Conditions: Non-functioning Pituitary Adenoma
Keywords: Non-functioning pituitary adenoma, pasireotide LAR, tumor volume
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This study assessed pasireotide LAR efficacy on patients with non-functioning pituitary adenomas concerning tumor growth.

Detailed description:

Arms:
arm 1: All patients will receive pasireotide LAR (long acting release) 60 mg every 28 ± 3 days for 24 weeks

Interventions: intervention 1: Pasireotide LAR
Intervention descriptions: intervention 1: 20 and 40 mg of powder in vials and 2 mL of vehicle in ampoules (for reconstitution) administered as a depot intragluteal IM (intramuscular) injection

Protocol document:
Prot_000.pdf: 
Novartis 
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Oncology Clinical Trial Protocol (Version No. 2.00) 
Protocol No. CSOM230D2401 
Clinical Development and Medical Affairs 
SOM230 Pasireotide 
Clinical Trial Protocol: CSOM230D2401 / NCT01283542 
An Open-Label, Single Arm, Phase II Study to Evaluate the 
Efficacy and Safety of Pasireotide LAR on the Treatment of 
Patients With Clinically Non-Functioning Pituitary 
Adenoma 
Authors 
 
 
Type of document 
Amended protocol version 
Version number 
v02 without tracked changes 
Development phase 
Phase II 
Date of publication 
03-26-2012
Property of Novartis 
Confidential 
It may not be used, disclosed, published or revealed in any way 
without consent by Novartis. 


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Table of Contents 
Clinical Development and Medical Affairs ................................................................................ 1 
Table of Contents ................................................................................................................ 2 
Table of Contents of Post-Text Supplements (PTS) ........................................................... 5 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 8 
Amendment 2 .................................................................................................................... 10 
Rationale for the Amendment ........................................................................................... 14 
Changes to the protocol ............................................................................................................ 14 
Synopsis of the oncology clinical trial protocol ................................................................ 21 
1 
Background ........................................................................................................................ 32 
1.1 
Summary of clinically non-functioning pituitary adenomas (NFPAs) .................. 32 
1.2 
Pasireotide overview (SOM230) ........................................................................... 37 
1.3 
Human experience ................................................................................................. 41 
1.3.1 
Clinical efficacy and safety of pasireotide LAR ................................... 41 
1.3.2 
Pasireotide clinical pharmacokinetics ................................................... 43 
2 
Study rationale / purpose ................................................................................................... 45 
3 
Objectives .......................................................................................................................... 47 
3.1 
Primary objective ................................................................................................... 47 
3.1.1 
Primary objective endpoint ................................................................... 47 
3.2 
Secondary objectives ............................................................................................. 47 
3.2.1 
Secondary objective endpoints .............................................................. 47 
 
 48 
 
 48 
4 
Study design ...................................................................................................................... 48 
5 
Population .......................................................................................................................... 50 
5.1 
Inclusion criteria .................................................................................................... 51 
5.2 
Exclusion criteria ................................................................................................... 51 
6 
Treatment ........................................................................................................................... 53 
6.1 
Investigational drug ............................................................................................... 53 
6.1.1 
Known untoward effects of the study drug / treatment ......................... 53 
6.1.2 
Supply ................................................................................................... 53 
6.1.3 
Preparation and storage ......................................................................... 54 
6.2 
Patient numbering .................................................................................................. 54 
6.3 
Treatment assignment ............................................................................................ 55 


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6.4 
Patient treatment .................................................................................................... 55 
6.4.1 
Follow-up for dose-limiting toxicities .................................................. 56 
6.4.2 
Allowed study drug adjustments ........................................................... 56 
6.4.3 
Other concurrent medication ................................................................. 57 
6.4.4 
Discontinuation of the study drug ......................................................... 57 
6.4.5 
Early patient discontinuation................................................................. 58 
7 
Visits and evaluations schedule ......................................................................................... 59 
7.1 
Information to be collected in case of screening failure ........................................ 67 
7.2 
Demographics / other baseline patient characteristics ........................................... 67 
7.3 
Treatments ............................................................................................................. 67 
7.4 
Efficacy .................................................................................................................. 67 
7.4.1 
Primary efficacy evaluation .................................................................. 68 
7.4.2 
Secondary efficacy evaluations ............................................................. 68 
 
 68 
7.5 
Safety ..................................................................................................................... 69 
7.5.1 
Adverse events ...................................................................................... 69 
7.5.2 
Special Safety ........................................................................................ 70 
7.5.3 
Physical examination, weight, height .................................................... 76 
7.5.4 
Vital signs.............................................................................................. 77 
7.5.5 
Performance status ................................................................................ 77 
7.5.6 
Laboratory evaluations .......................................................................... 77 
7.5.7 
Radiology tests ...................................................................................... 80 
7.5.8 
Electrocardiogram (ECG) ..................................................................... 81 
7.5.9 
Visual evaluations ................................................................................. 81 
7.6 
Tolerability ............................................................................................................ 82 
7.7 
Patient reported outcomes ...................................................................................... 82 
8 
Safety monitoring .............................................................................................................. 82 
8.1 
Serious adverse event reporting ............................................................................. 82 
8.2 
Pregnancy .............................................................................................................. 83 
9 
Data review and management ........................................................................................... 84 
9.1 
Site monitoring ...................................................................................................... 84 
9.2 
Data collection (eCRF) .......................................................................................... 84 
9.3 
Database management and quality control ............................................................ 84 
10 Statistic methods and data analysis ................................................................................... 85 
10.1 
Analysis populations .............................................................................................. 85 
10.2 
Demographics / other baseline patient characteristics ........................................... 86 
10.3 
Treatments (study drug, concurrent therapies, compliance) .................................. 86 


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10.4 
Primary objective ................................................................................................... 86 
10.4.1 
Variable ................................................................................................. 86 
10.4.2 
Statistical analysis ................................................................................. 86 
10.4.3 
Control of missing values / censoring / discontinuations...................... 87 
10.4.4 
Support Analysis ................................................................................... 87 
10.5 
Secondary objectives ............................................................................................. 87 
10.5.1 
Efficacy variables and analysis ............................................................. 87 
 
 88 
10.5.3 
Safety analyses and parameters ............................................................. 88 
10.5.4 
Tolerability ............................................................................................ 89 
10.6 
Sample Size Calculation ........................................................................................ 89 
Table 10.1: Probability of  ≥ 2 responders in a 19 patient sample. ................................... 89 
Table 10.2: Resulting 90% CI for different numbers of responders ................................. 90 
11 Administrative procedures ................................................................................................. 90 
11.1 
Enrollment compliance .......................................................................................... 90 
11.2 
Ethic and regulatory compliance ........................................................................... 90 
11.3 
Investigator’s and REC’s responsibilities .............................................................. 90 
11.4 
Informed Consent Form ......................................................................................... 90 
11.5 
Protocol amendments ............................................................................................. 91 
11.5.1 
History of amendments ......................................................................... 91 
11.6 
Discontinuation of the study .................................................................................. 92 
11.7 
Supply and new supply, storage of the drug, and traceability / accountability 
of the study drug .................................................................................................... 92 
12 Protocol compliance .......................................................................................................... 92 
13 Publication policy .............................................................................................................. 93 
14 References (available upon request) .................................................................................. 93 
 


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Table of Contents of Post-Text Supplements (PTS) 
1. Instructions about the handling and preparation of pasireotide LAR. 


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List of figures 
Figure 1-1 
Treatment algorithm for clinical NFPA (Dekker et al. 2008) .................... 34 
Figure 1-2 
Mean plasma concentration (SD) profiles over time for pasireotide in 
patients with acromegaly (left panel) and carcinoid patients (right panel) 
after three monthly IM injections of 20 mg, 40 mg, or 60 mg of pasireotide 
LAR [CSOM230C2110] ............................................................................ 41 
Figure 1-3 
Mean plasma concentration (SD) profiles over time for pasireotide after a 
single IM injection of 40 mg (N = 5) or 60 mg (N = 5) of pasireotide LAR 
formulation in healthy volunteers [CSOM230C2101] .............................. 44 
Figure 1-4 
Mean plasma concentration (SD) profiles over time for pasireotide in 
patients with acromegaly (left panel) and patients with carcinoid tumor 
(right panel) after three monthly IM injections of 20 mg, 40 mg, or 60 mg 
of pasireotide LAR [CSOM230C2110] ..................................................... 45 
Figure 4-1 
Scheme of NFPA Study with Pasireotide LAR: Main Phase .................... 50 
Figure 4-2 
Scheme of NFPA Study with Pasireotide LAR: Extension Phase ............. 50 
Figure 7-1 
Scenario A: Procedure for QTcF Prolongations Occurring on the Planned 
Pasireotide LAR Dosing Visits .................................................................. 73 
Figure 7-2 
Scenario B: Procedure for QTcF Prolongations Occurring on visits 3 and 6 
Planned Only for Patients Receiving Pasireotide LAR ............................. 74 
 


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List of tables 
Table 1-1 
Pituitary adenomas, main associated hypersecreted hormone, and related 
clinical syndrome ....................................................................................... 32 
Table 1-2 
Binding profile of dopamine receptor agonists, cabergoline and 
bromocriptine (Pivonello et al 2007) ......................................................... 35 
Table 1-3 
Summary of Cabergoline Clinical Trials for NFPA .................................. 35 
Table 1-4 
Summary of Octreotide Clinical Trials for NFPA ..................................... 36 
Table 1-5 
Binding profile of octreotide, pasireotide, and lanreotida in hsst 1-5. The 
results are mean values ± IC50 SEM shown in mmol/L. Adapted from 
Bruns et al 2002 ......................................................................................... 37 
Table 1-6 
Number (percentage) of responders among patients with acromegaly with 
mean GH level ≤ 5 mg/mL and IGF-1 level within normal limits compared 
to controls of equivalent age and gender after three monthly IM injections 
of 20 mg, 40 mg, or 60 mg of pasireotide LAR formulation – Study 
[CSOM230C2110] ..................................................................................... 40 
Table 1-7 
Number (percentage) of responders among patients with acromegaly with 
a GH mean level ≤ 2.5 ng/mL and IGF-1 level within normal limits for 
controls of equivalent age and gender after three monthly IM injections of 
20 mg, 40 mg, or 60 mg of pasireotide LAR formulation (2b) 
[CSOM230C2110] ..................................................................................... 42 
Table 6-1 
Handling and preparation of pasireotide LAR dose .................................. 54 
Table 6-2 
Guideline for treatment of patients experiencing adverse events .............. 56 
Table 7-1 
Visits and evaluations schedule for the Main Study .................................. 60 
Table 7-2 
Visits and evaluations schedule for the Extension Study .......................... 64 
Table 7-3 
Eastern Cooperative Oncology Group (ECOG) performance status scale 77 
 


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List of abbreviations 
BID 
twice a day 
-GT 
Gamma-glutamyl transpeptidase 
ACTH 
ALP 
Adrenocorticotropic Hormone 
Alkaline phosphatase 
ALT 
ANA 
Anti-HAV 
Anti-HBc 
Anti-HCV 
Anti-HEV 
Alanine Aminotransferase/Glutamic-Pyruvic Transaminase/GPT 
Antinuclear antibody 
Antibody against Hepatitis A virus 
Antibody against Hepatitis B core virus 
Antibody against Hepatitis C virus 
Antibody against Hepatitis E virus 
GCP 
Good Clinical Practice 
BUN 
blood urea nitrogen 
REC 
Research Ethics Committee 
CMV 
Cytomegalovirus 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CSR 
clinical study report 
CTC/CTCAE 
Common Toxicity Criteria/Common Terminology Criteria for Adverse Events  
d 
Day 
LDH 
SD 
Lactate dehydrogenase 
Standard deviation 
AE 
adverse event 
SAE 
EBV 
serious adverse event 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
HBs-Ag 
electronic Case Report Form 
Hepatitis B surface antigen 
EOS 
End of Study 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone  
GH 
growth hormone 
HbA1c 
hemoglobin subtype A1c (glycated hemoglobin) 
Hgb 
hemoglobin 
HCT 
Hematocrit 
HDL 
high density lipoprotein 
HSST 
human somatostatin receptors  
IB 
investigator’s brochure 
CI 
confidence interval 
ICH 
International Conference on Harmonization  
IGF-1 
IgM 
insulin-like growth factor I 
Immunoglobulin M 


