 86 healthy 
male and female subjects. 
Based on the predicted exposure levels, the predicted maximum mean QTcF on osilodrostat 30 
mg is 6.3 ms (CI 5.13, 7.42). 
The results remained below the QTcF effect of regulatory concern (i.e., an upper boundary of 
the 90% CI < 10 ms) and fully support the use of LCI699 doses up to 30 mg b.i.d. 
2 
Objectives and endpoints 
Objectives and related endpoints are described in Table 2-1 below.  
Table 2-1 
Objectives and related endpoints  
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
● To evaluate long term safety data 
Endpoint(s) for primary objective(s)  
● Frequency and severity of AEs/SAEs;  
Secondary Objective(s) 
● To evaluate clinical benefit as assessed 
Endpoint(s) for secondary objective(s) 
● Proportion of patients with clinical benefit as assessed by the 
Investigator at scheduled visits 


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


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Figure 3-1 
Study Design  
 
4 
Rationale  
The purpose of this study is to evaluate the long-term safety of osilodrostat and to allow its 
continued supply to subjects who are currently receiving osilodrostat treatment in a Global 
Novartis- sponsored study that has reached its study objectives.  
These subjects are judged by the parent study Investigator as benefiting from continued 
treatment with osilodrostat and by the fact that, they would not be able to access osilodrostat 
outside a clinical trial. 
4.1 
Rationale for study design 
This is a multi-center, open-label, phase IIb roll-over study to evaluate the long-term safety of 
osilodrostat in subjects who have completed the parent studies and are judged by the parent 
study Investigator as benefiting from treatment. 
This roll-over study will not include a screening phase, at the completion of the parent study, 
as subjects will directly transfer from the parent studies. When their participation in the parent 
study has finished, eligible patients will start receiving osilodrostat only after they have signed 
the Informed Consent and have met the selection criteria for this roll-over study. 
 
4.2 
Rationale for dose/regimen and duration of treatment 
At the time of transition to this roll-over study, the starting dose should be the same as the last 
dose that was given at the last visit in the parent study. During the roll-over study, dose 
modification may be done at the discretion of the Investigator following the guidelines in 
Section 6.5. 
The maximum dose may not exceed 30 mg bid, which is the same maximum dose also applied 
in the parent studies.    
Osilodrostat (LCI699) will be given in form of film-coated tablets for oral administration, and 
available in the following dose strengths: 1 mg, 5 mg and 10 mg. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs  
Not applicable. 
 
Parent Novartis
Study 
 
   
 
Osilodrostat 
 
  
 
 
 
 
 
 
Osilodrostat is 
permanently discontinued 
 
Roll-over 
Recordati 
Study 
    Osilodrostat 
End of Roll-over
Recordati 
Study 


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4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
4.5 
Risks and benefits 
There is still an unmet need in the treatment of CD: despite available therapies, a substantial 
number of subjects do not achieve normalization of cortisol, lose biochemical control over time 
or present medication-related adverse reactions and may stop treatment because of this.  
In order to mitigate the potential risks related to the administration of osilodrostat, some 
procedures will be taking place: 
• The starting dose should be the same as the dose provided in the parent osilodrostat study 
at the time of transition to the roll-over study. However, the investigator can change the 
dose based on the subject’s response; the maximal dose should not exceed 30 mg b.i.d. 
• Subjects will be evaluated by the treating investigator for clinical benefit and safety  based 
on the following assessments:  
• Physical examination (every 12 weeks) 
• Body weight / blood pressure (every 12 weeks), 12-lead safety ECG (every 24 
weeks), blood chemistry and hematology (every 24 weeks), 11-deoxycortisol and 11 
deoxycorticosterone (every 24 weeks), testosterone (every 24 weeks), Urinary Free 
Cortisol (UFC) (every 12 weeks), serum cortisol as clinically indicated, plasma 
ACTH (every 12 weeks) and pituitary MRI (every 48 weeks or more frequently if 
clinically needed). 
• AEs and SAEs will be reported continuously and evaluated by the investigator at each 
visit. 
• Drug administration record for dosing of osilodrostat will be completed at baseline and 
during treatment visits. 
• For females, urinary pregnancy test will be performed at each visit (every 12 weeks) and 
monthly, at home.   
• Upon administration of the last drug dose, discontinuation from the study or study end, the 
patient will have a follow-up visit 30 days later.  
• The protocol provides specific guidance for dose modifications and/or stopping rules, due 
to osilodrostat-related toxicities. In addition, a safety follow-up for liver toxicity and 
management of QT prolongation have also been included.  
Potential subject benefits 
There is an unmet medical need in subjects with CS since this is a rare and serious disease but 
with limited medical treatment options. 
An open label, proof-of-concept, single-arm study (CLCI699C2201, LINC 2) has been 
conducted to assess the safety and tolerability of osilodrostat in patients with CD after 10 weeks 
of treatment.  
In this study, 12 CD patients received osilodrostat orally for 10 weeks. The drug was given at 
the starting dose of 2 mg b.i.d., and was progressively increased on the basis of the urinary 


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cortisol levels till their normalization or a maximum dose of 50 mg b.i.d. was achieved. After 
10 weeks of treatment, all 12 patients normalized urinary cortisol levels or achieved a > 50% 
reduction in urinary cortisol levels. The reduction of urinary cortisol levels was accompanied 
by a trend towards a decrease in BP. Osilodrostat was generally well tolerated, with the most 
frequently reported adverse events being fatigue (58.3%), nausea (41.7%), diarrhea (25%), 
headache (25%), hypokalemia (25%), muscle spasms (25%) and vomiting (25%).  
Recently, an amended extension of the phase II study (CLCI699C2201, LINC 2) is currently 
ongoing with the overall objective of evaluating the efficacy and safety of osilodrostat for a 
longer period of time. After 22 weeks of treatment, 15 out of 19 patients (78.9%) had 
normalized UFC. The decrease in urinary cortisol levels was associated with improvements in 
the glucose and lipid profiles. Adverse events during this extension of the study included GI 
disturbances (nausea and diarrhea in 31.6%), asthenia (31.6%) and adrenal insufficiency 
(31.6%), together with an increase in ACTH, cortisol and aldosterone precursors, and an 
increase in testosterone, which, in some women was associated with onset or worsening of acne 
and hirsutism.  
There was a trend toward improved fasting glucose and HbA1c in patients with diabetes at 
baseline, and an improved fasting lipid profile in patients with dyslipidemia at baseline.  
After the initial 22 weeks (core study), patients were invited to enter the extension study up to 
month 31. Safety and efficacy results have shown that the drug’s profile will fulfill the unmet 
need in the medical management of endogenous hypercortisolism because: 
• Normal UFC was maintained for >2.5 years in a majority of patients. 
• None of the patients with normalization of cortisol experienced escape from response 
• Clinical  measures improved, particularly body weight and BMI 
• Occurrences of the most commonly reported AEs decreased over time 
Therefore, osilodrostat seems to be a promising drug for the treatment of CD, with a satisfactory 
safety and tolerability profile. 
Risks of osilodrostat treatment in study population 
Known risks of treatment with LCI699 in patients with CS include: QT prolongation, 
hypocortisolism/adrenal insufficiency, AEs related to the accumulation of precursor molecules, 
including: increased or decreased blood pressure, hypokalemia or hyperkalemia, hyponatremia, 
weight gain, edema, and increase in the synthesis of sex steroids (primarily adrenal androgens 
in women) that may lead to menstrual changes and hirsutism in women and acne in either men 
or women. Skin rash has been observed. Corticotroph tumor progression, with or without 
compressive symptoms, is a potential risk. 
Neutropenia has been observed in a small number of patients with CD receiving 
osilodrostat. Preliminary assessment suggests that these events might be associated with 
cortisol levels that are either below normal or have had a rapid and substantial decline from 
baseline. In the observed cases, neutropenia rapidly reverses either spontaneously (typically 
after dose decrease) or with discontinuation of osilodrostat. 


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


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Pregnant or nursing (lactating) women 
4. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 1 week of study after stopping medication. Highly effective 
contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation. at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to baseline). The vasectomized male partner 
should be the sole partner for that subject 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment, and must be used in combination with a 
barrier method (male condom). 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or total hysterectomy, or tubal ligation at least six weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment, it will be considered not of child bearing 
potential. 
6 
Treatment 
Study treatment and investigational treatment refer to osilodrostat. 
6.1 
Study treatment 
The study treatment consists of osilodrostat (LCI699), in the form of film-coated tablets for oral 
administration, in the following tablet strengths: 1 mg, 5 mg and 10 mg. Each strength has a 
unique size, color and imprint (Y1, Y2 and Y3) on each tablet which can be used for specific 
identification. 


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6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply type 
Sponsor (global 
or local) 
Osilodrostat 
Film-coated tablet up to 
30 mg 
Oral use 
Open label 
bulk supply 
Bulk product 
supplied by 
Novartis  
Finished product: 
supplied by IQVIA 
Vendor* or 
Novartis 
∗ 
Upon sponsorship approval status 
The starting dose of study treatment for patients in this study should be the same as the dose 
provided in the parent osilodrostat study at the time of transition to the roll-over study.  
However, the investigator can change the dose and frequency of osilodrostat administration 
based upon the subject’s response but should not exceed 30 mg b.i.d.  
Study drug should be taken twice a day (b.i.d.). For example a subject on a 2 mg b.i.d. dose will 
take 2 mg in the morning and 2 mg in the evening, providing a total daily dose of 4 mg. Study 
drug should be taken at approximately the same time each day, with about 12 hours between 
each dose administration. Osilodrostat can be dosed without regard to food. If vomiting occurs 
during the course of treatment, patients should not take the study drug again before the next 
scheduled dose. Subjects should be instructed not to make up missed doses. A missed dose is 
defined as a case when the dose is not taken within 4 hours after the usual dosing time.  
At every quarterly visit (every 12 weeks ± 2 weeks) patients will receive sufficient supply of 
osilodrostat to cover a period of at least 3 months until the next scheduled visit.  
Subjects should be requested to bring their unused study drug, including the empty packs, to 
the clinic at each visit. Compliance should be verified and documented by the Investigator’s 
staff by counting the number of dispersible tablets consumed between visits. The Investigator 
(or his/her designee) will document dosage administration and all dose changes during the study 
in the eCRF. The site must maintain an overall drug accountability log for the study, as well as 
individual accountability records for each patient. The dose, amount dispensed, amount 
received, and amount remaining unused must be recorded in the source document. Drug 
accountability will be noted by the field monitor during site visits and at the completion of the 
study. The patient will return all unused study drug at each dispensing visit and at the end of 
the study. 
6.1.2 
Additional study treatments  
Not applicable. 
6.1.3 
Treatment arms/group  
Subjects will receive the same dose as the dose provided in the parent osilodrostat study at the 
time of transition to the roll-over study. 


