Conditions: Cushing's Disease Acromegaly Neuroendocrine Tumors Pituitary Tumors Ectopic ACTH Secreting (EAS) Tumors Dumping Syndrome Prostate Cancer Melanoma Negative for bRAF Melanoma Negative for nRAS
Keywords: SOM230, roll-over study pasireotide LAR Cushing's disease Acromegaly neuroendocrine tumorsNETs pituitary tumors Ectopic ACTH secreting EAS Dumping Syndrome metastatic prostate cancer, metastatic melanoma bRAF nRAS
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 337
Healthy volunteers: no

Brief summary:
The purpose of this study is to allow continued use of pasireotide in patients who are on pasireotide treatment in a Novartis-sponsored study and are benefiting from the treatment as judged by the investigator.

Detailed description:
This is a multi-center, open label, phase IV study to provide continued supply of pasireotide to patients being treated in a current Novartis-sponsored study and who are benefiting from treatment with pasireotide alone or in combination with another treatment for Cushing's Disease and Acromegaly . Eligible patients are to be consented and can then continue treatment with pasireotide alone or in combination with another treatment for Cushing's Disease and Acromegaly in this protocol. All patients at their scheduled visits will have drug dispensing information and reported adverse events and serious adverse events collected.

A patient will reach the end of study when pasireotide treatment is permanently discontinued and the end of treatment visit has been performed. All patients must be followed up for safety evaluations for 3 months following the last dose of pasireotide LAR treatment and for 1 month following the last dose of pasireotide s.c. treatment.

The study is expected to remain open for approximately 10 years or until such time that enrolled patients no longer need treatment with pasireotide or are able to obtain commercial supply according to local regulations for their medical condition.

Arms:
arm 1: 0.3mg, 0.6mg and 0.9mg. Doses to be taken BID or TID, dependent on parent study guidelines. Cabergoline may be combined in this arm for Cushing's Disease and Acromegaly patients. arm 2: 10mg, 20mg, 40mg and 60mg. All doses to be taken q28days. Strength is dependent on parent study guidelines.

Interventions: intervention 1: Pasireotide intervention 2: Cabergoline intervention 3: Pasireotide LAR
Intervention descriptions: intervention 1: Administered subcutaneously in strengths 0.3mg, 0.6mg and 0.9mg. Doses to be taken BID or TID, dependent on parent study guidelines. intervention 2: Cabergoline tablet 0.5mg or 1.0mg taken by mouth once daily may be combined with subcutaneous formulation of pasireotide for Cushing's Disease or Acromegaly. Dose is dependent on parent study guidelines. intervention 3: Long Acting Release is administered by a single intramuscular (i.m.) monthly injection. The strengths are 10mg, 20mg, 40mg and 60mg. All doses to be taken q28days. Strength is dependent on parent study guidelines.

Protocol document:
ICF_002.pdf: 
 
 
 
 
Recordati Research and Development 
SOM230 (pasireotide) Signifor 
Patient Information and Informed Consent 
Clinical Protocol CSOM230B2412 
An open label, multi-center pasireotide roll-over protocol for patients who have 
completed a previous Novartis sponsored pasireotide study and are judged by 
the investigator to benefit from continued pasireotide treatment 
Document type: 
Patient Information and Informed Consent (Clean) 
Based on: 
Amended Protocol Version No. 05 dated 02-Nov-2021 
EudraCT N°: 
2013-000267-84 
Release date: 
02 Nov 2021 
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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Informed Consent Form Summary of Changes 
You may have signed a previous version of the informed consent for this study, however a 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 ongoing patients who 
have been previously consented. If you have any questions please ask the study doctor and/or 
staff assigned to the trial to answer them. 
 
 
Section  
Brief description of new change and/or new text 
Informed consent 
A new reason has been added in this Informed Consent 
Form to explain when the study doctor may remove you 
from this study:  
7. The study drug has become available through specific 
support programmes in your country. 
This ICF amendment is applicable to Brazil, France, 
Germany, India, Italy, Malaysia, Mexico, Peru and 
Thailand. 
 
 


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Informed consent 
You are invited to voluntarily join in a clinical research study that will involve taking the drug 
SOM230/pasireotide (Signifor®) and any medication given in combination with pasireotide (to 
treat Cushing’s disease or acromegaly). The intention of this study is to allow continued use of 
pasireotide and any medication given in combination with pasireotide (to treat Cushing’s 
disease or acromegaly), to patients who have completed their respective parent protocol 
(previous Novartis trial you have been participating in) and to collect long term safety data. 
You have recently completed a Novartis sponsored trial (parent study number……… _) and 
have been benefitting from treatment with pasireotide and any medication given in combination 
with pasireotide (to treat Cushing’s disease or acromegaly) as determined by the 
investigator/Study Doctor. 
Before you agree to join in this study, you need to know the risks and benefits so you can make 
an informed decision. This process is known as “informed consent”. 
This consent form tells you about the study that you may wish to join. Please read the 
information carefully and discuss it with anyone you want. This may include a friend or a 
relative. If you have questions please ask the Study Doctor or study staff to answer them. 
Once you know about the study, you will be asked to sign this form to join this study. Your 
decision to take part in this study is voluntary. That means you are free to decide to join this 
study or not join this study and refusal to join will not affect your medical care. You are also 
free to leave the study at any time and without any reason. If you choose not to join in this 
study, or decide to withdraw you can discuss regular medical care / alternative treatments with 
the Study Doctor. 
We may learn about new things that make you want to stop being in the study. If this happens, 
you will be informed. You can then decide if you want to continue to be in the study. 
The Study Doctor may remove you from this study for any justified reason according to the 
protocol. Examples why you may be taken out of the study are: 
1. Staying in the study would be harmful. 
2. You need treatment not allowed in this study. 
3. You fail to follow instructions. 
4. The investigator feels this treatment is no longer in your best interest. 
5. You become pregnant. 
6. The study is cancelled. 
7. The study drug has become available through specific support programmes in your country 
(applicable to Brazil, France, Germany, India, Italy, Malaysia, Mexico, Peru and Thailand). 
8. The study drug becomes commercially available and reimbursed in your country. 
If you should decide to leave the study you should tell the Study Doctor or study staff. They 
will make sure that proper procedures are followed and that a final visit is made for your safety. 
Study Treatment 
On this study you will receive pasireotide as prescribed in your parent protocol (the pasireotide 
study you recently completed). Your starting dose of pasireotide and any medication given in 


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combination with pasireotide (to treat Cushing’s disease or acromegaly), will be the same as 
the dose that was given to you in your previous pasireotide study. During the study, your 
Study Doctor may change the dose depending on how you respond to pasireotide and any 
medication given in combination with pasireotide (to treat Cushing’s disease or acromegaly). 
In addition, any unused study drug and empty packages must be returned to the Study Doctors 
at your study visits. At the end of the study or when you leave the study you should return any 
study medication still in your possession to the Study Doctors. 
Please tell your Study Doctor or study staff if you have any unusual symptoms. 
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. 
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 doctors. 
Trial purpose and conduct 
This is a clinical research study to evaluate long term safety. This trial is sponsored by the 
pharmaceutical company named Recordati. Once you give your consent to join this study and 
are eligible to participate and enroll in the study, you will receive pasireotide either 
subcutaneous or long acting release formulation and any medication given in combination 
with pasireotide (to treat Cushing’s disease or acromegaly). Recordati will make a continued 
supply of pasireotide and any medication given in combination with pasireotide (to treat 
Cushing’s disease or acromegaly), available to you at no cost. 
Pasireotide s.c. is a short acting formulation administered subcutaneously two or three times a 
day. This formulation has been tested in healthy volunteers and in patients with acromegaly, 
Cushing’s disease and neuroendocrine tumors. 
Pasireotide LAR is a long acting formulation administered intramuscularly every 28 days. It 
has been studied in healthy volunteers and in patients with acromegaly, Cushing’s disease, 
and neuroendocrine tumors. 
Once you enroll in the study, if you were receiving pasireotide LAR formulation in your 
parent protocol, you will continue to come to your Study Doctor’s office/clinic/study site 
every month to receive your long acting release intramuscular injection. If you were receiving 
pasireotide subcutaneous formulation, you will be given up to a 3-month supply of the drug. 
You will also be given any medication that you are taking in combination with pasireotide to 
treat Cushing’s disease or acromegaly, at your scheduled study visits. Female patients of child 
bearing potential will be required to have a pregnancy test at this first visit before enrolling. 
No other blood or medical evaluations are specifically required on this study, beside monthly 
at home urine pregnancy tests for women of child bearing potential. However, your Study 
Doctor may continue evaluations as part of the normal management of your disease and/or 
standard of care. 


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You will be asked to come to the Study Doctor’s office/clinic/study site for a study visit based 
on the schedule that matches your parent protocol, depending on the study drug formulation 
netyou were receiving (i.e., monthly for LAR formulation and every three months for s.c. 
formulation). During this visit, general information about your health will be collected including 
confirmation that you are still responding to treatment, and you will receive a re -supply of 
study medication. Your Study Doctor will attest to you still receiving benefit. 
You will be able to take the study drug(s) for as long as the Study Doctor thinks it is in your 
best interest. You will be taken off the study if you have intolerable side effects, if the 
Study Doctor no longer thinks it is in your best interest, if you are not compliant to study 
requirements or if you withdraw your consent. 
If you stop study medication on this study or leave the study, you should tell the Study Doctor 
or study staff. They will ensure that proper procedures are followed and that a final visit is 
made for your safety. 
Your Study Doctor will need to know general information about your health status up to 3 
months after your last dose of study medication (30 days if you are receiving the pasireotide 
subcutaneous formulation and 84 days if you are receiving the pasireotide LAR formulation). 
Once you stop taking the study medication(s), and have had your final visit there will be 
no further follow-up visits. During your final safety follow up visit, female patients of 
childbearing potential are required to have a pregnancy test.  
Patients must comply with all study requirements. If you do not or are unable to fulfill the 
study requirements, you will be discontinued from the study. 
Patients’ responsibility 
It is very important that you come to all the study visits and that you follow your Study 
Doctor’s instructions. Tell the Study Doctor about any medications you are taking during the 
study. This includes prescription medicines, over-the-counter medicines and vitamins. This is 
very important. Please tell your Study Doctor or site staff if you have any unusual symptoms. 
By signing this consent form, you agree to follow your doctor’s instructions and attend all 
study-related visits. 
Study treatment discontinuation 
Please inform your doctor or study staff if you decide to interrupt or stop taking the study 
treatment(s). You will be asked to return to the study site as soon as possible to check how 
you are. You should bring your study treatment(s) to the clinic. Also the Study Doctor may 
choose to discontinue your study treatment(s). 
You may be asked to continue with study visits after stopping study treatment(s) so that all or 
a selection of assessments can be performed. 
If you cannot or do not want to continue to attend study visits while off study treatment(s), 
your Study Doctor or study staff may ask if they can contact you by telephone until the end 
of the study to check on how you are doing. You may decline contact by telephone if you so 
choose. 


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Withdrawal of your consent to participate in this study 
You may decide that you not only want to stop study treatment(s) but also don`t want to come 
to any further visits, and don`t want to have any further assessments or contact by the study 
staff. This is considered as withdrawal of your consent from participation in this study. It is 
important that you inform your Study Doctor of your decision to withdraw your consent in 
writing or in a manner compatible with local laws, cultures, and norms. 
Recordati will continue to retain and use all research results and any biological samples that 
have already been collected for the study evaluation (as per local regulations). 
You can discuss further regular medical care with the Study Doctor. The choice to withdraw 
from research participation will not affect your medical care. 
Risks and inconveniences 
Risks are possible side effects of the study medicine. Pasireotide could cause side effects 
like abdominal pain, nausea, vomiting, loose stools, diarrhea, mild dizziness and headache. 
It could also affect hormones, like insulin, which regulate blood sugar levels and the glucose 
in your blood may increase during treatment. Therefore, your doctor may monitor your 
blood glucose during this study if he/she feels it necessary. 
A small number of cases of QT prolongation have been reported in some participants in 
pasireotide clinical trials. QT is one of the measurements taken during the ECG (heart tracing) 
and increases (prolongation) in QT may lead to an irregular heartbeat which in rare instances 
can develop into a sudden, life-threatening condition. The majority of cases that were reported 
in the pasireotide clinical trials resolved or improved spontaneously without discontinuation 
of the study drug. 
A small number of cases of concomitant increases in blood liver enzymes and bilirubin have 
been reported in some participants in pasireotide clinical trials. Blood liver enzymes and 
bilirubin are important measurements to evaluate liver health and function and a concomitant 
increase may lead to liver damage which in rare instances can progress to liver failure, a life-
threatening condition. In the pasireotide clinical trials, subjects and patients were generally 
asymptomatic and remained clinically well and liver function returned to normal after 
discontinuation of pasireotide. However, if you were to experience abnormal yellowing of the 
skin or eyes, or dark colored urine while in this study, you should notify your doctor 
immediately as these could be symptoms of liver problems. Though the risk is small, these 
findings may indicate a potential risk for liver failure associated with the treatment of 
pasireotide. 
Problems or side effects that are not now known could also occur. You will be given any new 
information that may affect your willingness to start or continue in the study. 
Your injection under the skin may cause pain at the injection site or cause local irritation such 
as swelling and redness. If any irritation occurs, it is expected to disappear after a short time. 
The safety profile of any other drugs that are given to you in combination with pasireotide, to 
treat Cushing’s disease or acromegaly, can be given to you as applicable.  Please ask your Study 
Doctor for possible side effects regarding any combination medications that you are given in 
your parent study.  


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Contraception and pregnancy 
Women who are pregnant or nursing a child cannot participate in this trial. 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 trial. You will be required to take monthly at home urine pregnancy 
tests if you are a woman of child bearing potential, and report the results to your Study 
coordinator/Study doctor. 
The risks to an unborn human fetus or a nursing child from the medications you are required 
to take in this study are not 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 respect your cultural and religious situation. Examples of highly effective 
birth control methods are: 
• Total abstinence (no sexual relations), 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 removal of both ovaries (woman's reproductive system that stores and releases 
eggs for fertilization and produces female sex hormones), total hysterectomy (surgical 
removal of the uterus and cervix) or tubal ligation (getting your “tubes tied”) at least six 
weeks before taking 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). 
• In case of use of oral contraception you should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
All sexually active male patients should use a condom during intercourse while taking study 
drug and for 30 days after pasireotide s.c. last dose and 84 days after pasireotide LAR last dose. 
Male patients should not father a child in this period. A condom is also required to be used by 
vasectomized men in order to prevent delivery of the drug via seminal fluid. 
If you become pregnant or suspect being pregnant during study treatment and within the 30 
day follow up period you must inform the Study Doctor immediately, and if on study treatment, 
you have to stop 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. 


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General information on pregnancy and contraception 
85 out of 100 sexually active women who do not use birth control can expect to become 
pregnant in a year. No matter which birth control you are using from the list above, it is 
important to follow the manufacturer directions. If you don’t, you raise your chance of getting 
pregnant. 
Hormonal contraception is available in the form of pills which need to be taken every day, 
injections, which lasts approximately 3 months and as implanted devices. Hormonal methods 
are associated with some risks like changes in your cycle, nausea, headache, changes in mood, 
weight gain, breast tenderness, and blood clots. 
Implanted devices are inserted into the uterus and can stay there for several years. They can 
cause cramps, bleeding, and infertility. It is important to know that not all women experience 
all of the adverse effects listed above. 
Benefits of treatment 
You may receive no direct benefit from being in this study. However, your taking part may 
help patients get better care in the future. 
Costs and compensation for participation in this study 
There will be no monetary costs to you for participating in this study. You will not be charged 
for the study drug(s) or any of the tests and procedures performed solely for research purposes. 
Compensation for injury resulting from the study 
It is important that you follow carefully all the instructions given by the Study Doctor and 
his/her staff regarding this study. 
If you become ill or are physically injured as a result of participation in this study, please contact 
the Study Doctor right away [investigator’s name and contact information]; (s)he will treat you 
or refer you for treatment. 
The reasonable costs of such treatment beyond that provided by your insurance will be 
covered by the Sponsor, Recordati. Record at i will provide payment for medical expenses 
for injuries: 
• if you received reasonable medical care, 
• if you followed instructions, 
• if the injury is related to the study drug or to properly performed study procedures that  are 
not part of your usual medical care, 
• that are not the result of the natural course of any underlying disease and/or pre-existing 
disease process present prior to the proper administration of pasireotide. 
In no way does signing this consent form waive your legal rights, nor does it relieve the 
investigators, Sponsor or 
involved institutions 
from their legal and professional 
responsibilities. 


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Alternative procedures or treatment 
Other procedure and/or medicines may be available to you. Listed below are all the diseases 
that are being treated in this trial and alternative treatment options for those diseases.  
Acromegaly: surgery, radiotherapy, medical therapy (e.g. other somatostatin analogs; GH 
receptor antagonists, dopamine agonist) 
Cushing’s disease: surgery, radiotherapy, medical therapy (e.g. other somatostatin analogs 
dopamine agonists, steroidogenesis inhibitors, glucocorticoid receptor antagonists) 
Dumping syndrome: octreotide, surgery  
Melanoma, NET and carcinoid: surgery, radiation, chemotherapy, immunotherapy  
You can ask your doctor about their potential benefits and risks of each of these treatment 
options. 
What will happen to my Personal Data? 
Data Protection laws vary by country. Many countries have very specific requirements 
regarding the informed consent of the data subject. The elements required to be included in the 
following subsections of the informed consent are: 
• definition of Personal Data. Please note with respect to Personal Data that in adult 
studies the code used to de-identify subjects should not display subject’s full date of birth 
(DD/MM/YY). However, in pediatric studies MM/YY may be a possibility especially for 
studies conducted in infants.  
• identification of individuals that will review medical records that will identify the subject 
by name; 
• that records identifying the subject will be kept confidential and that any published results 
will not reveal the identity of the  subject ; 
• that by signing the informed consent the subject or his/her legal guardian authorizes 
access to medical records; 
• identification of types of data collected and  a simple and thorough explanation of the 
purposes of collection and processing of data; 
• identification of categories of third parties that may have access to the data or to whom 
the data may be transferred, in particular persons or organization that are acting as data 
processors (Recordati affiliates, CROs, outsourcing companies, labs, etc.). In some EU 
countries, this data may need to be specific. Please contact your data privacy legal 
representative to determine level of specificity in your country; a statement, if 
appropriate, that the data may be transferred to countries that do not provide an adequate 
level of data protection as in the study country (generally any country outside of the EEA, 
Canada, Argentina, Switzerland, Israel, New Zealand, Uruguay, Andorra, Faroe, or 
Guernsey).; 
• explanation of the extent to which study participants have the right to access information 
held about them to correct inaccuracies and any limits to those rights; 
• date or event upon which the consent may not be considered to be valid anymore. 


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What is Personal Data? 
The study doctor will collect your Personal Data meaning your name, initials, address, gender, 
age/date of birth and health information.   
If necessary, the study doctor may contact your doctor to collect more medical information. 
He/she may check your health information on public records if allowed by local law. 
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. 
Recordati, which has appointed as its data processing representative in the European Union 
Recordati Rare Diseases Italy s.r.l. with registered office in Civitali 1, 20148 Milan (Italy), will 
receive 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 
Recordati 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. Recordati has 
contracted the Clinical Research Organizations IQVIA and PPD for the data processing 
activities for the purpose of this study. 
 
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 drug 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 drug.  
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 drug. 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 technology based 
solutions 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 
authorize such access to your Personal Data including your original medical records. 
(USE THE FOLLOWING TEXT FOR TRIALS IN THE US) 
The individuals mentioned in bullets 2 & 3 of the Section ‘Who Can see my Personal Data’ 
may use your Personal Data, including any of your remaining coded biological samples, for 


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additional medical and/or scientific research and development projects that are outside of the 
current study purpose and objectives. 
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 
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 may operate 
these systems.  Your Personal Data 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. 
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’s 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 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).   


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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 
(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) 
or 
the 
Recordati 
Data 
Protection 
Officer 
at 
GroupDPO@recordati.com  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.  
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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Contacts 
If you have questions about the research, please contact: (insert name and the phone number; 
usually the investigator and/or study nurse/study coordinator). 
 
Role 
 
Name 
 
Telephone Number 
Principal Investigator 
 
 
 
 
Study Nurse/ Coordinator 
 
 
 
 
 
If you have questions related to your rights as a research subject, please contact: (insert name 
of the IRB/IEC and the phone number (ICH q)). 
 
Role 
 
Name 
 
Telephone Number 
IRB/EC 
 
 
 
 
 
In the event of a research-related injury, please contact (insert name and phone number (ICH 
q) (EIC 7)). 
 
Role 
 
Name 
 
Telephone Number 
Principal Investigator 
 
 
 
 
 


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Sample signature page (using HIPPA approved wording, for US) 
Protocol number and version: CSOM230B2412, Version 05.07 dated 02-Nov-2021 
Protocol title: An open label, multi-center pasireotide roll-over protocol for patients who 
have completed a previous Novartis-sponsored pasireotide study and are judged by the 
investigator to benefit from continued pasireotide treatment 
I have read this document/had its contents explained to me. I understand the purpose of this 
study and what will happen to me in this study. I do freely give my consent to join in this study, 
as described to me in this document. I understand that I will receive a copy of this document as 
signed below. 
By signing this consent form, I authorize the use, access, and sharing of my personal medical 
information as described in the section “Confidentiality and Authorization approval to collect, 
use, and disclose Personal Medical Information and Biological samples”. This consent is valid 
unless and until I revoke it. 
 
type/print name 
 
 
 
 
Patient 
 
Signature 
 
Date 
 
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Witness 
(if patient gives oral, not 
signed consent) 
 
Signature 
 
Date 
 
type/print name 
 
 
 
 
Legal representative 
(legally authorized to act as 
personal representative to 
sign for [name of patient]) 
 
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Date 
 
type/print name 
 
 
 
 
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Date 
 
 
type/print name 
 
 
 
 
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(who presented/explained the 
document) 
 
Signature 
 
Date 


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Protocol No. CSOM230B2412 
 
Sample signature page (Rest of World) 
Protocol number and version: CSOM230B2412, Version 05.07 dated 02-Nov-2021 
Protocol title: An open label, multi-center pasireotide roll-over protocol for patients who 
have completed a previous Novartis-sponsored pasireotide study and are judged by the 
investigator to benefit from continued pasireotide treatment 
I have read this document/had its contents explained to me. I understand the purpose of this 
study and what will happen to me in this study. I do freely give my consent to join in this study, 
as described to me in this document. I understand that I will receive a copy of this document as 
signed below. 
By signing this consent form, I authorize the use, access, and sharing of my personal data as 
described in the section “Confidentiality and Authorization to collect, use, and disclose Personal 
Medical Information and Biological Samples”. This consent is valid unless and until I revoke 
it. 
 