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IM 
intramuscular(ly) 
IMS 
Integrated Medical Safety 
IN 
investigator notification 
ITT 
intent-to-treat 
IV  
intravenous(ly) 
LAR 
long-acting release  
LDL 
low density lipoprotein 
LH 
luteinizing hormone  
LLN 
lower limit of normal 
ULN 
LFT 
upper limit of normal 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities  
MRI 
magnetic resonance imaging 
MSAS 
Memorial Symptom Assessment Scale 
NFMA 
clinically non-functioning pituitary macroadenoma  
NFPA 
clinically non-functioning pituitary adenoma 
OGTT 
WHO 
Oral glucose tolerance test 
World Health Organization 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PRL 
Prolactin 
PS 
q 
Performance status 
every 
RAP 
report analysis plan 
RT-PCR  
reverse transcriptase-polymerase chain reaction  
SAP 
standard automated perimetry 
PFS 
progression-free survival 
RFS 
relapse-free survival 
SC 
subcutaneous(ly) 
SGOT 
serum glutamic-oxaloacetic transaminase  
SGPT 
serum glutamic-pyruvic transaminase 
SMC 
Study Management Committee 
sst 
somatostatin receptor subtype 
SSTR 
somatostatin receptor 
SUSAR 
suspected unexpected serious adverse reaction  
PT 
prothrombin time 
TSH 
thyroid-stimulating hormone  
APTT 
activated partial thromboplastin time 
VEGF 
vascular endothelial growth factor  
WBC 
White blood cells 
 


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Amendment 2 
Rationale for the amendment 
This amendment has been implemented to address the following items of the original protocol 
published for the study: 
This protocol amendment includes additional liver safety measures as a result of internal 
medical review of pasireotide trials. During this review, 3 healthy volunteers have been 
identified with increased liver function tests. Three patients have met Hy’s Law criteria (i.e., 
ALT > 3 x ULN with total bilirubin > 2 x ULN, without increase in alkaline phosphatase and 
any other identified cause for the abnormal findings). One patient received pasireotide 600 µg 
twice a day s.c. for 7 days, whereas the second patient received pasireotide 1950 g twice a 
day s.c. for 5 days. The third patient (pasireotide 600 µg twice a day s.c. for 7 days) showed 
increased ALT and total bilirubin meeting Hy’s Law criteria, but alkaline phosphatase was not 
evaluated and the patient received a potentially confounding concomitant medication. ALT 
values for all 3 patients were higher than 3 x ULN, but < 4 x ULN, and total bilirubin values 
were < 4 x ULN. All 3 cases were asymptomatic, with onset 10 days after the initial 
administration of s.c. pasireotide, and were reversible with the discontinuation of pasireotide. 
None of the cases has been reported as an adverse event, and the patients completed the 
respective studies according to the protocol. 
An assessment of the categorical abnormalities of liver enzymes was completed by the s.c. 
pasireotide development program (until October 2011). The 3 healthy volunteers meeting the 
Hy’s Law criteria (including the patient without ALP value) were included among the 654 
healthy volunteers, as shown below. None of the patients with Cushing’s disease, carcinoid 
syndrome, or acromegaly in the development program met Hy’s Law criteria. 
 654 healthy volunteers have been exposed to s.c. pasireotide: 
 3 out of 654 (0.5%) met the Hy’s Law biochemical criteria 
 16 out of 654 (2.4%) patients experienced ALT or AST > 3x ULN  
 3 out of 654 (0.5%) healthy volunteers experienced ALT or AST > 5x ULN 
 17 out of 654 (2.6%) patients experienced total bilirubin 2x ULN (including 7 patients 
with preexisting liver disease and increased total bilirubin) 
 156 patients in phase 1 and phase 2 studies have been exposed to s.c. pasireotide: 
 None of the patients met the Hy’s Law biochemical criteria 
 6 out of 156 (3.8%) patients experienced ALT or AST > 3x ULN 
 4 out of 156 (2.6%) patients experienced ALT or AST > 5x ULN 
 2 out of 156 (1.3%) patients experienced total bilirubin ≥ 2x ULN 
 162 patients with Cushing’s syndrome in phase 3 studies have been exposed to (s.c.) 
pasireotide: 
 None of the patients met the Hy’s Law biochemical criteria 


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 8 out of 162 (4.9%) patients experienced ALT or AST > 3x ULN 
 1 out of 162 (0.6%) patients experienced ALT or AST > 5x ULN 
 None of the 162 patients with Cushing’s syndrome experienced total bilirubin ≥ 2x 
ULN 
 The pasireotide Compassionate Use Program (approximately 200 patients up to October 
2011) 
was 
also 
analyzed. 
One 
single 
patient 
with 
Cushing’s 
syndrome 
(PHHO2010AU13717) who had been mentioned in an Investigator Notification in 
September 2010 was identified as meeting Hy’s Law criteria. 
 A review of unblinded data from the clinical program with the long-acting release (LAR) 
formulation of pasireotide did not show any cases meeting Hy’s Law criteria. 
 As a consequence from these observations, better liver safety measures must be taken to 
ensure patient safety. 
As of the date of publication of this amendment, approximately 112 patients had been 
screened worldwide for the treatment. There is no expected impact from this amendment on 
the duration of enrollment or the publication of results. 
Protocol changes 
Changes in specific sections of the protocol are shown in the protocol version with tracked 
changes, using red strikethrough font for exclusions and underlined red font for insertions. 
The main changes performed in the protocol, and the sections affected are detailed below: 
 Protocol synopsis 
 Changes to the main body of the protocol (see items below) were also implemented in 
the relevant sections of the protocol synopsis. 
 5.2 Exclusion criteria 
 Exclusion criterion 8 has been replaced with a more detailed exclusion criterion still 
including the old information from exclusion criterion 8 
 Updated exclusion criteria 18 and 29 
 Added 2 new liver-related exclusion criteria: 30 and 31 
 Table 6.2 Guidelines for the treatment of patients experiencing adverse events 
 Clarification that for liver safety monitoring, the instructions detailed in section 
7.5.2.3 must be followed 
 6.6.5.1 End of treatment 
 Added new liver-related discontinuation criteria 
 7 Visits and evaluation schedule 
 Added new visit (V401) on study day 48 (week 7) for the evaluation of liver function, 
vital signs, adverse events, and concurrent medication 


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 Separation between Chemistry and liver function tests and addition of a new line for 
assessments of liver function tests to describe the additional liver enzyme evaluation 
timepoints 
 Added new line for HBs-Ag and anti-HCV evaluations performed at screening 
 Separation of lines for APTT and PT coagulation parameters and addition of 4 PT 
evaluations on visits V3, V4, V401, and V5 
 Footnote E: added visit V401 to clarify that this visit is necessary only for patients 
treated with pasireotide LAR 
 Added footnote 14 to clarify that the new liver function and coagulation evaluations 
only apply to patients treated with pasireotide LAR 
 7.5 Safety 
 Added new section 7.5.2.3 Liver safety monitoring. This section describes how to 
treat patients who experience liver function increases especifically defined by the 
protocol 
 Added Figure 7-3 graphically describing liver safety monitoring procedures outlined 
on section 7.5.2.3 
 7.5.5.2 Coagulation 
 Added further timepoints for the evaluation of PT coagulation parameter for patients 
treated with pasireotide LAR 
 7.5.5.3 Chemistry 
 Definition of liver function test panel and addition of further timepoints for liver 
function evaluations for patients treated with pasireotide LAR 
 7.5.7 Radiology tests 
 Clarification that an abdominal ultrasound is required in case of abnormal liver 
function criteria 
 Table 7.2 Blood collection plan for pasireotide LAR pharmacokinetics 
 Added line for unscheduled blood sample collection for pharmacokinetics in case of 
abnormal liver function criteria 
 10.5.4.2 Laboratory abnormalities 
 Added further liver function analysis for additional liver safety evaluations  
 Annex 3.1, Table 3.1 Evaluations and visit schedule 
 Added new visit (E402) on study day 76 (week 11) for the evaluation of liver 
function, adverse events, and concurrent medication in the extension study 
 Separation between Chemistry and liver function tests and addition of a new line for 
liver function evaluations to describe additional timepoints for liver enzyme 
evaluations 


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 Separation of APTT and PT coagulation parameter lines and addition of 5 PT 
evaluations on visits E2, E3, E4, E402, and E5 
 Footnote C: added visit E402 to clarify that this visit is only required for patients 
starting pasireotide LAR treatment in the extension study 
 Added footnote K to clarify that new liver function and coagulation evaluations apply 
only to patients starting treatment with pasireotide LAR in the extension study 
 Annex 3, Table 3-2 Blood collection plan for pasireotide LAR pharmacokinetics 
 Added line for unscheduled blood sample collection for pharmacokinetics in case of 
abnormal liver function criteria 
 Annex 3, 6.3 Safety analysis and parameters 
 Added further liver function analysis for additional liver safety evaluations 
 Annex 3, 9.1 Special safety-related procedures 
 Added liver safety monitoring process and reference to the equivalent main study 
section for details of this procedure 
A copy of this protocol amendment will be submitted to the Research Ethics Committee 
(REC) and Health Authorities. Changes to this protocol reflect the measures already 
implemented as part of the Expedited Safety Notification (dated November 18, 2011); 
however, previous approval by the REC is still required for implementation. Furthermore, the 
changes performed herein affect the Informed Consent Form, and the sites must update and 
submit for approval an Informed Consent Form taking into account the changes described in 
this protocol amendment. 


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Rationale for the Amendment 
 
Changes to the protocol 
The additions to the protocol related to the inclusion of the Extension Phase and the changes 
in specific sections of the protocol are described in the protocol version with tracked changes, 
using red strikethrough font for exclusions and red underlined font for insertions. 
 
Rationale for the amendment 
This amendment was implemented to address the following items of the original study 
protocol: 
 Extension of the duration of treatment from week 24 to week 96: 
 In order to allow further long term safety and efficacy evaluation of the treatment with 
pasireotide LAR, patients who have derived benefit from treatment with this 
medication, according to the evaluation of the physician in charge, will be offered a 
72-week extension period (i.e., patients will be followed up until week 96 and will 
have another safety follow-up visit on week 100) 
 A scheme including extension treatment was added (figure 4-2), in addition to the test 
schedule for the extension portion of the study (table 7-2). Thus, the changes 
implemented by this amendment are expected to be clarified 
 The duration of response evaluation for patients considered responsive until week 24 
and the percentage of patients remaining with stable disease have been added to the 
objectives, in order to evaluate the duration of study medication efficacy 
 For consistency purposes, in the pasireotide clinical trials program (SOM230), patients 
with uncontrolled diabetes and/or blood glucose values consistently above 275 mg/dL 
instead of 200 mg/dL must be withdrawn from the study, regardless of appropriate 
therapeutic interventions and/or whether HbA1c value is = 10 % instead of higher than 8% 
 Clarification on the procedure used for QTcF prolongations. 
 Correction of discrepancies and typographical errors or addition of absent secondary 
information seen in the original protocol: 
 In order to be consistent with the study design, the term “randomization” has been 
replaced with “enrollment visit (Visit 2)”, as there will be no randomization in this 
study, since it is single-armed 
 Changes to the protocol synopsis in order to maintain consistency with the protocol 
 Clarification that only glucose and insulin will be evaluated, and not OGTT (oral glucose 
tolerance test) 


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 Clarification that the ECG and campimetry evaluations will be performed locally 
 