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


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In a clinical DDI study, LCI699 was found to be a moderate inhibitor of CYP1A2 (2.5-fold 
increase in substrate exposure), a weak to moderate inhibitor of CYP2C19 (1.9-fold increase in 
substrate exposure), and a weak inhibitor of CYP2D6 and CYP3A4/5 (1.5-fold increase in 
substrate exposure). Therefore concomitant medications that are known substrates of these 
enzymes (see Appendix 1) and which have a narrow therapeutic index should be used with 
caution. 
The subject and the Investigator should be aware of potential signs of overdose of the 
concomitant medication and in the event of suspected toxicities; administration of either the 
substrate or LCI699 should be discontinued according to Investigator’s judgment. 
6.2.2 
Prohibited medication 
Use of the following concomitant medication is prohibited during the study: 
• Other drug treatments for CD or CS; 
• Medications with a “known risk to cause Torsades des Pointes (TdP)” and “possible risk 
to cause TdP”; 
• Eplerenone and glucocorticoids, except under certain conditions: 
• Eplerenone may be used if necessary in acute post-myocardial infarction management, 
and in the event of refractory hypokalemia in patients with hypertension or edema; 
glucocorticoids may be used as required for the short-term treatment of hypocortisolism 
or adrenal insufficiency. 
• Glucocorticoids (e.g., prednisone, prednisolone, and dexamethasone) may be used as 
required for the short-term treatment of hypocortisolism or adrenal insufficiency. If 
glucocorticoids are used in stress doses, or as replacement therapy, for > 4 weeks, then 
the investigator should consider temporary interruption of LCI699, weaning and 
discontinuation of glucocorticoid therapy, or early discontinuation from the study. 
6.2.2.1 
Concomitant medications with a “Known risk to cause TdP” and with 
a “Possible risk to cause TdP”. 
Preclinical and clinical data indicate that there is a risk of QTc prolongation in humans (see 
Section 6.5.1.2). Therefore, the use of medications with a “known risk to cause TdP” and 
with a “possible risk to cause TdP” concomitantly with LCI699 is prohibited. If a subject 
requires a long-term medication from the two categories mentioned above, and there is no 
appropriate alternative medication available, they should be discontinued from the study.  
However, if a subject requires such a drug for short-term therapy, e.g., antibiotics for active 
infection, then the LCI699 treatment may be interrupted temporarily while this drug is 
administered after a thorough risk-benefit assessment. This does not require the subject to 
discontinue from the study prematurely. Washout periods for LCI699 and the short-term 
prohibited drug in many cases may not be possible; this is acceptable if the benefit of the drug 
outweighs the risk of withholding LCI699 therapy in the investigator’s judgment. In such 
cases, a discussion with the Recordati Medical Monitor is recommended. 
Please refer to Section 14.2 Appendix 2 for an e-link to a list of medications that have a 
“known risk to cause TdP” and “possible risk to cause TdP”. Investigators are advised to 


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utilize this website when considering the addition of a new concomitant medication, as the lists 
are periodically updated. If necessary, a discussion can be held with the Recordati Medical 
Monitor when considering the use of medications with a “known risk to cause TdP” and with 
a “possible risk to cause TdP”A list of drugs with a “known risk to cause TdP” and with a 
“possible risk to cause TdP” can be found at crediblemeds.org\ 
6.3 
Subject numbering, treatment assignment, randomization  
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Recordati to the investigative site) with a sequential 
subject number suffixed to it, so that each subject is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next sequential 
Subject No. available. 
6.3.2 
Treatment assignment, randomization 
All consented subjects who satisfy all the inclusion and exclusion criteria, are eligible to receive 
osilodrostat. 
6.4 
Treatment blinding  
Not applicable. 
6.5 
Dose modification 
6.5.1 
Dose modifications 
6.5.1.1 
Dose modification and dose delay 
The osilodrostat dose should be adjusted until normalization of cortisol. The treating physician 
can increase the dose as needed, up to 30 mg b.i.d.  
For subjects who are unable to tolerate the current dose, dose adjustments can be done at 
investigator’s discretion. The guidelines below may be followed: 
• If the subject has not reached normalization of cortisol, but does not tolerate the current 
dose, administration of an intermediate dose (between the current and preceding dose) or 
repeated administration of the preceding, tolerated dose should be considered. 
• If the subject has reached normalization of cortisol, but the current dose is no longer 
tolerated, an intermediate dose between the current dose and previous dose should be 
considered. 
• If the subject had reached normalization of cortisol, but the current dose is no longer 
efficacious based on cortisol measurements, dose escalation should resume. 


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


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


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> 5.0 - 10.0 x ULN 
Withhold study drug. Repeat LFTsa as soon as possible, preferably 
within 48-72 hours from awareness of the abnormal results; monitor 
LFTsa weekly, or more frequently if clinically indicated, until resolved 
to ≤ 3.0 x ULN. Then: 
If resolved in ≤ 14 days, restart study drug and maintain dose level 
If resolved in > 14 days, restart study drug and decrease dose by one 
level 
If not resolved after 4 weeks, discontinue patient from study treatment 
> 10.0 x ULN  
Permanently discontinue study drug. Repeat LFTsa as soon as 
possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsa weekly, or more frequently if clinically 
indicated, until resolved to ≤3 x ULN. 
Combined b, c elevations of AST or ALT and total bilirubin 
For patients with normal baseline ALT 
and AST and total bilirubin value: 
AST or ALT >3.0 x ULN combined with 
total bilirubin >2.0 x ULN without 
evidence of cholestasisc  
OR   
For patients with elevated baseline AST 
or ALT or total bilirubin value: 
[AST or ALT>2x baseline AND > 3.0 
xULN] OR [AST or ALT > 8.0 xULN], 
combined with [total bilirubin >2x 
baseline AND >2.0 xULN 
Permanently discontinue patient from study drug treatment.  
 
Repeat as soon as possible, preferably within 48 hours from 
awareness of the abnormal results, then with weekly monitoring of 
LFTsa, or more frequently if clinically indicated, until AST, ALT, or 
bilirubin have returned to baseline or stabilized over 4 weeks.   
Refer to Section 6.5.3 for additional follow-up evaluations as 
applicable. 
All dose modifications should be based on the worst preceding toxicity. 
Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x 
ULN), and alkaline phosphatase (fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.) 
“Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold. 
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose 
or at one dose lower if meeting a criterion for dose reduction 
“Cholestasis” defined as: ALP elevation (>2xULN and R value (ALT/ALP in x ULN) < 2).   
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It 
denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular ( R 
≥ 5), or mixed (R >2 and < 5) liver injury 
*Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin 
determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator. 
If the subject has interruption of osilodrostat for more than 4 weeks, the investigator should 
consider early discontinuation from the study. 
6.5.1.2 
Follow-up for QT prolongation  
In the event that QT prolongation is detected during routine investigation, the following 
guidance is provided to be followed by the investigator: 
• If a QTcF > 480 msec is observed or an increase of the QTcF of >60 msec compared to 
baseline QTcF assessment of the roll-over, then two additional ECGs, each 2-3 minutes 
apart, need to be taken after the initial ECG. The mean QTcF from the triplicate ECGs will 
be determined. If the mean QTcF is > 480 msec or the mean QTcF increase is >60 msec 
compared to baseline, the patient has to interrupt study treatment while an urgent cardiology 


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consultation is obtained to re-evaluate the ECG and perform a clinical consultation. If 
immediate treatment is required for subject safety, this should be initiated at the study site 
without delay and without waiting for confirmation by a cardiologist. 
Based on the cardiologist consultation, the following should occur: 
• If a mean QTcF > 480 msec is NOT confirmed, no further action needs to be taken.  
• If the cardiologist confirms a mean QTcF > 500 msec, the subject has to discontinue 
according to the discontinuation procedure described in Section 9.1.1. The subject must 
remain under observation until the QTcF is < 480 msec and serum electrolytes, calcium, 
and magnesium are measured and the results normal. This observation may be done at the 
site, in an Emergency Room, or a cardiology clinic, as appropriate and depending upon local 
resources. 
• If the cardiologist confirms that QTcF > 480 msec, osilodrostat treatment is temporarily 
interrupted and a thorough evaluation is performed to assess the patient for acute 
cardiovascular risk, and for possible underlying heart disease that needs additional 
evaluation and management.  
a. If based upon the assessment by the cardiologist, the investigator considers that there 
is an acute cardiovascular safety risk and that the patient should not continue with:study 
medication, the patient needs to be discontinued immediately (discontinuation criteria 
described in Section 9.1.1). 
b. If based upon the assessment by the cardiologist, the investigator considers that there 
is not an acute cardiovascular safety risk; the patient can continue to receive study 
medication. 


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


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The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis. 
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory evaluations, 
detailed history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory evaluations should include ALT, AST, albumin, creatine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2 .  A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is performed 
in the study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 10.1.2) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
 The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit using pill counts (if applicable) and 
information provided by the subject. This information should be captured in the source 


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


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


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


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


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


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


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


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The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. Study treatment must be 
discontinued under the following circumstances: 
• Emergence of the following adverse events: 
 
• Hypertension defined as office mean sitting systolic BP> 180 mmHg or mean sitting 
diastolic BP> 110 mmHg ( confirmed and persistent, persistent is defined as 
unresolved with osilodrostat dose and/or other concomitant medication changes) 
• Any of the following laboratory abnormalities (confirmed): 
• Hyperkalemia (serum potassium > 6.0 mmol/L). 
• Hypokalemia (serum potassium <2.8 mmol/L). 
• Any of the following laboratory abnormalities (confirmed and persistent): 
• Hyperkalemia (serum potassium > 5.5 mmol/L). 
• Hypokalemia (serum potassium <3.0 mmol/L). 
• Hyponatremia (serum potassium <130 mmol/L). 
• AST or ALT >3.0 x ULN combined with total bilirubin >2.0 1 ULN without evidence 
of cholestasis. 
• QTcF > 500 msec, if confirmed by a cardiologist (see Section 6.5.1.2),  
• QTcF > 480 msec or QTcF increase is >60 msec compared to baseline if the investigator 
determines it is no longer safe for the patient to continue in the study, based on ECGs, 
cardiac examination, and recommendation from a cardiologist. 
• 
 Pituitary tumor growth, if the tumor is < 2mm from the optic chiasm, or symptoms of 
actual compression of the optic chiasm emerge (visual field loss, cranial nerve palsies, 
diplopia) confirmed by MRI of the pituitary. 
• Protocol deviations 
• Lost to follow-up 
• Study terminated by the sponsor 
• Administrative problems 
• Physician decision 
• Subject/guardian withdraw consent 
• Subject has completed treatment based on study duration 
When current treatment becomes commercially available in the applicable country, the 
patient will be withdrawn from the study.  
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the subject 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 