 
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Date 
 
 
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(if patient is a minor) 
 
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signed consent) 
 
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document) 
 
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Protocol No. CSOM230B2412 
 
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document) 
 
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Prot_000.pdf: 
 
 
 
 
Recordati Research and Development 
SOM230 (pasireotide)  
Clinical Trial Protocol CSOM230B2412 
An open label, multi-center pasireotide roll-over protocol for patients who have 
completed a previous Novartis-sponsored pasireotide study and are judged by 
the investigator to benefit from continued pasireotide treatment 
Document type 
Amended Protocol Version 
EUDRACT number 
2013-000267-84 
Version number 
05 (Clean) 
Development phase 
IV 
Document status 
Final version 
Release date 
02-Nov-2021 
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 
List of figures ...................................................................................................................... 7 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 11 
Amendment 5 (02-Nov-2021) ........................................................................................... 12 
Amendment 4 (06 May-2020) ........................................................................................... 13 
Amendment 3 (08-Mar-2019) ........................................................................................... 14 
Amendment 2 (29-Sep-2017) ............................................................................................ 16 
Amendment 01 .................................................................................................................. 19 
Protocol summary: ............................................................................................................. 21 
1 
Background ........................................................................................................................ 23 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 23 
1.1.1 
Overview of Cushing’s disease (CD) .................................................... 23 
1.1.2 
Overview of acromegaly ....................................................................... 24 
1.1.3 
Overview of neuroendocrine tumors (NETs) ........................................ 24 
1.1.4 
Overview of other pituitary tumors and of Ectopic ACTH secreting 
(EAS) tumors ........................................................................................ 25 
1.1.5 
Overview of patients with dumping syndrome ..................................... 26 
1.1.6 
Overview of other indications ............................................................... 26 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 26 
1.2.1 
Overview of pasireotide s.c. and LAR .................................................. 26 
2 
Rationale ............................................................................................................................ 30 
2.1 
Study rationale and purpose ................................................................................... 30 
2.2 
Rationale for the study design ............................................................................... 31 
2.3 
Rationale for dose and regimen selection .............................................................. 31 
2.4 
Rationale for choice of combination drugs ............................................................ 31 
2.5 
Rationale for choice of comparators drugs ............................................................ 32 
2.6 
Risks and benefits .................................................................................................. 32 
3 
Objectives and endpoints ................................................................................................... 35 
4 
Study design ...................................................................................................................... 35 
4.1 
Description of study design ................................................................................... 35 
4.2 
Timing of interim analyses and design adaptations ............................................... 36 
4.3 
Definition of end of the study ................................................................................ 36 
4.4 
Early study termination .......................................................................................... 36 
5 
Population .......................................................................................................................... 37 


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5.1 
Patient population .................................................................................................. 37 
5.2 
Inclusion criteria .................................................................................................... 37 
5.3 
Exclusion criteria ................................................................................................... 37 
6 
Treatment ........................................................................................................................... 38 
6.1 
Study treatment ...................................................................................................... 38 
6.1.1 
Study treatment and investigational treatment refer to pasireotide 
alone or in combination with another treatment for Cushing’s 
Disease and AcromegalyDosing regimen Pasireotide .......................... 39 
6.1.2 
Dosing regimen for patients on Pasireotide in combination with 
cabergoline treatment ............................................................................ 39 
6.1.3 
Dosing regimen for patients on Pasireotide in combination with 
another treatment for Cushing’s Disease or Acromegaly ..................... 40 
6.1.4 
Ancillary treatments .............................................................................. 40 
6.1.5 
Rescue medication ................................................................................ 40 
6.1.6 
Guidelines for continuation of treatment .............................................. 40 
6.1.7 
Treatment duration ................................................................................ 40 
6.2 
Dose modification guidelines ................................................................................ 40 
6.2.1 
Starting dose rationale ........................................................................... 40 
6.3 
Concomitant medications ...................................................................................... 41 
6.3.1 
Prohibited concomitant therapy ............................................................ 41 
6.4 
Patient numbering, treatment assignment or randomization ................................. 41 
6.4.1 
Patient numbering ................................................................................. 41 
6.4.2 
Treatment assignment or randomization ............................................... 41 
6.4.3 
Treatment blinding ................................................................................ 41 
6.5 
Study drug preparation and dispensation ............................................................... 41 
6.5.1 
Study treatment packaging and labeling ............................................... 41 
6.5.2 
Drug supply and storage ........................................................................ 42 
6.5.3 
Study drug compliance and accountability ........................................... 42 
6.5.4 
Disposal and destruction ....................................................................... 43 
7 
Visit schedule and assessments ......................................................................................... 43 
7.1 
Study flow and visit schedule ................................................................................ 43 
7.1.1 
Molecular pre-screening ........................................................................ 45 
7.1.2 
Screening ............................................................................................... 45 
7.1.3 
Treatment period ................................................................................... 45 
7.1.4 
Pregnancy and assessment of fertility ................................................... 46 
7.1.5 
Discontinuation of study treatment ....................................................... 46 
7.1.6 
Withdrawal of consent .......................................................................... 48 


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7.1.7 
Follow up for safety evaluations ........................................................... 48 
7.1.8 
Lost to follow-up ................................................................................... 49 
7.2 
Assessment types ................................................................................................... 49 
7.2.1 
Efficacy assessments ............................................................................. 49 
7.2.2 
Safety and tolerability assessments ....................................................... 49 
7.2.3 
Resource utilization ............................................................................... 49 
7.2.4 
Patient reported outcomes ..................................................................... 50 
8 
Safety monitoring and reporting ........................................................................................ 50 
8.1 
Adverse events ....................................................................................................... 50 
8.1.1 
Definitions and reporting ...................................................................... 50 
8.1.2 
Laboratory test abnormalities ................................................................ 51 
8.1.3 
Adverse events of special interest ......................................................... 52 
8.2 
Serious adverse events ........................................................................................... 52 
8.2.1 
Definitions ............................................................................................. 52 
8.2.2 
Reporting ............................................................................................... 52 
8.3 
Emergency unblinding of treatment assignment ................................................... 54 
8.4 
Pregnancies ............................................................................................................ 54 
8.5 
Warnings and precautions ...................................................................................... 54 
8.6 
Data Monitoring Committee .................................................................................. 54 
8.7 
Steering Committee ............................................................................................... 54 
9 
Data collection and management ....................................................................................... 55 
9.1 
Data confidentiality ............................................................................................... 55 
9.2 
Site monitoring ...................................................................................................... 55 
9.3 
Data collection ....................................................................................................... 56 
9.4 
Database management and quality control ............................................................ 56 
10 Statistical methods and data analysis ................................................................................ 56 
10.1 
Analysis sets .......................................................................................................... 56 
10.1.1 
Full Analysis Set ................................................................................... 56 
10.1.2 
Safety Set .............................................................................................. 56 
10.1.3 
Dose-determining analysis set............................................................... 57 
10.2 
Patient demographics/other baseline characteristics ............................................. 57 
10.3 
Treatments (study treatment, compliance) ............................................................ 57 
10.4 
Primary objective ................................................................................................... 57 
10.4.1 
Variable ................................................................................................. 57 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 57 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 57 


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10.4.4 
Supportive analyses ............................................................................... 57 
10.5 
Secondary objectives ............................................................................................. 57 
10.5.1 
Key secondary objective(s) ................................................................... 57 
10.5.2 
Other secondary efficacy objectives ..................................................... 57 
10.5.3 
Safety objectives ................................................................................... 57 
10.6 
Interim analysis ...................................................................................................... 58 
10.7 
Sample size calculation .......................................................................................... 58 
10.8 
Power for analysis of key secondary variables ...................................................... 58 
11 Ethical considerations and administrative procedures ...................................................... 58 
11.1 
Regulatory and ethical compliance ........................................................................ 58 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 59 
11.3 
Informed consent procedures ................................................................................. 59 
11.4 
Discontinuation of the study .................................................................................. 59 
11.5 
Publication of study protocol and results............................................................... 60 
11.6 
Study documentation, record keeping and retention of documents ....................... 60 
11.7 
Confidentiality of study documents and patient records ....................................... 61 
11.8 
Audits and inspections ........................................................................................... 61 
11.9 
Financial disclosures .............................................................................................. 61 
12 Protocol adherence ............................................................................................................ 61 
12.1 
Amendments to the protocol .................................................................................. 61 
13 References (available upon request) .................................................................................. 62 
14 Appendices ........................................................................................................................ 65 
14.1 
Appendix 1: Medications known to be associated with QT interval 
prolongation ........................................................................................................... 65 
14.2 
Appendix 2: Recommended hepatic safety management guidance ...................... 66 
14.3 
Appendix 3: Recommended guidance for follow up in case of QT-related 
findings during routine ECG ................................................................................. 68 
14.4 
Appendix 4: Recomended guidance for fasting blood glucose management ........ 70 
14.5 
Appendix 5: Dose modification information for acromegaly or carcinoid 
patients receiving pasireotide LAR (from protocol CSOM230C2110, 
CSOM230C2305, CSOM230C2402 and CSOM230C2413) ................................ 72 
14.6 
Appendix 6: Dose modification information for Cushing’s patients receiving 
pasireotide LAR (from protocol SOM230G2304) ................................................ 74 
14.7 
Appendix 7: Dose modification information for dumping syndrome patients 
receiving pasireotide s.c or LAR (from protocol SOM230X2203) ....................... 75 
14.8 
Appendix 8: Dose modification information for patients with metastatic 
melanoma or metastatic Merkel cell carcinoma receiving pasireotide s.c 
(from protocol SOM230X2404) ............................................................................ 78 


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14.8.1 
Guidance for diarrhea management ...................................................... 79 
14.8.2 
Dose and treatment schedule ................................................................. 81 
14.9 
Appendix 9: Dose modification information for patients with rare tumors of 
neuroendocrine origin receiving pasireotide LAR (from protocol 
SOM230D2203) .................................................................................................... 82 
14.10 Appendix 10: Dose modification information for patients with 
neuroendocrine tumors receiving pasireotide LAR (from protocol 
SOM230D2101) .................................................................................................... 83 
14.10.1 
Dose modification and dose delay ........................................................ 84 
14.10.2 
Treatment interruption and treatment discontinuation .......................... 84 
14.10.3 
Guidance for diarrhea management ...................................................... 87 
14.11 Appendix 11: Dose modification information for patients with Cushing’s 
receiving pasireotide s.c or acromegaly receiving pasireotide LAR (from 
protocols SOM230B2219 and SOM230B2305) .................................................... 90 
14.11.1 
Dose modifications for patients from protocol SOM230B2219 ........... 90 
14.11.2 
Dose modifications for patients from protocol SOM230B2305 ........... 90 
14.12 Appendix 12: Dose modification information for patients with Cushing’s 
receiving pasireotide s.c in combination with cabergoline (SOM230B2411) ....... 92 


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List of figures 
Figure 4-1 
Study design .......................................................................................... 36 
Figure 14-1 
Recommended LFT management guidance .......................................... 67 
Figure 14-2 
Recommended guidance for ECG follow up ........................................ 69 
Figure 14-3 
Recommended guidance for fasting self-monitoring blood glucose 
management .......................................................................................... 71 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 35 
Table 6-1 
Dose and treatment schedule ................................................................. 39 
Table 6-2 
Packaging and labeling ......................................................................... 42 
Table 6-3 
Supply and storage of study treatments ................................................ 42 
Table 7-1 
Visit evaluation schedule ...................................................................... 44 
Table 14-1 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 72 
Table 14-2 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2110 ..................................................................................... 72 
Table 14-3 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2305 ..................................................................................... 73 
Table 14-4 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2402 ..................................................................................... 73 
Table 14-5 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 74 
Table 14-6 
Follow up evaluation (after treatment interruption) .............................. 76 
Table 14-7 
Dose reduction steps for pasireotide LAR monthly dosing q28d ......... 76 
Table 14-8 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 77 
Table 14-9 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia for patients from protocol 
SOM230X2402 ..................................................................................... 79 
Table 14-10 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 82 
Table 14-11 
Follow-up evaluations for selected toxicties ......................................... 83 
Table 14-12 
Criteria for interruption and re-initiation of pasireotide LAR .............. 84 
Table 14-13 
Dose modification for AEs, excluding LFT increase, QT 
prolongation and hyperglycemia ........................................................... 91 
Table 14-14 
Dose and treatment schedule ................................................................. 92 


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Table 14-15 
Pasireotide and cabergoline dose modification steps for pasireotide 
un-treated patients ................................................................................. 93 
Table 14-16 
Pasireotide and cabergoline dose modification steps for patients 
currently treated with maximal tolerated doses of pasireotide 
monotherapy .......................................................................................... 94 
 


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List of abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
b.i.d. 
twice a day 
bpm 
Beats per minute 
CD 
Cushing’s disease 
CMO&PS 
Chief Medical Office & Patient Safety 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
FPFV 
First Patient First Visit 
FPG 
Fasting plasma glucose 
GDD 
Global Drug Development 
GH 
Growth Hormone  
GIP 
Glucose-dependent insulinotropic peptide 
GLP-1 
Glucagon-like peptide-1 
HBsAG 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
IB 
Investigators Brochure 
ICH 
International Conference on Harmonization 
IGF-1 
Insulin-like growth factor 1 
i.m. 
Intramuscular 
IRB 
Institutional Review Board 
IEC 
Independent Ethics Committee 
i.v. 
Intravenous(ly) 
LAR 
Long Acting Release 
MCC 
Merkel cell carcinoma 
MTD 
Maximum tolerated dose 
mUFC 
Mean urinary free cortisol 
NETs 
Neuroendocrine tumors 
OGTT 
Oral Glucose Tolerance Test 
PK 
Pharmacokinetic 
pNET 
Pancreatic neuroendocrine tumors 
q.d. 
Once per day 
QTcB 
QT corrected (Bazett) 
QTcF 
QT corrected (Fridericia) 
QTcI 
QT corrected (individualized) 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
s.c. 
Subcutaneous 
SSA 
Somatostatin analog 
sst123 
Somatostatin receptor subtypes 
sst5 
Somatostatin receptor subtypes 


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TdP 
Torsades de pointes 
ULN 
Upper limit of normal 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Patient Number 
A unique identifying number assigned to each patient who enrolls in the 
study 
Parent study 
The original Novartis-sponsored study where the patient was first 
enrolled and received pasireotide treatment. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed for 
progression and/or survival 
Roll-over study 
A roll-over study allows patients from multiple parent studies spanning 
multiple indications to continue to be treated within one study after the 
completion of the parent study/ies 
Study treatment 
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-
investigational treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature patient 
withdrawal 


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Amendment 5 (02-Nov-2021) 
Amendment rationale 
It is anticipated that pasireotide will not be commercially available and reimbursed in all 
participating countries at study end. In order to ensure that patients deriving clinical benefit 
from pasireotide will continue receiving treatment with this drug outside the frame of the 
clinical trial, they will be allowed to obtain pasireotide through country-specific programmes 
as soon as they become available – even prior to the end of the study. This will ensure treatment 
continuity. 
The following protocol amendment is applicable to Brazil, France, Germany, India, Italy, 
Malaysia, Mexico, Peru and Thailand. 
 
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. 
 
1. Section 4.3: Definition of end of the study:  the language was updated to state that even 
prior to the end of this study, patients will be allowed to receive pasireotide through 
country-specific programmes outside the frame of this clinical trial. 
2. Section 7.1.3: Treatment period: updated language to clarify that even prior to the end 
of this study, patients will be allowed to receive pasireotide through country-specific 
programmes outside the frame of this clinical trial. 
3. Section 7.1.5.1: Criteria for premature withdrawal: added language confirming that– 
even prior to the end of the study- patients will be allowed to receive pasireotide outside 
the frame of this clinical trial through country-specific programmes. 
IRBs/IECs  
A copy of this amended protocol 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 4 (06 May-2020) 
Amendment rationale  
Novartis has signed an agreement to transfer the worldwide rights of Signifor® and  Signifor® 
LAR to Recordati. Within the framework of such agreement, the two Companies agreed a 
sponsorship transfer of this study with pasireotide from Novartis to Recordati. 
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.  
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 or of IQVIA on behalf of Recordati, as 
applicable. 
IRBs/IECs  
A copy of this amended protocol 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 3 (08-Mar-2019) 
Amendment rationale  
The main purpose of this amendment is to: 
• Update the trial selection criteria to allow patients from Novartis-sponsored trials, being 
treated with pasireotide alone or in combination with another treatment for Cushing’s 
Disease and Acromegaly, to participate in this study.   Several of the participating parent 
protocols permit for pasireotide to be administered in combination with another medical 
therapy.  Revising the selection criteria would ensure those patients receiving clinical 
benefit would have continued access to the combination treatment.  Combination treatment 
through this rollover would only be available for patients with Cushing’s Disease or 
Acromegaly.  
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. 
1. Protocol summary: Removed the exclusion criteria related to patients participating in 
combination treatment studies. 
2. Protocol summary: In the Investigational and reference therapy section – Combination 
therapy as per the parent protocol wording added. 
3. Section 1.2.1.2.1: Updated wording to include results from SOM230G2304 and 
SOM230C2402 trials that are now completed. 
4. Section 2.3 Rationale for dose and regimen selection: Language added to clarify that any 
medication given in combination with pasireotide must follow the dose ranges and regimen 
of the parent protocol.    
5. Section 2.4 Rationale for choice of combination drugs: language added to clarify that 
patients have been receiving combination treatment in the parent studies or an additional 
medication for acromegaly or Cushing’s disease have been added based on the 
investigator’s opinion.  Rationale language for cabergoline treatment was also added. 
6. Section 4.1: Deleted repetitive language 
7. Figure 4-1: Updated to add combination treatment language 
8. Section 5.3 Exclusion Criteria: Removed exclusion criteria number 2 related to patients 
participating in combination treatment.   
9. Section 6.1.2: Added section regarding dosing regimen for patients on combination 
treatment with cabergoline. 
10. Section 6.1.3: Added section regarding dosing guidelines for combination treatment. 
11. Section 6.1.7: Repetitive language deleted 
12. Section 6.2.1: Starting dose rationale: Language added to clarify that the starting dose of 
any medication given in combination with pasireotide must follow the last dose given in the 
parent protocol.    
13. Section 6.4.2: removed section as not applicable as this trial does not have randomization. 
14. Section 6.5.1: Updated to add language for combination treatment 


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15. Table 6-2: Dose strengths added for both pasireotide LAR and s.c. 
16. Table 6-3: Updated to add wording on combination treatment storage 
17. Section 7.1.3 Treatment Period: Corrected the timing of the visits to quarterly visits every 
12 weeks +/- 2 weeks. 
18. Section 8.1.1 Definitions and Reporting: Updated the language to define the safety reporting 
period as 30 days for s.c. formulation of pasireotide and 84 days for LAR formulation.   
19. Appendix 12 Dose modification information for patients with Cushing’s receiving 
pasireotide s.c in combination with cabergoline (SOM230B2411): The appendix added to 
provide guidance of permitted doses and dose modifications.   
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 2 (29-Sep-2017) 
Amendment rationale  
The main purpose of this amendment is to: 
• Include language on the trial end date to meet the regulatory guidelines of the Medicine and 
Health Research Authority (MHRA), in the United Kingdom (UK).   
• This trial was deemed to be a voluntary PASS (post-authorization safety study) by Novartis 
Regulatory Affairs in 2016.  An interim analysis will be performed in 2017, and every 2 
years thereafter, until the final database lock.   
• This amendment will also help to clarify the visit schedules for patients taking pasireotide 
s.c. and those taking pasireotide LAR, and further highlights the required timelines for using 
highly effective methods of contraception after last dose of study medication.   
This roll-over study has been opened since 10-Jun-2013 and has enrolled a total of 301 patients 
with 259 patients ongoing. 
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. 
• Protocol Summary, Study Design Section: A trial end date was added for the UK. 
• Section 2.1 Study Rationale: Updated the language to clarify that patients will continue to 
receive study drug as long as the patient continues to receive clinical benefit as judged by 
the Investigator or one of the discontinuation criteria is met. 
• Section 4.1 Description of study design: Clarified that all patients can begin treatment with 
study drug as soon as they enter the trial and that all patients are expected to report to the 
study site for the first visit to begin study participation. 
• Section 4.1 Description of study design: Clarified the study visit schedule for patients taking 
pasireotide LAR versus those taking pasireotide s.c. and the permissible visit windows for 
those visits. 
• Section 4.1 Description of study design: Added language on the trial end date and updated 
the language that patients will continue to receive pasireotide as long as the patient continues 
to receive clinical benefit as judged by the Investigator or one of the discontinuation criteria 
is met. 
• Section 4.2 Timing of interim analysis and design adaptations: Added language that an 
interim analysis will be performed in 2017 and every 2 years thereafter until the final 
database lock. 
• Section 4.3 Definition of end of the study: Updated the language to provide a specific trial 
end date. 
• Section 5.3 Exclusion Criteria: Corrected the timing of the use of highly effective methods 
of contraception. Contraception must be used for 30 days after the final dose of pasireotide 
s.c. and 84 days after the final dose of pasireotide LAR. 
• Section 6.1.5 Treatment duration: A trial end date was added. 


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• Section 7.1.3 Treatment period: Clarified the study visit schedule for patients taking 
pasireotide LAR versus those taking pasireotide s.c. and the permissible visit windows for 
those visits.  The requirement for 5 study visits in the first year was removed as there are no 
safety concerns with the trial and there was no added value in the patients coming to clinic 
for an additional visit in the first year.         
• Section 7.1.3 Treatment duration: A trial end date was added. 
• Section 7.1.4 Pregnancy and assessment of fertility: Corrected the timing of the use of 
highly effective methods of contraception. Contraception must be used for 30 days after the 
final dose of pasireotide s.c. and 84 days after the final dose of pasireotide long-acting. 
• Section 7.1.5 Discontinuation of study treatment: Added language to provide instruction to 
investigators on patient discontinuation and corrected the reporting period for safety events 
after the patients last dose of medication is 30 days for patients on pasiroetide s.c and 84 
days for patients on pasireotide long-acting.    
• Section 7.1.5.1 Criteria for premature withdrawal: Added language confirming that when 
current treatment becomes commercially available and reimbursed in the indication, the 
patient will have to be withdrawn from the study and will have completed the treatment 
duration from the trial.  
• Section 7.1.5.1 Criteria for premature patient withdrawal: Clarified that routine examination 
is standard of care.   
• Section 7.1.7 Follow up for safety evaluations: The language was updated to state that 
patient must have safety evaluations 84 days after the last dose of study treatment for the 
pasireotide long-acting and 1 month (30 days) after s.c. dose. 
• Section 7.2.2 Safety and Tolerability Assessments: Language added to clarify that 
investigators can perform safety assessments using their local laboratories as needed per 
investigator judgement.   
• Section 8.2.2 Reporting: The section was updated to replace Drug Safety & Epidemiology 
(DS&E) with Chief Medical Office & Patient Safety (CMO&PS).  The safety reporting 
language was updated to state that patient must have safety evaluations 84 days after the 
last dose of study treatment for the LAR and 1 month (30 days) after s.c. dose. 
• Section 8.4 Pregnancies: The section was updated to replace Drug Safety & Epidemiology 
(DS&E) with Chief Medical Office & Patient Safety (CMO&PS) 
• Section 10.5.3.1 Analysis set and grouping for analyses: Clarify the duration of the safety 
follow-up period between s.c. formulation and LAR formulation. 
• Section 10.6 Interim Analysis: Added language that an interim analysis will be performed 
in 2017 and every 2 years thereafter until the final database lock.   
• Appendix 1 Medication known to be associated with QT interval prolongation: Removed 
the list of drugs with possible association with QT prolongation and added the website 
where the current list of medications can be located.   
• Appendix 2 Hepatic safety management: Updated the title to indicate this is a recommended 
guidance for hepatic management and clarified that routine examination is standard of care.   
• Appendix 3 Recommended follow-up in case of QT-related findings during routine ECG: 
Clarified this is recommended guidance.  


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• Figure 14-2: Updated title to indicate this is recommended guidance for ECG follow-up. 
• Appendix 4 Fasting blood glucose management: Clarified this is recommended guidance. 
• Figure 14-3: Updated title to indicate this is a recommended guidance for fasting self-
monitoring blood glucose management. 
• Appendix 5: Updated the title to reflect this is the dose modification information for patients 
from the parent protocol CSOM230C2110, CSOM230C2305, CSOM230C2402 and 
CSOM230C2413.   
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 


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Amendment 01 
Amendment rationale 
With this amendment, in order to clarify the main objective of this study, the previous secondary 
objective “To collect long-term data on serious adverse events and adverse events of special 
interest” has been elevated to primary objective. In addition, the protocol has been amended to 
clarify the safety monitoring guidance and to include the collection of all AEs (including non-
serious AEs) and an investigator attestation of continued clinical benefit. 
The study continues to allow continued access to pasireotide for patients treated with the 
compound in previous Novartis sponsored studies for as long as they benefit from it. This roll-
over study has been opened since 10-Jun-2013 currently with a total of 95 patients enrolled and 
80 patients ongoing. 
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 following changes have been implemented: 
The Protocol summary is also updated correspondingly 
Section 2.1: Update to the study rationale to include the primary endpoint to evaluate long term 
safety date. 
Section 2.6: The inclusion of the Risk-Benefit section 
Table 3-1: Updated with revised study objectives and endpoints. The primary objective is to 
evaluate long term safety data. The secondary objective is to evaluate clinical benefit as 
assessed by the investigator. 
Section 4.1: Updated to clarify that all adverse events and serious adverse events will be 
collected continuously throughout the study and to specify that at every visit, the investigator 
is required to confirm that the patient continues to have clinical benefit and may continue 
receiving study treatment. 
Section 6.1.5: Updated to specify that at every visit, the investigator is required to confirm that 
the patient continues to have clinical benefit and may continue receiving study treatment 
Section 6.2: Revised to refer to Appendices regarding dose modification guidelines 
Section 6.5: Clarification of drug labeling process 
Table 7-1: Updated to include collection of relevant medical history, continuous collection of 
all AEs and SAEs, investigator confirmation of clinical benefit from study treatment at every 
visit, the collection of all adverse events and clarification of the visits for LAR and S.C. 
formulation for the duration of the trial. Also to include the at home monthly pregnancy tests 
monitoring 
Section 7.1.3: Updated to specify that the investigator is required to confirm that the patient 
continues to have clinical benefit at every visit and may continue receiving study treatment. 


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Section 7.1.4: Inclusion of Pregnancy and Assessment of Fertility. Also revised language for 
highly effective contraception. 
Section 7.1.5.1: Minor updates to the criteria for premature patient withdrawal from the trial 
Section 7.2.2: Update to clarify the safety monitoring guidelines 
Section 8: Updated with new AE/SAE reporting process. 
Section 9: Clarification to personal identifiable patient information collection 
Section 10: Updated statistical analysis section based on revised study objectives. 
Section 14: Update to Appendences to reflect revised standard global language for the 
recommended safety assessments and dose modification 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require Health Authority and IRB/IEC 
approval prior to implementation. 


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Protocol summary: 
Protocol number 
CSOM230B2412 
Title 
An open label, multi-center pasireotide roll-over protocol for patients who have 
completed a previous Novartis-sponsored pasireotide study and are judged by the 
investigator to benefit from continued pasireotide treatment 
Brief title 
Study to allow access to pasireotide for patients benefiting from pasireotide 
treatment in a Novartis-sponsored study. 
Sponsor and Clinical Phase 
Recordati IV 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to evaluate long term safety data and allow continued 
use of pasireotide in patients who are on pasireotide treatment in a Novartis-
sponsored study and are benefiting from the treatment as judged by the investigator. 
Primary Objective(s) 
To evaluate long term safety data, SAEs and AEs 
Secondary Objective 
To evaluate clinical benefit as assessed by the investigator 
Study design 
This is a multi-center, open label, phase IV study to provide continued supply of 
pasireotide to patients being treated in a current Novartis-sponsored study and who 
are benefiting from treatment with pasireotide. Eligible patients are to be consented 
and can then continue treatment with pasireotide in this protocol. All patients at their 
scheduled visits will have drug dispensing information and reported adverse events 
and serious adverse events collected. 
A patient will reach the end of study when pasireotide treatment is permanently 
discontinued and the end of treatment visit has been performed. All patients must be 
followed up for safety evaluations for 84 days following the last dose of pasireotide 
long acting release (LAR) treatment and for 1 month 30 days following the last dose 
of pasireotide subcutaneous (s.c.) treatment. The study is expected to remain open 
for approximately 10 years 
from First Patient First Visit (FPFV) (or until 10June2023 in the UK).  Patients will 
continue to be treated in this study until they are no longer benefiting from their 
pasireotide treatment as judged by the Investigator or until one of the protocol 
discontinuation criteria is met.   
Population 
Patients who are currently enrolled in a Novartis-sponsored study, that has fulfilled 
all required assessments and who are benefiting from treatment with pasireotide. 
Parent studies eligible to participate in the roll-over study will be decided by 
Recordati 
Inclusion criteria 
• 
Patient is currently  enrolled in a Novartis- sponsored study receiving pasireotide 
and has fulfilled all their requirements in the parent study. 
Patient is currently benefiting from the treatment with pasireotide, as determined by 
the investigator. 
• 
Patient has demonstrated compliance, as assessed by the investigator, with the 
parent study requirements. 
Exclusion criteria 
Patient has been permanently discontinued from pasireotide study treatment in 
the parent study due to unacceptable toxicity, non-compliance to study 
procedures, withdrawal of consent or any other reason. 
Investigational and 
reference therapy 
Pasireotide s.c: should follow parent study doses 
Pasireotide LAR: should follow parent study doses 
Combination therapy as per parent protocol 
Efficacy assessments 
Not applicable 
Safety assessments 
All adverse events and serious adverse events will be collected continuously 
throughout the study. Safety monitoring should follow the guidance in the locally 
approved prescribing information (for locally approved indications) or the 
requirements described in the current Investigator Brochure (for indications that are 
not yet approved locally). Additional guidance is provided in the appendices. 