Changes to the protocol 
Additions to the protocol regarding the inclusion of the Extension Phase and changes in 
specific sections of the protocol are shown in the version with tracked changes, using red 
strikethrough font for exclusions and red underlined font for insertions. 
The main changes performed in the protocol and the affected sections are detailed below: 
 Protocol synopsis 
 Changes in the main body of the protocol (refer to the items below) were also 
implemented in the relevant sections of the protocol synopsis 
 The duration of response evaluation, the additional evaluation timepoints for patients 
in the extension phase, and the evaluation of the percentage of patients with stable 
disease have been added to the secondary objective endpoints 
 3.2 Secondary objectives 
  Weeks 48, 72 and 96 have been added as evaluation timepoints for the effect of 
pasireotide LAR in mean tumor volume variation, mean percent tumor volume 
variation, proportion of patients reaching tumor volume decrease of at least ≥ 20%, in 
the pituitary function, and in the alpha subunit levels 
 The following secondary objectives have been added: 
 Duration of response for extension phase patients considered as responders 
 Percentage of patients remaining with stable tumor volume during the study 
 3.2.1 Secondary objective endpoints 
 Weeks 48, 72, and 96 have been added as evaluation timepoints for mean tumor 
volume change, percent tumor volume change, proportion of patients reaching tumor 
volume decrease of at least ≥ 20%, change in the grading score for disease-related 
symptoms, incidence of pituitary hormone dysfunction, proportion of patients reaching 
alpha subunit decrease of at least 50%, and proportion of patients reaching alpha 
subunit normalization 
 The following secondary objective endpoints have been added: 
 Number and proportion of patients who remained responsive throughout the 
extension phase treatment period (according to the magnetic resonance imaging 
evaluations on weeks 48, 72, and 96) among patients who had been considered as 
responders 
 Percentage of patients remaining with stable tumor volume throughout the study 
(according to magnetic resonance imaging evaluations on weeks 24, 48, 72, and 
96) 
 Evaluation of whether there was a difference in response between patients on 
pasireotide LAR 40 and 60 mg doses, if applicable 
 
 


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 4 Study design 
 
Weeks 48, 72, and 96 have been added as evaluation timepoints for: sella turcica 
MRI, alpha subunit and pituitary hormone levels 
 
 
 
 The study design has been changed, with the addition of an extension phase after the Main 
Phase (first 24 weeks) for patients who derived benefit from pasireotide LAR 
 Figure 4-2 has been added, showing the Extension Phase Study scheme 
 5 Population 
 The number of sites participating in the study has been increased, corresponding to 10 
- 13 total, instead of 10 - 12 
 5.2 Exclusion criteria 
 The term “randomization” has been replaced with “enrollment visit (Visit 2)”, as there 
will be no randomization in this study 
 6.2 Patient numbering 
 The information that no other data will be entered in the clinical database for patients 
considered as screening failure has been deleted 
 6.4 Patient treatment 
 End of Study (EOS) Visit: added definition of end of extension phase, which will have 
a duration of up to 92 weeks or approximately 2 years, or until pasireotide or other 
effective therapy becomes comercially available, or until clinical benefit is no longer 
seen (whichever occurs first) 
 The Extension Phase has been added to the patient treatment item with the treatment 
description: 
 Patients will receive pasireotide LAR IM at Visit 10 and will have the first 
extension study visit scheduled, which will occur within 28 (± 3) days after Visit 
10 
 Treatment with pasireotide LAR will be administered by the site’s healthcare 
professional staff every 28 (± 3) days 
 The dose will continue to be 60 mg. If a patient is receiving 40 mg due to 
tolerability problems and such problems have been resolved, there may be a dose 
escalation to 60 mg, at the physician’s discretion. If the adverse event reoccurs, the 
dose will be decreased to 40 mg and will be kept until completion of the Extension 
Phase or until study discontinuation 
 Safety Follow-up 
 Extension phase added to the safety follow-up 
 6.4.2 Allowed study drug adjustments 


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 Added explanation for dose escalation from 40 mg to 60 mg for extension phase 
patients who had their doses decreased due to tolerability problems. Additionally, if 
the adverse event reoccurs, the dose will be decreased to 40 mg and the patient must 
keep this dose 
 6.4.4 Discontinuation of the study drug 
 End of Study and safety visits timepoints added to 28 ± 3 days and 56 ± 3 days after 
the administration of the last dose of the study medication, respectively, for extension 
phase patients who discontinue treatment 
 7 Visits and evaluations schedule 
 On Table 7-1 
 The information that a ± 3 day window will be allowed for scheduled visits has 
been deleted. 
 Clarification on item 10 that if the visual field evaluation at Screening is performed 
no more than 14 days after Visit 2, it may be considered baseline data and there is 
no need to repeat it for Visit 2 
 Item 15 deleted: At the Screening Visit and Visit 10 (EOS), blood glucose and insulin will 
be measured at fasting at timepoint 0 during OGTT, and will be considered as baseline 
data for OGTT. Regarding this change, the glucose and insulin OGTT evaluation has 
also been deleted from the table 
 Added Table 7-2 Visits and evaluations schedule for the Extension Study with its 
specifications 
 7.3 Treatments 
 Replacement of the word responsibility with accountability 
 It has been clarified that Extension Phase patients will receive the medication starting 
on Week 24 and every 4 weeks (28 ± 3 days) thereafter, until Week 92 
 7.4.1 Primary efficacy evaluation 
 Evaluation timepoints added on Weeks 48, 72, and 96 in the Extension Phase 
 7.4.2 Secondary efficacy evaluations 
 Visits 13, 16, 19, 22, 25, and 28 of the Extension Phase added for recording of disease-
related symptoms 
 Clarification that symptoms not described in the section will be evaluated as absent or 
present 
 Weeks 48, 72, and 96 added for efficacy evaluation 
 
7.5.2.1 Changes in blood glucose 
 
2008 ADA Position statement replaced by the 2010 statement 
 
For consistency purposes, in the pasireotide clinical trials program (SOM230), blood 
glucose minimum levels have been changed from 200 to 275 mg/dL, as well as HbA1c 
percentage from 8 to 10% 


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 7.5.2.2 Changes in QT interval 
 It has been clarified that if the ECG is abnormal at Visit 10 and no additional 
pasireotide LAR dose is administered, then the follow-up is at the investigator’s 
discretion 
 It has been clarified that, on Scenario B of ECG change, the Holter ECG test must be 
recorded as soon as possible, within 7 days after the initial abnormal ECG, and not 30 
minutes before dosing on the next pasireotide LAR administration day 
 Figure 7-1 
 Week 6 has been replaced with week 7 for QTcF evaluation  
 Deleted recommendation for PK sample collection 
 Figure 7-2 
 Week 7 has been replaced with week 6 for QTcF evaluation 
 Deleted recommendation of Holter ECG on visit 4 or visit 8 
 Deleted recommendation for PK sample collection 
 7.5.3 Physical examination, weight, height 
 CRF has been corrected to eCRF 
 7.5.4 Vital signs 
 Visits 13, 16, 19, 22, 25, 28, and 29 have been added for the evaluation of vital signs 
in the extension phase 
 7.5.5 Performance Status 
 Visits 13, 16, 19, 22, 25, 28, and 29 have been added for the evaluation of 
Performance Status in the extension phase 
 7.5.6.1 Hematology and Coagulation 
 It has been clarified that the hematology parameters will be evaluated in the Screening 
Period and before administration of the study drug, and assessment on Visit 2 has been 
deleted 
 It has been clarified that in the Extension Phase the evaluations will be performed first 
on Visit 10, and every 6 months thereafter  
 7.5.6.2 Chemistry 
 Deleted Chemistry evaluation on Visit 2  
 Chloride and inorganic phosphorus tests have been added to the chemistry evaluation 
 Deleted OGTT evaluation  
 It has been clarified that fasting blood glucose, insulin, fasting chemistry evaluations, 
and HbA1c will also be performed on Weeks 48, 72, and 96 in the Extension Phase, 
and that the vitamin B12 and folic acid evaluations will also be performed on weeks 
48 and 96 in the Extension Phase 
 
 
 
 
 
 7.5.6.4 Urinalysis 


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 It has been clarified that urine evaluations will also be performed on weeks 48, 72, and 
96 in the Extension Phase 
 7.5.6.5 Pregnancy test 
 It has been clarified that the pregnancy test will be performed on weeks 48, 72, and 96 
in the Extension Phase 
 7.5.7 Radiology tests 
 It has been clarified that the gallbladder ultrasound will be performed on weeks 48 and 
96 in the Extension Phase 
 It has been clarified that the MRI scans will be performed on Weeks 48, 72, and 96 in 
the Extension Phase 
 7.5.8 Electrocardiogram (ECG) 
 It has been clarified that, in the Extension Phase, the ECG will be performed on weeks 
36, 48, 60, 72, 84, and 96 
 The information that three copies of the ECGs will be made and one will be submitted 
for evaluation by an ECG central evaluator has been deleted 
 7.5.9 Visual evaluations 
 Deleted recommendation that the visual field test must be performed and processed 
according to the guidelines of the central evaluator’s facility, which will be distributed 
to the sites before study start 
 9.3 Database management and quality control 
 It has been clarified that the results from the laboratory samples that will be centrally 
processed will be submitted to the investigator and not to Novartis (or the designated 
CRO) 
 The information that the captured biomarker sampling information will be handled by 
a CRO designated by Novartis and that it will be electronically collected and 
transfered by a Novartis internal sample tracking system has been deleted 
 10 Statistical methods and data analysis 
 It has been clarified that a final analysis will be performed when all Extension patients 
complete their last visit and will be reported either as an additional clinical study 
report or as a Main Phase report amendment 
 It has been clarified that statistical methods similar to those of the main phase will be 
used in the analysis throughout the extension phase, as appropriate 
 
 
 
 
 
 
 11.5.1 History of amendments 
 Clarifies the reason for amendment 


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REC Approval 
A copy of this amended protocol will be submitted to the Research Ethics Committee (REC) 
and to the Health Authorities. 
The changes described in this amendment require REC approval previous to implementation. 
Additionally, if the changes made herein affect the Informed Consent Form, the sites must 
update a reviewed Informed Consent Form and submit it for approval, considering the 
changes described in this protocol amendment. 
 


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Synopsis of the oncology clinical trial protocol  
Investigational drug 
Pasireotide LAR (SOM 230) 
Protocol number 
CSOM230D2401 
Study phase 
II 
Study title 
An Open-Label, Single Arm, Phase II Study to Evaluate the Efficacy and 
Safety of Pasireotide LAR on the Treatment of Patients with Clinically 
Non-Functioning Pituitary Adenoma  
Background 
Pre-clinical: 
Pasireotide (SOM230) is a new cyclohexapeptide containing the structural 
elements [(2-aminoethyl) amino carbonyl oxy]-L-proline, phenylglycine, 
and tyrosine (benzyl). It is a somatostatin analogue with a wide binding 
profile to its receptors, which may result in better efficacy in the current 
indications of octreotide (e.g., acromegaly and gastro-entero-pancreatic 
neuroendocrine tumors) and potential efficacy in new indications. Like 
natural somatostatin and other somatostatin analogues, pasireotide 
performs its pharmacological activity by binding to somatostatin (sst) 
receptors. Pasireotide shows a unique high-affinity binding profile to four 
of the five known human somatostatin receptors (sst1, 2, 3 and 5). 
Compared to octreotide, pasireotide has a binding affinity 30 to 40 times 
higher for sst1 and sst5 receptors, 5 times higher for sst3 receptors, and a 
comparable affinity for sst2 receptors. Pasireotide has two formulations in 
complete clinical development, namely, the SC (subcutaneous) and the IM 
(intramuscular) LAR (long-acting release) formulations. 
 
Pharmacokinetics: 
In healthy volunteers [CSOM230C2101], single IM injections of 40 mg and 
60 mg of pasireotide LAR showed typical long-acting release 
concentrations, which were characterized by an initial peak on day 1, 
followed by a long-acting release. Pasireotide LAR has been tested in 
patients with acromegaly and patients with carcinoid tumors who received 
IM injections once a month for three months at 20, 40 and 60 mg doses in 
a Phase I study [CSOM230C2110]. The PK analysis has shown that 
steady-state was reached with three monthly injections of pasireotide LAR. 
Pasireotide residual plasma concentrations (pre-dose) on days 28, 56, and 
84 indicated that the pharmacokinetic exposures were approximately 
dose-proportional. The pharmacokinetic exposure proportion among study 
populations was healthy volunteers : patients with acromegaly : patients 
with carcinoid tumors = ~ 1 : 1 : 2 for pasireotide LAR, similarly to the 
proportion for subcutaneous pasireotide. 
 