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


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


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


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• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.  
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.  
All malignant neoplasms will be assessed as serious under “medically significant” if other 
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Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.  
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the patient has stopped study treatment must 
be reported to IQVIA within 24 hours of learning of its occurrence. IQVIA, in its turn, will 
promptly inform Recordati. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. 
The date of the informed consent signed for this roll-over study (the roll-over date) is important 
to determine how SAEs should be reported: 
• Any SAEs occurred prior to that date should be reported for the parent protocol, including 
all the follow up information relevant to such SAEs. 
• New SAEs with an onset date on or after the roll-over date will be reported for this 
protocol. 
It is important to use the right SAE form with the correct protocol number for these two 
scenarios, to avoid confusion in SAE processing. For a patient already on the roll-over protocol 
but follow up information is reported for the previous SAEs in the parent protocol, it must be 
clearly labeled that this is for the parent protocol number. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, IQVIA (in agreement with 
Recordati) may urgently require further information from the investigator for health authority 
reporting. IQVIA (on behalf of Recordati) may need to issue an Investigator Notification (IN) 
to inform all investigators involved in any study with the same study treatment that this SAE 
has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period after end of treatment should only be reported 
to IQVIA Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 


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


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11 
Data Collection and Database management  
11.1 
Data collection 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control 
Recordati personnel (or designated CRO, IQVIA) will review the data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology. 
Data about all study treatment (s) dispensed to the subject and all dosage changes will be tracked 
using an Interactive Response Technology (IRT). 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Recordati development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, an IQVIA 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, IQVIA employs several methods 
of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The field 
monitor will visit the site to check the completeness of subject records, the accuracy of data 
capture / data entry, the adherence to the protocol and to Good Clinical Practice, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 


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


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


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12.5 
Analysis of secondary endpoints 
The secondary efficacy objective of the study is to evaluate clinical benefit as assessed by the 
Investigator. Proportions of patients with clinical benefit as assessed by the Investigator will be 
summarized at scheduled visits. Categorical data will be presented as frequencies and 
percentages. 
The secondary safety objective of the study is to evaluate long term safety, assessed using 
laboratory data, vital signs (blood pressure and body weight), ECG and pituitary MRI. Details 
of the specific analyses for each type of safety endpoint is given in Section 12.5.1. 
12.5.1 
Safety endpoints  
12.5.1.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used.  
The overall observation period will be divided into two mutually exclusive segments: 
1. on-treatment period: from day of first dose of study medication in this study to 30 days 
after last dose of study medication 
2. post-treatment period: starting at day 31 after last dose of study medication. 
12.5.1.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events during the on-treatment period will be 
tabulated.  
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths and serious adverse events (including those from post-treatment periods) will 
be listed and those collected during post-treatment period will be flagged. 
12.5.1.3 Laboratory abnormalities 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory evaluations where grades are not defined by CTCAE v4.03, results will be 
categorized as low/normal/high based on laboratory normal ranges. 


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Laboratory data will be listed and summarized as appropriate. Details of specific analyses will 
be given in the Statistical Analysis Plan. 
12.5.1.4 Other safety data 
Vital signs 
Vital signs (BP and body weight) will be listed and summarized as appropriate. Details of 
specific analyses will be given in the Statistical Analysis Plan. 
Pituitary MRI 
Tumor volume and longest dimension will be evaluated as defined in Section 8.4.6  
The longest dimension (in mm) and tumor volume (if evaluated) will be will be listed and 
summarized as appropriate. Details of specific analyses will be given in the Statistical Analysis 
Plan. 
12.6 
Analysis of exploratory endpoints 
Not applicable. 
12.7 
Interim analyses  
No formal interim analysis is planned for this study. Interim analysis may be performed for 
regulatory purposes if deemed necessary. 
12.8 
Sample size calculation  
Not applicable. 
13 
Ethical considerations and administrative procedures  
13.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to IQVIA 
monitors, auditors, Recordati/ Quality Assurance representatives, designated agents of 


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


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


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


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Protocol No. CLCI699C2X01B 
 
 
Sedney C, Morris J, Giannini C, et al (2012). Radiation-associated sarcoma of the skull base 
after irradiation for pituitary adenoma. Rare Tumors 4(1): e7. 
Sheehan J, Xu Z, Salvetti D, et al (2013). Results of Gamma Knife surgery for Cushing’s 
disease. J Neurosurg 119:1486–1492. 
Sonino N, Zielezny M, Fava G, et al (1996). Risk factors and long-term outcome in pituitary- 
dependent Cushing’s disease. Journal of Clinical Endocrinology and Metabolism; 81(7), 
2647-2652. 
Valassi E, et al (2012). Clinical consequences of Cushing’s syndrome. Pituitary. 15: 319-329. 


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Protocol No. CLCI699C2X01B 
 
 
16 
Appendices  
16.1 
Appendix 1: List of drugs to be used with caution with LCI699 
Osilodrostat should be used with caution when co-administered with CYP1A2 and CYP2C19 
substrates with a narrow therapeutic index such as theophylline, tizanidine and mephenytoin.  
Please refer to Section 5.1.5 of the current IB for further information”.  
16.2 
Appendix 2: Medications with a “Known risk to cause TdP” and 
with a “Possible risk to cause TdP” 
The following e-link provides a list of medications with a “known risk to cause TdP” and with 
a “possible risk to cause TdP”. These medications are prohibited to be used concomitantly with 
LCI699: crediblemeds.org. 
Investigators are advised to utilize this website when considering the addition of a new 
concomitant medication, as the lists are periodically updated. If necessary, a discussion can be 
held with the Recordati Medical Monitor when considering the use of medications with a 
“known risk to cause TdP” and “possible risk to cause TdP”. 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
Version 3.2 
Date: 5 July2023 
 
CONFIDENTIAL 
 
BIOM 
 
 
 
 
 
 
 
CLCI699C2X01B 
 
An open-label, multi-center, roll-over study to assess 
long term safety in patients with endogenous Cushing’s 
syndrome who have completed a prior Novartis-
sponsored osilodrostat(LCI699)study and are judged by 
the investigator to benefit from continued treatment 
with osilodrostat. 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 
3.2 
Date 
5 July 2023 
Total Page Number 
31 
Attachment 
3 


 
             Statistical Analysis Plan 
 
 
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Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
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Revision History 
 
Date 
Version 
Summary of Changes 
8 May 2018 
1.0 
First Version 
13 January 2021 
1.1 
Change of sponsor – reformatting according with SOP 
06BM13R02 
16 July 2021 
2.0 
Implementation of protocol amendment 01 
Introduction of interim analyses for safety 
14 April 2023 
3.0 
Implementation of protocol amendment 02 
Identification of the data from parent studies to 
complete baseline visit (W1D1) 
Deletion of output for section 10, 11 and 12 
26 May 2023 
3.1 (not issued) 
Introduction calculation of CTCAE grading for lab 
parameters 
 
26 June 2023 
3.2 
Update based on specific issues identified during 
interim analyses 
 
 


 
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Approval Page 
 
 
 
Document Title: 
An open-label, multi-center, roll-over study to assess long term 
safety in patients with endogenous Cushing’s syndrome who have completed a prior 
Novartis-sponsored osilodrostat (LCI699) study and are judged by the investigator to 
benefit from continued treatment with osilodrostat  
Version 3.2 
 
 
Prepared by: 
 
Name (Title) 
Signature 
Date 
Alessandro Antonellini 
Head of Statistics and Data 
Management 
 
 
 
 
 
Approved by: 
 
Name (Title) 
Signature 
Date 
 
Massimo Casi 
Study Manager 
 
 
 
 
 
 
 
 
Effective Date: 
05 July 2023  
 
 
 
 


 
             Statistical Analysis Plan 
 
 
Page 4 of 31 
 
Study Code: CLCI699C2X01B 
 
 
Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
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Contents 
 
1 
LIST OF ABBREVIATIONS ............................................................................................ 6 
2 
INTRODUCTION .............................................................................................................. 6 
2.1 
CLINICAL OBJECTIVES ......................................................................................... 6 
2.2 
STATISTICAL DESIGN / MODEL.......................................................................... 6 
2.3 
INTERIM ANALYSES ............................................................................................. 7 
2.3.1 
Timing of interim analyses and design adaptations ................................ 9 
2.4 
STATISTICAL SOFTWARE .................................................................................... 9 
3 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ..................................... 9 
4 
STATISTICAL METHODS .............................................................................................. 9 
4.1 
DATA ANALYSIS GENERAL INFORMATION ................................................... 9 
4.1.1 
General definitions .................................................................................. 9 
4.2 
PATIENT DISPOSITION, DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS ......................................................................................................... 10 
4.2.1 
Patient disposition ................................................................................. 10 
4.2.2 
Patient demographics and other baseline characteristics ...................... 11 
4.3 
TREATMENTS (STUDY TREATMENT, RESCUE MEDICATION, 
CONCOMITANT THERAPIES, COMPLIANCE) ............................................................ 11 
4.3.1 
Study treatment / compliance ............................................................... 11 
4.4 
Measures for COVID-19 impact .............................................................................. 11 
5 
VARIABLES AND ENDPOINTS ................................................................................... 11 
5.1 
HANDLING OF MISSING DATA AND OUTLIERS ........................................... 12 
5.1.1 
Study drug ............................................................................................. 12 
5.1.2 
AE date imputation ............................................................................... 13 
5.2 
DERIVATION RULES ............................................................................................ 15 
5.2.1 
AEs coding/grading .............................................................................. 15 
5.2.2 
Study day .............................................................................................. 15 
5.3 
DATA FROM PARENT STUDIES ........................................................................ 15 
6 
ANALYSIS POPULATIONS .......................................................................................... 16 
6.1 
RELEVANT PROTOCOL DEVIATIONS ............................................................. 16 
6.2 
DEFINITION OF POPULATIONS FOR ANALYSIS ........................................... 16 
6.2.1 
Full Analysis Set ................................................................................... 16 
6.2.2 
Safety Set .............................................................................................. 16 
6.2.3 
Subgroup of interest .............................................................................. 16 
7 
PLANNED ANALYSES ................................................................................................. 16 
7.1 
ANALYSIS OF THE PRIMARY OBJECTIVE ...................................................... 16 
7.1.1 
Primary endpoint ................................................................................... 17 
7.1.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
7.2 
ANALYSIS OF SECONDARY EFFICACY OBJECTIVE(S) ............................... 17 
7.2.1 
Secondary endpoints ............................................................................. 17 
7.3 
EXTENT OF EXPOSURE ....................................................................................... 17 
7.4 
SAFETY ANALYSIS .............................................................................................. 17 
7.4.1 
Adverse events (AEs) ........................................................................... 17 
7.4.2 
Laboratory parameters .......................................................................... 18 


 
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7.4.3 
Vital Signs ............................................................................................. 19 
7.4.4 
ECG ...................................................................................................... 19 
7.4.5 
Tumor volume and longest dimension .................................................. 20 
7.4.6 
Deaths ................................................................................................... 20 
8 
ATTACHMENTS ............................................................................................................ 21 
8.1 
LIST OF AES OF SPECIAL INTEREST ................................................................ 21 
8.2 
DATA FROM PARENT STUDIES ......................................................................... 24 
8.3 
GRADING FOR LAB TESTS (V5.0) ...................................................................... 28 
 
 
 


 
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1 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
CSR 
Clinical Study Report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 
2 
INTRODUCTION  
This statistical analysis plan (SAP) describes all planned analyses for the clinical study 
report (CSR) of study CLCI699C2X01B, an open label multi-center roll over study to assess 
long term safety in patients with endogenous Cushing’s syndrome who have completed a 
prior Novartis –sponsored osilodrostat (LCI699) study and are judged by the investigator 
to benefit from the continued treatment. 
2.1 
CLINICAL OBJECTIVES  
The purpose of the study is to evaluate the long-term safety.  
 