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Other assessments 
Not applicable 
Data analysis 
The assessment of safety will be based mainly on the frequency and severity of AEs 
and SAEs. Proportion of patients with clinical benefit as assessed by the investigator 
will be summarized at scheduled visits. Safety information on patients from this 
protocol will link to the patient identifiers from the parent study. 
Key words 
SOM230, pasireotide, roll-over study, pasireotide LAR 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1 
Overview of Cushing’s disease (CD) 
Cushing’s disease (CD) is a rare but debilitating disease. Patients have excessive 
adrenocorticotropic hormone (ACTH) secretion from a benign pituitary adenoma, which 
stimulates the adrenal glands to produce excess cortisol. The incidence of Cushing’s disease 
ranges from 1-3 patients per million per year. Cushing’s disease is associated with severe 
morbidity and premature mortality and most commonly affects adults aged 20-50 years of age, 
primarily females. 
The most common pathological finding in these patients is bilateral hyperplasia of the adrenal 
cortex and cortisol hypersecretion due to excessive ACTH secretion. The primary clinical signs 
and symptoms of Cushing’s disease are due to hypercortisolism, such as change in body habitus, 
hirsutism, wasting of musculature, hypertension, weight gain, and decreased insulin sensitivity 
with disorders in glucose metabolism, Because of these alterations patients with Cushing’s 
disease have increased morbidity and mortality. 
While surgical removal of the adenoma is first line therapy for CD, the success rate of surgery 
is between 65-90% for microadenomas (tumors < 1 cm) with recurrence rates between 10 to 
20% after 10 years. The surgical cure rate for macroadenomas (>1 cm) is less than 65% and 
recurrence rates as high as 45% (Biller et al 2008). When surgery and/or irradiation fail, or for 
those patients for whom such therapies are not an option, the remaining alternatives are 
pharmacological treatment or bilateral adrenalectomy. No drugs are currently approved for the 
treatment of Cushing’s disease and the ones which physicians have available for use are fraught 
with suboptimal results and significant side effects (Miller 1993, Nieman 2002, Biller et al 
2008) and the majority are limited to inhibit steroidogenesis at the adrenals, not targeting the 
pituitary adenoma. Bilateral adrenalectomy is a definite cure of Cushing’s disease but results in 
irreversible primary adrenal insufficiency and patients need lifelong replacement therapy with 
glucocorticoids and mineralocotricoids and have a higher likelihood to develop Nelson’s 
syndrome (Sonino 1996, Assie 2004, Assie 2007). There is an unmet medical need for the 
treatment of CD as medical treatment options are limited. 
A confirmatory Phase 3 study [SOM230B2305] has been completed to support the filing of 
pasireotide s.c. for the treatment of patients with Cushing’s disease for whom medical therapy 
is appropriate. The 900 µg b.i.d group met the pre-specified criteria for the primary efficacy 
endpoint. Robust reductions in mUFC occurred relatively quickly, within the first month, and 
were sustained over the course of Months 6 and 12. Both doses were efficacious in lowering 
mUFC, with the Month 6 median percent change from baseline being -47.9% for both doses. 
The Month 12 median percent changes from baseline were -62.4% and -67.6% for 900 and 600 
µg b.i.d., respectively. Pasireotide s.c. received approval in EU in April 2012 for the treatment 
of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery 
has failed. 


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1.1.2 
Overview of acromegaly 
Acromegaly is a rare, seriously debilitating condition characterized by chronic hypersecretion 
of (GH) growth hormone, which, in over 95% of patients, is caused by a GH-secreting pituitary 
adenoma. It is estimated that about 3 out of every million people develop acromegaly each year 
and that 40 to 60 out of every million people suffer from the disease at any one time (Melmed 
et al 1998). 
The clinical manifestations of acromegaly are due to the peripheral actions of the GH excess 
and elevated insulin-like growth factor 1 (IGF-1) concentrations and/or local tumor mass effect. 
The symptoms and signs of acromegaly can be divided into 3 categories: physical changes due 
to excessive amounts of GH and IGF-1, metabolic effects of excessive amounts of GH, and 
local effects of the pituitary tumor (Becker et al 2000). 
The therapeutic goals in acromegaly are to reduce mortality to the expected age and sex adjusted 
rates by using treatments that remove the tumor mass or control its growth and restore GH 
secretion and action to normal. The biochemical goals of therapy are to reduce the circulating 
IGF-1 levels to normal for age and sex and to reduce serum GH concentrations to < 2.5µg/L 
(mean GH concentration of a 5-point profile within a 2-hour time period) or to less than 1µg/L 
after an oral glucose load (Giustina et al 2000). 
A multicenter, randomized, double-blinded, phase III, study [SOM230C2305] completed its 
core phase and the first year of the extension phase, and patients receiving pasireotide LAR are 
still being followed. This pivotal study compared the safety and efficacy of 40 mg of pasireotide 
LAR with 20 mg of octreotide LAR in patients with active acromegaly at 12 months of 
treatment. The primary objective was to compare the proportion of patients with a reduction of 
mean GH level to < 2.5µg/L and normalization of IGF-1 to within normal limits (age and sex 
related) between the two treatment groups at 12 months. The study met its primary endpoint, 
showing superiority of pasireotide versus octreotide. 
1.1.3 
Overview of neuroendocrine tumors (NETs) 
Neuroendocrine tumors (NETs) are a genetically diverse group of rare malignant tumors that 
arise from neuroendocrine cells throughout the body. The WHO classification of NETs has 
recently gained acceptance in the literature due to better prognostic relevance. In this anatomic 
nomenclature, neuroendocrine tumors are distinguished on the basis of primary tumor 
localization (e.g. gastrointestinal, lung, or pancreas), rather than the previous embryonic 
categories (Kloppel et al 2004). 
The incidence of NETs is approximately 2 per 100,000 per year. However, NETs has been 
reported with increasing frequency over the years from 1973 to 2004 (Yao et al 2008). 
NETs can be clinically symptomatic (functional) due to hormone or other product 
hypersecretion or clinically silent (nonfunctional). Approximately 50-60% of NETs are 
nonfunctional, i.e. do not cause clinical symptoms due to hypersecretion (Modlin et al 2008). 
Most patients with NETs present with metastatic disease at the time of diagnosis, with regional 
or distant metastasis seen in 50% of patients (Yao et al 2008). Up to 75% of patients that present 
with NETs of the mid- or hindgut region, and approximately 60% of patients with pancreatic 
NETs (pNET) have liver metastases (Falconi et al 2006). 


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Currently, surgical resection represents the traditional first-line therapy of NETs (Plöckinger 
and Wiedenmann 2007). The prognosis following complete surgical resection is generally 
favorable (Schurr et al 2007). However, curative surgery is often not possible because the 
majority of patients present with metastatic disease. 
In patients with inoperable NET, the treatment goal is to control tumor growth, to control 
symptoms if the tumor is functional, and to prolong survival time. Biotherapy with currently 
approved somatostatin analogs (SSAs) remains the mainstay of symptomatic therapy for NET. 
The PROMID study has shown that octreotide LAR was able to increase time to progression 
(TTP) when compared to placebo from 6.0 months to 14.3 months in patients with advanced 
(unresectable or metastatic) NET of the midgut or unknown primary tumor location (Rinke et 
al 2009). Other available treatment options for patients with NETs are: Interferon-alpha (Öberg 
2000, Arnold 2005); cytotoxic chemotherapy as single-agent or in combination (5FU, 
streptozotocine, doxorubicin, cisplatin, etc.) (Toumpanakis 2007); temozolomide (Ekeblad 
2007). For patients with PNET, two new therapies were approved by the FDA in May 2011: 
everolimus an mTOR inhibitor and sunitinib which is a multikinase inhibitor. Pasireotide s.c. 
and LAR were evaluated in patients with NETs in two phase 1 [SOM230D2201] and 
[SOM230C2110] (patients with carcinoid syndrome), one phase 2 [SOM230D2203] 
(gastrinomas, glucagonomas, insulinomas, VIPomas) and one phase 3 [SOM230C2303] 
(metastatic functioning carcinoid tumors) studies. The optimal anti-proliferative dose for 
pasireotide LAR monotherapy in NET is currently being explored in the MTD study 
[SOM230D2101]. 
1.1.4 
Overview of other pituitary tumors and of Ectopic ACTH secreting 
(EAS) tumors 
Pituitary adenomas are benign neoplasms arising from one of the five anterior pituitary cell 
types. The clinical and hormonal syndrome associated with pituitary adenomas depend on the 
cell type from which they are derived. Tumors arising from lactotrope (PRL), somatotrope 
(GH), corticotrope (ACTH), thyrotrope (TSH), or gonadotrope (LH, FSH) cells hypersecrete 
their respective hormones. About one-third of all pituitary adenomas are clinically non-
functioning (nonfunctional pituitary adenomas, NFPA) and produce no distinct clinical 
hypersecretory syndrome. Nelson’s syndrome is associated with local corticotroph (ACTH) 
pituitary tumor re-growth, extension or invasion, following a therapeutic bilateral 
adrenalectomy to control hypercortisolism, as a result of the removal of the negative feedback 
or cortisol on hypothalamic corticotropin-releasing hormone. Symptoms result from local tumor 
expansion, and from effects on other pituitary hormones and on ACTH related symptoms. 
Hypersectretion of ACTH can also occur from non-pituitary tumors and is designated as Ectopic 
ACTH secreting (EAS) tumors. The majority of these patients have non-resectable, advanced 
or metastatic tumors. Symptoms are related to hypersecretion and tumor burden or mass. 
Prognosis is usually very poor. 
Medical therapy is the main measure to alleviate the symptoms of the above diseases by 
controlling hyper-secretion of respective hormones. Somatostatin analogues are currently used 
as a medical therapy option in some of these patients. A phase 2 proof of concept study 
SOM230D2203 is ongoing evaluating the effect of pasireotide LAR in these tumors. 


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1.1.5 
Overview of patients with dumping syndrome 
“Dumping syndrome” is a debilitating complication of esophageal and gastric surgeries (such 
as bariatric and gastric cancer surgeries) estimated to occur in 5-50% of patients (Arts et al 
2009). In summary, dumping syndrome consists of (1) a too rapid gastric emptying, (2) an 
inappropriate release of GI hormones (as a reaction to the rapid delivery of carbohydrates to the 
duodenum) and (3) a hyperinsulinemic response to a too rapid absorption of glucose. (Tack et 
al 2009). The diagnosis is confirmed by an adapted 3-hour Oral Glucose Tolerance Test 
(OGTT) with 75g of glucose evaluating the presence of early changes (30 min) in hematocrit 
and pulse rate and late (120, 180 min) hypoglycemia (Tack et al 2009). 
Currently there are no approved medications to treat dumping syndrome. Dietary measures and 
addition of food additives such as guar gum and pectin are implemented to prevent late dumping 
symptoms (Arts et al 2009), (Andersen et al 1989), (Hariu and Lami 1983). Medications that 
delay carbohydrate absorption such as alpha-glucosidase inhibitors (e.g. acarbose) have been 
used in clinical practice. However, acarbose improves only the symptoms of late dumping and 
often results in bloating, flatulence or diarrhea that usually hampers treatment compliance 
(Lyons et al 1985). 
In addition, a relative large body of literature (Arts et al 2009), (Tack et al 2009) (Hopman et al 
1988), (Primrose and Johnston 1989), (Tulassay et al 1989) (Geer et al 1990), (Richards et al 
1990), (Gray et al 1991) and (Hasler et al 1996) suggests that octreotide (both s.c. and LAR 
formulations) may be effective. 
Clinical studies in healthy volunteers [CSOM230B2216] have demonstrated that pasireotide 
suppresses insulin secretion, with no changes in hepatic or peripheral insulin sensitivity. In 
addition, pasireotide significantly decreases incretin response (glugagon-like peptide-1) [GLP-
1] and (glucose-dependent insulinotropic peptide) [GIP] right after glucose ingestion during the 
OGTT until 90- 120 minutes CSOM230B2216. Since it has been shown that the somatostatin 
inhibition of GLP-1 secretion is mediated by Somatostatin-28 mainly through activation of sst5 
and with a lesser effect by sst2 (Chisholm and Greenberg 2002), this suppression is expected to 
be stronger with pasireotide than with octreotide. A phase 2 study [CSOM230X2203] is 
ongoing to evaluate the effect of pasireotide s.c. and LAR in patients with dumping syndrome. 
1.1.6 
Overview of other indications 
Pasireotide s.c. and LAR are being studied in several other indications e.g: metastatic prostate 
cancer [SOM230DE04], metastatic melanoma negative for bRAF and nRAS mutations 
[SOM230X2404], polycystic liver/renal disease and in post-operative pancreatic fistula. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of pasireotide s.c. and LAR 
Pasireotide is a cyclohexapeptide somatostatin analogue that exhibits a unique binding profile, 
binding with high affinity to four of the five known human somatostatin receptors subtypes. 
Somatostatin analogs activate these receptors with different potencies (Schmid and Schoeffter 
2004) and this activation results in a reduced cellular activity and inhibition of hormone 


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secretion. Somatostatin receptors are strongly expressed in many tumors, especially in 
neuroendocrine tumors (Oberg et al 2004), and also in pituitary tumors where hormones are 
excessively secreted, e.g. in acromegaly (Freda 2002) and Cushing’s disease (Van der Hoek et 
al 2005). Compared to Sandostatin® (octreotide acetate), pasireotide exhibits a binding affinity 
which is 30-40 times higher for human sst1 and sst5, 5 times higher for human sst3, and a 
comparable affinity (a 2.5 fold lower) for sst2 receptors. 
Pasireotide s.c. is a short acting formulation administered subcutaneously two or three times a 
day. This formulation has been tested in healthy volunteers and in patients with acromegaly, 
Cushing’s disease and metastatic carcinoid tumors. 
Pasireotide LAR is a long acting formulation administered intramuscularly every 28 days. It 
has been studied in healthy volunteers and in patients with acromegaly, Cushing’s disease, and 
metastatic carcinoid tumors. 
1.2.1.1 
Non-clinical experience 
Pre-clinical pharmacology data on binding affinity and functional activity in vitro and efficacy 
on hormone secretion in vivo have been obtained with the s.c. formulation in rats, dogs, mice 
and monkeys. 
Extensive safety studies have been performed in mice, rats, rabbits and monkeys to support the 
administration of pasireotide. These studies include acute, subchronic and chronic toxicity 
studies, carcinogenicity studies of transgenic mice, local tolerance studies, reproduction studies, 
as well as in vitro and in vivo genotoxicity studies. Most of these studies were performed using 
the s.c. route of administration and the vast majority of the findings were considered related to 
the pharmacology of pasireotide. 
Pre-clinical long-term systemic safety profiles have been well-established for pasireotide s.c. 
The pre-clinical data from pharmacology, safety, and DMPK studies provided the basis for 
clinical development of pasireotide s.c. 
A detailed summary of available pre-clinical data is provided in the latest version of the 
pasireotide [Investigator’s Brochure]. 
1.2.1.2 
Clinical experience 
1.2.1.2.1 Clinical efficacy of pasireotide s.c. and LAR 
Pasireotide s.c. 
The pasireotide s.c. formulation has shown efficacy in a Phase III Study [CSOM230B2305] in 
162 patients with moderate to severe Cushing’s disease (CD). In addition, pasireotide s.c. was 
also evaluated in three phase II studies, two in patients with CD [CSOM230B2208], 
[CSOM230B2208E], 
two 
in 
patients 
with 
acromegaly 
[CSOM230B2201], 
[CSOM230B2201E] and one with patients metastatic carcinoid tumors [CSOM230B2202]. 
A detailed summary of available clinical efficacy data is provided in the [Investigator 
Brochure]. 


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Pasireotide LAR 
Pasireotide LAR formulation has shown efficacy in a randomized placebo-controlled Phase 3 
study [SOM230C2305] designed to compare pasireotide LAR to octreotide LAR in patients 
with acromegaly. A phase III study (CSOM230G2304) has demonstrated that Pasireotide LAR 
normalized mUFC concentration in about 40% of patients with Cushing’s disease at month 7 
and had a similar safety profile to that of twice-daily subcutaneous pasireotide.  Results of 
another clinical study have indicated that pasireotide is a safe and effective treatment in patients 
with acromegaly. Efficacy of pasireotide in patients not controlled with other somatostatin 
analogues was already demonstrated in the PAOLA study (Study CSOM230C2402).  This trial 
was a double blinded controlled study, in which patients randomized to the active control 
(octreotide LAR 30mg or lanreotide ATG 120mg) did not achieve biochemical control with 
further treatment, whereas patients randomly allocated to pasireotide LAR 40 mg or 60 mg were 
able to achieve biochemical control for the very first time [at 24 weeks, 10 (15%) patients in 
the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group]. Therefore, 
it is thought that an earlier treatment change to pasireotide LAR might be beneficial for these 
patients. 
1.2.1.2.2 Clinical safety of pasireotide s.c. and LAR 
Pasireotide s.c. 
Single and multiple doses of pasireotide s.c. have generally been well tolerated by healthy 
volunteers. The most commonly reported adverse events (AEs) were GI related such as mild 
diarrhea and nausea, requiring no treatment or study discontinuation. The frequency of these 
AEs appeared to decrease overtime in multiple-dose studies. 
Hyperglycemia was the most important side effect and was observed across all indications. 
Blood glucose tended to rise with increasing dose, and appeared to be more notable in patients 
who had a history of hyperglycemia or diabetes mellitus prior to receiving pasireotide. 
However, hyperglycemia in these patients was responsive to appropriate diabetic management 
such as adjustments in oral antidiabetic treatment, or in some cases the addition of insulin. 
Pasireotide’s effect on QT prolongation was demonstrated by two thorough QT (TQT) studies 
[SOM230B2113] and [SOM230B2125]. The second TQT study SOM230B2125 was designed 
to evaluate the effect of pasireotide on cardiac intervals using an individualized correction 
method to account for the known bradycardic effect of pasireotide. It was conducted as a follow-
up to Study SOM230B2113, which showed that pasireotide at the Maximum Tolerated Dose 
(MTD) of 1950 μg b.i.d dose induced prolongation of QTcF, whereas no relevant effect on 
QTcB was observed. The second TQT study confirmed an effect of pasireotide on QTcI of 
pasireotide at both the 600 μg bid and the 1950 μg bid dose. The maximal placebo-subtracted 
change from baseline in QTcI was seen at 2 hours post dose, at which time the mean (90% CI) 
difference was 13.19 ms (11.38; 15.01) for pasireotide 600 μg bid, and 16.12 ms (14.30; 17.95) 
for pasireotide 1950 μg b.i.d. Both pasireotide doses decreased heart rate, with a maximal 
difference to placebo observed at 1 hour for pasireotide 600 μg b.i.d (-10.39 bpm), and at 0.5 
hours for pasireotide 1950 μg bid (-14.91 bpm). There were no subjects with QTcI or QTcF 
values that were increased more than 60 ms from baseline, or that exceeded 500 ms on Day 5, 
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Three healthy volunteers who received pasireotide s.c. had biochemical changes that met Hy’s 
Law criteria (i.e. ALT > 3 x ULN with concurrent total bilirubin >2 x ULN, without increases 
in alkaline phosphatase and no other cause(s) identified for the abnormal findings). All 3 cases 
were asymptomatic, presented within 7 days after initial pasireotide s.c. administration, and 
were reversible after discontinuation of pasireotide. None of the cases were reported as an 
adverse event and the subjects completed the respective studies per protocol. 
One patient with Cushing’s disease fulfilled biochemical criteria for Hy’s Law nine days after 
receiving pasireotide 600 µg b.i.d. Study medication was discontinued due to the event and 
fourteen days after the discontinuation of pasireotide the patient's bilirubin decreased to 
1.6xULN) and ALT was still elevated at 5.8-fold. Liver chemistry tests were normal 45 days 
after the discontinuation of pasireotide. Follow-up information indicated that liver function tests 
were consistent with hepatitis. 
Pasireotide LAR 
Pasireotide LAR has been well tolerated by healthy volunteers and by patients. In healthy 
volunteers, pasireotide LAR has been well tolerated following single i.m. injection up to the 
highest tested dose of 60 mg LAR [CSOM230C2101]. The most common adverse events were 
gastrointestinal. Diarrhea was experienced by most of the subjects and was sometimes 
associated with flatulence and abdominal pain. The gastrointestinal events were mild or 
moderate in severity. Mild injection site pain was reported and typically resolved within a day. 
These events did not result in discontinuation from the study. 
Pasireotide LAR formulation has also been evaluated in a randomized phase 3 study in patients 
with acromegaly [SOM230C2305]. In the pasireotide group, the highest proportion of study 
drug-related AEs was reported for hyperglycemia-related AEs (58.4%), followed by gallbladder 
and biliary-related AEs (34.8%) diarrhea-related AEs (33.1%), bradycardia-related AEs 
(11.2%), pancreatitis-related AEs (11.2%) and nausea-related AEs (10. 1%). Overall the 
adverse events were similar in both arms with the exception of hyperglycemia, which was found 
to be more frequent in the pasireotide LAR arm. 
The safety and efficacy of Pasireotide LAR was confirmed in a phase 3, multicenter, 12-month 
trial in which 150 patients were randomized to receive either Pasireotide 10 mg or 30 mg 
[SOM230G2304]. The most common adverse events were hyperglycaemia (36 [49%] in the 10 
mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis 
(15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] 
and 16 [21%]). The observed safety profile of long-acting pasireotide was consistent with that 
of twice-daily pasireotide in patients with Cushing’s disease. 
Further details on pasireotide clinical safety can be found in the [Investigator Brochure]. 
1.2.1.2.3 Clinical pharmaokinetics of pasireotide 
Pasireotide s.c 
In healthy volunteers, results from the human ADME study [CSOM230B2112] with a single 
s.c. dose of 600 µg 14C-labelled pasireotide showed that pasireotide is mainly eliminated via 


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hepatic clearance, and renal clearance makes a small contribution to the elimination of 
pasireotide in man. No circulating metabolite was detected. 
In healthy volunteers, following a single s.c. injection, pasireotide pharmacokinetics 
demonstrated fast absorption, extensive distribution, low clearance, and long half-life 
[CSOM230B2101], [CSOM230B2106] and [CSOM230C2101]). The PK exposures (Cmax and 
AUCinf) were approximately dose-proportional for a wide dose range from 2.5 to 1500 µg. The 
drug was rapidly absorbed with a median Tmax of 0.25-0.5 hr post dose. 
Following q.d. dosing of s.c. injections in healthy volunteers, the steady state appeared to be 
achieved within 3 days [CSOM230B2102]. The CL/F, Tmax, and T1/2 at steady state 
CSOM230B2102 were similar to those estimated following single doses CSOM230B2101, 
CSOM230B2106, and CSOM230C2101), indicating that the PK of pasireotide s.c. is linear and 
time-independent. 
Pasireotide LAR 
Pasireotide LAR formulation has been evaluated in healthy volunteers, acromegaly patients, 
and carcinoid patients. Following a single intramuscular (i.m.) injection the LAR formulation 
demonstrated a controlled-release type of concentration versus time profile with an initial spike 
phase on day 1 (Cmax,p1), followed by a dip from Days 2 to 7, a second higher peak (Cmax,p2) 
at approximately day 21, and then a declining phase over the next 6 weeks until the last PK 
sampling point. PK exposure was dose-proportional for the tested doses 40-60 mg. The relative 
bioavailability of pasireotide LAR to pasireotide s.c. was complete. PK simulation based on 
healthy volunteer data demonstrated that steady state could be achieved after 3 monthly 
injections. 
Further details on pasireotide clinical pharmacokinetics can be found in the [Investigator 
Brochure]. 
2 
Rationale 
2.1 
Study rationale and purpose 
The purpose of this rollover study is to evaluate long term safety data and allow continued 
supply of pasireotide (s.c. and/or LAR) to patients who are currently receiving treatment in a 
Novartis-sponsored trial and have fulfilled all required assessments in the parent study, are 
benefiting from the treatment as judged by the investigator and are unable to access pasireotide 
treatment outside of a clinical study. Parent studies eligible to participate in the roll-over study 
will be decided by Recordati. Investigator initiated trials (IITs) will not be included. The patient 
must have fulfilled all required assessments in the parent study and the parent study must be in 
the process of being completed or terminated and reported. 
Patients will continue to receive pasireotide alone or in combination with another treatment for 
Cushing’s Disease and Acromegaly, as long as they continue to benefit as per Investigator 
assessment, or until one of the discontinuation criteria is met (please refer to Section 7.1.5). 