Clinical Trials: 
The pasireotide LAR formulation has been investigated in three studies: 
[CSOM230C2101] in healthy volunteers, [CSOM230C2110] in patients 
with acromegaly and carcinoid tumors, and [CSOM230C2305] – the 
registration program currently ongoing in patients with acromegaly. The 
[CSOM230C2101] study evaluating single intramuscular (IM) doses of  
pasireotide LAR 40 and 60 mg (N = 5 by dose cohort) in healthy 
volunteers has shown that pasireotide LAR was well tolerated and that 
there was no difference in the frequency of AEs observed between 
pasireotide LAR and octreotide LAR. The most common AE was diarrhea, 
sometimes 
associated 
to 
abdominal 
pain 
and/or 
flatulence. 
Gastrointestinal events were mild or moderate in intensity. Approximately 
half of the subjects reported mild transient pain at the injection site. Two 
volunteers on the 60 mg dose showed mildly increased fasting blood 


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glucose (< 123 mg/dL) levels, with all values returning to normal 28 days 
after the LAR injection. The [CSOM230C2110] study has evaluated single 
IM doses of pasireotide LAR of up to 60 mg in patients with acromegaly or 
carcinoid disease. Preliminary results of the clinical efficacy, safety, and 
pharmacokinetics / pharmacodynamics (PK/PD) analysis are available for 
35 patients with acromegaly, including 10, 12, and 13 patients in 
pasireotide LAR dose groups of 20, 40, and 60 mg. This study has also 
shown that pasireotide LAR was generally well tolerated, and that the 
most common AEs seen were gastrointestinal and mild in intensity. The 
[CSOM230C2305] study is evaluating the efficacy and safety of 
pasireotide LAR in patients with acromegaly (without medical care) 
compared to octreotide LAR. This study is still ongoing. 
Purpose / rationale 
Pasireotide LAR (SOM230) is a new somatostatin analogue with 
properties similar to those of natural somatostatin and, specifically, high-
affinity and functional activity to sst 1, sst 2, sst 3, and sst 5. Pasireotide 
has been shown to inhibit GH and prolactin secretion of in vitro pituitary 
adenomas, in vitro and in vivo ACTH, and in vivo GH/IGF-1. Additionally, 
pasireotide has inhibited the proliferation of endothelial VEGF-stimulated 
cells. A pre-clinical trial showed that pasireotide avoids NFPA cell viability 
by inhibiting VEGF secretion, indicating that this multi-receptor SSTR 
agonist may be useful as a medical therapy for NFPA. Pasireotide LAR 
has been tested in clinical trials in healthy volunteers [CSOM230C2101] 
and in 2 patient populations (i.e., acromegaly and carcinoid disease 
[CSOM230C2101]). However, there are no previous reports regarding the 
clinical use of pasireotide LAR in NFPAs. 
 
Based on these findings and on the need for a medical therapy that may 
be used pre-surgically to improve surgical results, leading to less patients 
with remaining tumors, or to control tumor growth or recurrence after 
surgery, avoiding the need for radiation therapy, pasireotide LAR may be a 
good option for treatment, both as pre-surgery therapy and in post-surgery 
tumor growth control. 
Objectives 
 
Primary: 
 
To evaluate the efficacy of pasireotide LAR in the proportion of 
patients with NFPA reaching treatment response. 
 
Secondary: 
 
To evaluate the effect of pasireotide LAR in mean tumor volume 
variation between baseline and treatment weeks 4, 12, 24, 48, 72, and 
96. 
 
To evaluate the effect of pasireotide LAR in mean percent tumor 
volume variation between baseline and treatment weeks 4, 12, 24, 48, 
72, and 96. 
 
To evaluate the effect of pasireotide LAR in the proportion of patients 
reaching tumor volume decrease of at least ≥ 20% after treatment 
weeks 4, 12, 48, 72, and 96. 
 
To evaluate the effect of pasireotide LAR on time to tumor response. 
 
To evaluate the effect of pasireotide LAR on disease-related 
symptoms* 
*Disease-related symptoms to be evaluated: headache, visual 
disorders, fatigue, decreased libido, erectile dysfunction (only for 
men), and menstrual irregularity or interruption (only for non-
menopausal women). 
 
To evaluate the effect of pasireotide LAR on the pituitary function on 


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weeks 4, 12, 24, 48, 72, and 96. 
 
To evaluate the effect of pasireotide LAR on the alpha subunit levels 
on weeks 4, 12, 24, 48, 72, and 96. 
 
To evaluate the overall safety and tolerability of pasireotide LAR. 
 
For extension phase: duration of response for patients considered as 
responders (i.e., patients reaching a tumor volume decrease of at 
least 20% compared to the initial tumor volume). 
 
To evaluate the percentage of patients remaining with stable tumor 
volume throughout the study. 
 
Endpoints (efficacy, 
safety) 
Primary Objective Endpoint: 
 
Proportion of patients with NFPA reaching tumor volume decrease of 
at least 20% after the 24-week treatment with pasireotide LAR. 
 
Secondary Objectives Outcomes: 
 
Mean tumor volume change evaluated by pituitary MRI between 
baseline and weeks 4, 12, 24, 48, 72, and 96. 
 
Percent tumor volume change evaluated by pituitary MRI between 
baseline and weeks 4, 12, 24, 48, 72, and 96. 
 
Proportion of patients reaching tumor volume decrease of at least ≥ 
20% after 4, 12, 48, 72, and 96 treatment weeks. 
 
Time to treatment response for treatment responders, defined as the 
time from the first injection to the first evaluation in which the patient 
reached a tumor volume decrease of at least ≥ 20%. 
 
Change in the grading score for disease-related symptoms between 
baseline and weeks 4, 12, 24, 48, 72, and 96. 
 
Incidence of pituitary hormone dysfunction on baseline and weeks 4, 
12, 24, 48, 72, and 96. 
 
Proportion of patients reaching alpha subunit decrease of at least 50% 
on weeks 4, 12, 24, 48, 72, and 96. 
 
Proportion of patients reaching alpha subunit normalization on weeks 
4, 12, 24, 48, 72, and 96. 
 
Percentage of adverse events with CTC grade ≥ 3 during treatment 
with pasireotide LAR. 
 
Percentage of patients with at least one adverse event with CTC 
grade ≥ 3. 
 
Incidence of all adverse events, incidence of abnormal laboratory 
values, and summary of laboratory evaluations. 
 
For the extension phase: among patients considered as responders 
(i.e., patients reaching a tumor volume decrease of at least 20% 
compared to the initial tumor volume), evaluate the number and 
proportion of patients remaining responsive throughout the extension 
phase treatment period (according to magnetic resonance imaging 
evaluations on weeks 48, 72, and 96). 
 
To evaluate the percentage of patients remaining with stable tumor 
volume throughout the study, i.e., patients mantaining a tumor volume 
variation of less than 20% in relation to baseline tumor volume 
(according to magnetic resonance imaging evaluations on weeks 24, 
48, 72, and 96). 


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Study design 
A Phase II, open-label, single-arm, prospective, multicenter study to 
evaluate the efficacy and safety of pasireotide LAR 60 mg in adult patients 
with NFPA. 
 
Main Phase: 
During the main phase of the study, visits will be performed every 28 ± 3 
days, with 2 extra safety visits on days 20 and 76. For all evaluations and 
visits of the Main Phase, see Table 7-1. 
 
Eligible patients will receive pasireotide LAR 60 mg every 28 ± 3 days for 
24 weeks, during the Main Phase of the study. Dose decreases to 40 mg 
will be allowed, due to safety issues. In case of rapid deterioration of the 
visual field or sudden visual loss, the patient will be discontinued from the 
study. 
 
Extension Phase: 
After the main phase of the study (first 24 weeks of treatment), patients 
who have derived benefit from treatment with pasireotide LAR, according 
to the evaluation by the physician in charge, will be offered the opportunity 
to enter the Extension Phase. Patients will continue to receive pasireotide 
LAR in 4-week intervals for up to 92 weeks or until pasireotide or other 
effective therapy becomes commercially available or until clinical benefit is 
no longer noticed (whichever occurs first). 
For all evaluations and visits in the Extension Phase, see Table 7-2. 
Population 
The population for this study is composed of adults diagnosed with NFPA 
who did not receive previous therapy (treatment-naïve) for the disease. 
Due to the difficulty to evaluate changes in tumor volume in 
microadenomas, and also because they may be mistakenly diagnosed as 
incidentalomas, only patients with macroadenomas (≥ 1 cm) may be 
enrolled in the study. 
Inclusion / exclusion 
criteria 
Inclusion: 
 
Male and female patients ≥ 18 years old 
 
Patients with clinically non-functioning pituitary macroadenomas ≥ 1 
cm 
 
No previous treatment for NFPA 
 
Eastern Cooperative Oncology Group (ECOG) Performance status 
(PS) of 0 to 1 
 
Written Informed Consent Form obtained before any screening 
procedure 
 
Exclusion: 
 
Patients requiring surgical intervention for relief of any sign or 
symptom related to tumor compression 
 
 


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 
Previous pituitary surgery  
 
Previous medical treatment for pituitary tumor 
 
Patients who received pituitary radiation within 10 years previous to 
the enrollment visit (visit 2) 
 
Prolactin (PRL) levels > 100 ng/mL (PRL evaluation must be 
performed with diluted samples in order to ensure prevention of the 
“hook effect”) 
 
Patients with optic chiasm compression, causing clinically significant 
acute defects on visual field 
 
Diabetic patients whose blood glucose is poorly controlled, as 
confirmed by HbA1C > 8% 
 
Patients with known gallblader or bile duct disease, acute or chronic 
pancreatitis 
(patients 
with 
asymptomatic 
cholelithiasis 
and 
asymptomatic dilation of the bile duct may be enrolled) 
 
Patients with abnormal coagulation (increased PT or APTT 30% 
above normal limits) or patients who received anticoagulants affecting 
PT (prothrombin time) or APTT (active partial thromboplastin time) 
 
Patients experiencing congestive heart failure (NYHA Class III or IV), 
unstable angina, persistent ventricular tachycardia, ventricular 
fibrillation, advanced heart blockade, or history of acute myocardial 
infarction within 24 weeks previous to the enrollment visit (visit 2) 
 
Screening (Visit 1) or baseline (pre-dose, visit 2) QTcF > 450 msec 
 
Patients with history of syncope or family history of sudden idiopathic 
death 
 
Patients with persistent or clinically significant cardiac arrhythmias 
 
Patients with Torsades de Pointes risk factors, such as uncorrected 
hypopotassemia, 
uncorrected 
hypomagnesemia, 
heart 
failure, 
clinically significant / symptomatic bradycardia, or high degree AV 
block 
 
Patients with concurrent disease(s) that may prolong QT interval, such 
as autonomous neuropathy (caused by diabetes or Parkinson’s 
disease), HIV, cirrhosis, uncontrolled hypothyroidism, or heart failure 
 
Patients taking medication(s) known to prolong QT interval 
 
Patients with liver disease or history of liver disease, such as cirrhosis, 
chronic active hepatitis B and C or persistent chronic hepatitis, or 
patients with ALT and/or AST > 2 x ULN, total blood bilirubin >1.5 x 
ULN, and blood albumin < 0.67 x LLN 
 
Patients with WBC count < 3x 109/L; Hgb < 90% LLN; platelets < 100x 
109/L 
 
Patients with any current or previous medical condition that, in the 
investigator’s opinion, may interfere with the conduction of the study or 
the evaluation of the study results 
 
Patients with history of immunological impairment, including a positive 
result for HIV tests (ELISA and Western blot). An HIV test will not be 
required; however, previous medical history will be analyzed 
 
Patients with known hypersensitivity to somatostatin analogues or any 
other pasireotide LAR component 
 
Patients with active malignant disease within the last five years 
(except for basal cell carcinoma or in situ cervix carcinoma) 
 
Patients with presence of uncontrolled, acute suspected, or active 
chronic infection 
 
 


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 
Pregnant or breastfeeding patients, or patients of childbearing 
potential, who do not adopt a clinically acceptable contraceptive 
method. If a woman is participating in the study, then a contraceptive 
method will be sufficient (pill or diaphragm), and the male partner must 
use condoms. If an oral contraceptive is used in addition to condoms, 
the patient must have adopted this method for at least 2 months prior 
to enrollment in the study, and must agree to continue to use the oral 
contraceptive throughout the study, and for three months after the end 
of the study. Sexually active male patients are required to use 
condoms throughout the study and for three months after the end of 
the study, as a precautionary measure (available data do not suggest 
any increase in reproductive risk with the study drugs) 
 
Study participants on an investigational drug 30 days before the 
enrollment visit (visit 2). Patients must have recovered from all side 
effects from other investigational therapies. 
 