2.2 
 STATISTICAL DESIGN / MODEL 
This is a multi-center, open label phase IIb study to evaluate the long-term safety of 
osilodrostat in subjects receiving osilodrostat from Global Novartis-sponsored studies 
which has fulfilled its requirement for the primary objective, and who are judged by the 
parent study investigator as benefiting from continued treatment with osilodrostat. 


 
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There will be no screening period for this study. Eligible subjects can start their treatment 
with osilodrostat as soon as they are enrolled in the study. The first study visit will be 
scheduled at the time of the last study visit for the parent study. Subjects must return to 
the study center at least on a quarterly basis (every 12 weeks ± 2 weeks) for safety and 
clinical benefit assessments, and resupply of study medication. Drug dispensing and 
administration information and adverse events will be collected. The subject may return to 
the clinic at any given time as per standard of care or treating physician recommendation. 
All adverse events and serious adverse events, including pregnancy, will be collected 
throughout the study. 
At every quarterly visit (every 12weeks ± 2 weeks), the Investigator is required to confirm 
that the subject continues to have clinical benefit and may continue receiving study 
treatment. 
Figure 2-1 Study Design 
 
 
 
 
 
 
 
 
2.3 
INTERIM ANALYSES 
In February 2021 the Pharmacovigilance Risk Assessment Committee (PRAC) requested 
the study sponsor to provide interim results of this roll-over study within the upcoming 
Periodic Safety Update Reports (PSURs).  Therefore, regular interim analyses have been 
performed during the course of the study which will be aligned with the submission dates 
for the PSUR.  
The final analysis will occur when all patients complete the study.  
For the interim analyses, the following tables/listings have been provided (tables marked 
with “*” will be prepared only in case of request from the PRAC): 
 
Tables 
• 
Patient disposition (FAS) 
• 
Demographics and baseline characteristics (FAS) 
• 
Disease history (FAS) 
• 
Duration of exposure to study drug during the overall study period excluding the 
parent study (Safety Set) 
• 
Dose summary during the overall study period excluding the parent study (Safety 
Set) 
Parent Novartis study  
 
 
Osilodrostat 
Roll over 
Recordati 
Study 
 
Osilodrostat 
End of Roll-over 
Recordati Study 
 
Osilodrostat is 
permanently 
discontinued 


 
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• 
Dose summary during the overall study period including the parent study (Safety 
Set) * 
• 
Overview of adverse events (Safety Set) 
• 
Adverse events, regardless of study drug relationship, by system organ class 
(Safety Set) 
• 
Adverse events, regardless of study drug relationship, in at least 10% patients (All 
Patients all grades) by preferred term (Safety Set) 
• 
Adverse events, suspected to be study drug related, in at least 5% patients (All 
Patients all grades) by preferred term (Safety Set) 
• 
Serious adverse events, regardless of study drug relationship, by preferred term 
(Safety Set) 
• 
Serious adverse events, suspected to be study drug related, by preferred term 
(Safety Set) 
• 
Adverse events of special interest, regardless of study drug relationship - Adrenal 
hormone precursor accumulation-related AEs (Safety Set) 
• 
Adverse events of special interest, regardless of study drug relationship - 
Hypocortisolism-related AEs (Safety Set) 
• 
Adverse events of special interest, regardless of study drug relationship - 
Arrhythmogenic potential AEs (Safety Set) 
• 
Adverse events of special interest, regardless of study drug relationship - Pituitary 
tumour enlargement-related AEs (Safety Set) 
• 
Adverse events of special interest, regardless of study drug relationship - QT 
prolongation AEs (Safety Set) 
 
Listings 
• 
Patient demographics (FAS) 
• 
Subject disposition (FAS) 
• 
Dose administration record (FAS) 
• 
Adverse events (FAS) 
• 
Serious adverse events (Safety set) 
• 
Adverse events leading to study drug discontinuation (Safety set) 
• 
Adrenal hormone precursor accumulation-related AEs (Safety Set) 
• 
Hypocortisolism-related AEs (Safety Set) 
• 
Arrhythmogenic potential AEs (Safety Set) 
• 
Pituitary tumour enlargement-related AEs (Safety Set) 
• 
QT prolongation AEs (Safety Set) 
• 
Laboratory values by patient (biochemistry/hematology) (Safety Set) * 
• 
Deaths (Safety Set) 


 
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Note that further outputs may be added as considered necessary. 
2.3.1 
 
Timing of interim analyses and design adaptations 
Interim analyses have been performed by the CRO at the following time points: 
• 
Q3 2021 
• 
Q1 2022 
• 
Q1 2023 
 
Further time points might be added until the end of the study as needed. 
 
2.4 
 STATISTICAL SOFTWARE 
SAS version 9.4 or higher will be used in all analyses. 
3 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
In this version the following changes have been added: 
• 
To align the analysis plan with the amended Protocol version 02, the analysis of 
additional safety endpoints has been included. 
• 
To comply with the PRAC request of adding to the PSUR of osilodrostat the available 
safety results of the study, corresponding interim analyses and relative times of 
analysis have been included. 
• 
To identify data from parent studies to complete baseline visit (W1D1). 
4 
STATISTICAL METHODS 
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis. 
4.1 
DATA ANALYSIS GENERAL INFORMATION 
The statistical analysis of these data will be performed in accordance with the data analysis 
section, Section 10, of the study protocol which is available in [Appendix 16.1.1 of the 
CSR]. Important information is given in the following sections and details are provided, as 
applicable, in [Appendix 16.1.9 of the CSR].  
In summary and analysis tables of continuous variables, standard descriptive statistics (N, 
mean, standard deviation [SD], median, minimum and maximum) will be presented. The 
minimum and maximum statistics will be presented in summary tables to the same number 
of significant figures as the original data. The mean, median, will be presented to one more 
significant figure than the original data, while SD will be presented to an additional 
significant figure. For derived variables one figure will be presented for mean, median, 
minimum, maximum and 25th and 75th percentiles (where requested) and two figures for 
SD.  
In summary tables of categorical variables, the number of non-missing observations by 
category will be presented with percentages. All percentages will be presented to one 
decimal place. 
4.1.1 
General definitions  
Baseline 


 
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For this study the baseline visit (W1D1) corresponds to the End of Treatment visit in the 
relative parent study. 
The data for all assessments (except Obtain inform consent, Confirmation of Clinical Benefit 
from Study Treatment, and End of phase disposition) will be taken from the parent study.  
Study Treatment  
Study drug and investigational treatment refer to osilodrostat. Patients are to use the study 
treatment based on the parent protocol. 
Date of first/last administration of study drug 
The start date of study drug is defined as the first date when a non-zero dose of study 
drug was administered in the roll-over study and recorded on the Dosage Administration 
Record (DAR) eCRF.   
The date of last administration of study drug is defined as the last date when a non-zero 
dose of study drug was administered and recorded on DAR eCRF. 
Date of first administration of study drug for total drug exposure 
For the calculation of the total drug exposure the start date of study drug is defined as the 
first date when a non-zero dose of study drug was administered in the parent study and 
recorded on the Dosage Administration Record (DAR) eCRF.   
4.2 
PATIENT DISPOSITION, DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
4.2.1 
Patient disposition 
Patient disposition will be summarized overall using the Safety Set. The number (%) of 
treated patients included in the Safety Set will be presented. The number (%) of patients 
in the Safety Set who are still on treatment, who discontinued the study treatment and the 
reason for discontinuation will be presented overall. 
The following summaries will be provided (with % based on the total number of Safety Set 
patients): 
• 
Number (%) of patients who are still on-treatment at the time of data cut-off or 
final data base lock; 
• 
Number (%) of patients who discontinued the study treatment; 
• 
Number (%) of patients with primary reason for end of study treatment (based on 
patient status entered in the ‘Treatment Disposition’ page); 
• 
Number (%) of patients who have entered the post-treatment follow-up safety 
evaluation (based on the ‘Study Disposition’ page); 
• 
Number (%) of patients who have discontinued from the post-treatment follow-up 
(based on the ‘Study Dispostion’ page); 
• 
Number (%) of patients with primary reason for end of study (based on patient 
status entered in the ‘Study Disposition’ page); 
Listings will be provided overall and by indication and formulation for disposition, informed 
consent, inclusion/exclusion criteria using the Safety Set. 


 
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4.2.2 
Patient demographics and other baseline characteristics 
Demographic information will be summarized and listed overall using the Safety Set. 
Demographic summary will include age and gender. 
Categorical data (e.g., gender, age groups: <65 years, and ≥65 years) will be summarized 
by frequency counts and percentages. Continuous data (e.g., age) will be summarized by 
descriptive statistics (N, mean, median, standard deviation, minimum and maximum, 25th 
and 75th percentiles). 
Demographic listing will include country, center, current patient ID, age and gender. 
Medical history and ongoing medical conditions, including disease-related conditions and 
symptoms entered on (e) CRF will be summarized and listed overall. Separate summaries 
will be presented for ongoing and historical medical conditions. The summaries will be 
presented by primary system organ class (SOC) and preferred term (PT). Medical history 
and current medical conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. The MedDRA version used for reporting will be specified 
in the CSR and as a footnote in the applicable tables/listings. 
A listing of parent study history (parent study number, parent patient ID) will also be 
provided using the Safety Set.  
4.3 
TREATMENTS (STUDY TREATMENT, RESCUE MEDICATION, 
CONCOMITANT THERAPIES, COMPLIANCE) 
4.3.1 
Study treatment / compliance 
Dose administration data will be summarized overall using the Safety Set. 
Dose adjustments and reason for adjustments will be summarized (by frequency and 
percentage) by dose reduction or dose interruption (or both). Doses at the time of 
reduction or interruption will be summarized by descriptive statistics (N, mean, median, 
standard deviation, minimum and maximum, 25th and 75th percentiles). 
4.4 
Measures for COVID-19 impact 
Given the nature of the study, currently it is not planned any specific adjustments 
impacting the analysis unless the amount of the COVID-19 related protocol deviations 
would become relevant. 
 
The types of protocol deviations that were expected due to the impact of COVID-19 
included changes in procedures, missing visits, planned visits not done at sites and patient 
discontinuations due to COVID-19 situation or patients’ health status. 
The list of the protocol deviations due to the COVID-19 is reported in the Protocol Deviation 
Management Plan and will be summarized overall and listed. 
5 
VARIABLES AND ENDPOINTS 
Objectives and related endpoints are described in Table 5-1 below altogether with the 
planned analysis of collected data. 
 