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2.2 
Rationale for the study design 
This is a multi-center, open label, phase IV, roll-over study of pasireotide in patients being 
treated in a current Novartis-sponsored study and who are benefiting from treatment with 
pasireotide alone or in combination with another treatment for Cushing’s Disease and 
Acromegaly. Combination therapy will only be permitted for patients with Cushing’s Disease 
or Acromegaly. 
The study will not include a screening phase as patients will transfer directly from parent studies 
and will commence treatment with pasireotide alone or in combination with another treatment 
for Cushing’s Disease and Acromegaly, as soon as they are consented and meet the inclusion 
criteria of the roll-over protocol. Since this study is intended to provide pasireotide supply and 
no formal analysis will be performed, there is no need for randomization, nor for bias reducing 
measures. 
2.3 
Rationale for dose and regimen selection 
The selected doses and regimen will be based on the dose ranges and regimen available in the 
parent study. The starting dose of pasireotide alone or in combination with another treatment 
for Cushing’s Disease and Acromegaly, should be the same dose as that which the patient was 
receiving in the parent study at roll over. After the starting dose, changes to pasireotide dose, 
and/or any medication given in combination with pasireotide for Cushing’s Disease or 
Acromegaly, will be based on the investigator’s judgment, but must follow the dose ranges 
provided in the parent study.  Please note combination treatment in this rollover trial is only 
allowable for Cushing’s Disease and Acromegaly parent protocols. 
Pasireotide will be provided as: 
1. Pasireotide s.c. – to be administered subcutaneously two or three times a day depending 
on the parent study dosing. 
2. Pasireotide LAR to be administered as intramuscular injection every 28 days. 
2.4 
Rationale for choice of combination drugs 
Patients suffering from Cushing’s disease or Acromegaly represent a challenge because of the 
reduced control of cortisol or GH/IGF-1 levels, respectively, by some medical therapies 
especially when given as montherapy. Due to this, whilst treatment is being administered, a 
close follow up is necessary to evaluate a response to the medication while assessing the 
addition of a second medication.  
In some patients, the administration of pasireotide alone did not normalize cortisol levels. Thus, 
a second medication with another mechanism of action is added to aid the restoration of cortisol 
or GH/IGF-1 levels to the normal range, respectively. 
For subjects on combination treatment with cabergoline + pasireotide only. The treatment of 
patients with CD requires a multimodality approach. Pasireotide has a favorable benefit/risk 
profile in Cushing’s Disease. However, a main reason for treatment discontinuation is due to 
insufficient therapeutic effect. Cabergoline is often used to decrease cortisol levels but it 
presents treatment escapes in many patients. Taking into consideration that biochemical 


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remission should be rapidly achieved to reverse morbidity and mortality, drugs can be combined 
to control cortisol production within an acceptable time frame. 
Advances in combination medical therapy have opened up new perspectives for acromegaly 
patients who are poorly controlled, or nonresponsive to presently available single drug 
therapies. SSAs have a role as the primary medical therapy in patients who have a low 
likelihood of surgical remission, or who are poor surgical candidates, as adjuvant therapy in 
these patients with persistently non suppressible GH or elevated IGF-I levels (or both) after 
pituitary surgery or during the interim period after RT. In patients who do not respond 
(biochemically) to medical monotherapy, combination therapy with SSAs and cabergoline or 
pegvisomant and cabergoline can be considered, on the basis of individual clinical 
considerations including tumour size and location.  
2.5 
Rationale for choice of comparators drugs 
Not applicable. 
2.6 
Risks and benefits 
Acromegaly is a serious, chronic, debilitating disease that is associated with high morbidity, 
shortened life expectancy, and a reduced quality of life. If untreated, acromegaly is associated 
with an average 10-year reduction in life expectancy, mainly due to cardiovascular, 
cerebrovascular, metabolic, and respiratory comorbidities. While successful pituitary surgery 
leads to long-term biochemical control in more than 70% of patients with well-circumscribed 
microadenomas, the success rate for macroadenomas is around 50%, and even less for invasive 
tumors. Radiotherapy is currently mainly used in patients with recurrent or persistent tumors, 
and carries the disadvantages of a relatively long latency period; furthermore, progressive 
anterior pituitary insufficiency develops in more than 50% of patients. Medical therapy using 
SSAs is being increasingly used as first-line treatment, especially in patients with low likelihood 
of cure by surgery, in whom surgery is contraindicated, or who refuse surgery. The efficacy of 
pasireotide LAR has been demonstrated to be superior to that of first-generation SSAs both in 
terms of the probability of a patient achieving biochemical control (GH reduction and 
normalization of IGF-1 levels), and in terms of relative reduction of IGF-1 levels from baseline. 
Superiority was demonstrated, both in medically naïve patients and in patients inadequately 
controlled on prior medical therapy. 
Cushing’s disease is a very rare, debilitating, and life-threatening disease that is caused by an 
adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma most commonly affecting 
adult females. The tumors are usually microadenomas (≤ 1 cm in diameter); macroadenomas 
are rare. The elevated levels of ACTH secreted by these tumors stimulate the adrenal glands to 
produce excess cortisol, thereby leading to the subsequent development of the clinical signs and 
symptoms of hypercortisolism. The primary clinical symptoms of Cushing’s disease include 
the following: changes in body habits due to increased fat accumulation; hirsutism; skin changes 
with easy bruising, purplish striae, reddening and ulceration of the cheeks; generalized 
weakness and fatigue; wasting of musculature; menstrual disorders in females; decreased 
fertility and/or libido; hypertension; weight gain; increased insulin resistance with alterations 
in glucose metabolism; dyslipidemia; depression, mood and behavior disorders; sleep 
disturbances and osteopenia/osteoporosis. Moreover, hypercortisolism is also associated with 


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immune deficiency and an increased risk for infections. As a result, patients with Cushing's 
disease have increased morbidity and a mortality rate 4 times higher than age- and gender-
matched subjects. The initial (i.e. first line) treatment of choice for Cushing’s disease is pituitary 
adenomectomy (transphenoidal surgery). For patients with recurrent or persistent disease, 
repeat transphenoidal surgery is also recommended if possible, but it is associated with lower 
efficacy than the initial surgery. Beyond this, radiotherapy and bilateral adrenalectomy are 
alternative treatment options. All 3 treatment modalities are associated with the potential for 
serious side effects. Pasireotide is the first pituitary-targeted medical therapy to demonstrate 
efficacy directly aimed at the underlying mechanism of Cushing’s disease (i.e. increased ACTH 
secretion), with associated robust and sustained decreases in UFC and serum cortisol. 
Additionally, improvements in the clinical signs and symptoms of Cushing’s disease were 
observed and were associated with decreases in UFC even in patients that did not completely 
normalize UFC; similar findings were observed for HRQL. 
Neuroendocrine tumors (NET) are rare malignant neoplasms that arise from the diffuse 
neuroendocrine system, which is made up of peptide- and amine producing cells with different 
hormonal profiles depending on their site of origin. Secretory symptoms of NETs occur when 
hormonal secretions released by the tumors reach the systemic circulation in a sufficient 
concentration and escape hepatic degradation; this occurs most frequently with hepatic 
metastases of NETs. Many NETs of non-pancreatic origin release vasoactive peptides and 
amines, such as serotonin and tachykinins, into the systemic circulation and cause a 
characteristic set of symptoms including flushing and diarrhea, and less commonly abdominal 
pain, telangiectasia, and bronchoconstriction. Depending on the tumor location, 10-50% of 
patients will have these symptoms. These symptoms occurring collectively are classically 
referred to as “carcinoid syndrome”. Surgical resection of the primary and metastatic lesions, if 
possible, remains the mainstay of treatment, and the only way to obtain a cure. Surgery is often 
not possible, however, as NETs are detected frequently in a more advanced tumor stage, 
regardless of primary location. In addition, approximately 60% of patients will continue to 
experience symptoms after surgery. In patients with inoperable GI NET, the treatment goal is 
to control tumor growth, to control any secretory symptoms that may be present, and to prolong 
survival. Somatostatin analogs (SSA) have been approved worldwide for the control of 
secretory symptoms of patients with NET for many years, and are widely used for symptom 
control in GI NETs. Over the past years, prospective data have become available to support the 
anti-proliferative role of somatostatin analogs. Given the broader binding capacity of 
pasireotide LAR, it is anticipated that it may have a greater impact on tumor stabilization than 
other SSAs such that significant benefit can be provided to patients that have progressed on 
currently available therapies. Evidence of efficacy was obtained in study CSOM230C2303. As 
there is no current standard of care for patients with advanced progressive functional GI NET, 
offering patients improved tumor stabilization will satisfy a high unmet need. Pasireotide LAR 
may provide a next step of therapy upon progression on other SSAs and provide patients an 
alternative to more toxic regimens such as standard cytotoxic chemotherapy that has limited 
benefit in this indication. In a post-hoc analysis from study CSOM230C2303, pasireotide LAR 
was shown to improve progression-free survival (PFS) by 5 months as assessed by 
investigators, compared to octreotide LAR. 
Dumping syndrome is a debilitating complication of esophageal and gastric surgeries (such as 
bariatric and gastric cancer surgeries) estimated to occur in 5-50% of patients. These surgical 


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procedures result in a reduced gastric capacity that causes rapid influx of nutrients to the small 
intestine, inducing a cascade of pathophysiological events and leading to early and late dumping 
syndrome symptoms. Dumping syndrome consists of (1) a too rapid gastric emptying, (2) an 
inappropriate release of GI hormones (as a reaction to the rapid delivery of carbohydrates to the 
duodenum) and (3) a hyperinsulinemic response to a too rapid absorption of glucose. Early 
symptoms comprise both gastrointestinal and vasomotor symptoms. Late dumping symptoms 
include hypoglycemia, perspiration, palpitations, hunger, fatigue, confusion, aggression, tremor 
and syncope. No drugs are currently approved for the treatment of Dumping syndrome. 
Pasireotide is a potent inhibitor of incretin and insulin secretion (via sst2 and sst5), which 
prevents postprandial hypoglycaemia. Additionally, it is a more potent inhibitor of glucagon-
like-peptide-1 (GLP-1) and peptide YY secretion than octreotide. Results from a phase II study 
(CSOM230X2203) suggest that pasireotide effectively controls postprandial hypoglycaemia in 
patients with dumping syndrome and provides improvements in the hematocrit level and pulse 
rate. 
Malignant melanoma (MM) is a highly invasive form of skin cancer that arises via 
transformation of the normal melanin-producing cells of the epidermis. Clinical outcome is 
dependent on the extent of disease at diagnosis with excellent survival rates (approximately 
90% at 5 years) described for patients with stage I disease. By contrast, patients with 
unresectable metastatic melanoma (stage III-IV) have a high 5-year mortality rate. Traditional 
therapies such as conventional chemotherapy (DTIC) and immunotherapies (IFN-α, IL-2) have 
not improved OS despite responses of short duration or benefit in a small number of patients. 
Newer therapies, including ipilimumab and vemurafenib, are now considered the standard of 
care because of their demonstrated survival benefit in patients with metastatic melanoma. Many 
patients, however, still experience disease progression after treatment, especially those whose 
melanoma does not express mutations in the BRAF gene (nearly half the overall melanoma 
patient population). Therefore, the development of new strategies to improve treatment of this 
life-threatening disease is essential. Merkel cell carcinoma (MCC) is a neuroendocrine 
carcinoma of the skin and hair follicles which often follows a particularly aggressive course. 
MCC is a rare tumor, accounting for less than 1% of cutaneous malignancies. Overall, the 2-
year mortality rate is 30-50%; few studies include a longer-term follow-up. To date, there is no 
standard protocol for the management of MCC and surgical treatment of large tumors especially 
in the head and neck region can be disfiguring. There is an urgent need for new therapies to 
treat patients with MCC. Pasireotide represents a new therapeutic option for patients with 
metastatic melanoma and Merkel cell carcinoma that has low toxicity and a good safety profile. 
Preclinical evidence and extensive clinical data and experience from the use of SSAs in patients 
with other endocrine and cancer disease states support the use of pasireotide in patients with 
malignant melanoma and Merkel cell carcinoma. 
Pasireotide is currently approved for use in Cushing’s disease (s.c. formulation) in over 80 
countries, and for use in acromegaly (i.m. LAR formulation) in over 30 countries worldwide. 
The safety profile of both formulations of pasireotide has been well characterized in a 
comprehensive development program and is similar to the established profile of SSAs, except 
for the higher incidence and magnitude of hyperglycemia, which is manageable with proper 
treatment with anti-diabetic medication. The mechanism of the pasireotide-induced 
hyperglycemia has been well characterized in mechanistic studies. It is primarily a consequence 
of decreased secretion of insulin and incretins, with no change in hepatic or peripheral insulin 


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sensitivity, is less severe in responders than non-responders, and is reversible upon 
discontinuation. The risk of hyperglycemia is minimized by monitoring of patients’ FPG and 
HbA1c levels and appropriate management. Additional expected pharmacodynamic effects of 
pasireotide are well known and are primarily GI disturbances, bradycardia, mild QT 
prolongations, cholelithiasis and transient elevations in serum levels of transaminases. These 
effects can be effectively monitored and managed, as detailed in the IB and in the label. No 
unexpected new findings have emerged with long-term exposure to pasireotide. 
Overall, pasireotide has a favorable benefit/risk profile in the discussed indications. Patients 
rolled-over to this study are those who have benefited from the treatment with pasireotide and 
continue to obtain this benefit with continuation of the treatment. The current label and IB fully 
characterize both efficacy and safety aspects of pasireotide, s.c. and LAR, to enable its 
appropriate use to maximize benefit while minimizing risks to patients. The risk to patients in 
this trial may be minimized by compliance with the eligibility criteria and study procedures, 
and close clinical monitoring. There may be unforeseen risks with pasireotide which could be 
serious. 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
 
To evaluate long term safety 
data i.e. SAEs and AEs 
Frequency and severity of 
AEs/SAEs 
Refer to Section 10.4  
Secondary 
 
 
To evaluate clinical benefit as 
assessed by the investigator. 
Proportion of patients with 
clinical benefit as assessed by 
the investigator at scheduled 
visits. 
Refer to Section 10.5  
Other secondary 
 
 
Not applicable 
Not applicable 
Refer to Section 10.5.2  
4 
Study design 
4.1 
Description of study design 
Those patients receiving pasireotide LAR must return to the study center monthly (+/- 7 days) 
to receive study medication.  Drug dispensing information will be collected and adverse events 
and clinical benefit will be assessed. Patients receiving pasireotide s.c. must return to the study 
center on a quarterly basis (every 12 weeks +/- 2 weeks) for resupply of study medication. Drug 
dispensing information will be collected and adverse events and clinical benefit will be 
assessed.  The patient 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.   


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At every visit, the investigator is required to confirm that the patient continues to have clinical 
benefit and may continue receiving study treatment. 
All adverse events and serious adverse events will be collected continuously throughout the 
study.  Information on patient pregnancies and pregnancies of pregnant partners will be 
collected.   
The study is expected to remain open for 10 years from FPFV (or until 10-Jun-2023 in the UK). 
Patients will continue to be treated in this roll-over study until they are no longer benefiting 
from their pasireotide treatment as judged by the investigator or until one of the discontinuation 
criteria is met (please refer to Section 7.1.5). At each visit the Investigator is required to confirm 
that the patient continues to derive clinical benefit and may continue receiving study treatment.   
A patient will reach the end of study when pasireotide treatment is permanently discontinued.   
Figure 4-1 
Study design 
 
 
*Note: The starting dose of pasireotide, and any combination treatment given for Cushing’s Disease or 
Acromegaly, should be the same dose as that which the patient was receiving in the parent study at 
roll over. 
4.2 
Timing of interim analyses and design adaptations 
Interim analyses will occur every 2 years beginning in 2017 and continuing until the final trial 
database lock.   
4.3 
Definition of end of the study 
End of study is defined as either 10 years from FPFV (or until 10-Jun-2023 in the UK) or when 
all patients on this study have permanently discontinued pasireotide treatment or have been able 
to obtain commercial supply according to local regulations or have been able to receive the drug  
through country-specific programmes outside of this clinical trial (applicable to Brazil, France, 
Germany, India, Italy, Malaysia, Mexico, Peru and Thailand)  and the end of treatment visit and 
all safety follow-up procedures have been performed for each patient, whichever comes first.   
 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Recordati. Should this be necessary, 
the patient should be informed as soon as possible and should stop taking study labeled drug. 
Parent Novartis 
Novartis Sponsored study: 
Pasireotide s.c. and/or LAR 
as monotherapy or in 
combination therapy
Roll-over study:
Pasireotide* at assigned 
dose and/or in addition to 
combination treatment
End of roll-over study:
Pasireotide is permanently 
discontinued


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Assessments should be performed as described in Section 7.1.3 for a prematurely withdrawn 
patient. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial. 
5 
Population 
5.1 
Patient population 
The 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. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Patient is currently participating in a Novartis-sponsored study receiving pasireotide (LAR 
and/or s.c.) on monotherapy or combination therapy (for Cushing’s Disease or 
Acromegaly),  and has fulfilled all required assessments in the parent study and patients that 
are benefiting from the study treatment have no other alternatives. 
2. Patient is currently benefiting from the treatment with pasireotide, as determined by the 
investigator 
3. Patient has demonstrated compliance, as assessed by the investigator, with the parent study 
requirements. 
4. Willingness and ability to comply with scheduled visits, treatment plans and any other study 
procedures. 
5. Written informed consent obtained prior to enrolling in roll-over study and receiving study 
medication. 
• If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patient has been permanently discontinued from pasireotide study treatment in the parent 
study due to unacceptable toxicity, non-compliance to study procedures, withdrawal of 
consent or any other reason. 
2. 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 test. 
3. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
the study treatment and for 30 days after the final dose of pasireotide s.c. and 84 days after 
the final dose of pasireotide LAR. Highly effective contraception is defined as either: 


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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patientt. 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) 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 enrolling). For female patients on the study 
the vasectomized male partner should be the sole partner for that patient. 
• 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 use of oral contraception women should have been stable on the same pill for 
a minimum of 3 months before taking study treatment. 
• Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child-bearing potential. 
• Sexually active males unless they use a condom during intercourse while taking drug 
and for 1 months after pasireotide s.c. last dose and 3 months after pasireotide LAR last 
dose and should not father a child in this period. A condom is required to be used also 
by vasectomized men in order to prevent delivery of the drug via seminal fluid. 
If a study patient or partner becomes pregnant or suspects being pregnant during the study 
treatment or within 1 month after the final dose of pasireotide s.c. or 84 days after the final dose 
of pasireotide LAR, the Study Doctor needs to be informed immediately and ongoing study 
treatment with pasireotide has to be stopped immediately. For patients taking pasireotide LAR, 
the future dose injections will be cancelled. 
6 
Treatment 
6.1 
Study treatment 
Terms related to study treatment are defined below: 


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6.1.1 
Study treatment and investigational treatment refer to pasireotide alone 
or in combination with another treatment for Cushing’s Disease and 
AcromegalyDosing regimen Pasireotide 
Table 6-1 
Dose and treatment schedule 
Study 
treatments 
Pharmaceutical 
form and route of 
administration 
Dose 
Frequency and/or Regimen 
Pasireotide 
Subcutaneous 
Dose ranges should be the same as 
stated in the parent study  
b.i.d. or t.i.d depending on the 
parent study guidance 
Pasireotide 
LAR 
Intramuscular 
Dose ranges should be the same as 
stated in the parent study 
q 28 days 
Pasireotide may be provided in two different formulations LAR or s.c. (Table 6-1), depending 
on the parent study. The starting dose of pasireotide should be the same dose as that which the 
patient was receiving in the parent study at roll over. Following the starting dose patients may 
have their dose changed based on investigator’s judgment and following the dose ranges used 
in the parent study. Patients are not allowed to receive doses that are not indicated in the parent 
study. 
The investigational treatment is to be stored in a secure locked area while under the 
responsibility of the investigator. Receipt and dispensing of investigational treatment must be 
recorded by an authorized person at the investigator’s site. 
Pasireotide for the roll-over study can be provided as local commercial material or global 
clinical study supply as appropriate. As per Recordati procedures, investigational treatment will 
be shipped directly to the investigational sites. 
6.1.2 
Dosing regimen for patients on Pasireotide in combination with 
cabergoline treatment 
Cabergoline is in the form of 0.5mg tablet. Cabergoline should be taken according to guidelines 
in the parent protocol.  It is usually taken after a full meal.  As per the parent study, if 
monotherapy with pasireotide does not allow the patient to receive biochemical control, 
cabergoline can be added at a starting dose of 0.5mg once daily.  If the patient does not achieve 
biochemical control with cabergoline 0.5mg once daily treatment, in combination with 
pasireotide, then the cabergoline dose can be escalated up to 1.0mg once daily.   
Dostinex is a generic form of cabergoline and can be used in the trial. If Dostinex is not available 
in a participating country, a different type of generic form can be used. For storage conditions, 
please refer to cabergoline Package Insert and SmPC.  
For specific study treatment dose modifications regarding cabergoline in the SOM230B2411 
trial, please refer to (appendix 12). 
Cabergoline is mainly recommended for patients with borderline or moderately increased 
plasma IGF-I levels (<1.5 X the upper limit of normal), even though it is sometimes effective 
(leading to normal IGF-I levels) in patients with high baseline IGF-1 levels. More recent studies 
suggest that cabergoline, a more selective dopamine-2 receptor agonist, may be effective in a 
larger percentage of patients by further lowering GH or IGF-1 levels. Doses vary from 0.3 to 7 


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mg/wk (one to seven administrations per week). The maximum suppression of GH has been 
achieved from 0.5 mg daily to 1 mg twice weekly.  
6.1.3 
Dosing regimen for patients on Pasireotide in combination with another 
treatment for Cushing’s Disease or Acromegaly 
Please follow all dosing guidelines outlined in the parent protocol for patients on any 
combination treatments.  
6.1.4 
Ancillary treatments 
Not applicable 
6.1.5 
Rescue medication 
Not applicable 
6.1.6 
Guidelines for continuation of treatment 
Not applicable 
6.1.7 
Treatment duration 
Patients will continue to receive pasiroetide alone or in combination with another treatment for 
Cushing’s Disease and Acromegaly, as long as they continue to derive benefit as per 
Investigator assessment, the drug becomes commercially available in their country, or until one 
of the discontinuation criteria is met (please refer to Section 7.1.5). At every visit, the 
investigator is required to confirm that the patient continues to have clinical benefit and may 
continue receiving study treatment. A patient will reach the end of the roll-over study when 
pasireotide treatment is permanently discontinued. 
6.2 
Dose modification guidelines 
The starting dose of pasireotide alone or in combination with another treatment for Cushing’s 
Disease and Acromegaly, should be the same dose as that which the patient was receiving in 
the parent study at roll over. Changes to pasireotide, and any medication given in combination 
with pasireotide dose, will be based on the investigator’s judgment. 
Please refer to Appendix 2 through Appendix 12 (Section 14.2 through Section 14.12) for dose 
modification guidelines. 
6.2.1 
Starting dose rationale 
The starting dose of pasireotide alone or in combination with another treatment for Cushing’s 
Disease and Acromegaly, should be the same as that which the patient was receiving in the 
parent study at the roll over. 


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6.3 
Concomitant medications 
6.3.1 
Prohibited concomitant therapy 
The use of concomitant medication with known risk of Torsades de pointes (TdP) is prohibited. 
In case a patient needs to take a medication with known risk of TdP, it will require study drug 
discontinuation prior to starting the medication. Please see Appendix 1 for further guidance on 
QT prolonging medication. 
Medications with a potential risk of TdP should be avoided whenever possible. 
Refer to Appendix 1 for guidance regarding medications which pose a known risk for QT 
prolongation. 
6.4 
Patient numbering, treatment assignment or randomization 
6.4.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is enrolled in the roll over study and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Recordati to the investigative site) with a sequential 
patient number suffixed to it, so that each subject is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next sequential 
Subject No. available to the investigator through the Oracle Clinical Remote Data Capture 
interface. Additionally, an e-CRF will be completed that identifies the patient by gender and 
data of birth and previous study, site/center and subject number. 
6.4.2 
Treatment assignment or randomization 
Not applicable 
6.4.3 
Treatment blinding 
Not applicable 
6.5 
Study drug preparation and dispensation 
All dosage prescribed to the patient and all dose changes during the study must be recorded on 
the Dosage Administration Record CRF. 
Investigator staff will identify the study treatment package(s) to dispense to the patient. 
Investigator staff will add the patient number on the label. For global supply the study 
medication packaging has a 2-part label. Immediately before dispensing the package, 
Investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique patient number. 
6.5.1 
Study treatment packaging and labeling  
Pasireotide for the roll-over study can be provided where appropriate as local commercial 
material or as global clinical study supply (Open label), packed and labeled under the 


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responsibility of the Sponsor’s Clinical Supply. Study treatment labels will be in the local 
language and comply with the legal requirements of each country. They will include storage 
conditions for the drug but no information about the patient. 
Combination treatments should be labeled and supplied in accordance with the parent protocol. 
When available, commercial treatment should be used as a first option. 
Table 6-2 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Pasireotide s.c. 
(0.3mg, 0.6mg and 
0.9mg) 
Solution for subcutaneous injection in ampoule 
Labeled as ‘SOM230’ (b.i.d. or t.i.d) 
Pasireotide LAR 
(10mg, 20mg, 
40mg and 60mg) 
Microparticle powder for suspension in vial 
Labeled as ‘SOM230 LAR’ (q28d) 
 
Solution for suspension (vehicle) in ampoule 
Labeled as ‘solvent’ (q28d) 
6.5.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, pasireotide alone or in combination with another 
treatment for Cushing’s Disease and Acromegaly, should be stored according to the instructions 
specified on the drug labels and in the [Investigator’s Brochure]. For patients receiving 
pasireotide s.c., a 3-month supply of pasireotide can be dispensed to the patient. Patients 
receiving pasireotide LAR, must return monthly to the participating site to receive their 
injections. During these visits, limited drug dispensing information will be collected and 
reported within the drug accountability log. 
Table 6-3 
Supply and storage of study treatments 
Study treatments 
Supply 
Storage 
Pasireotide s.c. 
local commercial material or global clinical study 
supply (open label) supplied by Sponsor  
Refer to study treatment label 
Pasireotide LAR 
 
Combination 
treatments 
local commercial material or global clinical study 
supply (open label) supplied by Sponsor 
Should be supplied in accordance with the parent 
protocol. Where available, commercial treatment 
should be used as a first option. 
Refer to study treatment label 
 
Refer to study treatment label 
6.5.3 
Study drug compliance and accountability 
6.5.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 


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6.5.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the IQVIA monitor or to the IQVIA address provided in the investigator 
folder at each site. 
6.5.3.3 
Handling of other study treatment 
Not applicable. 
6.5.4 
Disposal and destruction 
The drug supply can only be destroyed once the study drug accountability check has been 
performed by the monitor. The study drug supply can be destroyed at the local Recordati 
facility, by Drug Supply group or by a third party, as appropriate. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
The table indicates which assessments produce data to be entered into the database (D) or 
remain in source documents only (S) (“Category” column). 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Reference 
Section 
Enrollment 
Visits during treatment phase 
End of study 
treatment 
(EoT) 
End of study 
/Safety 
Follow-up 
Visit Number 
 
 
1 
Visit 2,3,4 etc. 
777 
778 
Demographic: Patients’ previous study, site, 
subject number, study dose, formulation and 
frequency, study indication 
D 
7.1.2.3 
x 
 
 
 
Informed consent 
D 
5.2/5.3/11.3  
x 
 
 
 
Relevant medical history/current medical 
conditions 
D 
7.1.2.3  
x 
 
 
 
Inclusion/exclusion criteria 
D 
5.2/5.3  
x 
 
 
 
Pasireotide s.c. dispensing  (+combined therapy 
if applicable) 
D 
6.1  
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
Pasireotide LAR dose administration  
(+combined therapy if applicable) 
D 
6.1  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Pregnancy Tests 
D 
7.1.4  
x 
Monthly (home) 
x 
x 
Investigator confirmation of continued clinical 
benefit from study treatment (at every visit) 
D 
6.1.5 
x 
Visit 2,3,4 etc. 
 