Patients with history of non-compliance to medical treatments, patients 
considered non-compliant, or any circumstance at the time of 
enrollment in the study that might prevent the completion of the entire 
study or required follow-up 
 
Patients experiencing improper use/abuse of alcohol or drugs, in the 
past or currently, within 12 months before visit 1 (screening) 
 
Presence of Hepatitis B surface antigen (HBs-Ag) 
 
Presence of antibody screen for Hepatitis C (anti-HCV) 
 
Patients undergoing major surgery / surgical therapy for any cause 
within 4 weeks before randomization 
 
Patients 
with 
confirmed 
hypothyroidism, 
hypoadrenalism, 
and 
hypogonadism (except physiological andropause and menopause), 
unless properly treated with stable doses of hormone replacement 
therapy for at least 3 months before study entry 
 
Patients on growth hormone replacement therapy 
 
Patients with uncontrolled cardiovascular, renal, or metabolic 
disorders 
 
Patients with severe neurological or psychiatric disorders 
 Patients with contraindication to MRI, such as, for example (but not 
limited to): brain aneurysm clips, cardiac pacemaker, internal wiring of 
cardiac pacemaker and temporary pacemaker, cochlear implants, 
hearing devices containing internal and non-removable parts, Swan-
Ganz catheter, aortic balloon, Zenith AAA Endovascular Graft, and 
other possible contraindications related to ferromagnetic materials 
identified in the patient’s interview. 
Patient numbering 
Each study patient is uniquely identified by a 6-digit patient number, which 
is a combination of the 3-digit site number and the 3-digit subject number.  
Investigational and 
control drugs 
Depot 
IM 
pasireotide 
LAR 
(long-acting 
release) 
injection. 
(Pasireotide LAR excipients include: mannitol, sodium carmellose (sodium 
carboxymethyl cellulose), poloxamer 188, and water for injection). 
Control drug 
Not applicable 
Dose, schedule, 
treatment cycle 
Main Phase: 
The study drug is pasireotide LAR at a 60 mg dose every 28 ± 3 days, for 
6 months, administered as intragluteal depot IM injection by the clinical 
staff or healthcare professional at each research site. The first 60 mg dose 
of IM pasireotide LAR will be administered on Visit 2, after all baseline 
evaluations are completed and the eligibility to participate in the study is 
confirmed. For patients unable to tolerate the dosage schedule specified in 


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the protocol, a dose decrease to 40 mg is allowed. Patients unable to 
tolerate the minimum pasireotide LAR dose of 40 mg will be discontinued 
from the study. 
 
Extension Phase: 
After the Main Phase of the study (first 24 weeks of treatment), patients 
benefiting from treatment with pasireotide LAR will be offered the 
opportunity to continue to receive pasireotide LAR, based on the 
physician’s evaluation and the patient’s wishes. Patients participating in 
the Extension Phase will be treated with pasireotide LAR for up to 92 
weeks, or until pasireotide or other effective therapy becomes 
commercially available, or until clinical benefit is no longer seen 
(whichever occurs first). 
 
Patients enrolled in the Extension Phase will receive pasireotide LAR at 
the same dose used during the Main Phase. The first dose will be 
administered on Visit 10 (End of Main Phase [EOS] Visit, which will 
correspond to the Extension Phase baseline visit) and will have the next 
Extension Phase visit scheduled, which will occur after 28 (± 3) days. 
Pasireotide LAR will be administered by the site’s healthcare professional 
staff every 28 (± 3) days during the Extension Phase. 
Patients who will not participate in the Extension Phase must perform Visit 
11 (Follow-up Visit) of the Main Phase. 
 
Supply, preparation, and 
administration  
Novartis will provide pasireotide LAR, as 20 and 40 mg of powder in vials 
and 2 mL of vehicle in ampoules (for reconstitution), provided in cartons. 
Pasireotide LAR must be prepared as follows: 
Dose (mg) 
Volume to be injected 
60 mg 
1 20 mg vial + 1 40 mg vial + 2 mL of vehicle; 
total volume to be injected 
40 mg 
1 40 mg vial + 2 mL of vehicle: total volume 
to be injected 
 
Visits and evaluations 
schedule 
Screening Visit: 
Performed from Day -28 to Day -1 (Visit 1). Patients will receive the 
Informed Consent Form and, after signing it, they will be subjected to 
evaluations, including demographics, diagnosis and extent of disease, 
relevant / current medical history, verification of inclusion / exclusion 
criteria, vital signs, physical examination, ECOG performance status, 
ECG, blood pregnancy test, hematology and coagulation test, urinalysis, 
glucose and fasting blood insulin, HbA1c, chemistry, vitamin B12 and folic 
acid, hormone evaluation, alpha subunit evaluation,
, visual 
field evaluation, gallblader ultrasound, pituitary / sella turcica MRI, and 
evaluation of concurrent medication and disease-related symptoms. 
 
Main Phase: 
Inclusion will occur on Day 0 (Visit 2). Visits will occur as scheduled: Visit 3 
(Day 20, Week 3), Visit 4 (Day 28, Week 4), Visit 5 (Day 56, Week 8), Visit 
6 (Day 76, Week 11), Visit 7 (Day 84, Week 12), Visit 8 (Day 112, Week 
16), Visit 9 (Day 140, Week 20), Visit 10 or End of Main Phase Visit (Day 
168, Week 24) and, if the patients do not enter the Extension Phase, 
Follow-up Visit on Week 28, Day 196. A ± 3-day deviation from the 
scheduled visit will be allowed. 


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Patients will receive the study medication on Visits 2, 4, 5, 7, 8, 9, and 10 
(if they enter the Extension Phase). 
Patients will perform hematology, urinalysis, fasting blood glucose, and 
chemistry tests, as well as a visual field evaluation and a gallblader 
ultrasound, as per table 7-1. 
ECG, ECOG performance status, and evaluation of symptoms and of 
potential AEs will be performed on all visits. 
A pituitary MRI with gadolinium will be performed on Visits 1, 4, 7, and 10. 
Hormone and alpha subunit evaluations will be performed on Visits 1, 4, 7, 
and 10. 
 
For all visits and evaluations, see Table 7-1. 
 
Extension Phase: 
Enrollment will occur on Day 168 ± 3 (Week 24, Visit 10). Patients enrolled 
in the Extension Phase will receive pasireotide LAR IM on Visit 10, or End 
of Main Phase (EOS) Visit, and will have the next Extension Phase visit 
scheduled, which will occur 28 (± 3) days after Visit 10. Treatment with 
pasireotide LAR will be administered every 28 (± 3) days (see Table 7-2). 
MRI and visual field evaluations will be performed every 24 weeks (Weeks 
24, 48, 72, and 96). ECG and symptom evaluations will occur every 12 
weeks (± 3 days) and other safety (hematology, coagulation, and 
chemistry) and efficacy evaluations will occur every 24 weeks (± 3 days). 
For all Extension Phase evaluations, refer to Table 7-2. 
 
If a patient reports sudden worsening of visual field, extra visual field 
examinations and MRIs will be allowed.  
Efficacy evaluation(s)  
Tumor volume, hormone response, and relevant disease-related 
symptoms will be evaluated. 
 
Primary evaluation: 
The primary efficacy parameter – tumor volume decrease ≥ 20% – will be 
evaluated by MRI with gadolinium contrast in the Screening Phase (this 
will be considered as baseline imaging) and on Weeks 4, 12, and 24. 
Response is defined as a ≥ 20% decrease in tumor volume. The primary 
endpoint is the proportion of patients reaching a tumor volume decrease 
≥ 20% after 24 weeks of treatment with pasireotide LAR. 
 
Secondary evaluations: 
Based on the tumor volume evaluations described above, variations in 
mean tumor volume and mean percent tumor volume change will be 
evaluated on Weeks 4, 12, and 24, as well as the time to response (i.e., 
time from the first dose of pasireotide LAR to the moment when the patient 
reaches a tumor volume decrease ≥ 20%). Tumor volume evaluations in 
the Extension Phase will occur on Weeks 48, 72, and 96, in addition to 
week 24, as described above. 
 
Other secondary efficacy parameters include disease-related symptoms 
reported by patients and recorded by the investigator or his/her designees. 
 


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The following disease-related symptoms will be evaluated: headache, 
visual disorders, fatigue, decreased libido. Only for men: erectile 
dysfunction. Only for non-menopausal women: irregular or interrupted 
menstrual cycles. The investigator will also ask patients to classify the 
symptoms above according to a 5-point scale (0 = absent, 1 = mild, 2 = 
moderate, 3 = severe, 4 = very severe). 
 
Hormone profiles, including growth hormone (GH), insulin-like growth 
factor I (IGF-1), follicle-stimulating hormone (FSH), luteinizing hormone 
(LH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone 
(TSH), prolactin (PRL), cortisol, free T4, and estradiol (only for women) or 
testosterone (only for men), will be evaluated in the screening period (and 
will be considered as baseline data) and on Weeks 4, 12, and 24 of the 
Main Phase. Extension Phase evaluations will be performed on Weeks 48, 
72, and 96, in addition to week 24, as described above. 
 
Subunit-alpha levels will be measured in the Screening Period (and will be 
considered as baseline data), on Weeks 4, 12, and 24 in the Main Phase, 
and on Weeks 48, 72, and 96 in the Extension Phase, in addition to week 
24, as described above. 
 
Special safety 
evaluation(s) 
Changes in blood glucose: 
Patients with history or recent diagnosis of fasting glucose impairment, 
glucose tolerability impairment, diabetes mellitus, or at risk of developing 
these conditions must monitor blood glucose via the fingerstick capillary 
glucose test twice a day (fasting and 2-hour postprandial). It is 
recommended that patients be encouraged to keep a blood glucose diary 
for appropriate control of the disease throughout the study, as well as 
present the data collected to the physician / diabetes expert for evaluation. 
The data will not be collected by the sponsor. 
 
It is advised that any patient presenting fasting plasma glucose > 130 
mg/dL (7.2 mmol/L), or 2-hour postprandial capillary glucose (PPG) ≥ 180 
mg/dL (10 mmol/L) in two consecutive measurements with an interval of 
approximately 14 days and/or HbA1c > 7% be evaluated by a diabetes 
expert for appropriate treatment. 
 
Changes in QT interval: 
If, at any visit, a QTcF > 480 msec is seen in patients receiving pasireotide 
LAR, the following actions will be taken: 
 
A visit to the cardiologist must be scheduled as soon as possible, but 
in no more than 7 days from the initial abnormal ECG, and the 
cardiologist must reevaluate the ECG (this may be done by the central 
cardiologist, if the study has one). 
 


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 
If a QTcF > 480 msec is NOT confirmed, no action will be taken. 
 
If a QTcF > 480 msec is confirmed, a cardiologist must perform a 
thorough examination (such as review of the baseline ECG, 
concurrent 
medication, 
and 
performance 
of 
cardiovascular 
examination (including at least one cardiac auscultation)) in order to 
evaluate the patient for cardiovascular risk factors. 
 
If, based on the cardiologist’s evaluation, the investigator considers 
that there is an acute cardiovascular safety risk, and that the patient 
should not continue to receive the study drug, or the patient meets any 
discontinuation criteria (section 6.4.5.1), he/she must be immediately 
discontinued. 
 If, after the cardiologist’s analysis, the investigator considers that there 
is no acute cardiovascular safety risk and that the patient may 
continue to receive the study drug, a Holter ECG (24 hours) must be 
performed, depending on when the initial ECG was performed.  
Patient-reported 
outcomes 
Not applicable. 
Pharmacokinetics 
Not applicable. 
Biomarker evaluations 
Not applicable.  
Statistical methods and 
data analyses 
Populations for Analysis: 
Full analysis set (FAS): comprises all patients successfully completing 
Screening and receiving at least one dose of the study medication. The 
FAS will be the primary set for efficacy analyses. 
Safety analysis set: comprises all patients receiving at least one dose of 
the study drug and who had at least one post-baseline safety evaluation. 
The analyses described in this section represent the analyses to be used 
in the Main Phase of the study. A final analysis will be performed when all 
Extension patients complete their last visit and will be reported either as 
an additional clinical study report or as an amendment to the Main Phase 
report. 
 
Primary Objective: 
The primary efficacy variable is the proportion of patients with NFPA 
reaching tumor response, defined as tumor volume decrease of at least 
20% after 24 weeks of treatment with pasireotide LAR. The response rate 
will be summarized in terms of incidence rates and the 90% confidence 
interval at the end of the Main period of the study (Week 24). The same 
analysis will be repeated for the PPS population. 
 