 
 


 
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Table 5-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
 
To evaluate long term safety data, 
i.e., SAEs and AEs 
Frequency and severity of 
AEs/SAEs 
The 
assessment 
of 
safety will be based on 
the 
frequency 
and 
severity 
of adverse 
events 
(AEs) 
and 
serious 
adverse 
events (SAEs) 
Secondary 
 
 
To evaluate clinical benefit as 
assessed by the investigator 
 
Proportion of patients with 
clinical benefit as assessed 
by 
the 
investigator 
at 
scheduled visits 
Proportion of patients 
with clinical benefit as 
assessed 
by 
the 
investigator 
will 
be 
summarized 
at 
scheduled visits 
Other secondary 
 
 
To evaluate other safety data and 
tumor size 
Lab 
parameters, 
vital 
signs, ECG, Tumor size 
and longest dimension  
Shift 
tables 
vs 
Baseline 
and 
proportions 
of 
patients with notable 
abnormalities 
or 
grade 3 or 4 
5.1 
 HANDLING OF MISSING DATA AND OUTLIERS 
5.1.1 
Study drug 
Below mentioned imputation rules will be used in case of missing or partial end date of 
study drug. 
Scenario 1 
If the last date of study drug is after the cut-off date or is completely missing and there is 
no end of treatment eCRF page and no death date the patient should be considered to be 
on-going and use the cutoff date for the analysis as the last dosing date. 
Scenario 2 
 
If the last date of study drug is completely or partially missing and there is EITHER an end 
of treatment eCRF page OR a death date available, then imputed last dose date: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT visit date, death date) 
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT visit date, death date) and Month < the month of min (EOT visit date, death date) 


 
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= min (EOT visit date, death date), for all other cases 
The imputed date will be compared with start date of study drug. 
If the imputed date < start date of study drug, then last date of study drug is set to start 
date of study drug; otherwise, use the imputed date. 
5.1.2 
AE date imputation 
Date imputation is the creation of a new, complete date from a partial one according to an 
agreed and acceptable algorithm. Missing date for AE will be handled according to rules 
specified below. A partial date is simply an incomplete date e.g., DDOCT2001: the days 
are missing from this DDMMMYYYY date. 
 
Partial AE start dates, if left partial, would ultimately mean the following: 
It would not be possible to place the AE in time. Therefore, the treatment/dosage at the 
time of the event would be unknown. So, the event could not be reported/summarized 
appropriately – if at all. 
Therefore, it is important to perform date imputation to ensure that as many data events 
are represented as correctly as possible. Of course, partial and/or missing dates should 
also be caught as edit checks and passed back to the investigator for resolution. 
 
There will be no attempt to impute the following: 
• 
Missing AE start dates 
• 
AE start dates missing the year 
• 
Partial/missing AE end dates 
 
Table 5-2 
AE/Treatment date abbreviations 
 
Day 
Month 
Year 
Partial AE start date 
<not used> 
AEM 
AEY 
Treatment start date (TRTSTD) 
<not used> 
TRTM 
TRTY 
 
The following matrix Table 5-3 describes the possible combinations and their associated 
imputations. In the light grey boxes the upper text indicates the imputation and the lower 
text the relationship of the AE start date to the treatment start date (TRTSTD). 
 
 
 
 
 
 
 
 
 


 
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Table 5-3 
AE partial date imputation algorithm 
 
 
AEM Missing 
 
AEM < TRTM 
 
AEM = TRTM 
 
AEM > TRTM 
 
AEY Missing 
NC 
  
NC 
 
NC 
 
NC 
 
AEY < TRTY 
Before TRTSTD 
(D) 
Before TRTSTD 
(C) 
Before TRTSTD 
(C) 
Before TRTSTD 
(C) 
AEY = TRTY 
Uncertain 
(B) 
Before TRTSTD 
(C) 
Uncertain 
(B) 
After TRTSTD 
(A) 
AEY > TRTY 
After TRTSTD 
(E) 
After TRTSTD 
(A) 
After TRTSTD 
(A) 
After TRTSTD 
(A) 
 
 
Table 5-4 
AE/treatment date relationship and imputation legend      
Relationship 
Before TRTSTD 
Indicates AE start date prior to Treatment Start Date  
After TRTSTD 
Indicates AE start date after Treatment Start Date 
Uncertain 
Insufficient to determine the relationship of AE start date 
to Treatment Start Date 
 
Imputation Calculation 
NC/Blank  
 
No convention/imputation 
(A) 
01MONYYYY 
(B) 
TRTSTD+1 
(C) 
15MONYYYY 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
 
The following Table 5-5 gives a few examples. 
 
Table 5-5 
AE imputation example scenarios 
Partial AE start 
date 
Treatment start 
date 
Relationship 
Imputation 
calculation 
Imputed date 
12mmyyyy 
20OCT2001 
Uncertain 
NC 
<blank> 
ddmmm2000 
20OCT2001 
Before 
(D) 
01JUL2000 
ddmmm2002 
20OCT2001 
After 
(E) 
01JAN2002 
ddmmm2001 
20OCT2001 
Uncertain 
(B) 
21OCT2001 
ddSEP2001 
20OCT2001 
Before 
(C) 
15SEP2001 
ddOCT2001 
20OCT2001 
Uncertain 
(B) 
21OCT2001 
ddNOV2001 
20OCT2001 
After 
(A) 
01NOV2001 
Any AEs with partial/missing dates will be displayed as such in the data listings. 


 
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Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
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Any AEs which are continuing as per data cut-off will be shown as ‘ongoing’ rather than 
the end date provided. 
5.2 
 DERIVATION RULES 
5.2.1 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 or higher.  
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, 
severe, and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 
(death) will be summarized separately.  
5.2.2 
Study day 
Definitions will be applied for all situations: 
• 
Study day for post-treatment event = event date – first dose date + 1 
• 
Study day for pre-treatment event = first dose date - event date 
The first day of study drug is study day 1.  
If duration is to be reported in weeks, duration in days will be divided by 7, likewise if in 
months, then duration in days will be divided by 30.4375 and if in years, duration in days 
will be divided by 365.25. 
5.3 
DATA FROM PARENT STUDIES 
Data referring to the disease history, as well as the height, were not collected in the study 
EDC but remained in the databases of the parent studies where the patients are coming 
from.  
In addition, the data from the end of the treatment (or last visit) in the parent studies, will 
be extracted by the parent studies databases and transferred by the sponsor to the CRO. 
The date of the EOT visit from the parent study will be matched with the date of the 
baseline (W1D1) to guarantee the proper correspondence. The cases with a discrepancy 
exceeding one week between the two dates will be evaluated case by case.  
For disease history they are the following ones:   
• 
Time (months) to first study osilodrostat dose since diagnosis  
• 
Classification at time of diagnosis  
• 
Cushing’s Disease Status  
• 
Any previous surgery  
• 
Any previous, non-LCI, treatments for Cushing’s disease  
• 
Any previous pituitary irradiation  
• 
Baseline mean UFC.  


 
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For W1D1 visit the data to be transferred will regard the following topics:   
• 
Vital signs (domain VS) 
• 
ECG (domain EG) 
• 
MRI (domains PR, FA) 
• 
Laboratory (domain LB) 
The data will be extracted as SAS datasets as close as possible to the domain structures 
reported in attachment 8.2. 
6 
ANALYSIS POPULATIONS 
6.1 
 RELEVANT PROTOCOL DEVIATIONS 
Protocol deviations will be categorized and tabulated overall and by indication and 
formulation into the following categories per ICH guidelines for CSR-reportable protocol 
deviations: 
• 
Patient developed study/treatment withdrawal criteria during the study, but was 
not withdrawn 
• 
Patient received the wrong treatment or incorrect dose 
• 
Patient took an excluded concomitant medication 
• 
Patient did not satisfy the entry criteria 
Other important deviations may also be identified and summarized, as necessary, which 
may impact the scientific value of the trial. 
All protocol deviations will be specified in the Study Specification Document (SSD).  
All protocol deviations will be listed overall and by indication and formulation using Safety 
Set. 
6.2 
DEFINITION OF POPULATIONS FOR ANALYSIS 
6.2.1 
Full Analysis Set 
6.2.2 
For this study, the definition of FAS is the same as the Safety Set and in the 
tables the Safety Set will be indicated. Safety Set 
The Safety Set includes all patients who received at least one dose of study medication 
(Osilodrostat) after enrolling into the roll-over protocol. 
6.2.3 
Subgroup of interest 
Not Applicable  
7 
PLANNED ANALYSES 
7.1 
ANALYSIS OF THE PRIMARY OBJECTIVE 
The primary objective is to evaluate long term safety as assessed by the occurrence of AEs 
/ SAEs. 


 
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Date: 05July2023 
 
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7.1.1 
Primary endpoint 
The assessment of safety will be based mainly on the frequency and severity of AEs, AESI 
and SAEs. See also Section 7.5. 
7.1.2 
Statistical hypothesis, model, and method of analysis 
The primary endpoint will be summarized descriptively, overall no formal analysis will be 
performed. No hypothesis will be tested. 
7.2 
ANALYSIS OF SECONDARY EFFICACY OBJECTIVE(S) 
The secondary objective of the study is to evaluate clinical benefit as assessed by the 
investigator. 
7.2.1 
Secondary endpoints 
Proportion of patients with clinical benefit as assessed by the investigator will be 
summarized at scheduled visits. Clinical benefit will be summarized overall using the Safety 
Set. 
7.3 
EXTENT OF EXPOSURE 
Definitions of duration of exposure, cumulative dose, average daily dose, as well as 
intermediate calculations, include: 
Osilodrostat:  
• 
Duration of exposure (weeks): (min (last date of rollover study drug, date of death, 
date of data cut-off) − first date of rollover study drug + 1)/7 
• 
Cumulative dose (µg): total dose of study drug taken by a patient in the rollover 
study 
• 
Number of dosing days (days): 
duration of exposure *7 − number of zero dose 
days  
• 
Average daily dose (µg/day): cumulative dose (µg) / number of dosing days (days) 
7.4 
SAFETY ANALYSIS 
Safety analyses will be performed on the Safety Set. The assessment of safety will be 
based mainly on the frequency of AEs, AESI and SAEs. 
7.4.1 
Adverse events (AEs) 
Treatment emergent AEs are defined as those that started on or after the study medication, 
or those that started before study medication but worsened afterwards. AEs starting after 
30 days after last dose of Osilodrostat treatment are not considered treatment emergent 
AEs. 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the post-treatment periods) will be listed and those collected during 
the post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) 
will be summarized by system organ class and/or preferred term, severity based on CTCAE 
grades (version 4.03 or higher), type of adverse event, relation to study treatment. The 
summary will include AEs regardless of study-drug relationship. The same analysis will be 
repeated for SAEs. 
All treatment emergent AEs and SAEs will be listed. In this listing, the information on the 
relationship to study treatment will be included. 