 
Serious adverse events (in safety database only) 
D 
8.2  
Continuous 
x 
AEs 
D 
8.1  
Continuous 
x 
End of treatment 
D 
7.1.5  
x 
 
x 
 
End of study 
D 
7.1.5  
 
 
 
x 


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7.1.1 
Molecular pre-screening 
Not applicable. 
7.1.2 
Screening 
There will be no screening period for this study. At the enrollment visit, the patient will need to 
complete a written informed consent. Once consented, patients will be evaluated for eligibility 
via the inclusion and exclusion criteria. 
7.1.2.1 
Eligibility screening 
Not applicable. 
7.1.2.2 
Information to be collected on screening failures 
Not applicable. 
7.1.2.3 
Patient demographics and other baseline characteristics 
For patients who are eligible to participate in this roll over study, an e-CRF will be completed 
that identifies the patients’ gender, data of birth and previous study, site /center and subject 
number. Study dose, formulation and frequency, study indication and relevant medical history 
will also be collected. 
7.1.3 
Treatment period 
The starting dose of pasireotide, and any medication given in combination with pasireotide,  
should be the same dose as that which the patient was receiving in the parent study at roll over.  
Those patients receiving pasireotide LAR must return to the study center monthly (+/- 7 days) 
to receive study medication.  Drug dispensing information will be collected and adverse events 
and clinical benefit will be assessed. Patients receiving pasireotide s.c. must return to the study 
center on a quarterly basis (every 12 weeks +/- 2 weeks) for resupply of study medication.  Drug 
dispensing information will be collected and adverse events and clinical benefit will be 
assessed.  The patient 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.  
The study is expected to remain open for approximately 10 years from FPFV (or until 10-Jun-
2023 in the UK) or when all patients on this study have permanently discontinued pasireotide 
treatment or have been able to obtain commercial supply according to local regulations or have 
been able to receive the drug through country-specific programmes outside of this clinical trial 
(applicable to Brazil, France, Germany, India, Italy, Malaysia, Mexico, Peru and Thailand)  and 
the end of treatment visit and all safety follow-up procedures have been performed for each 
patient, whichever comes first.  At every visit, the investigator is required to confirm that the 
patient continues to have clinical benefit and may continue receiving study treatment. 


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7.1.4 
Pregnancy and assessment of fertility 
Since highly effective contraception is required during the study, female patients of child 
bearing potential are required to test negative for a pregnancy (either with serum testing if 
routinely/locally available or urine pregnancy test) before enrolling into the study. 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during the study and 
for 30 days after the final dose of pasireotide s.c. and 84 days after the final dose of pasireotide 
LAR. 
Highly effective contraception is defined as either: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 
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) 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 enrolling). For female patients on the study the 
vasectomized male partner should be the sole partner for that patient. 
• 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. 
If patient has tested negative at the end of study on the parent study, no pregnancy testing is 
required if enrollment into this study is carried out on the same day or within a maximum of 5 
days from each other. 
Female patients of child bearing potential are required to perform monthly home urine 
pregnancy tests and complete a simple diary with the dates and the outcome of the home urinary 
test while on study treatment and during safety follow-up (30 days after the final dose of 
pasireotide s.c. and 84 days after the final dose of pasireotide LAR). 
A pregnancy test (either with serum testing if routinely/locally available or urine pregnancy 
test) on female patients of child bearing potential is required at the final study visit. 
Any positive results will be recorded in the database and followed up as per Section 8.4. 
7.1.5 
Discontinuation of study treatment 
Patient may voluntarily discontinue from the study treatment for any reason at any time.  If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages.  
They may be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reasons.   


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At the time the patient discontinues study treatment, a visit should be scheduled as soon as 
possible, at which time the assessments listed for the End of Treatment (EOT) visit will be 
performed. End of Treatment information will be completed in the eCRF giving the date and 
reason for stopping the study treatment (see Section 7.1.5.1). 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations 1 month following last dose of 
the s.c. dose or 3 months for patients receiving LAR, following last dose. The completion of 
the Study Evaluation Completion CRF page will be required any time a patient discontinues 
from the study and must be completed 30 days after the end of treatment. 
7.1.5.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients may be withdrawn from the study if any of the following 
occur: 
• Death. 
• Lost to follow-up. 
• Staying in the study would be harmful. 
• Patient/guardian decision. 
• Physician decision. 
• Non-compliance to protocol requirements. 
• Protocol deviation. 
• Pregnancy. 
• Study terminated by sponsor. 
• Study treatment has become available through country-specific programmes outside of this 
clinical trial (applicable to Brazil, France, Germany, India, Italy, Malaysia, Mexico, Peru 
and Thailand). 
Study treatment has become commercially available and reimbursed (when current treatment 
becomes commercially available and reimbursed in that indication, the patient will have to be 
withdrawn from the study and will have completed the study as per protocol).   
In addition to the general withdrawal criteria, the following criteria may also require study 
treatment discontinuation: 
If any of the criteria below are met during routine examinations that are part of standard of care, 
study medication should be discontinued immediately. Re-challenge of study medication is 
prohibited once discontinuation criteria are met. 
Hepatic-related discontinuation criteria 
• Jaundice or other signs of clinically significant liver dysfunction 
• ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and ALP < 2 x ULN 
• ALT or AST > 5 x ULN and ≤ 8 x ULN persistent for more than 2 weeks 
• ALT or AST > 8 x ULN 
QT related discontinuation criteria 


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• Confirmed QTcF >500 ms and discontinuation recommended by a cardiologist 
• QTcF > 480 msec, if the investigator determines it is no longer safe for the patient to 
continue in the study, based on ECGs, cardiac examination and recommendation from 
a cardiologist. 
• Clinically significant arrhythmias including: 
1. Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms of 
hemodynamic compromise. 
2. Sustained ventricular tachycardia (>30 s) irrespective of symptoms. 
3. Recurrent non-sustained VT (≥ 3 beats) during any 24-hour monitoring period. 
4. Clinically significant brady-arrhythmia or third degree AV block. 
5. Need to use a drug with known risk of TdP. 
Hyperglycemia related discontinuation criteria 
• Uncontrolled diabetes mellitus (DM), consistently high glucose values FPG ≥ 240 
mg/dL (13.3 mmol/L) or HbA1c value ≥ 10 % despite appropriate management of 
diabetes including diet and/or exercise with or without optimal anti-diabetic therapy 
7.1.5.2 
Replacement policy 
Not applicable. 
7.1.6 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 
longer, and does not want any further visits or assessments, and does not want any further study 
related contact. 
Recordati will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up. 
7.1.7 
Follow up for safety evaluations 
All patients must have safety evaluations 84 days after the last dose of study treatment for the 
LAR and 1 month (30 days) after s.c. dose. 
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 


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Data collected should be added to the Adverse Events eCRF. 
7.1.8 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Not applicable. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by collecting adverse events/serious adverse events at every visit. For 
details on AE/SAE collection and reporting, refer to Section 8. 
In addition, the following applies for safety monitoring: 
• For locally approved indications, the safety monitoring guidance in the locally approved 
prescribing information applies 
• For indications that are not yet approved locally, the safety monitoring requirements 
described in Section 7.2 of the current Investigator Brochure must be followed 
 
Patients may have safety assessments performed by the clinics local laboratory as per 
investigators judgement and standard of care at any time during the study period. 
7.2.2.1 
Hepatic related findings 
For any hepatic related findings during routine follow up, refer to Appendix 2. 
7.2.2.2 
QT-related finding 
For any QT-related finding during routine follow up, refer to Appendix 3. 
7.2.2.3 
Hyperglycemia related findings 
For any hyperglycemia related finding during routine follow up, refer to Appendix 4. 
7.2.2.4 
Additional bio-marker assessments 
Not applicable. 
7.2.3 
Resource utilization 
Not applicable. 


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7.2.4 
Patient reported outcomes 
Not applicable. 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Any ongoing adverse events from the parent study will be captured as medical history in the 
roll-over database. Any AE that begins (or worsens) after signing of the informed consent for 
the roll-over and during the 30-day (or 28-day) or 84-day (12 week) safety follow up period 
defined in the parent protocol should be reported in both clinical databases. 
Adverse event monitoring should be continued for at least 30 days for patients receiving the s.c. 
formulation and 84 days for those receiving the LAR formulation (or 5 half-lives), whichever 
is longer) following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event. 
Adverse events will be assessed according to the current version of Common Terminology 
Criteria for Adverse Events (CTCAE). 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected through the EOT 
eCRF page. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (start and end dates) 
3. Its relationship to the study treatment (reasonable possibility that AE is related: No, Yes) 


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4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 
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. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 


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8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days for patients on the s.c 
formulation and 84 days for patients on the LAR formulation after the patient has stopped study 
treatment must be reported to IQVIA Safety office within 24 hours of learning of its occurrence. 
IQVIA, in its turn, will promptly inform Recordati. 
 
Any SAE that begins or worsens after signing of the informed consent for the roll-over and 
during the safety follow up period defined in the parent protocol should be reported as an 
adverse event in both clinical databases; however, only one SAE report will be sent to IQVIA. 


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• Any SAE that begins or worsens during the safety follow-up period specified in the parent 
study should have an SAE report submitted to IQVIA with the parent protocol study 
number. 
• Any SAE that begins or worsens after the safety follow-up period specified in the parent 
study should have an SAE report submitted to IQVIA with the roll-over protocol study 
number. 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
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 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. 
Any SAEs experienced after the 30 day/84 day safety evaluation follow-up period (or 5 half-
lives, if half-life is established, whichever is longer) should only be reported to IQVIA if the 
investigator suspects a causal relationship to the study treatment. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to IQVIA. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Reference Safety Information section of the 
Investigator’s Brochure or Package Insert (new occurrence) and is thought to be related to the 
Recordati study treatment, IQVIA (on behalf of Recordati) may urgently require further 
information from the investigator for Health Authority reporting. Recordati may need to issue 
an Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 


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committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. Recordati may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same drug that this SAE has been 
reported. 
8.3 
Emergency unblinding of treatment assignment 
Not applicable. This is an open-label study. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to IQVIA within 24 hours of learning of its occurrence. IQVIA, in its turn, will 
promptly inform Recordati. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to IQVIA. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study treatment any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
The protocol must specify how long the newborn will be followed up (just birth, or xyz months). 
Further advice on the length of post-natal follow up can be sought from Recordati and should 
be driven by the type of congenital abnormality expected. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided pasireotide 
[Investigator Brochure]. For all other combination treatments, please refer to the relevant 
prescribing brochure for warnings and precautions.  Additional safety information collected 
between [Investigator Brochure] updates will be communicated in the form of INs. This 
information will be included in the patient informed consent and should be discussed with the 
patient during the study as needed. 
8.6 
Data Monitoring Committee 
Not applicable. 
8.7 
Steering Committee 
Not applicable. 


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9 
Data collection and management 
9.1 
Data confidentiality 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research patient to revoke their authorization for use of their PHI. 
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Recordati 
personnel (or designated CRO, IQVIA) will review the protocol and eCRFs with the 
investigators and their staff. During the study, the field monitor will visit the site regularly to 
check the completeness of patient records, the accuracy of entries on the eCRFs, the adherence 
to the protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 


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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. IQVIA monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the eCRFs are performed 
according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRFs is 
complete, accurate, and that entry and updates are performed in a timely manner. 
9.4 
Database management and quality control 
For studies using eCRFs, Recordati personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint written 
agreement between the Global Head of Biostatistics and Data Management and the Global Head 
of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
10.1 
Analysis sets 
The following analysis sets will be used for statistical analysis and data reporting. 
10.1.1 
Full Analysis Set 
Not applicable. 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication after 
enrolling into the roll-over protocol. 


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10.1.3 
Dose-determining analysis set 
Not applicable. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data characteristics will be summarized descriptively for the 
Safety Set. 
10.3 
Treatments (study treatment, compliance) 
Dose administration data will be summarized using the Safety Set. 
10.4 
Primary objective 
The primary objective is to evaluate long term safety as assessed by the occurrence of 
AEs/SAEs. 
10.4.1 
Variable 
See Section 10.5.3. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis will be tested. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Not applicable. 
10.4.4 
Supportive analyses 
No supportive analysis will be performed. 
10.5 
Secondary objectives 
10.5.1 
Key secondary objective(s) 
Not applicable. 
10.5.2 
Other secondary efficacy objectives 
The secondary objective of the study is to evaluate clinical benefit as assessed by the 
investigator. Proportion of patients with clinical benefit as assessed by the investigator will be 
summarized at scheduled visits. 
10.5.3 
Safety objectives 
The assessment of safety will be based mainly on the frequency and severity of AEs, AESI and 
SAEs. 
10.5.3.1 Analysis set and grouping for the analyses 
The overall observation period will be divided into two mutually exclusive segments: 


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1. on-treatment period: from day of first dose of study medication in the roll-over study to 3 
months (day 84) following the last dose of pasireotide LAR treatment and to 1 month (day 
30) following the last dose of pasireotide s.c. treatment.  
2. post-treatment period: starting at 3 months+1 day (day 85) following the last dose of 
pasireotide LAR treatment and at 1 month+1 day (day 31) following the last dose of 
pasireotide s.c. treatment. 
10.5.3.2 Adverse events (AEs) 
Summary tables of 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 will be summarized by system organ class 
and/or preferred term, severity (based on CTCAE grades), type of adverse event, relation to 
study treatment. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event. 
10.5.3.3 Other safety data 
Not applicable. 
10.5.3.4 Tolerability 
Not applicable. 
10.6 
Interim analysis 
This study has also been categorized as voluntary European Post Authorization Safety Study 
(PASS). Therefore, regular interim analyses will be performed during the course of the study 
as need by the Sponsor and will occur every 2 years beginning in 2017 and continuing until the 
study end. Details will be specified in the statistical analysis plan. The final analysis will occur 
when all patients complete the study. 
10.7 
Sample size calculation 
Not applicable. 
10.8 
Power for analysis of key secondary variables 
Not applicable. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 


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regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to IQVIA monitors, auditors, 
Recordati Clinical Quality Assurance representatives, designated agents of Recordati, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their CRFs. 
IQVIA (on behalf of Recordati) will provide to investigators, in a separate document, a 
proposed informed consent form (ICF) that is considered appropriate for this study and 
complies with the ICH GCP guideline and regulatory requirements. Any changes to this ICF 
suggested by the investigator must be agreed to by Recordati before submission to the 
IRB/IEC/REB, and a copy of the approved version must be provided to the IQVIA monitor 
after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
Male participant will be asked to provide, the Female Partner of Male Participant form, to their 
partners.   
Additional consent form 
Not applicable. 
11.4 
Discontinuation of the study 
Recordati reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. 


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11.5 
Publication of study protocol and results 
Recordati assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Recordati-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 


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


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13 
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solution to the dumping syndrome after gastrectomy or vagotomy. Br. J. Surg; 76(2): 140-44. 
Richards WO, Geer R, O'Dorisio TM, et al (1990) Octreotide acetate induces fasting small 
bowel motility in patients with dumping syndrome. J. Surg. Res; 49(6):483-487. 
Rinke A, Muller H-H, Schade-Brittinger C, et al (2009) Placebo-controlled, double-blind, 
prospective, randomized study of the effect of Octreotide LAR in the control of tumor growth 
in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study 
group. J Clin Oncol; 27(28):4656-63. 
Schmid HA, Schoeffter P (2004) Functional activity of the multiligand analog SOM230 at 
human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine 
tumors. Neuroendocrinology; 80(Suppl 1): 47-50. 
Schurr PG, Strate T, Rese K, et al (2007) Aggressive Surgery Improves Long-term Survival in 
Neuroendocrine Pancreatic Tumors. Ann Surg; 245(2):273-81. 
Sonino N, Zielezny M, Fava GA, et al (1996) Risk factors and long-term outcome in pituitary-
dependent Cushing’s disease: a single centre audit. J Clin Endocrinol Metab; 81(7):2647-52. 
Tack J, Arts J, Caenepeel P, et al (2009) Pathophysiology, Diagnosis and Management of 
Postoperative Dumping Syndrome Nature Reviews Gastroenterology & Hepatology. Nat Rev 
Gastroenterol Hepatol; 6(10):583-90. 
Toumpanakis C, Meyer T, Caplin ME (2007) Cytotoxic treatment including 
embolization/chemoembolization for neuroendocrine tumours. Best Practice Research 
Clinical Endocrinology Metabolism; 21(1):131-44. 
Tulassay Z, Tulassay T, Gupta R, et al (1989) Long acting somatostatin analog in dumping 
syndrome. Br. J. Surg; 76(12):1294-1295. 


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Van der Hoek J, et al (2005) Distinct functional properties of native somatostatin receptor 
subtype 5 compared with subtype 2 in the regulation of ACTH release by coritcotroph tumor 
cells. Am J Phsyiol Endocrinol Metab; 289(2):E278-87. 
Yao JC, Phan AT, Chang DZ, et al (2008) Efficacy of RAD001 (everolimus) and octreotide 
LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II 
study. J Clin Oncol; 10(26):4311-8. 


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14 
Appendices 
14.1 
Appendix 1: Medications known to be associated with QT 
interval prolongation 
The list of drugs is generally recognized to have a possible association with QT prolongation 
can be found at //crediblemeds.org. This list is not considered to be all inclusive and any 
questions regarding the QT prolongation potential should be discussed with the Recordati 
Medical Monitor.  


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14.2 
Appendix 2: Recommended hepatic safety management 
guidance 
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
If any of the criteria below are observed at any routine examinations (standard of care), 
• ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN. 
• ALT or AST > 5 x ULN and ≤ 8 x ULN. 
• ALT or AST > 8 x ULN, patient should be discontinued. 
The following should be performed immediately within 72 hours of awareness of the 
abnormality (for further details refer to Figure 14-1): 
• Perform liver-directed medical history and physical examination (i.e. assess occupational 
hazards, concomitant medications including OTC meds, inter-current illness, etc). 
• Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if 
total bilirubin is > 2.0 x ULN), Alb, PT (INR), ALP, and GGT. 
• Perform hepatitis screen: anti-HAV, IgM (to confirm acute Hepatitis A), HbsAg, Anti-
HBc, anti-HCV (if positive, PCR viral load should be assessed), Anti-HEV, ANA 
antibodies, anti-smooth muscle anti-bodies, CMV and EBV. 
• Perform abdominal ultrasound (liver and biliary tree). 
Liver chemistry tests (LFTs) should be monitored every 3-4 days until resolution or return to 
baseline status. 
Patients or subjects may need to be discontinued if the abnormal liver function criteria are met 
upon LFT retesting. Progress reports of the event should be maintained until resolution or 
stabilization (i.e. no further elevation after 2 consecutive assessments). 
For ALT or AST > 5 x ULN and ≤ 8 x ULN, the following must occur (in addition to the safety 
follow up procedures noted above). 
• Study medication should be temporarily interrupted and liver chemistry tests monitored 
every 3-4 days until resolution or return to baseline. 
• If resolution (ALT and AST ≤ 5 ULN) or return to baseline does not occur after 2 weeks, 
the patient should be discontinued. 
• If ALT or AST return to less than 5 x ULN study drug can be resumed and patient can 
continue study per protocol. 
• If ALT or AST rises above 5 x ULN any time after study drug is resumed, then study drug 
should be discontinued immediately. 
If any of these criteria are met and deemed an adverse event by the investigator, the event must 
be recorded on the Adverse Event (e) CRF page; if the event is deemed serious by the 
investigator, then proceed with completing the SAE form. In addition, any significant findings 
from the physical examination should be recorded on the Adverse Event (e) CRF page. 


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Figure 14-1 
Recommended LFT management guidance 
 


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14.3 
Appendix 3: Recommended guidance for follow up in case of QT-
related findings during routine ECG 
If at any routine ECG a QTcF> 500msec is observed, triplicate ECGs, each 2-3 minutes apart, 
need to be collected approximately 1 hour after the initial ECG. The mean QTcF from the 
triplicate ECGs will be determined and if the mean QTcF > 500msec, study treatment should 
be interrupted until a cardiologist has re-evaluated the ECG. Patient reassessment should be 
performed as early as possible but within 7 days of the initial abnormal ECG by a cardiologist 
for cardiovascular risk factors and a decision regarding study continuation. 
If mean QTcF >480msec / ≤ 500msec is observed, the repeat ECG assessment must be 
performed as soon as practical but within 7 days of the initial abnormal ECG. In addition, the 
following steps need to be taken (for more details refer to Figure 14-2 below): 
• If a QTcF >480msec / ≤ 500 msec is confirmed and QTcF change from pretreatment 
exceeds 60 msec, cardiology consultation must be sought as soon as practical (within 7 
days) for ECG re-evaluation and clinical assessment for cardiovascular risk factors and a 
decision regarding study continuation. 
• If a QTcF > 480msec / ≤ 500msec is confirmed and QTcF change from pretreatment < 60 
ms, more frequent ECG follow-up is advised. 