Secondary Objectives: 
All secondary efficacy analyses will be based in the full analysis set (FAS). 
The safety analysis set will be used for all safety analyses. The secondary 
efficacy endpoints are described in section 3.3.2. 
 
Safety: 
The safety evaluation will be based mainly on the frequency of adverse 
events (AEs) and on the number of patients with laboratory values outside 
the reference ranges. Other safety data, such as physical examination, 
weight, height, vital signs, ECOG performance status, radiology tests, 
ECGs, MRIs, and visual evaluations, will be summarized as appropriate. 
 


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Calculation of the Sample Size: 
The sample size of 19 patients has been selected regardless of statistical 
power. A response rate (tumor volume decrease ≥ 20%) of at least 10% of 
patients is considered clinically significant for this population. If the actual 
response rate is 10%, the probability of obtaining two or more responders 
among the 16 patients is 58%. In this study, the exact 90% CI will also be 
obtained. The table below shows the exact 90% CI when 2 - 6 patients, 
among the 19 patients, respond. Considering a drop-out rate of 20%, 23 
patients will be enrolled in order to obtain 19 evaluable patients for the 
final analysis.  
Responders / n 
Lower confidence limit 
Upper confidence lim
2/19 
1.9% 
29.6% 
3/19 
4.4% 
35.9% 
4/19 
7.5% 
41.9% 
5/19 
11% 
47.6% 
6/19 
14.7% 
53% 
 
 
Planned Dates 
FPFV: August 2011 
 
LPFV: April 2012 
 
Number of patients, 
sites, and location of the 
sites 
Total number of patients: 23 
Number of sites: 13 
Location of the sites: Brazil 
 
 


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1 
Background 
1.1 
Summary of clinically non-functioning pituitary adenomas 
(NFPAs) 
Approximately 10% of intracranial neoplasms are pituitary gland tumors, the most common 
being pituitary adenoma, with an annual incidence of 0.5 to 8.2 subjects per 100,000 (Asa 
2008)(Ezzat et al 2004)(Jane et al 2003). Tumors from this heterogeneous group have been 
commonly classified by their sizes: lesions < 1 cm are considered microadenomas and those ≥ 
1 cm are macroadenomas (Ezzat et al 2004)(Jaffe 2006). 
Pituitary adenomas are frequently not diagnosed and may be asymptomatic. Up to 1 in every 
600 people may present non-diagnosed macroadenomas (Ezzat et al 2004). A recent meta-
analysis has reported an estimated prevalence rate of 16.7% for asymptomatic individuals, 
14.4% for postmortem, and 22.5% for radiological studies (Ezzat et al 2004). 
The types of pituitary adenomas are presented on Table 1-1. Specific hormones are secreted 
by corticotropic, somatotropic, thyrotropic, gonadotropic, and lactotropic adenomas. NFPAs 
do not cause any specific clinical syndrome, but patients may experience symptoms related to 
hypopituitarism and mass effect, such as headache, visual impairment, and fatigue. NFPAs are 
responsible for approximately 25% to 35% of surgically resected tumors (Jane et al 2003). 
 
Table 1-1 
Pituitary adenomas, main associated hypersecreted hormone, and 
related clinical syndrome  
Pituitary ademona 
Main associated hypersecreted 
hormone 
Clinical syndrome related to 
hormone hypersecretion  
Corticotropic adenoma 
Adrenocorticotropic hormone 
(ACTH) 
Cushing’s disease 
Somatotropic adenoma 
Growth hormone (GH) 
Acromegaly / Gigantism 
Thyrotropic adenoma 
Thyroid-stimulating hormone (TSH) 
Hyperthyroidism (may be 
asymptomatic) 
Gonadotropic adenoma 
Luteinizing hormone (LH) 
Follicle-stimulating hormone (FSH) 
and subunits 
Usually asymptomatic 
Lactotropic adenoma 
Prolactin (PRL) 
Galactorrhea, hypogonadism, 
amenorrhea, infertility, 
impotence 
Clinically non-functioning 
pituitary adenoma (NFPA) 
Clinically insignificant hormone 
secretion (alpha subunit may be 
increased)  
Usually asymptomatic 
 


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All pituitary macroadenomas may cause symptoms related to the tumor mass (tumor 
compression symptoms), such as headache, visual field impairment, and hypopituitarism-
related symptoms. 
Hypopituitarism may occur in pituitary macroadenomas as a result of (a) compression of the 
pituitary stalk, leading to a decrease of hypothalamic hormones reaching the pituitary gland; 
(b) compression of the normal pituitary tissue; and (3) hypothalamic involvement of the 
pituitary tumor (Dekkers et al 2008). The hypogonadism seen with these adenomas is 
frequently associated to the increase in blood prolactin levels (usually < 200 ng/mL) (Jaffe 
2006). Patients with hypopituitarism are at increased risk of mortality due to cardiovascular, 
cerebrovascular, and/or respiratory disease (Bates et al. 1996)(Rosen et al. 1990)(Bulow et al 
1997)(Nilsson et al 2000)(Tomlinson et al 2001). 
Hypopituitarism due to NFPA may produce different symptoms. Four out of five patients with 
NFPA experience secondary hypothyroidism, and 3 out of 5 experience secondary adrenal 
failure (Jaffe 2006). Most patients also experience signs and symptoms of hypogonadism, 
frequently as a result of direct compression by a large adenoma and growth hormone (GH) 
deficiency (Jaffe 2006). Approximately 60% to 80% of patients experience visual field 
defects, a consequence of tumor pressure on the optic chiasm (Jaffe 2006)(Dekkers et al 
2007). In some cases, these tumors compress other surrounding brain tissues and lead to 
dysfunctions in the cranial nerves (Jaffe 2006)(Vance 2008). Frequently, patients experience 
headache, although this event is not diagnosed (Vance 2008). 
The evaluation of the tumor volume and location of the pituitary adenoma are performed more 
efficiently by magnetic resonance imaging (MRI) (Dekkers et al 2008). Screening hormone 
tests that may determine pituitary deficiency include ACTH, cortisol, TSH, free thyroxin (T4), 
insulin-like growth factor I (IGF-1), luteinizing hormone (LH), follicle-stimulating hormone 
(FSH), and testosterone (in men) (Vance 2008). Prolactin is also useful for diagnosis, but it 
must be diluted if the patient presents a large lesion, in order to avoid the “hook effect” and a 
possible mistaken diagnosis (Vance 2008) (the hook effect may be defined as falsely low 
values in an immunoassay when an extremely large amount of antigens affects the binding 
ability of the antibody added). 
The medical treatment of choice for patients with NFPA is transsphenoidal surgery (Dekkers 
et al 2008), a procedure aiming at eradicating the tumor and improving visual field defects, 
whenever present (Dekkers et al 2007). In a series (N = 109), it was reported that, after 
surgery, only 21% of patients reached a complete recovery of the visual field and 63% 
reached partial improvement of the visual field, as well as experienced significant 
improvement in LH/FSH and TSH deficiencies (P < 0.01 e P < 0.05, respectively) (Dekkers et 
al 2006). Complete excision of the tumor is essential to avoid recurrence and prolong survival 
(Woollons et al 2000). The recurrence-free survival (RFS) rates in five years in post-surgery 
MRIs were as high as 84% in the absence of residual tumor, but as low as 30% in the presence 
of residual tumor (Greenman et al 2003). However, the complete resection of the tumor may 
only be reached in 36% of cases (Ferrante et al 2006). 


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Before 1992, many patients with NFPA underwent post-surgery radiation therapy (Greenman 
et al 2003). However, radiation therapy is associated to long-term adverse effects, which 
include increased incidence of pituitary deficiencies, atrophy of the optical nerve, visual 
deterioration, increased risk of long-term brain tumors, and neurocognitive or 
neurophysiological impairment (Dekkers et al 2008)(Ferrante et al 2006). Thus, post-surgery 
preventive radiation therapy is frequently avoided, being restricted to patients with evidence 
of remaining tumor increase (Bradley et al 1994)(Turner et al 1999). A NFPA treatment 
algorithm is shown below (Figure 1-1). 
Dekkers et al assessed quality of life (QoL) in 99 adult patients in remission during long-term 
follow-up after surgical treatment (n = 99) and additional radiation therapy treatment (n = 37) 
for clinically non-functioning pituitary macroadenoma (NFMA) (Dekkers et al 2006). They 
concluded that, after these successful treatments for NFMA, QoL decreased considerably in 
the patients. 
 
 
Figure 1-1 
Treatment algorithm for clinical NFPA (Dekker et al. 2008) 
 
In addition to the surgical and radiation procedures, two approaches for medical treatment 
have been investigated: one dopamine-based and one somatostatin-based. 
 
Dopamine, the main catecholamine neurotransmitter in the human central nervous system, 
controls a number of functions by binding to dopamine receptors on cell surfaces (Pivonello et 
al 2007). Five different types of dopamine receptors have been identified: D1, D2, D3, D4, and 
D5. These receptors may be subdivided into two groups: those similar to D1, including D1 and 
D5, and those similar to D2, including the two D2 variants (D2short and D2long), in addition to D3 
and D4. The D2 receptor is expressed in the anterior and intermediary lobes of the normal 
pituitary gland, as well as in pituitary tumors that do not secrete prolactin (Pivonello et al 
Clinically non-functioning pituitary macroadenoma 
Visual field defects or tumor compressing the optic chiasm * 
Yes 
Yes 
Yes 
Transsphenoidal surgery 
4 months MRI performed in post-surgery. 
Is there a remaining tumor? 
No 
No 
Expected approach 
1. 
Expected approach with MRI 
every 1-2 years 
2. 
Consider radiation therapy in 
selected cases 
Assessments of the visual field and by 
MRI every 6 - 18 months. Is there a visual 
field defect or a tumor close to the optic 
chiasm? 
Transsphenoidal surgery 


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2004). As a result, blocking the D2 receptor agonist was thought to be effective against 
NFPAs. Cabergoline is a D2 receptor agonist with high affinity both to D2 receptor variants 
and receptors similar to D2, D3, and D4 (Pivonello et al 2004), in addition to presenting an 
affinity higher than that of the other D2 receptor agonist, bromocriptine (see Table 1-2). 
(Pivonello et al 2007). 
Table 1-2 
Binding profile of dopamine receptor agonists, cabergoline and 
bromocriptine (Pivonello et al 2007) 
Agent 
D2 
D3 
D4 
 
D2short 
D2long 
 
 
 
Emax 
(%) 
IC50 (nM) 
Emax 
(%) 
IC50 (nM) 
Emax 
(%) 
IC50 (nM) 
Emax 
(%) 
IC50 (nM) 
Dopamine 
100 
350 
100 
320 
100 
11 
100 
100 
Bromocriptine 
41 
4.5 
28 
3.9 
68 
4.2 
0 
>1000 
Cabergoline 
102 
0.53 
75 
0.41 
86 
0.78 
49 
81 
Emax: maximum efficacy calculated as a percentage of dopamine concentration with maximum efficacy (100%); IC50: 
concentration leading to 50% inhibition 
The results of the treatment with cabergoline for patients with NFPA have not been 
encouraging or consistent. Additionally, these clinical trials enrolled a small number of 
patients (see Table 1-3) (Pivonello et al 2004)(Lohmann et al 2001)(Colao et al 2000). 
 
Table 1-3 
Summary of Cabergoline Clinical Trials for NFPA  
Study 
N 
Cabergoline Dose 
Duration 
(Months) 
Tumor 
Volume 
Visual Field 
 
 
 
 
Changes 
from 
baseline 
Changes 
 
 
 
 
% of Patients 
% of Patients 
Pivonello et al 2004 
9 
1 - 3 mg/wk 
12 
Decrease: 56% 
Increase: 44% 
Improvement: 4/5 
(80%) 
Lohmann et al 2001 
13 
0.25 - 1.0 mg/wk 
12 
Decrease: 54% 
Unchanged: 
38% 
Increase: 8% 
Improvement: 2/9 
(22%) 
Colao et al 2000 
10 
5 patients receiving 
quinagolide, followed by 
cabergoline: 0.5 mg/wk 
up to no more than 1.5 
mg twice a week; 5 
patients received 
quinagolide alone 
6 months 
with 
quinagolide, 
followed by 
6 months 
with 
cabergoline 
Decrease: 0% 
with quinagolide 
+ cabergoline; 
Decrease: 20% 
with quinagolide 
alone 
Improvement: 2/5 
(40%) (1 
quinagolide + 
cabergoline;1 
quinagolide alone) 
 
Somatostatin is an endogenous peptide that modulates different exocrine and endocrine 
secretions. There are five known somatostatin receptors: sst 1, 2, 3, 4, and 5, expressed in 
different tissues under normal physiological conditions. Somatostatin analogues act by 
binding to these receptors with different affinities (Schmid and Schoeffter 2004). Binding to 
the receptor triggers a cell signaling cascade that ultimately results in decreased cell activity 
and hormone secretion inhibition. Somatostatin receptors are strongly expressed in many solid 
tumors, especially pituitary tumors and neuroendocrine tumors in which hormones are 
excessively secreted [for example, acromegaly (Freda 2002), GEP/NETs (Modlin 2009), and 


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Cushing’s Disease (Van der Hoek et al 2005), as well as NFPA (Miller et al., 1995; Panetta 
and Patel, 1995; Taboada et al., 2007)]. Specific somatostatin receptors have been identified 
in NFPAs cell membranes (de Bruin et al 1992). 
 