 
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Adverse events will be coded using the Medical dictionary for regulatory activities 
(MedDRA) terminology using the latest available MedDRA version at the time of the 
analyses and the information of MedDRA version will be specified in the footnote of relevant 
outputs. 
The following selection of AEs will be listed and summarized separately using Safety Set. 
AEs will be summarized for all grades and for grade 3 or 4 side-by-side. 
• 
AEs 
• 
SAEs 
• 
AEs leading to study drug discontinuation 
• 
AEs requiring dose adjustment or interruption 
• 
AEs requiring additional therapy 
• 
Adverse events of special interest (AESI) 
 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment-emergent adverse events which are not serious adverse events with an 
incidence greater than 2% and on treatment-emergent serious adverse events and SAE 
suspected to be related to study treatment will be provided by system organ class and 
preferred term on the Safety Set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• 
A single occurrence will be counted if there is ≤ 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
• 
More than one occurrence will be counted if there is > 1 day gap between the end 
date of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, 
if at least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT. 
 
Adverse events of special interest / grouping of AEs 
The specific categories of AEs of special interest list for LCI699 are listed in attachment 
8.1. 
7.4.2 
Laboratory parameters 
Laboratory data summaries will include all assessments available for the lab parameters 
collected no later than 30 days of safety follow-up whichever is later after the last study 
treatment administration date using data from all sources. All laboratory assessments 
will be listed and those collected later than 30 days after the last study treatment date 
will be flagged in the listings. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 or higher. The calculation 
of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. CTCAE version 5.0 will be applied and an 
extract of the tests that can be graded is reported in attachment 8.3. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high 
values, summaries will be done separately and labeled by direction, e.g., sodium will be 
summarized as hyponatremia and hypernatremia. 


 
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For laboratory tests where grades are not defined by CTCAE, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE: 
• 
Summary table for AEs of grades 3 or 4 
• 
Shift tables using CTCAE grades to compare baseline to the worst on-treatment 
value  
• 
Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient 
will be counted only once for the worst grade observed post-baseline 
For laboratory tests where grades are not defined by CTCAE, 
• 
Shift tables using the low/normal/high/ (low and high) classification to compare 
baseline to the worst on-treatment value 
The following listings will be produced for the laboratory data (hematology, and 
biochemistry): 
• 
Listing of all laboratory data with values flagged to show the corresponding CTC 
grades the classifications relative to the laboratory reference ranges 
• 
Listing of notable laboratory abnormalities (i.e., CTC grade 3 or 4 laboratory 
toxicities). 
7.4.3 
Vital Signs 
All vital signs data (body weight (kg) and systolic/diastolic blood pressure (mmHg)) will 
be listed by patient and visit/time. Shift tables based on notable values will be provided 
for vital signs. Change over time from baseline will be summarized. 
 
Vital signs (sitting BP, HR & body weight) reporting of results will include: 
• 
shift table baseline to worst on-treatment result 
• 
table with descriptive statistics at baseline, one or several post-baseline time points 
and change from baseline to this/these post-baseline time points. 
Notable Values for vital signs will include: 
• 
Systolic blood pressure [mmHg] at baseline: >=180 mmHg / <=90 mmHg –  
• 
Diastolic blood pressure [mmHg] at baseline: >=105 mmHg / <=50 mmHg                   
 
Notably abnormal vital signs on treatment:  
• 
Systolic blood pressure [mmHg] on treatment: >=180 mmHg with increase from                     
baseline of >=20 mmHg / <=90 mmHg with decrease from baseline of >=20 
mmHg;  
• 
Diastolic blood pressure [mmHg] on treatment: >=105 mmHg with increase from 
baseline of >=15 mmHg/<=50 mmHg with decrease from baseline of >=15 mmHg; 
7.4.4 
Weight on treatment: Increase >=10% / Decrease >=5%ECG 
ECG data will be summarized with: 
• 
shift table baseline to worst on-treatment result for overall assessments 
• 
number and percentage of patients with clinically notable abnormalities will be 
summarized 
• 
listing of ECG evaluations for all patients with at least one abnormality.  
A “notable abnormality” is defined as: 
For PR are: 


 
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• 
> 200 ms post-baseline and ≤ 200 ms at baseline 
• 
Increase > 25% compared to baseline to a post-baseline value > 200 ms 
For QRS are: 
• 
> 110 ms post-baseline and ≤ 110 ms at baseline 
• 
Increase > 25% compared to baseline to a post-baseline value > 110 ms 
For QT and QTcF are: 
• 
> 450 ms at any post-baseline and ≤ 450 ms at baseline 
• 
> 480 ms at any post-baseline and ≤ 480 ms at baseline 
• 
> 500 ms at any post-baseline and ≤ 500 ms at baseline 
• 
an increase from baseline > 30 ms at any post-baseline 
• 
an increase from baseline > 60 ms at any post-baseline 
For HR are: 
• 
Increase >25% and HR >100 bpm 
• 
Decrease >25% and HR <50 bpm 
7.4.5 
Tumor volume and longest dimension 
For tumor volume evaluated by MRI scanning, descriptive summary of actual tumor 
volumes as well as its change from baseline will be provided at visits where evaluation is 
scheduled. For MRI images (or CT) that are not interpretable for tumor volume, the 
longest dimension (in mm) will be summarized instead. Due to evaluation schedule, this 
analysis will only be performed for the overall study period. 
7.4.6 
Deaths 
Separate summaries for on-treatment death and all deaths (including on-treatment and 
post-treatment) will be produced by primary system organ class and preferred term overall 
using the Safety Set. On-treatment and all deaths will be listed overall, and post treatment 
deaths will be flagged. 
 
 
 


 
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8 
ATTACHMENTS 
 
8.1 
LIST OF AES OF SPECIAL INTEREST 
 
PT_NAME 
PT_CODE Safety Topic Of Interest 
11-deoxycorticosterone increased 
10081511 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
11-deoxycortisol increased 
10081510 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Acne 
10000496 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Acquired apparent mineralocorticoid 
excess 
10080230 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Androgenetic alopecia 
10068168 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Androgens increased 
10002265 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Blood potassium decreased 
10005724 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Blood pressure diastolic increased 
10005739 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Blood pressure increased 
10005750 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Blood pressure systolic increased 
10005760 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Blood sodium increased 
10005803 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Blood testosterone free increased 
10053785 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Blood testosterone increased 
10005815 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Endocrine hypertension 
10057615 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Generalised oedema 
10018092 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hair growth abnormal 
10019044 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hirsutism 
10020112 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hydroxycorticosteroids increased 
10020534 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hydroxycorticosteroids urine increased 10020539 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hyperandrogenism 
10065597 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hypernatraemia 
10020679 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 


 
             Statistical Analysis Plan 
 
 
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PT_NAME 
PT_CODE Safety Topic Of Interest 
Hypertension 
10020772 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hypertrichosis 
10020864 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hypokalaemia 
10021015 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Hypokalaemic syndrome 
10021017 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Localised oedema 
10048961 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Oedema 
10030095 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Oedema peripheral 
10030124 AESI Adrenal Hormone Precursor 
Accumulation-related AEs 
Cardiac arrest 
10007515 AESI Arrhythmogenic potential AEs 
Cardiac death 
10049993 AESI Arrhythmogenic potential AEs 
Cardiac fibrillation 
10061592 AESI Arrhythmogenic potential AEs 
Cardio-respiratory arrest 
10007617 AESI Arrhythmogenic potential AEs 
Loss of consciousness 
10024855 AESI Arrhythmogenic potential AEs 
Sudden cardiac death 
10049418 AESI Arrhythmogenic potential AEs 
Sudden death 
10042434 AESI Arrhythmogenic potential AEs 
Syncope 
10042772 AESI Arrhythmogenic potential AEs 
Torsade de pointes 
10044066 AESI Arrhythmogenic potential AEs 
Ventricular arrhythmia 
10047281 AESI Arrhythmogenic potential AEs 
Ventricular fibrillation 
10047290 AESI Arrhythmogenic potential AEs 
Ventricular flutter 
10047294 AESI Arrhythmogenic potential AEs 
Ventricular tachyarrhythmia 
10065341 AESI Arrhythmogenic potential AEs 
Ventricular tachycardia 
10047302 AESI Arrhythmogenic potential AEs 
Addison's disease 
10001130 AESI Hypocortisolism related AEs 
Adrenal insufficiency 
10001367 AESI Hypocortisolism related AEs 
Adrenal suppression 
10001382 AESI Hypocortisolism related AEs 
Adrenocortical insufficiency acute 
10001389 AESI Hypocortisolism related AEs 
Cortisol decreased 
10011198 AESI Hypocortisolism related AEs 
Cortisol free urine decreased 
10011201 AESI Hypocortisolism related AEs 
Glucocorticoid deficiency 
10072079 AESI Hypocortisolism related AEs 
Glucocorticoids decreased 
10061466 AESI Hypocortisolism related AEs 
Primary adrenal insufficiency 
10052381 AESI Hypocortisolism related AEs 
Secondary adrenocortical insufficiency 
10039807 AESI Hypocortisolism related AEs 
Steroid withdrawal syndrome 
10042028 AESI Hypocortisolism related AEs 
ACTH-producing pituitary tumour 
10000613 AESI Pituitary tumor enlargement-related AEs 
Cavernous sinus syndrome 
10079769 AESI Pituitary tumor enlargement-related AEs 
Chiasma syndrome 
10067348 AESI Pituitary tumor enlargement-related AEs 
Diplopia 
10013036 AESI Pituitary tumor enlargement-related AEs 
Extraocular muscle paresis 
10015829 AESI Pituitary tumor enlargement-related AEs 