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Figure 14-2 
Recommended guidance for ECG follow up 
 


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14.4 
Appendix 4: Recomended guidance for fasting blood glucose 
management 
Hyperglycemia 
Two clinical studies ([SOM230B2216] and [SOM230B2124]) have been conducted in healthy 
volunteers to further understand the mechanism of pasireotide-induced hyperglycemia and to 
evaluate the potential clinical utility of anti-diabetes agents in the management of pasireotide-
induced hyperglycemia. Data from SOM230B2216 indicate that pasireotide decreases insulin, 
GLP-1 and GIP secretion, particularly in the postprandial period. Results from SOM230B2124 
suggest that the incretin-based therapies (GLP-1 analogues and DPP-4 inhibitors) may have the 
best potential to manage the hyperglycemia associated with pasireotide. In phase II and III 
studies, some patients with Cushing’s disease, acromegaly or neuroendocrine tumor required 
insulin to treat hyperglycemia. 
Glucose monitoring 
All patients need to be educated on the signs and symptoms of hyperglycemia. Patients must 
monitor their fasting blood glucose by fingerstick at home. It is recommended that a diary of 
the blood glucose values is used for appropriate management throughout the study. The 
collected data should be presented to the physician/diabetes specialist for evaluation. This data 
will not be collected by the sponsor. 
Blood glucose monitoring 
Close and frequent glucose monitoring is recommended during pasireotide treatment. 
• If any fasting values above 100 mg/dL are observed, the guidelines in Figure 14-3 are to 
be followed. These guidelines are based on the current recommendations from the 2012 
ADA and EASD aiming at a glycemic treatment goal of FPG <130 mg/dL (<7.2 mmol/L) 
(Inzucchi, SE et al. DiabetesCare June 2012 vol. 35 no. 6 1364-1379). Appropriate 
actions, such as initiation of anti-hyperglycemic therapy (and referral to diabetes 
specialist), are to be taken by the investigator as outlined on Figure 14-3. 
• If fasting blood glucose values dictate initiation of anti-hyperglycemic treatment (i.e., 
confirmed >130 mg/dL by self-monitoring), a fasting plasma glucose sample can be 
collected prior to initiation of anti-hyperglycemic treatment. 
• In case of dose increase, the glucose monitoring frequency should be increased following 
the recommendations described above at treatment initiation 
FPG and HbA1c monitoring 
• If FPG > 130 mg/dL or HbA1c ≥ 6.5 %, intervention for hyperglycemia needs to be 
implemented 
• If FPG > 160 mg/dL or HbA1c >7.5%, despite optimal anti-diabetic therapy, referral to a 
diabetologist is recommended. 
• If grade 3 hyperglycemia (FPG >250 mg/dL; >13.9 mmol/L) at any point in the study, 
despite appropriate anti-diabetic medication, pasireotide dose should be reduced 
• If consistently high glucose values [FPG ≥ 240 mg/dL (13.3 mmol/L) or HbA1c ≥ 10 %] 
despite appropriate management of diabetes including diet and/or exercise with or without 


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optimal anti-diabetic therapy and study drug dose reduction, patient must be discontinued 
from study treatment as outlined in Section 7.1.5.1. After the last study dose was received, 
patients have to monitor their fasting blood glucose for 1 month 
Figure 14-3 
Recommended guidance for fasting self-monitoring blood glucose 
management 
 


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14.5 
Appendix 5: Dose modification information for acromegaly or 
carcinoid patients receiving pasireotide LAR (from protocol 
CSOM230C2110, CSOM230C2305, CSOM230C2402 and 
CSOM230C2413) 
At any time during the roll-over, the pasireotide LAR dose may be increased up to a maximum 
dose of 60 mg per injection if biochemical control is not achieved, i.e. when their GH level ≥ 
2.5μg/L and/or IGF-1> ULN (age and sex related). Also the pasireotide LAR dose may be 
reduced if a patient is experiencing a drug related toxicity. The dose should be adjusted in 20 
mg steps, e.g. the pasireotide LAR dose can be adjusted from 60 mg to 40 mg or from 40 mg to 
20 mg. The decision to change the dose is to be made by the investigator or designee, and the 
dose change must be recorded in the Dosage Administration Record CRF. Patients should return 
to the previous dose once the tolerability issue resolves. 
Study C2413 specific: The minimum dose to be administered is 10 mg for patients with IGF-1 
levels falling below the lower limit of normal and have controlled mean GH levels. The IGF-1 
values are required to be confirmed to be below LLN on two consecutive assessments. If 
biochemical control is maintained, the patient can continue on the lower dose for the remainder 
of the trial. If biochemical control is lost, the dose should be increased. The 10 mg dose should 
be obtained from the 20 mg vial. 
Table 14-1 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
CTCAE grade ≤ 2 
No drug adjustments 
CTCAE grade ≥ 3 and 
assessed as study 
drug related 
Reduce pasireotide to the next lower dose level. 
• 
If the AE improves to grade ≤ 2 before the next administration, increase 
dose back to the prior dose. 
• 
If the dose is increased and the AE recurs at a grade ≥ 3, the dose 
should be reduced again. The patient should stay on this lower dose and 
no further dose titrations are allowed. 
• 
If the AE does not improve to grade ≤ 2, the dose is to be reduced 
further. If the AE does not improve to grade ≤ 2 on the minimum study 
dose, the treatment should be stopped. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in 
, 
 and 
. 
Table 14-2 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2110 
Dose (mg) 
Volume to be injected 
20 mg 
2 x 10 mg vial + 2 mL vehicle: whole volume to be injected or 1 x 20 mg vial + 2 mL 
vehicle: whole volume to be injected 
40 mg 
1 x 40 mg vial + 2 mL vehicle: whole volume to be injected 
60mg 
2 x 10 mg vial + 1 x 40 mg vial + 2 mL vehicle; whole volume to be injected or 1 x 20 mg 
vial + 1 x 40 mg vial + 2 mL vehicle; whole volume to be injected 


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Table 14-3 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2305 
Dose (mg) 
Volume to be injected 
20 mg 
1 x 20mg vial + 2 mL vehicle, whole volume to be injected 
40 mg 
1 x 40mg vial + 2 mL vehicle, whole volume to be injected 
60 mg 
1 x 20mg + 1 x 40mg vial + 2 mL vehicle, whole volume to be injected 
Table 14-4 
Dose adjustments for pasireotide LAR for patients from 
SOM230C2402 
Dose (mg) 
Volume to be injected 
40 mg 
1 x 20 mg vial + 1 x 20 mg vial + 2 mL vehicle, whole volume to be injected 
60 mg 
1 x 20 mg + 1 x 40 mg vial + 2 mL vehicle, whole volume to be injected 


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14.6 
Appendix 6: Dose modification information for Cushing’s 
patients receiving pasireotide LAR (from protocol 
SOM230G2304) 
Dose up-titration 
Patients will receive the same dose of pasireotide LAR as the last dose in the parent study. The 
maximum dose to be administered is 40 mg. Dose can be increased from 10 to 30 mg and from 
30 to 40 mg. During the roll-over study, the timing of the dose adjustments will be based on 
mUFC values, at the investigators discretion but must include a duration of at least 3 months 
on a current dose prior to up-titration and no tolerability issues are present. Patients receiving 
the 40 mg dose after Month 12 without tolerability issues that require a dose reduction will 
remain at this dose regardless of mUFC status (≤ 1x ULN or > 1 xULN). 
Dose down-titration 
Patients with tolerability issues can have their dose decreased as deemed necessary by the 
investigator (see Table 14-5). The dose can be increased again after the tolerability issue 
resolves. Patients unable to tolerate a minimum dose of 5 mg will be discontinued. 
These changes must be recorded on the Dosage Administration Record CRF. 
Table 14-5 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
AE CTC grade ≤ 2 
No drug adjustments 
AE CTC grade ≥ 3 and 
assessed as study drug 
related 
Reduce pasireotide LAR i.m. dose from: 
 
40mg to 30 mg 
 
30 mg to 10 mg 
 
10 mg to 5mg 
 
5mg - discontinue 
If AE improves to grade ≤ 2 before the next administration, increase dose 
to that prior to the dose reduction unless investigator opinion is to remain 
on current dose. If the dose is increased and the AE recurs at CTC grade 
≥ 3, the dose should be reduced again and the patient should stay on this 
lower dose and no further dose titrations are allowed. 
During the first 7 months of treatment, only 1 blinded dose decrease is 
allowed. If the AE persists at grade ≥ 3 after reduction, the patient is to be 
discontinued. 
After the first 7 months, If AE does not improve to grade ≤ 2 the dose is to 
be reduced further until the 5 mg dose is reached. If the AE does not 
improve to grade ≤ 2 on the minimum dose (5 mg) the patient will be 
withdrawn. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in 
, 
 and 
. 


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14.7 
Appendix 7: Dose modification information for dumping 
syndrome patients receiving pasireotide s.c or LAR (from 
protocol SOM230X2203) 
During the roll-over, dose increase will be allowed up to 60 mg (30, 40 and 60 mg) in the event 
that control is lost (glucose levels < 60 mg/dL at 90,120, 150 or 180 min during the OGTT or 
presence of symptoms). The up- titration must be in increments of 10 mg with the exception of 
patients receiving 40 mg when an increment of 20 mg (from 40 mg to 60 mg) is allowed. 
In case a dose reduction is needed due to toxicity (Table 14-8), the dose can be reduced to the 
immediate lower dose level (Table 14-7) and can be kept at this level if necessary. The lowest 
dose level allowed is 10 mg. In case a dose reduction is needed due to toxicity at 10mg, the 
patient can have a dose interruption up to 28 days from the intended day of the scheduled dose 
or can be discontinued and followed up for toxicity as defined in Table 14-6. If a patient requires 
a dose interruption of more than 28 days due to toxicity, then the patient must be discontinued 
from the study and followed up for toxicity Table 14-6. When treatment is interrupted or 
permanently discontinued due to an AE or abnormal laboratory value the patient must be 
followed at least once a week for 4 weeks, and subsequently in 4-week intervals, until resolution 
or stabilization of the event, whichever occurs first. 
Patients will be followed for adverse events and serious adverse events for 56 days following 
the last dose of pasireotide LAR treatment and for 28 days in case of discontinuation during 
pasireotide s.c. treatment. 
Table 14-6 outlines the follow-up required for toxicities of specific types and CTCAE grades- 


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Table 14-6 
Follow up evaluation (after treatment interruption) 
Toxicity 
Follow-up evaluation (after treatment interruption) 
Hematology 
If ≥ CTCAE grade 3 neutropenia or ≥ CTCAE grade 3 thrombocytopenia has been 
demonstrated, these parameters must be assessed at least twice a week until 
resolution to ≤ CTCAE grade 1 and then at least weekly until stabilization. 
Renal 
If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must be 
assessed at least twice a week until resolution to ≤ CTCAE grade 1 or baseline to and 
then at least weekly until stabilization. 
Hepatic 
For details on hepatic safety management, please refer to Appendix 2: Hepatic Safety 
Management 
Pancreatic 
If amylase and/or lipase ≥ CTCAE grade 3 has been demonstrated, these parameters 
must be assessed once at 2-4 days and once again at 7 days (± 1 day) and be 
repeated twice a week until resolution to ≤ CTCAE grade 2 and then at least weekly 
until stabilization. 
A CT scan or other imaging study to assess the pancreas, liver and gallbladder must 
be performed within 1 week of the first occurrence of any ≥ CTCAE grade 3 of 
amylase and/or lipase. 
In patients with serum triglycerides ≥ 500 mg/dL, urine amylase needs to be tested. 
Endocrine/ 
metabolic 
For details on hyperglycemia management, please refer to Appendix 4: ‘Fasting blood 
glucose management’. 
Cardiac 
For details on the follow-up and treatment of QT prolongation, please refer to 
Appendix 3 ‘Recommended follow up in case of QT-related findings during routine 
ECG’ 
Non-
laboratory 
Patients who experience non-laboratory AEs must be evaluated at least once a week 
following demonstration of the toxicity until resolution of the toxicity until stabilization 
of the toxicity, or until study completion. 
Table 14-7 
Dose reduction steps for pasireotide LAR monthly dosing q28d 
Dose reduction* 
 
Dose level - 0 
Dose level - 1 
Study Phase 
Pasireotide LAR 
60 mg q28d 
40 mg q28d 
Extension phase 
Pasireotide LAR 
40 mg q28d 
30 mg q28d 
Extension phase 
Pasireotide LAR 
30 mg q28d 
20 mg q28d 
Extension phase 
Pasireotide LAR 
20 mg q28d 
10 mg q28d *** 
LAR or Extension phases 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
*** The lowest dose allowed 10 mg. 


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Table 14-8 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
CTCAE grade ≤ 2 
No drug adjustments 
CTCAE grade ≥ 3 and 
assessed as study 
drug related 
Reduce pasireotide to the next lower dose level. 
• 
If the AE improves to grade ≤ 2 before the next administration, increase 
dose back to the prior dose. 
• 
If the dose is increased and the AE recurs at a grade ≥ 3, the dose 
should be reduced again. The patient should stay on this lower dose and 
no further dose titrations are allowed. 
• 
If the AE does not improve to grade ≤ 2, the dose is to be reduced 
further. If the AE does not improve to grade ≤ 2 on the minimum study 
dose, the treatment should be stopped. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in Appendix 2, 
 and 
. 


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14.8 
Appendix 8: Dose modification information for patients with 
metastatic melanoma or metastatic Merkel cell carcinoma 
receiving pasireotide s.c (from protocol SOM230X2404) 
Patients will continue receiving the dose of pasiroetide LAR q28 d at the same dose received 
during the follow-up period (20, 40, 60 or 80 mg). 
In case a dose reduction is needed due to toxicity, the dose can be reduced to the immediate 
lower dose level (from 80 mg q 28 d to 60 mg q 28 d, from 60 mg q 28 d to 40 mg q 28 d, and 
from 40 mg q 28 d to 20 mg q 28 d) and can be kept at this level if necessary for the duration 
of the study or until disease progression or death. However, the dose will not be re-escalated 
once reduced. In case patients receiving 20 mg q 28 d need to reduce the dose further, they 
should be discontinued from the study. If a patient requires a dose interruption of > 7 
consecutive days from the intended day of the scheduled dose, then the patient must be 
discontinued from the study and only follow up for toxicity defined in (reference table below). 
When treatment is interrupted or permanently discontinued due to an AE or abnormal laboratory 
value the patient must be followed at least once a week for 4 weeks, and subsequently in 4-
week intervals, until resolution or stabilization of the event, whichever occurs first. 
Patients who experience non-laboratory AEs should be evaluated at least once a week following 
demonstration of the toxicity until a resolution of the toxicity or study treatment completion 
occurs. 
Treatment interruption and treatment discontinuation 
Patients experiencing unacceptable toxicity (AE grade 3 or higher) that the investigator 
considers directly attributable to pasireotide should have their dose reduced or should be 
withdrawn from the study. (reference table below) should be regarded as a guideline for the 
treatment of patients experiencing Adverse Events which are judged to be drug related. Any 
deviation from these guidelines should be discussed and approved by the sponsor. 
Adverse events are described as mild (Grade 1), moderate (Grade 2), severe (Grade 3) or life-
threatening (Grade 4). Guidelines for treatment of patients experiencing adverse events are 
indicated below (reference table below). 


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Table 14-9 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia for patients from protocol SOM230X2402 
Patients 
Adverse event 
Action 
All 
AE grade ≤ 2 (mild to 
moderate) 
No drug adjustments 
 
AE grade ≥ 3 (severe to life-
threatening) and judged as 
drug related*# 
Reduce dose by 20 mg q 28 d to the next dose level as 
described above in this appendix (Appendix 8). 
Once the dose is reduced, the patient will stay on the 
lowered dose for the entire duration of the roll-over 
If AE recurs at grade ≥ 3, reduce dose by 20 mg q 28 d 
again and remain at lower dose. If AE does not improve 
to grade ≤ 2 the dose is to be reduced further (following 
the guidance as described above in this appendix 
(Appendix 8). If the AE does not improve to grade ≤ 2 on 
the minimum dose (20 mg q 28 d), patient is to 
discontinue treatment and followed for safety. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in Appendix 2, 
 and 
. For management of diarrhea, please 
refer to (reference below section) 
14.8.1 
Guidance for diarrhea management 
General recommendations: 
• Stop all lactose-containing products, alcohol 
• Stop laxatives, bulk fiber (Metamucil, Procter & Gamble), and stool softeners (docusate 
sodium; Colace, Roberts) 
• Drink 8 to 10 large glasses of clear liquids per day (water, Pedialyte (Ross),Gatorade 
(Quaker), broth) 
• Eat frequent small meals (bananas, rice, applesauce, Ensure, toast) 
• Stop high-osmolar food supplements such as Ensure Plus and Jevity Plus (with fiber) 
It is recommended that patients be provided loperamide tablets. It is mandatory that patients are 
instructed on the use of loperamide at cycle 1 in order to manage signs or symptoms of diarrhea 
at home. Patients should be instructed to start oral loperamide (initial administration of 4mg, 
then 2mg every 4 hours (maximum of 16 mg/day) at the first sign of loose stool or symptoms 
of abdominal pain. These instructions should be provided at each cycle and the site should 
ensure that the patient understood the instruction. At the beginning of each cycle, each patient 
should be specifically questioned regarding any experience of diarrhea or diarrhea related 
symptoms. If symptoms were experienced, then the site should question the patient regarding 
the actions taken for these symptoms. 
Treatment of diarrhea grade 1 or 2 
Diarrhea grade 1 or 2 will be treated with standard loperamide (initial at first administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool). 


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12-24 hours later: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide after 12-hours diarrhea-free interval 
Diarrhea unresolved 
Persisting diarrhea grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections with monitoring of patients condition to rule out 
dehydration, sepsis, ileus) medical check and selected workup if patient does not need 
hospitalization (see section Diarrhea workup and additional test in the particular trial protocol). 
Observe patient for response to antidiarrheal treatment. 
Persisting diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide 
(initial 4 mg, then 2 mg every 2 hours) and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of i.v. fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (perform 
appropriate additional testing). Observe patient for response. 
After 12-24 hours: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide and/or other treatment after 12-hours diarrhea-free interval 
Diarrhea unresolved 
• If diarrhea still persisting (NCI CTC grades 1 and 2), after 2x 24 hours with high dose 
loperamide and opiates then admit to hospital and employ measures as for grade 3 and 4 
until diarrhea resolved 
• If diarrhea still persisting and progressed to NCI grades 3 and 4, employ measures 
described below. 
Treatment of diarrhea grade 3 or 4 
Severe diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide (initial 
4 mg, then 2 mg every 2 hours and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of i.v. fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (see section 
Diarrhea workup and additional test in the particular trial protocol). Observe patient for 
response. 
After 12-24 hours: 
• If diarrhea persisting administer s.c. Sandostatin/octreotide (100-500 µg tid) 


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• Continue IV fluids and antibiotics as needed 
• If diarrhea grade 3 or 4 still persists patients should receive opium tincture or 
dihydrocodeine tartrate injections s.c. or i.m. 
• If diarrhea grade 3 or 4 is still persisting s.c. Sandostatin/octreotide (500-1000 µg tid) 
should be administered. 
• To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 2 
weeks. Treatment should be continued only when diarrhea resolved. 
Diarrhea workup 
Perform appropriate tests (Fine and Schiller 1999). 
Spot stool analysis 
• Collect stool separating it from urine (special containers, analysis immediately, 
exceptionally freeze samples) 
• Blood 
• Fecal leukocytes (Wright's staining and microscopy) or 
• Clostridium difficile toxin 
• Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immonunosuppressed 
patients), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic etc., 
possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water) 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is likely 
to be fragile with evidence of colitis and thus great care and caution must be exercised in 
undertaking these invasive procedures. 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy of 
proximal jejunum to assess extent of inflammatory jejunitis 
• Sigmoidoscopy - reassessment of colitis 
14.8.2 
Dose and treatment schedule 
Study treatments 
in the follow-up 
phase 
Pharmaceutical 
form and route of 
administration 
Total 
Monthly 
Dose 
Frequency 
and/or 
Regimen 
Vials Used 
Pasireotide LAR, 
im 
intramuscular (i.m.) 
20mg 
20 mg q 28 d 
1 vial of 20 mg powder, 
(+1 vial of 2 ml vehicle) 
Pasireotide LAR, 
im 
intramuscular (i.m.) 
40 mg 
40 mg q 28 d 
1 vial of 40 mg powder, 
(+1 vial of 2 ml vehicle) 
Pasireotide LAR, 
im 
intramuscular (i.m.) 
60 mg 
60 mg q 28 d 
1 vial of 20 mg + 1 vial of 40 
mg or 1 vial of 60 mg 
powder, 
(+ 1 vial of 2 ml vehicle) 
Pasireotide LAR, 
im 
intramuscular (i.m.) 
80 mg 
80 mg q 28 d 
2 vials of 40 mg powder, 
(+ 1 vial of 2 ml vehicle) 


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14.9 
Appendix 9: Dose modification information for patients with rare 
tumors of neuroendocrine origin receiving pasireotide LAR (from 
protocol SOM230D2203) 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to keep the patient on study drug. 
Study drug for this study will be pasireotide LAR at 60 mg every 28 days. If tolerability issues 
occur, the treatment dose may be reduced to pasireotide LAR at 40 mg with next scheduled 
injection. A patient receiving 40 mg showing further tolerability issues may reduce the dose 
level to 20 mg at the next injection. The investigator may, at his or her discretion, increase the 
patient’s dose of study medication after resolution of tolerability issue. However, patients not 
able to tolerate the minimum pasireotide LAR dose of 20 mg will be discontinued from study. 
Patients who have not achieved symptom control or in whom adequate control is not maintained 
are permitted to use rescue dose of pasireotide s.c. up to 600 µg b.i.d to control their symptoms 
at anytime during the study duration. If tolerability issues arise upon use of s.c. injections for 
rescue purposes, these injections should be stopped. Once the tolerability issue has resolved, 
the s.c. injections may be resumed if needed. The rescue s.c. dose may not exceed 600 µg b.i.d. 
All dose changes must be recorded on the Dosage Administration Record CRF. 
Table 14-10 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
CTCAE grade ≤ 2 
No drug adjustments 
CTCAE grade ≥ 3 and 
assessed as study 
drug related 
Reduce pasireotide to the next lower dose level. 
• 
If the AE improves to grade ≤ 2 before the next administration, increase 
dose back to the prior dose. 
• 
If the dose is increased and the AE recurs at a grade ≥ 3, the dose 
should be reduced again. The patient should stay on this lower dose and 
no further dose titrations are allowed. 
• 
If the AE does not improve to grade ≤ 2, the dose is to be reduced 
further. If the AE does not improve to grade ≤ 2 on the minimum study 
dose, the treatment should be stopped. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in Appendix 2, 
 and 
. 


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14.10 
Appendix 10: Dose modification information for patients with 
neuroendocrine tumors receiving pasireotide LAR (from protocol 
SOM230D2101) 
Patients continuing into the roll-over study will receive the same dose of pasireotide LAR every 
28 days as the last dose administered during the parent study. 
When treatment is interrupted or permanently discontinued due to an AE or abnormal laboratory 
value the patient must be followed at least once a week for 8 weeks, and subsequently in 4-
week intervals, until resolution or stabilization of the event, whichever comes first. If a patient 
requires a dose delay of > 21 days from the intended day of the scheduled dose, then the patient 
must be discontinued from the study. However, the patient will be followed up for toxicity as 
previously described. All patients will be followed for adverse events and serious adverse events 
for at least 56 days following the last dose of pasireotide LAR treatment. 
Table 14-11 outlines the follow-up required for toxicities of specific types and CTCAE grades. 
Table 14-11 
Follow-up evaluations for selected toxicties 
Toxicity 
Follow-up evaluation 
Hematology 
If ≥ CTCAE grade 3 neutropenia or ≥ CTCAE grade 3 thrombocytopenia have been 
demonstrated, these parameters must be repeated at least twice a week until 
resolution to ≤ CTCAE grade 1 to allow for initiation of re-treatment, and then at 
least weekly until either initiation of retreatment or until stabilization. 
Renal 
If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must be 
repeated at least twice a week until resolution to ≤ CTCAE grade 1 or baseline to 
allow for initiation of re-treatment, and then at least weekly until either initiation of 
re-treatment or until stabilization. 
Hepatic 
For details on hepatic safety management, please refer to Appendix 2: Hepatic 
Safety Management 
Pancreatic 
If amylase and/or lipase ≥ CTCAE grade 3 has been demonstrated, these 
parameters must be assessed once at 2-4 days and once again at 7 days (± 1 day) 
and be repeated twice a week until resolution to ≤ CTCAE grade 2 to allow for 
initiation of re-treatment, and then at least weekly until either resolution to ≤ CTCAE 
grade 1 or until stabilization. 
A CT scan or other imaging study to assess the pancreas, liver and gallbladder 
must be performed within 1 week of the first occurrence of any ≥ CTCAE grade 3 of 
amylase and/or lipase. 
In patients with serum triglycerides ≥ 500 mg/dL, urine amylase needs to be tested. 
Endocrine/ 
metabolic 
For details on hyperglycemia management, please refer to Appendix 4: ‘Fasting 
blood glucose management’. 
Cardiac 
For details on the follow-up and treatment of QT prolongation, please refer to 
Appendix 3 ‘Recommended follow up in case of QT-related findings during routine 
ECG’ 
Non-laboratory 
Patients who experience non-laboratory DLTs must be evaluated at least once a 
week following demonstration of the toxicity until resolution of the toxicity to allow for 
re-treatment, until stabilization of the toxicity, or until study completion. 


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14.10.1 Dose modification and dose delay 
The patient should be followed as described in Table 14-12 until the toxicity in question has 
resolved to CTCAE grade 1 or to the patients’ baseline value, or until the toxicity is deemed 
irreversible. 
Patients who cannot be treated with pasireotide LAR within 21 days of the intended dosing day 
due to drug-related toxicity should have weekly follow-ups that include a physical examination, 
vital signs including weight, performance status, ECGs, and assessment of adverse events and 
concomitant medication. Following toxicity, ECG, hematology, renal and liver function tests 
should be performed as appropriate. 
If a patient requires a dose delay of > 21 days from the intended day of the next scheduled dose 
of pasireotide LAR, then the patient must be discontinued from the study. Patients who 
discontinue from the study for a study drug-related adverse event or an abnormal laboratory 
value, must be followed as described in Table 14-11. 
For each patient, only one dose reduction will be allowed after which the patient should be 
discontinued from the study. For each patient, once a dose level reduction has occurred, the 
dose level may not be re-escalated during subsequent treatment cycles with pasireotide LAR. 
Dose reduction for pasireotide LAR means treatment at a lower pasireotide LAR dose level. 
Dose modification for patients treated at the starting dose of 80 mg will be 60 mg. 
All interruptions or changes to study drug administration must be recorded on the Dosage and 
Administration Record eCRF. 
14.10.2 Treatment interruption and treatment discontinuation 
All dose modifications should be based on the worst preceding toxicity. 
Each patient is only allowed one dose reduction. In addition, a patient must discontinue 
treatment with pasireotide LAR if, after treatment is resumed at a lower dose, the toxicity recurs 
with the same or worse severity 
Table 14-12 
Criteria for interruption and re-initiation of pasireotide LAR 
Recommended dose modifications for pasireotide LAR 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of 
therapy 
No toxicity 
Maintain dose level 
Hematologic 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 
1500/mm3) 
Maintain dose level 
Grade 2 (ANC < 1500 - 
1000/mm3) 
Maintain dose level 
Grade 3 (ANC < 1000 - 
500/mm3) 
Omit dose until resolved to ≤ Grade 2, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 


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Recommended dose modifications for pasireotide LAR 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of 
therapy 
Grade 4 (ANC < 500/mm3) 
Omit dose until resolved to ≤ Grade 2, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN - 
75,000/mm3) 
Maintain dose level 
Grade 2 (PLT < 75,000 - 
50,000/mm3) 
Maintain dose level 
Grade 3 (PLT < 50,000 - 
25,000/mm3) 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Grade 4 (PLT < 25,000/mm3) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Febrile neutropenia (ANC < 1.0 
x 109/L, fever ≥ 38.5°C) 
Omit dose until resolved, then  1 dose level 
Renal 
Serum creatinine 
 
< 2 x ULN 
Maintain dose level 
2-3 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 6.0 x ULN) 
Omit dose and discontinue patient from study treatment 
Grade 4 (> 6.0 x ULN) 
Omit dose and discontinue patient from study treatment 
Hepatic 
Bilirubin 
 
< 2 x ULN 
Maintain dose level 
2-3 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
Grade 4 (> 10.0 x ULN) 
Omit dose and discontinue patient from study treatment 
NOTE: If grade 3 or 4 hyperbilirubinemia is due to the indirect 
(unconjugated) 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 
AST or ALT 
Grade 1 (> ULN - 2.5 x ULN) 
Maintain dose level 
Grade 2 (> 2.5 - 5.0 x ULN) 
Maintain dose level 


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Recommended dose modifications for pasireotide LAR 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of 
therapy 
( >5.0 and ≤ 8 x ULN) 
If ALT or AST return to less than 5 x ULN study drug can be 
resumed and patient can continue study per protocol. 
If persistent for more than 14 days, discontinue patient from study 
treatment. 
In the event of a re-occurrence, discontinue patient from study 
treatment. 
(> 8 x ULN) 
Omit dose and discontinue patient from study treatment 
Pancreatic 
Pancreatitis 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Maintain dose level 
Maintain dose level 
Omit dose and discontinue patient from study treatment 
Omit dose and discontinue patient from study treatment 
Amylase and/or lipase 
Grade 1 (> ULN - 1.5 x ULN) 
Grade 2 (> 1.5 - 2.0 x ULN) 
Grade 3 (> 2.0 - 5.0 x ULN) 
 
 
 
 
 
Grade 4 (> 5.0 x ULN) 
 
Maintain dose level 
Maintain dose level 
For asymptomatic: 
Omit dose until resolved to ≤ Grade 1, then 
- If resolved ≤ 7 days, then maintain dose level 
- If resolved > 7 days, then  1 dose level 
For symptomatic: 
Omit dose and discontinue patient from study treatment 
Omit dose and discontinue patient from study treatment 
A CT scan or other imaging study to assess the pancreas, liver and 
gallbladder must be performed within 1 week of the first occurrence 
of any ≥ CTCAE grade 3 of amylase and/or lipase. 
Endocrine/metabolic 
Fasting plasma glucose (FPS) 
or 2-hour postprandial capillary 
glucose (PPG) 
FPG <126 mg/dL or PPG < 140 
mg/dL 
Grade 1 (> ULN – 160 mg/dL) 
Grade 2 (> 160 – 250 mg/dL) 
Grade 3 (> 250 – 500 mg/dL) 
Grade 5 (> 500 mg/dL) 
 
 
 
Maintain dose level 
Please refer to Appendix 14.2 ‘Guideline for study drug-induced 
hyperglycemia’ 
Cardiac 
Cardiac - prolonged QTc 
interval 
- QTcF > 480 ms and ≤ 500 ms 
 
 
If at any time a QTcF > 480 ms and ≤ 500 ms is observed a 
cardiology consultation must be sought to re-evaluate the abnormal 
ECG finding. 