Octreotide is a somatostatin synthetic analogue that has shown preferential binding to sst2 
receptor (Colao et al 2008) (See Section 1.2). As with cabergoline, studies on octreotide for 
the treatment of NFPAs were small and had unsatisfactory results in terms of tumor reduction 
(see Table 1-4). (Colao et al 1999)(Broson-Chazot et al 1997) (Warnet et al 1997)(Plockinger 
et al 1994)(Merola et al 1993)(Gasperi et al 1993)(de Bruin et al 1992). 
 
Table 1-4 
Summary of Octreotide Clinical Trials for NFPA 
Study 
N 
Octreotide Dose 
Duration 
Tumor Volume 
Visual Field 
 
 
(Months) 
Changes from 
baseline 
Changes 
 
 
 
 
% of Patients 
% of Patients 
Colao et al 1999 
9 
0.3 - 0.6 mg/day 
SC 
6-12 
Decreased: 0% 
Unchanged: 78% 
Increased: 22% 
Not reported 
Broson-Chazot et al 
1997 
16 
0.3 mg/day SC 
1 
Unchanged: 100% 
Improved: 50% 
Unchanged: 38% 
Worsened: 12%  
Warnet et al 1997 
29 
0.6 mg/day SC 
2 
7 evaluable patients 
Decreased: 43% 
Unchanged: 43% 
Increased: 14% 
22 evaluable patients 
Improved: 41% 
Unchanged: 41% 
Worsened: 18% 
Plockinger et al 1994 
14 
0.3 - 1.5 mg/day 
SC 
3 (pre-
surgery) 
Decreased: 0% 
Unchanged: 86% 
Increased: 14% 
Not reported 
Merola et al 1993 
19 
0.15 - 0.3 mg/day 
SC 
1-12 
Decreased: 5% 
Unchanged: 95% 
9 evaluable patients 
Improved: 11% 
Unchanged: 89% 
Gasperi et al 1993 
8 
0.3 mg/day SC 
3-6 
Decreased: 0% 
Unchanged: 75% 
Increased: 25% 
5 evaluable patients 
Improved: 20% 
Unchanged: 60% 
Worsened: 20% 
de Bruin et al 1992 
4 
1.2 mg/day SC 
3-6 
Unchanged: 100% 
Improved: 75% 
Unchanged: 25% 
 
 
Combination therapy with dopamine receptor agonist cabergoline and somatostatin analogue 
octreotide in 10 patients with NFPA produced similar results (Andersen et al 2001). Tumor 
volume decreased in 6 patients (60%), remained unchanged in 3 (30%), and increased in 1 
(10%) patient. Visual acuity improved in 3 (30%) patients and remained unchanged in the 
other 7 (70%) patients. 


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A clinical therapy able to control tumor growth and possibly capable of decreasing tumor size 
would be highly advantageous to patients with NFPA. These therapies could be used pre-
surgically to improve surgical result, leading to few patients with remaining tumors, or to 
control tumor growth or recurrence after surgery, thus avoiding the need for radiation therapy. 
Another possible benefit related to tumor decrease would be the receovery from 
hypopituitarism. 
1.2 
Pasireotide overview (SOM230) 
Pasireotide (SOM230) is a new cyclohexapeptide containing the structural elements [(2-
amynoethyl) amino carbonyl oxy]-L-proline, phenylglycine, and thyrosine (benzyl). It is a 
somatostatin analogue with a wider receptor binding profile that may result in a better efficacy 
in the present indications of octreotide (e.g., acromegaly and gastro-entero-hepatic tumors) 
and potential efficacy in new indications. Like natural somatostatin and other somatostatin 
analogues, pasireotide performs its pharmacological activity through somatostatin (stt) 
receptors binding. 
 
Somatostatin analogues approved for clinical use (octreotide and lanreotide) have high 
affinity to sst2, with moderate or negligible affinity to the remaining somatostatin receptors. 
Pasireotide shows a unique high affinity binding profile to four of the five known human 
somatostatin receptors (sst1, 2, 3, and 5). Compared to octreotide, pasireotide shows a binding 
affinity 30 to 40-fold higher for sst1 and sst5 receptors, 5-fold higher for sst3 receptors, and 
comparable for sst2 receptors (see Table 1-5). A detailed summary of the available pre-
clinical data is provided in the Investigator’s Brochure. The lanreotide binding profile is 
similar to that of octreotide (Table 1-5). 
 
Table 1-5 
Binding profile of octreotide, pasireotide, and lanreotida in hsst 1-5. The 
results are mean values ± IC50 SEM shown in mmol/L. Adapted from Bruns 
et al 2002 
Compound 
sst1 
sst2 
sst3 
sst4 
sst5 
Octreotide acetate 
(SMS 201-995) 
280  80 
0.38  0.08 
7.1  1.4 
>1000 
6.3  1.0 
Lanreotide 
180  20 
0.54  0.08 
14  9 
230  40 
17  5 
Pasireotide (SDZ 
227-230) 
9.3  0.1 
1.0  0.1 
1.5  0.3 
>100 
0.16  0.01 
IC50 Ratio: 
octreotide acetate / 
pasireotide  
30 
0.38 
4.7 
-- 
39.4 
IC50 Ratio: 
lanreotide / 
pasireotide 
19.4 
0.54 
9.3 
-- 
106 
 


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There are two pasireotide formulations under complete clinical development, i.e., SC 
(subcutaneous) and IM (intramuscular) LAR (long-acting release) formulations. A detailed 
summary of the available pre-clinical data is provided in the Investigator’s Brochure. 
 
Pasireotide has been well tolerated when administered subcutaneously (SC) to healthy 
volunteers as continuous infusion for seven days [CSOM230B2108] with total daily doses of 
up to 2025 µg. Subcutaneous pasireotide has been subsequently evaluated in two phase II 
studies with 45 patients with metastatic carcinoid tumors and carcinoid syndrome symptoms 
[CSOM230B2202] and in 39 patients with Cushing’s Disease [CSOM230B2208] at doses of 
up to 1200 µg BID. SC pasireotide has been well tolerated, with gastrointestinal events as the 
most common adverse events (AEs). Hyperglycemia has also been seen and appeared more 
marked in patients with history of hyperglycemia or diabetes mellitus. However, blood 
glucose in these patients was easily controlled by adjusting oral anti-hyperglycemic agents or, 
in some cases, by adding insulin. Details and available data from these studies 
[CSOM230B2202], [CSOM230B2208] are described in the Investigator’s Brochure for SC 
pasireotide. 
 
Efficacy and safety data are available from a Phase II study [CSOM230B2201] in patients 
with recurrent, persistent or de novo acromegaly. After initial treatment with SC octreotide  
100 µg TID for 28 days, patients received pasireotide 200 µg SC BID, 400 µg SC BID, and 
600 µg SC BID randomly for 28 days each (total period of the study: 16 weeks). Overall, 60 
patients received treatment with pasireotide during this study. Regarding the previous medical 
treatment for acromegaly at study enrollment, 67% of patients received previous therapy with 
somastotatin analogue, 10% received medical treatment for acromegaly, but did not receive 
somatostatin analogues (no treatment with somatostatin analogue), and 23% of patients 
experienced de novo disease. Sixty patients were evaluated for safety. All dosage levels of 
200, 400, and 600 µg of SC pasireotide BID were, usually, well tolerated. The adverse events 
were predominantly gastrointestinal, including nausea (23%), diarrhea (20%), and abdominal 
pain (10%), and mild or moderate in severity. Overall, the events resolved spontaneously 
during continuous treatment. Other AEs occurring with a frequency ≥ 5% were headache 
(12%), increased glycated hemoglobin (7%), dizziness (5%), bronchitis (5%), nasopharyngitis 
(5%), and back pain (5%). For 13 (22%) of the 60 patients in the safety population, AEs of 
metabolism and nutritional disorders were reported, including diabetes mellitus (4 patients), 
non-insulin dependent diabetes mellitus (2 patients), impaired glucose tolerability (2 patients), 
hyperglycemia (1 patient), hypoglycemia (2 patients), hypocalemia (1 patient), and 
hyponatremia (1 patient). Eight of these patients had a pre-existing history of diabetes or 
glucose intolerability at baseline. For five (8%) patients, an increase in blood glucose was 
reported. These events did not require treatment or were effectively controlled by changes in 
the anti-hyperglicemic medication. Only one patient, who had pre-existing diabetes at 
baseline, was discontinued from the 3-month treatment with pasireotide due to worsening of 
glycemic control. Glycated hemoglobin (SD) (n = 58) was within the upper limit of normal at 
baseline at 6.01% (0.57), increasing to 6.45% (0.84) during the 12-week treatment period with 
pasireotide. This change was not significant. There were no reports of deaths or reported 
serious AEs considered related to pasireotide during this study. 
 


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Gallbladder ultrasound scans showed that 3.7% of patients with normal gallbladder 
ultrasounds at baseline had gallstones after treatment with pasireotide. Colelithiasis is a 
known side effect associated to the therapy with somatostatin analogues, which is normally 
asymptomatic. Long-term data on gallbladder abnormalities related to pasireotide are not yet 
available. 
 
Other details and data available from the study [CSOM230B2201] are described in the 
Investigator’s Brochure for SC pasireotide. 
 
Pasireotide LAR was evaluated in two further studies, one in healthy volunteers 
[CSOM230C2101] and one in patients, which is still ongoing [CSOM230C2110]. Preliminary 
data from the study in healthy volunteers [CSOM230C2101] evaluating single IM pasireotide 
LAR doses of up to 60 mg (N = 5 per cohort) show that pasireotide LAR was well tolerated 
and that the adverse events seen are comparable to those seen with octreotide LAR. The most 
common adverse event was diarrhea, which was sometimes associated to abdominal pain 
and/or flatulence. Gastrointestinal events were mild to moderate in severity. Approximately 
half of the subjects reported transient mild pain at the injection site. Two volunteers who 
received a 60 mg dose experienced mild increases in fasting blood glucose (< 123 mg/dL), 
with all values returning to normal 28 days after the LAR injection. 
Pasireotide LAR pharmacokinetics was evaluated in healthy volunteers after a single IM 
injection of 40 or 60 mg. Pasireotide exposure was dose-proportional, with long-acting release 
phase Cmax of 9.6 ± 5.1 ng/mL and 15.8 ± 3.3 ng/mL for 40 and 60 mg doses, respectively. 
Simulation with multiple doses suggested that this form of LAR is appropriate for monthly 
dosing (every 28 days). The simulated residual concentrations at steady-state (Cresidual,ss) were 
5.5 and 11.5 ng/mL at 40 and 60 mg, respectively. 
 
Other details and data available from the study in healthy volunteers [CSOM230C2101] are 
described in the [Investigator’s Brochure] for pasireotide LAR. 
 
Pasireotide LAR is being tested in a study in patients, which is still ongoing 
[CSOM230C2110]. It is a Phase I, multicenter, open-label, randomized study to evaluate the 
pharmacokinetics, safety, and tolerability of monthly doses (dosing every 28 days) of 20, 40, 
and 60 mg of pasireotide LAR as depot IM injections administered to patients with 
acromegaly and patients with 1carcinoid disease. Thirty-five patients with acromegaly and 42 
carcinoid patients were enrolled (approximately 10 patients per dose cohort by indication). 
Patients in this study receive pasireotide, given as depot intragluteal IM injection once every 
28 days, for 3 months. The preliminary efficacy, safety, and clinical PK/PD analysis results 
are available for 35 patients with acromegaly, including 10, 12, and 13 patients in dose groups 
of 20, 40, and 60 mg of pasireotide LAR. The efficacy results are shown on Table 1-6. 
 