 
             Statistical Analysis Plan 
 
 
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PT_NAME 
PT_CODE Safety Topic Of Interest 
III nerve disorder 
10053644 AESI Pituitary tumor enlargement-related AEs 
III nerve injury 
10021281 AESI Pituitary tumor enlargement-related AEs 
III nerve paralysis 
10021283 AESI Pituitary tumor enlargement-related AEs 
III nerve paresis 
10054202 AESI Pituitary tumor enlargement-related AEs 
IV nerve disorder 
10065836 AESI Pituitary tumor enlargement-related AEs 
IV nerve injury 
10023108 AESI Pituitary tumor enlargement-related AEs 
IV nerve paralysis 
10023110 AESI Pituitary tumor enlargement-related AEs 
IV nerve paresis 
10054201 AESI Pituitary tumor enlargement-related AEs 
Microvascular cranial nerve palsy 
10079491 AESI Pituitary tumor enlargement-related AEs 
Neoplasm progression 
10061309 AESI Pituitary tumor enlargement-related AEs 
Neoplasm recurrence 
10061864 AESI Pituitary tumor enlargement-related AEs 
Optic nerve compression 
10076302 AESI Pituitary tumor enlargement-related AEs 
Pituitary apoplexy 
10056447 AESI Pituitary tumor enlargement-related AEs 
Pituitary enlargement 
10048675 AESI Pituitary tumor enlargement-related AEs 
Pituitary haemorrhage 
10049760 AESI Pituitary tumor enlargement-related AEs 
Pituitary infarction 
10035092 AESI Pituitary tumor enlargement-related AEs 
Pituitary tumour 
10035104 AESI Pituitary tumor enlargement-related AEs 
Pituitary tumour benign 
10061538 AESI Pituitary tumor enlargement-related AEs 
Pituitary tumour recurrent 
10057316 AESI Pituitary tumor enlargement-related AEs 
Tumour compression 
10068268 AESI Pituitary tumor enlargement-related AEs 
Tumour invasion 
10064390 AESI Pituitary tumor enlargement-related AEs 
VI nerve disorder 
10053646 AESI Pituitary tumor enlargement-related AEs 
VI nerve injury 
10047639 AESI Pituitary tumor enlargement-related AEs 
VI nerve paralysis 
10047641 AESI Pituitary tumor enlargement-related AEs 
VI nerve paresis 
10071044 AESI Pituitary tumor enlargement-related AEs 
Visual field defect 
10047555 AESI Pituitary tumor enlargement-related AEs 
Electrocardiogram QT interval 
abnormal 
10063748 AESI QT prolongation AEs 
Electrocardiogram QT prolonged 
10014387 AESI QT prolongation AEs 
Long QT syndrome 
10024803 AESI QT prolongation AEs 
 
 
 
 


 
             Statistical Analysis Plan 
 
 
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8.2 
DATA FROM PARENT STUDIES 
 
DATASET 
VARIABLE 
LENGTH 
LABEL 
ATTRIB 
PR 
STUDYID 
200 Study Identifier 
Character 
PR 
DOMAIN 
200 Domain Abbreviation 
Character 
PR 
USUBJID 
200 Unique Subject Identifier 
Character 
PR 
PRSEQ 
8 Sequence Number 
Numeric 
PR 
PRTRT 
200 Reported Name of Procedure 
Character 
PR 
PRCAT 
200 Category 
Character 
PR 
PRINDC 
200 Indication 
Character 
PR 
PRDOSE 
8 Dose 
Numeric 
PR 
PRDOSU 
200 Dose Units 
Character 
PR 
PRLOC 
200 Location of Procedure 
Character 
PR 
PRLAT 
200 Laterality 
Character 
PR 
VISITNUM 
8 Visit Number 
Numeric 
PR 
VISIT 
200 Visit Name 
Character 
PR 
VISITDY 
8 Planned Study Day of Visit 
Numeric 
PR 
EPOCH 
200 Epoch 
Character 
PR 
PRSTDTC 
200 Start Date/Time of Procedure 
Character 
PR 
PRENDTC 
200 End Date/Time of Procedure 
Character 
PR 
PRSTDY 
8 Study Day of Start of Procedure 
Numeric 
PR 
PRENDY 
8 Study Day of End of Procedure 
Numeric 
FA 
STUDYID 
200 Study Identifier 
Character 
FA 
DOMAIN 
200 Domain Abbreviation 
Character 
FA 
USUBJID 
200 Unique Subject Identifier 
Character 
FA 
FASEQ 
8 Sequence Number 
Numeric 
FA 
FATESTCD 
200 Findings About Test Short Name 
Character 
FA 
FATEST 
200 Findings About Test Name 
Character 
FA 
FAOBJ 
200 Object of the Observation 
Character 
FA 
FACAT 
200 Category for Findings About 
Character 
FA 
FAORRES 
200 Result or Finding in Original Units 
Character 
FA 
FAORRESU 
200 Original Units 
Character 
FA 
FASTRESC 
200 Character Result/Finding in Std Format Character 
FA 
FASTRESU 
200 Standard Units 
Character 
FA 
FASTAT 
200 Completion Status 
Character 
FA 
FAREASND 
200 Reason Not Performed 
Character 
FA 
FAMETHOD 
200 Method of Test or Examination 
Character 
FA 
VISITNUM 
8 Visit Number 
Numeric 
FA 
VISIT 
200 Visit Name 
Character 


 
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DATASET 
VARIABLE 
LENGTH 
LABEL 
ATTRIB 
FA 
VISITDY 
8 Planned Study Day of Visit 
Numeric 
FA 
EPOCH 
200 Epoch 
Character 
FA 
FADTC 
200 Date/Time of Collection 
Character 
FA 
FADY 
8 Study Day of Collection 
Numeric 
LB 
STUDYID 
200 Study Identifier 
Character 
LB 
DOMAIN 
200 Domain Abbreviation 
Character 
LB 
USUBJID 
200 Unique Subject Identifier 
Character 
LB 
LBSEQ 
8 Sequence Number 
Numeric 
LB 
LBREFID 
200 Specimen ID 
Character 
LB 
LBTESTCD 
200 Lab Test or Examination Short Name 
Character 
LB 
LBTEST 
200 Lab Test or Examination Name 
Character 
LB 
LBCAT 
200 Category for Lab Test 
Character 
LB 
LBORRES 
200 Result or Finding in Original Units 
Character 
LB 
LBORRESU 
200 Original Units 
Character 
LB 
LBORNRLO 
200 
Reference Range Lower Limit in Orig 
Unit 
Character 
LB 
LBORNRHI 
200 
Reference Range Upper Limit in Orig 
Unit 
Character 
LB 
LBSTRESC 
200 Character Result/Finding in Std Format Character 
LB 
LBSTRESN 
8 
Numeric Result/Finding in Standard 
Units 
Numeric 
LB 
LBSTRESU 
200 Standard Units 
Character 
LB 
LBSTNRLO 
8 
Reference Range Lower Limit-Std 
Units 
Numeric 
LB 
LBSTNRHI 
8 
Reference Range Upper Limit-Std 
Units 
Numeric 
LB 
LBSTNRC 
200 
Reference Range for Char Rslt-Std 
Units 
Character 
LB 
LBNRIND 
200 Reference Range Indicator 
Character 
LB 
LBSTAT 
200 Completion Status 
Character 
LB 
LBREASND 
200 Reason Test Not Done 
Character 
LB 
LBNAM 
200 Vendor Name 
Character 
LB 
LBSPEC 
200 Specimen Type 
Character 
LB 
LBSPCCND 
200 Specimen Condition 
Character 
LB 
LBMETHOD 
200 Method of Test or Examination 
Character 
LB 
LBBLFL 
200 Baseline Flag 
Character 
LB 
VISITNUM 
8 Visit Number 
Numeric 
LB 
VISIT 
200 Visit Name 
Character 
LB 
VISITDY 
8 Planned Study Day of Visit 
Numeric 


 
             Statistical Analysis Plan 
 
 
Page 26 of 31 
 
Study Code: CLCI699C2X01B 
 
 
Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
BIOM 
 
 
DATASET 
VARIABLE 
LENGTH 
LABEL 
ATTRIB 
LB 
EPOCH 
200 Epoch 
Character 
LB 
LBDTC 
200 Date/Time of Specimen Collection 
Character 
LB 
LBENDTC 
200 End Date/Time of Specimen Collection 
Character 
LB 
LBDY 
8 Study Day of Specimen Collection 
Numeric 
VS 
STUDYID 
200 Study Identifier 
Character 
VS 
DOMAIN 
200 Domain Abbreviation 
Character 
VS 
USUBJID 
200 Unique Subject Identifier 
Character 
VS 
VSSEQ 
8 Sequence Number 
Numeric 
VS 
VSTESTCD 
200 Vital Signs Test Short Name 
Character 
VS 
VSTEST 
200 Vital Signs Test Name 
Character 
VS 
VSORRES 
200 Result or Finding in Original Units 
Character 
VS 
VSORRESU 
200 Original Units 
Character 
VS 
VSSTRESC 
200 Character Result/Finding in Std Format Character 
VS 
VSSTRESN 
8 
Numeric Result/Finding in Standard 
Units 
Numeric 
VS 
VSSTRESU 
200 Standard Units 
Character 
VS 
VSBLFL 
200 Baseline Flag 
Character 
VS 
VISITNUM 
8 Visit Number 
Numeric 
VS 
VISIT 
200 Visit Name 
Character 
VS 
VISITDY 
8 Planned Study Day of Visit 
Numeric 
VS 
EPOCH 
200 Epoch 
Character 
VS 
VSDTC 
200 Date/Time of Measurements 
Character 
VS 
VSDY 
8 Study Day of Vital Signs 
Numeric 
EG 
STUDYID 
200 Study Identifier 
Character 
EG 
DOMAIN 
200 Domain Abbreviation 
Character 
EG 
USUBJID 
200 Unique Subject Identifier 
Character 
EG 
EGSEQ 
8 Sequence Number 
Numeric 
EG 
EGTESTCD 
200 ECG Test or Examination Short Name 
Character 
EG 
EGTEST 
200 ECG Test or Examination Name 
Character 
EG 
EGCAT 
200 Category for ECG 
Character 
EG 
EGORRES 
200 Result or Finding in Original Units 
Character 
EG 
EGORRESU 
200 Original Units 
Character 
EG 
EGSTRESC 
200 Character Result/Finding in Std Format Character 
EG 
EGSTRESN 
8 
Numeric Result/Finding in Standard 
Units 
Numeric 
EG 
EGSTRESU 
200 Standard Units 
Character 
EG 
EGMETHOD 
200 Method of ECG Test 
Character 
EG 
EGBLFL 
200 Baseline Flag 
Character 


 
             Statistical Analysis Plan 
 
 
Page 27 of 31 
 
Study Code: CLCI699C2X01B 
 
 
Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
BIOM 
 
 
DATASET 
VARIABLE 
LENGTH 
LABEL 
ATTRIB 
EG 
VISITNUM 
8 Visit Number 
Numeric 
EG 
VISIT 
200 Visit Name 
Character 
EG 
VISITDY 
8 Planned Study Day of Visit 
Numeric 
EG 
EPOCH 
200 Epoch 
Character 
EG 
EGDTC 
200 Date/Time of ECG 
Character 
EG 
EGDY 
8 Study Day of ECG 
Numeric 
 