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Recommended dose modifications for pasireotide LAR 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of 
therapy 
- QTcF > 500 msec 
1. Triplicate ECGs (2-3 minutes apart) need to be taken 
approximately 1 hour after the initial ECG. 
2. If the mean QTcF is > 500 ms, the patient must postpone study 
treatment until a cardiologist has re-evaluated the ECG. 
3. The re-evaluation of ECG needs to be done as soon as 
practical but within 7 days of the initial abnormal ECG. 
4. If the cardiologist confirms a mean QTcF > 500 ms, the patient 
must be discontinued. 
Cardiac general 
Grade 1 or 2 
Grade 3 
Grade 4 
 
Maintain dose level 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Omit dose and discontinue patient from study treatment 
Other adverse events 
Grade 1 or 2 
Grade 3 
Grade 4 
Maintain dose level 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Omit dose and discontinue patient from study treatment 
14.10.3 Guidance for diarrhea management 
General recommendations: 
• Stop all lactose-containing products, alcohol 
• Stop laxatives, bulk fiber (Metamucil, Procter & Gamble), and stool softeners (docusate 
sodium; Colace, Roberts) 
• Drink 8 to 10 large glasses of clear liquids per day (water, Pedialyte (Ross),Gatorade 
(Quaker), broth) 
• Eat frequent small meals (bananas, rice, applesauce, Ensure, toast) 
• Stop high-osmolar food supplements such as Ensure Plus and Jevity Plus (with fiber) 
It is recommended that patients be provided loperamide tablets. It is mandatory that patients are 
instructed on the use of loperamide at cycle 1 in order to manage signs or symptoms of diarrhea 
at home. Patients should be instructed to start oral loperamide (initial administration of 4mg, 
then 2mg every 4 hours (maximum of 16 mg/day) at the first sign of loose stool or symptoms 
of abdominal pain. These instructions should be provided at each cycle and the site should 
ensure that the patient understood the instruction. At the beginning of each cycle, each patient 
should be specifically questioned regarding any experience of diarrhea or diarrhea related 
symptoms. If symptoms were experienced, then the site should question the patient regarding 
the actions taken for these symptoms. 
Treatment of diarrhea grade 1 or 2 
Diarrhea grade 1 or 2 will be treated with standard loperamide (initial at first administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool). 


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12-24 hours later: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide after 12-hours diarrhea-free interval 
Diarrhea unresolved 
Persisting diarrhea grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections with monitoring of patients condition to rule out 
dehydration, sepsis, ileus) medical check and selected workup if patient does not need 
hospitalization (see section Diarrhea workup and additional test in the particular trial protocol). 
Observe patient for response to antidiarrheal treatment. 
Persisting diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide 
(initial 4 mg, then 2 mg every 2 hours) and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of i.v. fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (perform 
appropriate additional testing). Observe patient for response. 
After 12-24 hours: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide and/or other treatment after 12-hours diarrhea-free interval 
Diarrhea unresolved 
• If diarrhea still persisting (NCI CTC grades 1 and 2), after 2x 24 hours with high dose 
loperamide and opiates then admit to hospital and employ measures as for grade 3 and 4 
until diarrhea resolved 
• If diarrhea still persisting and progressed to NCI grades 3 and 4, employ measures 
described below. 
Treatment of diarrhea grade 3 or 4 
Severe diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide (initial 
4 mg, then 2 mg every 2 hours and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of i.v. fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (see section 
Diarrhea workup and additional test in the particular trial protocol). Observe patient for 
response. 
After 12-24 hours: 
• If diarrhea persisting administer s.c. Sandostatin/octreotide (100-500 µg tid) 


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• Continue IV fluids and antibiotics as needed 
• If diarrhea grade 3 or 4 still persists patients should receive opium tincture or 
dihydrocodeine tartrate injections s.c. or i.m. 
• If diarrhea grade 3 or 4 is still persisting s.c. Sandostatin/octreotide (500-1000 µg tid) 
should be administered. 
• To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 2 
weeks. Treatment should be continued only when diarrhea resolved. 
Diarrhea workup 
Perform appropriate tests (Fine and Schiller 1999). 
Spot stool analysis 
• Collect stool separating it from urine (special containers, analysis immediately, 
exceptionally freeze samples) 
• Blood 
• Fecal leukocytes (Wright's staining and microscopy) or 
• Clostridium difficile toxin 
• Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immonunosuppressed 
patients), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic etc., 
possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water) 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is likely 
to be fragile with evidence of colitis and thus great care and caution must be exercised in 
undertaking these invasive procedures. 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy of 
proximal jejunum to assess extent of inflammatory jejunitis 
• Sigmoidoscopy - reassessment of colitis 


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14.11 
Appendix 11: Dose modification information for patients with 
Cushing’s receiving pasireotide s.c or acromegaly receiving 
pasireotide LAR (from protocols SOM230B2219 and 
SOM230B2305) 
Cushing’s disease: Pasireotide (SOM230) s.c. injection: 300, 600 or 900 µg b.i.d.; Acromegaly: 
Pasireotide (SOM230) i.m. LAR: 20, 40 or 60 mg every 28 days 
14.11.1 Dose modifications for patients from protocol SOM230B2219 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following guidelines 
need to be applied: 
Cushing’s disease: At any time during the study the pasireotide dose may be reduced by 300 µg 
b.i.d for safety or tolerability reasons. Dose may be increased to 600 or 900 µg b.i.d if 
tolerability issues have resolved per investigator’s discretion. 
Acromegaly: Dose up-titration of pasireotide LAR to 60 mg i.m. once/28 days will be allowed 
in patients without adequate levels of GH and IGF-1 (no reduction of mean GH level to <2.5 
µg/L and no normalization of IGF-1 to within normal limits (age and sex related)) as determined 
locally. A dose reduction by 20 mg will be permitted in case of tolerability issues, but the patient 
may return to previous dose once tolerability issues are resolved. 
Dose should also be modified for adverse events as described in Table 14-13. 
Any dose change must be recorded on the respective Dosage Administration Record CRF. 
14.11.2 Dose modifications for patients from protocol SOM230B2305 
For patients who are unable to tolerate the protocol-specified dose level, dose adjustments are 
permitted in order to keep the patient on study drug. (Refer to Table 14-13). At any time during 
the study, patients with an early morning (between 8 and 10am) serum cortisol < 3 µg/dl and a 
UFC measurement < LLN or symptoms suggestive of hypoadrenalism (e.g. postural 
hypotension, nausea, and abdominal pain) and a UFC measurement <LLN should have their 
dose reduced. 
During the roll-over, the investigator may reduce the dose in 300 µg s.c. b.i.d. steps at any time 
if the patient does not tolerate the given pasireotide dose. The minimum dose to be administered 
will be 300 µg s.c. b.i.d.. If the patient does not tolerate the 300 µg s.c. b.i.d. dose, he/she will 
be withdrawn from the study. 
These changes must be recorded on the Dosage Administration Record. 


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Table 14-13 
Dose modification for AEs, excluding LFT increase, QT prolongation 
and hyperglycemia 
Adverse event 
Action 
CTCAE grade ≤ 2 
No drug adjustments 
CTCAE grade ≥ 3 and 
assessed as study drug 
related 
Reduce pasireotide to the next dose level. 
If the AE improves to grade ≤ 2 before the next administration, increase 
dose back to the prior dose. If the dose is increased and the AE recurs at a 
grade ≥ 3, the dose should be reduced again. The patient should stay on 
this lower dose and no further dose titrations are allowed. 
If the AE does not improve to grade ≤ 2, the dose is to be reduced further. 
If the AE does not improve to grade ≤ 2 on the minimum study dose, the 
treatment should be stopped. The patient should be discontinued and 
followed up for safety. 
For the management of LFT increase, QT prolongation, and hyperglycemia refer to specific 
instructions provided in Appendix 2, 
 and 
. 


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14.12 
Appendix 12: Dose modification information for patients with 
Cushing’s receiving pasireotide s.c in combination with 
cabergoline (SOM230B2411) 
Table 14-14 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen 
Pasireotide 
Subcutaneous 
0.3mg, 0.6mg, and 0.9mg 
Twice a day 
Cabergoline 
Oral 
0.5mg or 1.0mg 
Once a day 
Pasireotide untreated patients: will begin their treatment with pasireotide 0.6mg twice a day 
monotherapy for 8 weeks. If biochemical control is not achieved by the end of the 8-week 
period, and the 0.6mg dose is well tolerated, the dose of pasireotide will be increased to 0.9mg 
twice a day for another 8 weeks. If biochemical control is still not achieved at 0.9mg twice a 
day and the dose is well tolerated, the combination treatment of pasireotide 0.9mg twice a day 
plus cabergoline 0.5mg once a day will be given for another 8 weeks. If biochemical control is 
not yet achieved either during or at the end of the 8-week period, cabergoline dose will be 
increased to 1.0mg once a day. 
If a patient shows high sensitivity to pasireotide 0.6mg bid resulting in cortisol values <LLN 
and/or signs/symptoms consistent with the diagnosis of hypocortisolism, the dose of pasireotide 
can be decreased to 0.3mg bid. Despite the dose reduction, some patients may still present with 
cortisol values <LLN and/or signs/symptoms consistent with hypocortisolism; in this case the 
dose of pasireotide can be further reduced to 0.3 mg qd in order to achieve and maintain normal 
cortisol levels. 
If the 0.9mg twice a day dose is not tolerated and biochemical control is not achieved, patient 
will begin combination treatment of pasireotide at 0.6mg twice a day plus cabergoline at 0.5mg 
once a day for 8 weeks. If during or at the end of the 8-week period, the biochemical control is 
not achieved, the combination dose will be increased to pasireotide at 0.6mg twice a day plus 
cabergoline at 1.0mg once a day for 8 weeks. The patient will continue with the highest 
combination dose of 0.6mg pasireotide twice a day plus 1.0mg cabergoline once a day, or  
0.9mg pasireotide twice a day plus 1.0mg of cabergoline once a day for 8 weeks. (see Table 14-
15) 
If patient does not tolerate 0.6mg twice a day, the dose of pasireotide should be decreased to 
0.3mg twice a day. If pasireotide 0.3mg twice a day does not lead to biochemical control after 
at least 8 weeks of treatment, combination with cabergoline as described above can be initiated 
(see Table 14-15). 
If patient cannot increase from 0.6mg twice a day to 0.9mg twice a day due to safety, and is not 
yet biochemically controlled, combination with cabergoline 0.5mg qd can be initiated right 
away with pasireotide at 0.6mg twice a day (see Table 14-15).   
If patient is being escalated to 0.9mg twice a day, but cannot tolerate the dose, dose should be 
reduced to 0.6mg twice a day. If the latter dose does not lead to biochemical control, 
combination with cabergoline as described above can be initiated (see Table 14-15). 


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If combination pasireotide and cabergoline 0.5mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 0.5mg every other day. If 0.5mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 14-15). 
If combination pasireotide and cabergoline 1.0mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 1.0mg every other day. If 1.0mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 14-15). 
The minimum treatment of any regimen is 8 weeks. Patients losing biochemical control at any 
time point after the 8 week period will have the dose of the study mediation increased 
immediately to the next level provided that the dose is well tolerated. 
Table 14-15 
Pasireotide and cabergoline dose modification steps for pasireotide 
un-treated patients 
Pasireotide: pasi 
Cabergoline: 
cabe 
Starting dose 
level 
Dose 
modification 
level – 1 
Dose 
modification 
level – 2 
Dose 
modification 
level - 3 
Dose 
medication 
level - 4 
Modification # 1 
0.6mg bid pasia 
0.3mg bid pasib 
0.3mg bid pasi 
+ 0.5mg cabe 
qdb 
0.3mg bid pasi 
+ 1.0mg cabe 
qd 
 
Modification # 2 
0.6mg bid pasib 
0.9mg bid pasib 
0.9mg bid pasi 
+ 0.5mg qd 
cabeb 
0.9mg bid pasi 
+ 1.0mg qd 
cabe 
 
Modification # 3 
0.6mg bid pasib  
0.9mg bid pasia 
0.6mg bid pasib 
0.6mg bid pasi 
+ 0.5mg cabe 
qdb 
0.6mg bid 
pasi + 
1.0mg cabe 
qd 
Modification # 4 
0.6mg bid pasic 
0.6mg bid pasi 
+ 0.5mg qd 
cabeb  
0.6mg bid pasi 
+ 1.0mg cabe 
qd 
 
 
Modification # 5 
0.9mg bid pasiab  0.6mg bid pasi 
+ 0.5mg qd 
cabeb 
0.6mg bid pasi 
+ 1.0mg qd 
cabe 
 
 
Modification # 6 
0.3, 0.6 or 
0.9mg bid pasi 
+ 0.5mg qd 
cabea 
0.3, 0.6 or 
0.9mg bid pasi 
+ 0.5mg every 
other day 
cabeab 
Discontinuation 
if no clinical 
benefit 
 
 
Modification # 7  
0.3, 0.6 or 
0.9mg bid pasi 
+ 1.0mg qd 
cabea 
0.3, 0.6 or 0.9 
mg bid pasi + 
1.0mg every 
other day 
cabeab 
Discontinuation 
if no clinical 
benefit 
 
 
aDose modification is initiated if the current dose is not tolerated 
bDose modification is initiated if biochemical control is not achieved 
cDose cannot be increased to the next level due to toxicity but biochemical control is not achieved 
Patients currently treated with maximal tolerated doses of pasireotide monotherapy: 
0.3mg bid, 0.6mg bid or 0.9mg bid, for at least 8 weeks but did not achieve biochemical control 
will begin their combination treatment of pasireotide at 0.3mg, 0.6mg  or 0.9mg bid plus 0.5mg 
of cabergoline once a day at study entry. They will continue the treatment for 8 weeks. If 


Recordati  
 Confidential 
Page 94 
Amended Protocol Version 05 (Clean) 
 
Protocol No. CSOM230B2412 
 
biochemical control is not achieved at the end of the 8-week period, the dose of cabergoline 
will be increased to 1.0mg once a day and continue with the combination treatment for the 
remainder of study treatment.  
If combination pasireotide and cabergoline 0.5mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 0.5mg every other day. If 0.5mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 14-16). 
If combination pasireotide and cabergoline 1.0mg once a day is not tolerated, the dose of 
cabergoline can be reduced to 1.0mg every other day. If 1.0mg every other day is not tolerated, 
and biochemical control is not achieved, patient should be considered for discontinuation if no 
clinical benefit is derived (see Table 14-16). 
The minimum treatment of any regimen is 8 weeks. Patients losing biochemical control at any 
time point after the 8-week treatment period at the starting combination dose will have the dose 
of the study mediation increased immediately to the next level provided that the dose is well 
tolerated (see Table 14-16). 
Table 14-16 
Pasireotide and cabergoline dose modification steps for patients 
currently treated with maximal tolerated doses of pasireotide 
monotherapy 
Pasireotide: pasi 
Cabergoline: cabe 
Starting dose level 
Dose modification 
level – 1 
Dose modification 
level – 2 
Modification # 1 
0.3, 0.6 or 0.9mg bid 
pasi + 0.5mg qd cabea 
0.3, 0.6 or 0.9mg bid pasi + 
0.5mg every other day cabea 
Discontinuation if no 
clinical benefit 
Modification # 2 
0.3, 0.6 or 0.9mg bid 
pasi + 0.5mg qd cabeb 
0.3, 0.6 or 0.9mg bid pasi + 
1.0mg qd cabea  
 
Modification # 3 
0.3, 0.6 or 0.9mg bid 
pasi + 1.0mg qd cabea 
0.3, 0.6 or 0.9 mg bid pasi + 
1.0mg every other day cabea 
0.3, 0.6 or 0.9mg bid pasi 
+ 0.5mg qd cabe 
aDose modification is initiated if the current dose is not tolerated 
bDose modification is initiated if biochemical control is not achieved 
 

SAP_001.pdf: 
 
             Statistical Analysis Plan 
 
 
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Study Code: CSOM230B2412 
 
 
Version 2.0 
Date: 15Mar2024 
 
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CSOM230B2412 
 
An open label, multi-center pasireotide roll-over study for 
patients who have completed a previous Novartis- 
sponsored pasireotide study and are judged by the 
investigator to benefit from continued pasireotide treatment 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 
2 
Date 
15 March 2024 
Total Page Number 
28 
Attachment 
2 
 
 
 
 


 
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Revision History 
 
Date 
Version 
Summary of Changes 
20 April 2017 
1.0 
First Version 
29 June 2017 
1.0 
Incorporated comments from LS, clinical team and statistical 
programming team 
6 September 
2019 
Amendment 1 
Addition of new parent studies to Table 2-1 
9 February 2021 
1.1 
Change of sponsor 
Reformatting according with SOP 06BM13R02 
29 September 
2023 
1.2 
Revision for final study report 
13 October 
2023 
1.3 
Correction of cut-off percentage for AEs tables 
15 March 2024 
2.0 
Update because of discrepancies identified during the 
the audit on Clinical Study Report 
- Alignement with protocol amendment 5 
- End of study definition 
 
 
 


 
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Version 2.0 
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Approval Page 
 
 
 
Document Title: 
An open label, multi-center pasireotide roll-over study for 
patients who have completed a previous Novartis- sponsored pasireotide study 
and are judged by the investigator to benefit from continued pasireotide 
treatment 
Version 2.0 
 
 
Prepared and approved by: 
 
Name (Title) 
Signature 
Date 
Alessandro Antonellini 
 
 
 
 
 
 
 
Effective Date: 
15 March 2024 
 
 
 
 
 


 
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Version 2.0 
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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 
Timing of interim analyses and design adaptations ................................................... 7 
2.4 
Definition of end of the study .................................................................................... 7 
2.5 
Early study termination .............................................................................................. 8 
2.6 
STATISTICAL SOFTWARE .................................................................................... 8 
3 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ..................................... 8 
4 
STATISTICAL METHODS .............................................................................................. 8 
4.1 
Data analysis general information .............................................................................. 8 
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 
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 ............................................................................... 12 
5.2 
DERIVATION RULES ............................................................................................ 14 
5.2.1 
AEs coding/grading .............................................................................. 14 
5.2.2 
Study day .............................................................................................. 15 
6 
ANALYSIS POPULATIONS .......................................................................................... 15 
6.1 
RELEVANT PROTOCOL DEVIATIONS ............................................................. 15 
6.2 
DEFINITION OF POPULATIONS FOR ANALYSIS ........................................... 15 
6.2.1 
Full Analysis Set ................................................................................... 15 
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 ................................................................................... 16 
7.1.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
7.2 
Analysis of secondary efficacy objective(s) ............................................................. 16 
7.2.1 
Secondary endpoints ............................................................................. 16 
7.3 
EXTENT OF EXPOSURE ....................................................................................... 16 
7.4 
SAFETY ANALYSIS .............................................................................................. 17 
7.4.1 
Adverse events (AEs) ........................................................................... 17 
7.4.2 
Deaths ................................................................................................... 18 
8 
ATTACHMENTS ............................................................................................................ 19 
8.1 
PROTOCOL DEVIATION LIST ............................................................................. 19 
8.2 
LIST 0F AES OF SPECIAL INTEREST ................................................................. 22 


 
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1 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DI 
Dose Intensity 
FAS 
Full Analysis Set 
EC 
Ethic Committee 
eCRF 
Electronic Case Report Form 
EOT 
End Of Treatment 
IIT 
Investigator Initiated Trial 
IRB 
Institutional Review Board 
LAR 
Long Active Release 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PASS 
Post Authorization Safety Study 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
s.c. 
Sub-cutaneous 
SOC 
System Organ Class 
 
2 
INTRODUCTION  
This statistical analysis plan (SAP) describes all planned analyses for the clinical study 
report (CSR) of study CSOM230B2412, an open-label, multi-center, Phase IV, roll-over 
study in patients who have completed a prior Novartis-sponsored pasireotide (SOM230) 
study and are judged by the investigator to benefit from continued treatment with 
pasireotide. 
The content of this SAP is based on protocol CSOM230B2412 Amendment 5.0. All decisions 
regarding final analysis, as defined in the SAP document, will be made prior to database 
lock. 
 
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 IV, roll-over study of pasireotide in patients being 
treated in previous Novartis Oncology-sponsored studies and who are benefiting from 
treatment with pasireotide by their parent study investigator. The parent studies that are 
eligible to participate in the roll-over study were decided by Novartis. Investigator initiated 
trials (IIT) will not be included. 


 
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There will be no screening period for this study. At the enrollment visit, the patient will be 
consented to the study and eligible patients can start their treatment with pasireotide. 
Patients must return to the clinic at any given time as per standard of care, however only 
four study visits per year (with the exception of 5 visits within the first year) will be 
recorded for patients receiving pasireotide s.c. and monthly visits for those patients 
receiving pasireotide LAR. 
All adverse events and serious adverse events will be collected continuously throughout 
the study. 
 
At every visit, the investigator is required to confirm that the patient continues to have 
clinical benefit and may continue receiving study treatment. 
Study design is described in Figure 2-1 below. 
Figure 2-1 Study Design 
 
 
 
*Note: The starting dose of pasireotide should be the same dose as that which the patient 
was receiving in the parent study at roll over. 
2.3 
 Timing of interim analyses and design adaptations 
This study has also been categorized as voluntary European Post Authorization Safety 
Study (PASS). Therefore, regular interim analyses will be performed during the course of 
the study. Interim analyses will be performed as need by the Sponsor and approximately 
at the following time points: 
• 
Q4 2017 
• 
Q4 2019 
• 
Q4 2021 
• 
Q4 2023 
2.4 
 Definition of end of the study 
End of study is defined as either 10 years from FPFV (or until 10-Jun-2023 in the UK) or when all 
patients on this study have permanently discontinued pasireotide treatment or have been able to 
obtain commercial supply according to local regulations or have been able to receive the drug 
through country-specific programmes outside of this clinical trial (applicable to Brazil, France, 
Germany, India, Italy, Malaysia, Mexico, Peru and Thailand) and the end of treatment visit and all 
safety follow-up procedures have been performed for each patient, whichever comes first. 


 
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2.5 
 Early study termination 
The study can be terminated at any time for any reason by Recordati. Should this be 
necessary, the patient should be informed as soon as possible and should stop taking 
study labeled drug. Assessments should be performed as described in Protocol Section 
7.1.3 for a prematurely withdrawn patient. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the patient’s interests. The investigator will be responsible for informing 
IRBs and/or ECs of the early termination of the trial. 
 
2.6 
 STATISTICAL SOFTWARE 
SAS version 9.4 or higher will be used in all analyses. 
 
3 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
Not applicable. 
 
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 by IQVIA personnel 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].  
Data included in the analysis 
Final analyses will be performed when all patients have been followed for 3 months (84 
days) following the last dose of pasireotide LAR treatment and for 1 month (30 days) 
following the last dose of pasireotide s.c. treatment. 
All events with start date before or on the cut-off date and end date after the cut-off date 
will be reported as ‘continuing at the cut-off date’. The same rule will be applied to events 
starting before or on the cut-off date and not having documented end date. This approach 
applies, in particular, to adverse event reports. For these events, the end date will not be 
imputed and therefore will not appear in the listings. 
It is planned that the data from all centers that participate in this trial will be pooled and 
analyzed. Unless otherwise specified, qualitative data will be described using frequency 
and percentages, while quantitative data, will be described using descriptive statistics: n, 
mean, standard deviation, median, minimum, and maximum. 
All data will be summarized and listed by indication (acromegaly, Cushing’s disease and 
Others) and formulation (s.c. and LAR). 


 
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For the formulation, the variable can be derived from the DAR panel from the DARTYP1C 
variable, the values captured are 533 and 838 which correspond to Pasireotide LAR and 
Pasireotide s.c., respectively. 
The indication will be derived based upon the parent study number from the HIS panel 
using the PRVSTY2C variable as described in the following Table 2-1 with the exception of 
parent study numbers CSOM230C2110E and CSOM230B2219. For those two parent 
studies, the indication will be derived from the parent study data sets as shown in Table 
2-2. 
 
Table 2-1 
Derivation of the indication information – Part 1 
 
Parent study number 
eCRF Indication 
Indication group 
CSOM230B2201E 
78 
Acromegaly 
Acromegaly 
 
CSOM230B2208E 
79 
Cushing's disease 
Cushing's disease 
CSOM230D2203 
81 
NET other pituitary and EAS 
Other diseases 
CSOM230B2305 
82 
Cushing's disease 
Cushing's disease 
CSOM230X2203 
83 
Dumping syndrome 
Other diseases 
CSOM230C2305 
84 
Acromegaly 
Acromegaly 
CSOM230G2304 
85 
Cushing's disease 
Cushing's disease 
CSOM230C1202 
86 
Acromegaly or pituitary 
Acromegaly 
CSOM230C2402 
87 
Acromegaly 
Acromegaly 
CSOM230X2404 
115 
Melanoma 
Other diseases 
CSOM230X2404 
116 
Melanoma 
Other diseases 
CSOM230C2413 
117 
Acromegaly 
Acromegaly 
CSOM230B2411 
125 
Cushing's disease 
Cushing's disease 
CSOM230XDE04 
126 
Prostate cancer 
Other diseases 
CSOM230D2401 
136 
Pituitary adenomas 
Other diseases 
CSOM230DIC03 
137 
NET 
Other diseases 
 
 
Table 2-2 
Derivation of the indication information – Part 2 
 
Parent study 
number 
eCRF 
code 
Parent 
data set 
Parent 
data set 
variable 
Indication Indication 
group 
CSOM230C2110E1 
80 
ADMG 
CLIND 
Carcinoid 
Other diseases 
CSOM230C2110E1 
80 
ADMG 
CLIND 
Acromegaly 
Acromegaly 
CSOM230B2219 
114 or AIDENT 
DISTYP3A 
Acromegaly 
Acromegaly 
113 
CSOM230B2219 
114 or AIDENT 
DISTYP3A 
Cushing's 
Cushing's 
113 
disease 
disease 
 
Treatment period 
The overall observation period will be divided into two mutually exclusive segments: 


 
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on-treatment period: from day of first dose of study medication in the roll-over study to 3 
months (84 days) following the last dose of pasireotide LAR treatment and to 1 month (30 
days) following the last dose of pasireotide s.c. treatment. 
post-treatment period: starting at 3 months+1 day (day 85) following the last dose of 
pasireotide LAR treatment and at 1 month+1 day (day 31) following the last dose of 
pasireotide s.c. treatment. 
Safety summaries (tables, figures) include only data from the on-treatment period. In 
addition, a separate summary for death including on treatment and post treatment deaths 
will be provided. In particular, summary tables for adverse events (AEs) will summarize 
only on-treatment events, with a start date during the on-treatment period (treatment-
emergent AEs). 
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the post-treatment period will be flagged. 
Study Treatment  
Study drug and investigational treatment refer to pasireotide. 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. 
Laboratory data 
Pregnancy tests will be listed overall and by indication and formulation. 
 
4.2 
Patient disposition, demographics and other baseline 
characteristics 
4.2.1 
Patient disposition 
Patient disposition will be summarized overall and by indication and formulation 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 ‘Study phase completion’ page); 


 
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• 
Number (%) of patients who have entered the post-treatment follow-up safety 
evaluation (based on the ‘Study completion’ page); 
• 
Number (%) of patients who have discontinued from the post-treatment follow-up 
(based on the ‘Study Completion’  page); 
• 
Number (%) of patients with primary reason for  end of  study (based on patient 
status entered in the ‘Study completion’ page); 
Listings will be provided overall and by indication and formulation for disposition, informed 
consent, inclusion/exclusion criteria using the Safety set. 
4.2.2 
Patient demographics and other baseline characteristics 
Demographic information will be summarized and listed overall and by indication and 
formulation using the Safety Set. Demographic summary will include age and gender. 
Categorical data (e.g. gender, age groups: 18 to <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 and by indication and 
formulation.  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, parent study 
indication and parent study formulation) 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 and by indication and formulation 
using the Safety Set. 
 
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 
 
 
Not applicable 
Not applicable 
Not applicable 
 
 
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) 
• 
= 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 


 
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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 5-1 
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). 
 
Table 5-2 
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 5-3 
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 
 


 
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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 5-4 
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. 
Any AEs which are continuing as per data cut-off will be shown as ‘ongoing’ rather than 
the end date provided. 
Incomplete date for death 
All dates must be completed with day, month and year. 
If the day or month is missing, death will be imputed to the maximum of the last contact 
date (excluding the date of death) and the following: 
• 
Missing day: 
15th of the month and year of death 
• 
Missing day and month:  July 1st of the year of death 
 
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.  


 
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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 not be used in this study; rather, information about deaths will be collected 
through the EOT eCRF page 
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. 
 
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. 
The main protocol deviations are listed in Attachment 8.1. Additional terms can be 
identified on the basis of the collected data during study. 
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 
Not applicable. 


 
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6.2.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication 
(Pasireotide) 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. 
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 7.4.1. 
7.1.2 
Statistical hypothesis, model, and method of analysis 
The primary  endpoint  will  be  summarized  descriptively  overall  and  by  indication  and 
formulation and 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 and by 
indication and formulation using the Safety Set. 
7.3 
EXTENT OF EXPOSURE 
Definitions of duration of exposure, cumulative dose, average daily dose, actual dose 
intensity (DI), as well as intermediate calculations, include: 
 
Pasireotide s.c.: 
• 
Duration of exposure (days): min(last date of rollover study drug, date of death, 
date of data cut-off) − first date of rollover study drug + 1 
• 
Cumulative dose (µg): total dose of study drug taken by a patient in the rollover 
study 
• 
Number of dosing days (days):   duration of exposure − number of zero dose days 
• 
Average daily dose (µg/day): cumulative dose (µg) / number of dosing days (days) 
• 
DI (µg/day): cumulative dose (µg) / duration of exposure (days) 
 
Pasireotide LAR: 
• 
Duration of exposure (months): (min(last date of rollover study drug+27, date of 
death, date of data cut-off) − first date of rollover study drug + 1)/30.4375 
• 
Cumulative dose (mg): total dose of study drug taken by a patient in the rollover 
study 


 
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• 
Number of dosing months (months): 
duration  of  exposure  −  number  of  
zero  dose months 
• 
Average monthly dose (mg/month): cumulative dose (mg) / number of dosing 
months (months) 
• 
DI (mg/month): cumulative dose (mg) / duration of exposure (months) 
 
 
Duration of exposure to study drug, average daily dose and DI will be summarized 
descriptively overall and by indication and formulation. 
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries and continuous summaries (i.e. mean, standard deviation etc.) 
using appropriate units of time. The duration of exposure to study drug will be categorized 
into time intervals; frequency counts and percentages of patients with exposure in each 
time interval will be presented. The derived parameters above will also be listed overall 
and by indication and formulation using Safety Set. 
 
Dose Changes 
 
The number and percentage of patients with dose interruption, reduction and increase will 
be summarized overall and by indication and formulation in the safety set. Dose 
interruption, reduction and increase are defined as follows: 
• 
Interruption is defined as any period of zero total daily dose followed by a 
non-zero dose. 
• 
Reduction is defined as any decrease from the immediate prior non-zero total 
daily dose. Zero daily doses are not regarded as reductions. 
• 
Increase is defined as any increase from the immediate prior non-zero total 
daily dose. 
The number and percentage of patients with dose interruption, reduction and increase, 
along with reasons for dose change will be summarized overall and by indication and 
formulation using Safety Set.For the purpose of summarizing interruptions and reasons, in 
case multiple entries for interruption that are entered on consecutive days (for pasireotide 
s.c.) or on consecutive months (for pasireotide LAR) with different reasons will be counted 
as separate interruptions. However, if the reason is the same in this mentioned multiple 
entries on consecutive days or months, then it will be counted as one interruption. Listings 
of all doses of the study drug along with dose reduction, increase and interruption and 
reasons for dose change will be presented. The derived parameters above will also be listed 
overall and by indication and formulation using Safety Set. 
 
7.4 
SAFETY ANALYSIS 
Safety analyses will be performed on 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 
84 days following the last dose of pasireotide LAR treatment and after 30 days following 
the last dose of pasireotide s.c. 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 


 
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(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), 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. 
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 5% 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 SOM230 are listed in attachment 
8.2. 
7.4.2 
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 and by indication and formulation using the Safety Set. On-treatment and all 


 
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deaths will be listed overall and by indication and formulation and post treatment deaths 
will be flagged. 
 
8 
ATTACHMENTS 
 
8.1 
MAIN PROTOCOL DEVIATION LIST 
Protocol Deviation Category 
Description  
Eligibility and Entry Criteria* 
 
I01 Patient is not currently enrolled in a Novartis 
sponsored study receiving pasireotide and has not 
fulfilled all their requirements in the parent study 
Eligibility and Entry Criteria* 
 
I02 Patient is not currently benefiting from the treatment 
with pasireotide 
Eligibility and Entry Criteria* 
 
I03 Patient has demonstrated non- compliance, as 
assessed by the investigator, with the parent study 
protocol requirements 
Eligibility and Entry Criteria* 
 
I04 Patient is unwilling and/or not able to comply with 
scheduled visits, treatment plans and any other study 
procedures 
Informed Consent Criteria* 
 
I05 Informed consent not signed at all. 
Informed Consent Criteria* 
 
I06 ICF not signed before patient received study drug 
Eligibility and Entry Criteria* 
 
E01 Patients terminated from the parent protocol and is 
not eligible to participate in the study. 
Eligibility and Entry Criteria* 
 
E02 Patient receiving pasireotide in combination with 
unapproved or experimental treatments 
Eligibility and Entry Criteria* 
 
E03 Sexually active male patient not using highly 
effective contraception 
Eligibility and Entry Criteria* 
 
E04 Pregnant or nursing (lactating) women enrolled into 
the study but did not receive study drug 
Eligibility and Entry Criteria* 
 
E05 Women of childbearing potential, not using highly 
Effective methods of contraception. 
Eligibility and Entry Criteria* 
 
E06 Patient is pregnant at study entry (first dose study 
drug was administered) 
Study Procedures Criteria* 
 
D01 Patient met hepatic discontinuation criteria and not 
withdrawn 
Study Procedures Criteria* 
 
D02 Patient met QT discontinuation criteria and not 
withdrawn 
Study Procedures Criteria* 
 
D03 Patient met hyperglycemic Discontinuation criteria 
and not withdrawn 


 
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Study Procedures Criteria* 
 
D04 Patient became pregnant during the study and was 
not withdrawn 
Study Procedures Criteria* 
 
D05 Investigator determines that patient is no longer 
benefiting from treatment but did not discontinue patient 
from study 
Study Procedures Criteria* 
 
Other Criteria for premature patient withdrawal was met 
and not withdrawn  
Investigation Product (IP) Compliance* 
 
S01 Missed injection of study medication 
Investigation Product (IP) Compliance* 
 
S02 Starting dose of pasireotide differs from last dose 
received in the parent study 
Investigation Product (IP) Compliance* 
 
S03 Parent protocol medication taken instead of 
CSOM230B2412 medication at visit 1 
Investigation Product (IP) Compliance* 
 
S04 Dose up/down titration not done as defined in parent 
protocol 
Investigation Product (IP) Compliance 
 
Time window between administration of pasireotide 
LAR/s.c. not according to the protocol (LAR 28 days ± 7 
days /  
s.c. 84 days ± 14 days from the IP administration date). 
Investigation Product (IP) Compliance 
 
Pharmaceutical formulation not administered as defined 
in the parent protocol  
Investigation Product (IP) Compliance* 
S06 Time window between administration of pasireotide 
LAR too short or too long (less than 14 days and more 
than 56 days from the last monthly injection). 
Investigation Product (IP) Compliance 
 
Patient was mistakenly provided Novartis labelled IP 
Investigation Product (IP) Compliance 
 
Patient was mistakenly provided expired IP 
Investigation Product (IP) Compliance 
 
Due to delays in obtaining regulatory approvals for 
sponsor change and due to unavailability of the Novartis 
labelled IP, Recordati labelled IP was used 
Investigation Product (IP) Compliance 
 
IP kit discarded by the site staff by mistake 
Concomitant Medication Criteria* 
 
M01 Patient took an excluded concomitant Medication 
Study Procedures Criteria 
 
IP storage temperature out of range. 
Study Procedures Criteria 
 
IP Temperature log is not available at site for a certain 
period 
Informed Consent Criteria* 
 
G01 Informed consent not Appropriately obtained (e.g. 
Incorrect version signed, new ICF version approved not 
signed on a consecutive visit, site personnel not 
delegated signed the ICF, etc.,) 
Informed Consent Criteria 
 
Other general ICF documentation errors (e.g. incomplete 
name/signature, boxes not checked where needed, 
missing initials on any ICF page where needed, etc.). 


 
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Source Document Criteria* 
 
G02 Source Documentation lost 
Administrative Criteria* 
 
G03 Study drug administration not properly documented 
in CRF and drug accountability logs 
Serious Adverse Event Criteria* 
 
G04 SAE not reported within 24 hours of learning of its 
occurrence 
Study Procedures Criteria* 
G06 Male patient is sexually active and does not use 
condoms during the study and for 1 months after 
pasireotide s.c. last dose and 3 months after pasireotide 
LAR last dose and should not father a child in this period. 
Study Procedures Criteria* 
 
G07 Investigator failed to question patient on any 
possible adverse events and serious adverse events 
Study Procedures Criteria* 
 
G08 Investigator failed to assess if the patient was 
continuing to receive clinical benefit at the visit. 
Study Procedures Criteria 
 
Investigator failed to document in eCRF if the patient was 
continuing to receive clinical benefit at the visit 
Visit Schedule Criteria* 
 
G10 Missed visit due to COVID-19 
Visit Schedule Criteria* 
 
G11 Visit done outside of study site due to COVID-19 
Study Procedures Criteria* 
 
G12 Assessment/ procedure changed due to COVID-19 
Study Procedures Criteria* 
 
G13 Drug supply method changed due to COVID-19 
Investigation Product (IP) Compliance* 
 
G14 Treatment not given due to COVID-19 
Other Criteria* 
 
G15 Discontinuation due to COVID-19 
Study Procedures Criteria* 
 
G16 Patient failed to adhere to protocol requirements or 
visit schedule 
Study Procedures Criteria* 
 
G17 Female patient of childbearing potential did not 
complete diary with dates and outcome of at-home urine 
pregnancy tests while on study treatment  
Study Procedures Criteria 
 
Site staff are allowed to work for limited hours due to 
Covid 19 restrictions 
 
 
 
 
 
 
 
 
 


 
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8.2 
LIST 0F AES OF SPECIAL INTEREST 
Category 
Adverse Event Term 
AESI Bradycardia related AEs 
Atrial conduction time prolongation (PT) 
  
Atrioventricular block (PT) 
  
Atrioventricular block complete (PT) 
  
Atrioventricular block second degree (PT) 
  
Atrioventricular dissociation (PT) 
  
Bradycardia (PT) 
  
Central bradycardia (PT) 
  
Conduction disorder (PT) 
  
Defect conduction intraventricular (PT) 
  
Electrocardiogram PQ interval prolonged (PT) 
  
Electrocardiogram PR prolongation (PT) 
  
Electrocardiogram QRS complex prolonged (PT) 
  
Electrocardiogram QT prolonged (PT) 
  
Long QT syndrome (PT) 
  
Paroxysmal atrioventricular block (PT) 
  
Sinoatrial block (PT) 
  
Sinus bradycardia (PT) 
AESI Coagulation related AEs 
Blood fibrinogen decreased (PT) 
  
Blood thrombin decreased (PT) 
  
Blood thromboplastin abnormal (PT) 
  
Blood thromboplastin decreased (PT) 
  
Coagulation factor IX level decreased (PT) 
  
Coagulation factor V level decreased (PT) 
  
Coagulation factor VII level decreased (PT) 
  
Coagulation factor X level decreased (PT) 
  
Coagulation factor decreased (PT) 
  
Hypofibrinogenaemia (PT) 
  
International normalised ratio abnormal (PT) 
  
Prothrombin level decreased (PT) 
  
Prothrombin time prolonged (PT) 
  
Prothrombin time ratio decreased (PT) 
  
Thrombin time prolonged (PT) 
AESI Gallbladder and biliary related AEs 
Bile duct necrosis (PT) 
  
Bile duct obstruction (PT) 
  
Bile duct stenosis (PT) 
  
Bile duct stone (PT) 


 
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Category 
Adverse Event Term 
  
Bile output abnormal (PT) 
  
Bile output decreased (PT) 
  
Bile output increased (PT) 
  
Biliary cirrhosis (PT) 
  
Biliary colic (PT) 
  
Biliary dilatation (PT) 
  
Biliary dyskinesia (PT) 
  
Biliary dyspepsia (PT) 
  
Biliary fibrosis (PT) 
  
Biliary fistula (PT) 
  
Biliary ischaemia (PT) 
  
Biliary tract disorder (PT) 
  
Bilirubin conjugated abnormal (PT) 
  
Bilirubin conjugated increased (PT) 
  
Bilirubin excretion disorder (PT) 
  
Bilirubin urine present (PT) 
  
Bilirubinuria (PT) 
  
Blood alkaline phosphatase abnormal (PT) 
  
Blood alkaline phosphatase increased (PT) 
  
Blood bilirubin abnormal (PT) 
  
Blood bilirubin increased (PT) 
  
Blood bilirubin unconjugated increased (PT) 
  
Cholangiogram abnormal (PT) 
  
Cholecystectomy (PT) 
  
Cholecystitis (PT) 
  
Cholecystitis acute (PT) 
  
Cholecystitis chronic (PT) 
  
Cholecystogram intravenous abnormal (PT) 
  
Cholecystogram oral abnormal (PT) 
  
Cholelithiasis (PT) 
  
Cholelithiasis migration (PT) 
  
Cholelithiasis obstructive (PT) 
  
Cholestasis (PT) 
  
Deficiency of bile secretion (PT) 
  
Endoscopy biliary tract abnormal (PT) 
  
Gallbladder disorder (PT) 
  
Gallbladder enlargement (PT) 
  
Gallbladder fibrosis (PT) 
  
Gallbladder fistula (PT) 
  
Gallbladder hypofunction (PT) 


 
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Category 
Adverse Event Term 
  
Gallbladder necrosis (PT) 
  
Gallbladder obstruction (PT) 
  
Gallbladder oedema (PT) 
  
Gallbladder operation (PT) 
  
Gallbladder palpable (PT) 
  
Haemobilia (PT) 
  
Hepatitis cholestatic (PT) 
  
Hepatobiliary disease (PT) 
  
Hyperbilirubinaemia (PT) 
  
Jaundice (PT) 
  
Jaundice cholestatic (PT) 
  
Jaundice extrahepatic obstructive (PT) 
  
Obstructive pancreatitis (PT) 
  
Perforation bile duct (PT) 
  
Pseudocholelithiasis (PT) 
  
Ultrasound biliary tract abnormal (PT) 
  
Urine bilirubin increased (PT) 
  
X-ray hepatobiliary abnormal (PT) 
AESI Growth hormone deficiency related AEs 
Blood growth hormone decreased (PT) 
  
Insulin-like growth factor decreased (PT) 
AESI Hyperglycemia-related AEs 
Blood glucose increased (PT) 
  
Blood insulin decreased (PT) 
  
Diabetes mellitus (PT) 
  
Diabetes mellitus inadequate control (PT) 
  
Diabetes with hyperosmolarity (PT) 
  
Diabetic coma (PT) 
  
Diabetic hyperglycaemic coma (PT) 
  
Diabetic hyperosmolar coma (PT) 
  
Diabetic ketoacidosis (PT) 
  
Diabetic ketoacidotic hyperglycaemic coma (PT) 
  
Diabetic ketosis (PT) 
  
Fructosamine increased (PT) 
  
Glucose tolerance decreased (PT) 
  
Glucose tolerance impaired (PT) 
  
Glucose tolerance test abnormal (PT) 
  
Glucose urine (PT) 
  
Glycosuria (PT) 
  
Glycosylated haemoglobin increased (PT) 
  
Hyperglycaemia (PT) 
  
Hyperglycaemic hyperosmolar nonketotic syndrome (PT) 


 
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Category 
Adverse Event Term 
  
Impaired fasting glucose (PT) 
  
Impaired insulin secretion (PT) 
  
Increased insulin requirement (PT) 
  
Insulin-requiring type 2 diabetes mellitus (PT) 
  
Ketoacidosis (PT) 
  
Ketonuria (PT) 
  
Ketosis (PT) 
  
Ketosis-prone diabetes mellitus (PT) 
  
Monogenic diabetes (PT) 
  
Type 1 diabetes mellitus (PT) 
  
Type 2 diabetes mellitus (PT) 
AESI Hypocortisolism related AEs 
Adrenal insufficiency (PT) 
  
Adrenal suppression (PT) 
  
Adrenocortical insufficiency acute (PT) 
  
Cortisol decreased (PT) 
  
Cortisol deficiency (PT) 
  
Cortisol free urine decreased (PT) 
  
Glucocorticoid deficiency (PT) 
  
Glucocorticoids decreased (PT) 
  
Secondary adrenocortical insufficiency (PT) 
  
Steroid withdrawal syndrome (PT) 
AESI Hypotension related AEs 
Blood pressure ambulatory decreased (PT) 
  
Blood pressure decreased (PT) 
  
Blood pressure diastolic decreased (PT) 
  
Blood pressure immeasurable (PT) 
  
Blood pressure orthostatic abnormal (PT) 
  
Blood pressure orthostatic decreased (PT) 
  
Blood pressure systolic decreased (PT) 
  
Hypotension (PT) 
  
Mean arterial pressure decreased (PT) 
AESI Hypothyroidism related AEs 
Blood thyroid stimulating hormone decreased (PT) 
  
Hypothyroidism (PT) 
  
Myxoedema (PT) 
  
Myxoedema coma (PT) 
  
Secondary hypothyroidism (PT) 
  
Thyroid dermatopathy (PT) 
  
Thyroid stimulating hormone deficiency (PT) 
  
Thyroxine free decreased (PT) 
  
Tri-iodothyronine decreased (PT) 
  
Tri-iodothyronine free decreased (PT) 


 
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Category 
Adverse Event Term 
AESI Injection site reaction related AEs 
Administration site abscess (PT) 
  
Immediate post-injection reaction (PT) 
  
Injection site atrophy (PT) 
  
Injection site bruising (PT) 
  
Injection site discolouration (PT) 
  
Injection site discomfort (PT) 
  
Injection site erosion (PT) 
  
Injection site erythema (PT) 
  
Injection site exfoliation (PT) 
  
Injection site granuloma (PT) 
  
Injection site haematoma (PT) 
  
Injection site haemorrhage (PT) 
  
Injection site hypersensitivity (PT) 
  
Injection site inflammation (PT) 
  
Injection site irritation (PT) 
  
Injection site necrosis (PT) 
  
Injection site nodule (PT) 
  
Injection site oedema (PT) 
  
Injection site pain (PT) 
  
Injection site pruritus (PT) 
  
Injection site rash (PT) 
  
Injection site reaction (PT) 
  
Injection site swelling (PT) 
  
Injection site urticaria (PT) 
AESI Liver safety related AEs 
Alanine aminotransferase abnormal (PT) 
  
Alanine aminotransferase increased (PT) 
  
Ammonia increased (PT) 
  
Aspartate aminotransferase abnormal (PT) 
  
Aspartate aminotransferase increased (PT) 
  
Blood cholinesterase abnormal (PT) 
  
Blood cholinesterase decreased (PT) 
  
Computerised tomogram liver abnormal (PT) 
  
Gamma-glutamyltransferase abnormal (PT) 
  
Gamma-glutamyltransferase increased (PT) 
  
Guanase increased (PT) 
  
Hepatic enzyme abnormal (PT) 
  
Hepatic enzyme decreased (PT) 
  
Hepatic enzyme increased (PT) 
  
Hepatic function abnormal (PT) 
  
Hepatobiliary scan abnormal (PT) 


 
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Category 
Adverse Event Term 
  
Hyperammonaemia (PT) 
  
Hypertransaminasaemia (PT) 
  
Liver function test increased (PT) 
  
Transaminases abnormal (PT) 
  
Transaminases increased (PT) 
  
Ultrasound liver abnormal (PT) 
  
Urine bilirubin increased (PT) 
AESI Low blood cell related AEs 
Anaemia (PT) 
  
Febrile neutropenia (PT) 
  
Haematocrit decreased (PT) 
  
Haemoglobin decreased (PT) 
  
Leukopenia (PT) 
  
Lymphocyte count decreased (PT) 
  
Lymphopenia (PT) 
  
Neutropenia (PT) 
  
Platelet count decreased (PT) 
  
Red blood cell count decreased (PT) 
  
Thrombocytopenia (PT) 
AESI Pancreatitis related AEs 
Abdominal compartment syndrome (PT) 
  
Blood trypsin increased (PT) 
  
Fat necrosis (PT) 
  
Hyperlipasaemia (PT) 
  
Lipase abnormal (PT) 
  
Lipase increased (PT) 
  
Pancreatic enzyme abnormality (PT) 
  
Pancreatic enzymes abnormal (PT) 
  
Pancreatic enzymes increased (PT) 
  
Pancreatitis (PT) 
  
Pancreatitis acute (PT) 
  
Pancreatitis haemorrhagic (PT) 
  
Pancreatitis necrotising (PT) 
  
Pancreatitis relapsing (PT) 
  
Peripancreatic fluid collection (PT) 
AESI QT-prolongation-related AEs 
Cardiac arrest (PT) 
  
Cardiac death (PT) 
  
Cardiac fibrillation (PT) 
  
Cardio-respiratory arrest (PT) 
  
Electrocardiogram QT interval abnormal (PT) 
  
Electrocardiogram QT prolonged (PT) 
  
Electrocardiogram repolarisation abnormality (PT) 


 
             Statistical Analysis Plan 
 
 
Page 28 of 28 
 
Study Code: CSOM230B2412 
 
 
Version 2.0 
Date: 15Mar2024 
 
CONFIDENTIAL 
 
BIOM 
 
 
Category 
Adverse Event Term 
  
Long QT syndrome (PT) 
  
Loss of consciousness (PT) 
  
Sudden cardiac death (PT) 
  
Sudden death (PT) 
  
Syncope (PT) 
  
Torsade de pointes (PT) 
  
Ventricular arrhythmia (PT) 
  
Ventricular fibrillation (PT) 
  
Ventricular flutter (PT) 
  
Ventricular tachyarrhythmia (PT) 
  
Ventricular tachycardia (PT)