 
             Statistical Analysis Plan 
 
 
Page 28 of 31 
 
Study Code: CLCI699C2X01B 
 
 
Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
BIOM 
 
 
8.3 
GRADING FOR LAB TESTS (V5.0) 
CTCAE Term  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  
Hypoalbuminemia  
<LLN - 3 g/dL; <LLN - 30 
g/L  
<3 - 2 g/dL; <30 - 20 g/L  
<2 g/dL; <20 g/L  
Life-threatening 
consequences; urgent 
intervention indicated  
Death  
Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.  
Alanine aminotransferase 
increased  
>ULN - 3.0 x ULN if 
baseline was normal; 1.5 - 
3.0 x baseline if baseline 
was abnormal  
>3.0 - 5.0 x ULN if 
baseline was normal; >3.0 
- 5.0 x baseline if baseline 
was abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; >5.0 
- 20.0 x baseline if 
baseline was abnormal  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal  
-  
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.  
Alkaline phosphatase 
increased  
>ULN - 2.5 x ULN if 
baseline was normal; 2.0 - 
2.5 x baseline if baseline 
was abnormal  
>2.5 - 5.0 x ULN if 
baseline was normal; >2.5 
- 5.0 x baseline if baseline 
was abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; >5.0 
- 20.0 x baseline if 
baseline was abnormal  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal  
-  
Definition: A finding based on laboratory test results that indicate an increase in the level of alkaline phosphatase in a blood specimen.  
Aspartate 
aminotransferase 
increased  
>ULN - 3.0 x ULN if 
baseline was normal; 1.5 - 
3.0 x baseline if baseline 
was abnormal  
>3.0 - 5.0 x ULN if 
baseline was normal; >3.0 
- 5.0 x baseline if baseline 
was abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; >5.0 
- 20.0 x baseline if 
baseline was abnormal  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal  
-  
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood specimen.  
Serum amylase increased  
>ULN - 1.5 x ULN  
>1.5 - 2.0 x ULN; >2.0 - 
5.0 x ULN and 
asymptomatic  
>2.0 - 5.0 x ULN with 
signs or symptoms; >5.0 x 
ULN and asymptomatic  
>5.0 x ULN and with 
signs or symptoms  
-  
Definition: A finding based on laboratory test results that indicate an increase in the levels of amylase in a serum specimen.  
Hypercalcemia  
Corrected serum calcium 
of >ULN - 11.5 mg/dL; 
>ULN - 2.9 mmol/L; 
Ionized calcium >ULN - 
1.5 mmol/L  
Corrected serum calcium 
of >11.5 - 12.5 mg/dL; 
>2.9 - 3.1 mmol/L; Ionized 
calcium >1.5 - 1.6 
mmol/L; symptomatic  
Corrected serum calcium 
of >12.5 - 13.5 mg/dL; 
>3.1 - 3.4 mmol/L; Ionized 
calcium >1.6 - 1.8 
mmol/L; hospitalization 
indicated  
Corrected serum calcium 
of >13.5 mg/dL; >3.4 
mmol/L; Ionized calcium 
>1.8 mmol/L; life-
threatening consequences  
Death  


 
             Statistical Analysis Plan 
 
 
Page 29 of 31 
 
Study Code: CLCI699C2X01B 
 
 
Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
BIOM 
 
 
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium (corrected for albumin) in blood.  
Hypocalcemia  
Corrected serum calcium 
of <LLN - 8.0 mg/dL; 
<LLN - 2.0 mmol/L; 
Ionized calcium <LLN - 
1.0 mmol/L  
Corrected serum calcium 
of <8.0 - 7.0 mg/dL; <2.0 - 
1.75 mmol/L; Ionized 
calcium <1.0 - 0.9 
mmol/L; symptomatic  
Corrected serum calcium 
of <7.0 - 6.0 mg/dL; <1.75 
- 1.5 mmol/L; Ionized 
calcium <0.9 - 0.8 
mmol/L; hospitalization 
indicated  
Corrected serum calcium 
of <6.0 mg/dL; <1.5 
mmol/L; Ionized calcium 
<0.8 mmol/L; life-
threatening consequences  
Death  
CPK increased  
>ULN - 2.5 x ULN  
>2.5 x ULN - 5 x ULN  
>5 x ULN - 10 x ULN  
>10 x ULN  
-  
Definition: A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen.  
Creatinine increased  
>ULN - 1.5 x ULN  
>1.5 - 3.0 x baseline; >1.5 
- 3.0 x ULN  
>3.0 x baseline; >3.0 - 6.0 
x ULN  
>6.0 x ULN  
-  
Definition: A finding based on laboratory test results that indicate increased levels of creatinine in a biological specimen.  
GGT increased  
>ULN - 2.5 x ULN if 
baseline was normal; 2.0 - 
2.5 x baseline if baseline 
was abnormal  
>2.5 - 5.0 x ULN if 
baseline was normal; >2.5 
- 5.0 x baseline if baseline 
was abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; >5.0 
- 20.0 x baseline if 
baseline was abnormal  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal  
-  
Definition: A finding based on laboratory test results that indicate higher than normal levels of the enzyme gamma-glutamyltransferase in the blood specimen. GGT (gamma-
glutamyltransferase ) catalyzes the transfer of a gamma glutamyl group from a gamma glutamyl peptide to another peptide, amino acids or water.  
Lipase increased  
>ULN - 1.5 x ULN  
>1.5 - 2.0 x ULN; >2.0 - 
5.0 x ULN and 
asymptomatic  
>2.0 - 5.0 x ULN with 
signs or symptoms; >5.0 x 
ULN and asymptomatic  
>5.0 x ULN and with 
signs or symptoms  
-  
Definition: A finding based on laboratory test results that indicate an increase in the level of lipase in a biological specimen.  
Hypermagnesemia  
>ULN - 3.0 mg/dL; >ULN 
- 1.23 mmol/L  
-  
>3.0 - 8.0 mg/dL; >1.23 - 
3.30 mmol/L  
>8.0 mg/dL; >3.30 
mmol/L; life-threatening 
consequences  
Death  
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of magnesium in the blood.  
Hypomagnesemia  
<LLN - 1.2 mg/dL; <LLN 
- 0.5 mmol/L  
<1.2 - 0.9 mg/dL; <0.5 - 
0.4 mmol/L  
<0.9 - 0.7 mg/dL; <0.4 - 
0.3 mmol/L  
<0.7 mg/dL; <0.3 mmol/L; 
life-threatening 
consequences  
Death  
Definition: A disorder characterized by laboratory test results that indicate a low concentration of magnesium in the blood.  
Hyperkalemia  
>ULN - 5.5 mmol/L  
>5.5 - 6.0 mmol/L; 
intervention initiated  
>6.0 - 7.0 mmol/L; 
hospitalization indicated  
>7.0 mmol/L; life-
threatening consequences  
Death  


 
             Statistical Analysis Plan 
 
 
Page 30 of 31 
 
Study Code: CLCI699C2X01B 
 
 
Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
BIOM 
 
 
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of potassium in the blood; associated with kidney failure or 
sometimes with the use of diuretic drugs.  
Hypokalemia  
<LLN - 3.0 mmol/L  
Symptomatic with <LLN - 
3.0 mmol/L; intervention 
indicated  
<3.0 - 2.5 mmol/L; 
hospitalization indicated  
<2.5 mmol/L; life-
threatening consequences  
Death  
Definition: A disorder characterized by laboratory test results that indicate a low concentration of potassium in the blood.  
Hypernatremia  
>ULN - 150 mmol/L  
>150 - 155 mmol/L; 
intervention initiated  
>155 - 160 mmol/L; 
hospitalization indicated  
>160 mmol/L; life-
threatening consequences  
Death  
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of sodium in the blood.  
Hyponatremia  
<LLN - 130 mmol/L  
125-129 mmol/L and 
asymptomatic  
125-129 mmol/L 
symptomatic; 120-124 
mmol/L regardless of 
symptoms  
<120 mmol/L; life-
threatening consequences  
Death  
Definition: A disorder characterized by laboratory test results that indicate a low concentration of sodium in the blood.  
Blood bilirubin increased  
>ULN - 1.5 x ULN if 
baseline was normal; > 1.0 
- 1.5 x baseline if baseline 
was abnormal  
>1.5 - 3.0 x ULN if 
baseline was normal; >1.5 
- 3.0 x baseline if baseline 
was abnormal  
>3.0 - 10.0 x ULN if 
baseline was normal; >3.0 
- 10.0 x baseline if 
baseline was abnormal  
>10.0 x ULN if baseline 
was normal; >10.0 x 
baseline if baseline was 
abnormal  
-  
Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice.  
Hemoglobin increased  
Increase in >0 - 2 g/dL  
Increase in >2 - 4 g/dL  
Increase in >4 g/dL  
-  
-  
Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin above normal.  
Anemia  
Hemoglobin (Hgb) <LLN 
- 10.0 g/dL; <LLN - 6.2 
mmol/L; <LLN - 100 g/L  
Hgb <10.0 - 8.0 g/dL; <6.2 
- 4.9 mmol/L; <100 - 80g/L  
Hgb <8.0 g/dL; <4.9 
mmol/L; <80 g/L; 
transfusion indicated  
Life-threatening 
consequences; urgent 
intervention indicated  
Death  
Definition: A disorder characterized by a reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous 
membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.  
White blood cell 
decreased  
<LLN - 3000/mm3; <LLN 
- 3.0 x 10e9 /L  
<3000 - 2000/mm3; <3.0 - 
2.0 x 10e9 /L  
<2000 - 1000/mm3; <2.0 - 
1.0 x 10e9 /L  
<1000/mm3; <1.0 x 10e9 
/L  
-  
Definition: A finding based on laboratory test results that indicate an decrease in number of white blood cells in a blood specimen.  
Leukocytosis  
-  
-  
>100,000/mm3  
Clinical manifestations of 
leucostasis; urgent 
intervention indicated  
Death  


 
             Statistical Analysis Plan 
 
 
Page 31 of 31 
 
Study Code: CLCI699C2X01B 
 
 
Version [Final] 
Date: 05July2023 
 
CONFIDENTIAL 
 
BIOM 
 
 
Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood.  
Navigational Note: -  
 
 
 
 
 
 
Lymphocyte count 
decreased  
<LLN - 800/mm3; <LLN - 
0.8 x 10e9/L  
<800 - 500/mm3; <0.8 - 
0.5 x 10e9 /L  
<500 - 200/mm3; <0.5 - 
0.2 x 10e9 /L  
<200/mm3; <0.2 x 10e9 
/L  
-  
Definition: A finding based on laboratory test results that indicate a decrease in number of lymphocytes in a blood specimen.  
Navigational Note: -  
Lymphocyte count 
increased  
-  
>4000/mm3 - 20,000/mm3  >20,000/mm3  
-  
-  
Definition: A finding based on laboratory test results that indicate an abnormal increase in the number of lymphocytes in the blood, effusions or bone marrow.  
Navigational Note: -  
Neutrophil count 
decreased  
<LLN - 1500/mm3; <LLN 
- 1.5 x 10e9 /L  
<1500 - 1000/mm3; <1.5 - 
1.0 x 10e9 /L  
<1000 - 500/mm3; <1.0 - 
0.5 x 10e9 /L  
<500/mm3; <0.5 x 10e9 
/L  
-  
Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen.  
Navigational Note: -  
Platelet count decreased  
<LLN - 75,000/mm3; 
<LLN - 75.0 x 10e9 /L  
<75,000 - 50,000/mm3; 
<75.0 - 50.0 x 10e9 /L  
<50,000 - 25,000/mm3; 
<50.0 - 25.0 x 10e9 /L  
<25,000/mm3; <25.0 x 
10e9 /L  
-  
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.  
Navigational Note: -