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Table 1-6 
Number (percentage) of responders among patients with acromegaly 
with mean GH level ≤ 5 mg/mL and IGF-1 level within normal limits 
compared to controls of equivalent age and gender after three 
monthly IM injections of 20 mg, 40 mg, or 60 mg of pasireotide LAR 
formulation – Study [CSOM230C2110] 
Dose 
20 mg 
(N = 10) 
40 mg 
(N = 12) 
60 mg 
(N = 13) 
Overall * 
4 (40%) 
4 (36%) 
7 (54%) 
Mean GH < 2.5 µg/L ** 
5 (50%) 
6 (50%) 
7 (54%) 
IGF-1 within normal limits 
compared to controls of 
equivalent age and gender  
5 (50%) 
7 (64%) 
8 (62%) 
* Patients with mean GH < 2.5 µg/L and IGF-1 within normal limits compared to controls of equivalent 
age and gender 
** Mean GH was obtained at -0 min. (pre-dose) and 30, 60, 90, and 120 minutes post-dose 
 
 
This study also showed that pasireotide LAR was generally well tolerated, and that the most 
common adverse events were gastrointestinal and mild in intensity. Although pre-clinical or 
clinical trials have not shown any specific cardiac toxicity issue related to pasireotide, a 
complete 
clinical 
QT/QTc 
evaluation 
was 
performed 
in 
healthy 
volunteers 
[CSOM230B2113]. In Part I of the study, 900 µg to 2100 µg doses of pasireotide were 
investigated, after which the maximum tolerated dose (MTD) of pasireotide was defined as 
1950 µg SC BID. The MTD was then used as the pasireotide dose in Part II of the study (i.e., 
a three-way crossover design using moxifloxacin, placebo, and 1950 µg of SC pasireotide 
BID). The effect of pasireotide (at the MTD) on the QTcF interval was shown. This effect was 
based on the upper limit of the 1-sided 95% CI for the difference compared to placebo in the 
QTcF change from baseline of > 10 ms, in one or more timepoints. Pasireotide and 
moxifloxacin showed maximum effect 2 hours after dosage (QTcF change of 17.5 ms and 8.5 
ms from baseline compared to placebo, respectively). Subjects receiving pasireotide also 
showed a HR decrease within 0 to 4 hours post-dose (maximum change versus baseline of 
10.7 bpm). The appropriate ECG monitoring of patients assigned to pasireotide LAR arms is 
implemented in the protocol. 
 
Other detailed information on clinical efficacy and safety of pasireotide LAR may be found in 
the Investigator’s Brochure. 
 
Mean concentration (SD) profiles over time for pasireotide are shown on Figure 1-2. PK 
analysis showed that steady state was reached with three montly injections of pasireotide 
LAR. Residual (pre-dose) plasma concentrations of pasireotide on days 28, 56, and 84 
indicated that PK exposures were almost dose-proportional. The PK exposure ratio between 
the study populations was healthy volunteers : patients with acromegaly : patients with 
carcinoid tumors = ~ 1 : 1 : 2 for pasireotide LAR, similarly to the proportion for SC 
pasireotide. 
 


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Figure 1-2 
Mean plasma concentration (SD) profiles over time for pasireotide in 
patients with acromegaly (left panel) and carcinoid patients (right 
panel) after three monthly IM injections of 20 mg, 40 mg, or 60 mg of 
pasireotide LAR [CSOM230C2110] 
 
 
In summary, results from clinical trials with pasireotide currently available indicate that it is a 
safe and effective treatment in patients with acromegaly. However, to date, there are no 
clinical data available from clinical trials in patients with clinically non-functioning pituitary 
adenomas. 
 
1.3 
Human experience 
Although the SC and LAR pasireotide formulations have not been tested in patients with 
NFPA, both formulations were tested in healthy volunteers [CSOM230C2101] and in patients 
with 
acromegaly 
{[CSOM230B2103], 
[CSOM230B2101], 
[CSOM230B2101E], 
[CSOM230C2110], and [CSOM230C2305]}, with carcinoid tumors {[CSOM230B2202], 
[CSOM230C2110] and [CSOM230C2303]}, and with Cushing’s Disease {[CSOM230B2208] 
and [CSOM230B2305]}. To date, clinical safety and efficacy data available from these 
studies suggest that pasireotide is well tolerated and has positive activity on the treatment of 
patients 
with 
acromegaly, 
Cushing’s 
Disease, 
and 
carcinoid 
tumor. 
Studies 
[CSOM230B2305], [CSOM230C2305] and [CSOM230C2303] are ongoing. 
 
1.3.1 
Clinical efficacy and safety of pasireotide LAR 
The pasireotide LAR formulation was studied in three studies: [CSOM230C2101], in healthy 
volunteers, [CSOM230C2110], in patients with acromegaly and carcinoid tumors, and 
[CSOM230C2305] – the registry program currently ongoing in patients with acromegaly. 


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Study [CSOM230C2101], evaluating single intramuscular (IM) doses of 40 and 60 mg of 
pasireotide LAR (N = 5 per dose cohort) in healthy volunteers showed that pasireotide LAR 
was well tolerated, and that there was no difference in the frequency of AEs seen between 
pasireotide LAR and octreotide LAR. The most common AE was diarrhea, which was 
sometimes associated to abdominal pain and/or flatulence. Gastrointestinal events were mild 
or moderate in intensity. Approximately half of the subjects reported mild transient pain at the 
injection site. Two volunteers on the 60 mg dose showed mild increases in fasting blood 
glucose (< 123 mg/dL), with all values returning to normal 28 days after the LAR injection. 
 
Study [CSOM230C2110] evaluated single IM pasireotide LAR doses of up to 60 mg in 
patients with acromegaly or carcinoid disease. The preliminary results of the clinical efficacy, 
safety, and pharmacokinetics/pharmacodynamics (PK/PD) analysis are available for 35 
patients with acromegaly, including 10, 12, and 13 patients in dose groups of 20, 40 and 60 
mg of pasireotide LAR, respectively, and are summarized on Table 1-7. 
Table 1-7 
Number (percentage) of responders among patients with acromegaly 
with a GH mean level ≤ 2.5 ng/mL and IGF-1 level within normal limits 
for controls of equivalent age and gender after three monthly IM 
injections of 20 mg, 40 mg, or 60 mg of pasireotide LAR formulation 
(2b) [CSOM230C2110] 
Dose 
20 mg 
(N = 10) 
40 mg 
(N = 12) 
60 mg 
(N = 13) 
Overall *  
4 (40%)  
4 (36%)  
7 (54%)  
Mean GH < 2.5 ng/mL **  
5 (50%)  
6 (50%)  
7 (54%)  
IGF-1 within normal limits for 
controls of equivalent age 
and gender  
5 (50%)  
7 (64%)  
8 (62%)  
* Patients with mean GH < 2.5 ng/mL and IGF-1 within normal limits for controls of equivalent 
age and gender 
** GH was collected at -30 and 0 min. (pre-dose). The mean of these first samples was 
calculated. The 4 remaining samples were collected post-dose and were not included in the 
mean calculation.  
 
This study has also shown that pasireotide LAR was generally well tolerated, and that the 
most common adverse events seen were gastrointestinal and mild in intensity. Although pre-
clinical or clinical trials have not revealed any specific cardiac toxicity issue related to 
pasireotide, a complete clinical evaluation of QT/QTc was performed in healthy volunteers 
[CSOM230B2113]. In Part I of the study, 900 µg to 2100 µg doses of pasireotide were 
investigated, after which the maximum tolerated dose (MTD) of pasireotide was defined as 
1950 µg SC BID. The MTD was then used as the pasireotide dose in Part II of the study (i.e., 
a 3-way crossover design using moxifloxacin, placebo and 1950 µg of SC pasireotide BID). 
The effect of pasireotide (at the MTD) on the QTcF interval was shown. This effect was based 
on the upper limit of the 1-sided 95% CI for the difference compared to placebo in QTcF 


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change from baseline of > 10 ms, in one or more timepoints. Pasireotide and moxifloxacin 
showed maximum effect 2 hours post-dose (QTcF change of 17.5 ms and 8.5 ms from 
baseline compared to placebo, respectively). Subjects receiving pasireotide also showed a HR 
decrease within 0 to 4 hours post-dose (maximum change versus baseline of 10.7 bpm). The 
appropriate monitoring of the ECG of patients assigned to pasireotide LAR arms is 
implemented in the protocol. Other detailed information on clinical efficacy and safety of 
pasireotide LAR may be found in the [Investigator’s Brochure]. 
 
Study [CSOM230C2305] is evaluating the efficacy and safety of pasireotide LAR in patients 
with acromegaly (without medical treatment) compared to octreotide LAR. This study is still 
ongoing. 
Other detailed information on clinical efficacy and safety of pasireotide LAR may be found in 
the [Investigator’s Brochure]. 
 
1.3.2 
Pasireotide clinical pharmacokinetics 
1.3.2.1 
Single pasireotide LAR injection in healthy volunteers 
In healthy volunteers [CSOM230C2101], single IM injections of pasireotide LAR 40 mg and 
60 mg showed types of long-acting release concentrations compared to time profiles 
characterized by an initial outburst on day 1, followed by a long-acting release (Figure 1-3). 


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Figure 1-3 
Mean plasma concentration (SD) profiles over time for pasireotide 
after a single IM injection of 40 mg (N = 5) or 60 mg (N = 5) of 
pasireotide LAR formulation in healthy volunteers [CSOM230C2101] 
Time (day)
0
10
20
30
40
50
60
70
SOM230 Plasma Conc. (ng/mL)
-5
0
5
10
15
20
40 mg LAR
60 mg LAR
 
1.3.2.2 
Multiple monthly injections of pasireotide LAR in patients with 
acromegaly and carcinoid tumors 
Pasireotide LAR was tested in patients with acromegaly and patients with carcinoid tumors 
receiving IM injections, three times a month, in dosage levels of 20, 40, and 60 mg in a Phase 
I study [CSOM230C2110]. The mean concentration (SD) profiles over time for pasireotide 
are shown on Figure 1-4. The PK analysis showed that steady state was reached within three 
monthly injections of pasireotide LAR. Residual plasma concentrations (pre-dose) of 
pasireotide on days 28, 56, and 84 indicated that the PK exposures were almost dose 
proportional. The PK exposure ratio among the study populations was healthy volunteers : 
patients with acromegaly : patients with carcinoid tumors = ~ 1 : 1 : 2 for pasireotide LAR, 
similarly to the proportion for SC pasireotide. 


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Figure 1-4 
Mean plasma concentration (SD) profiles over time for pasireotide in 
patients with acromegaly (left panel) and patients with carcinoid 
tumor (right panel) after three monthly IM injections of 20 mg, 40 mg, 
or 60 mg of pasireotide LAR [CSOM230C2110] 
Time (day)
-14
0
14
28
42
56
70
84
98
SOM230 Plasma Conc. (ng/mL)
-5
0
5
10
15
20
25
20 mg LAR Acro (N=10)
40 mg LAR Acro (N=12)
60 mg LAR Acro (N=13)
Time (day)
-14
0
14
28
42
56
70
84
98
SOM230 Plasma Conc. (ng/mL)
-10
0
10
20
30
40
50
20 mg LAR Car (N=12)
40 mg LAR Car (N=14)
60 mg LAR Car (N=16)
 
 
2 
Study rationale / purpose 
The purpose of this phase II, prospective, multicenter, open-label, single-arm study is to 
evaluate the efficacy and safety of pasireotide LAR in patients with clinically non-functioning 
pituitary adenomas (NFPAs). 
 
Pituitary adenomas seem to be associated to intact transmembrane G protein-coupled 
somatostatin receptors and to the increased expression of the vascular endothelial growth 
factor (VEGF), which is correlated to vascularization and to the increase in tumor 
proliferation (Onofri et al 2006)(Turner et al 2003). Particularly, NFPAs showed a 
significantly higher expression of VEGF protein (3.2 times, P < 0.05) than normal pituitary 
glands (McCabe et al 2002). 
 
Miller et al. showed SSTR1, 2, and 5 expression in clinically non-functioning pituitary 
adenomas (Miller et al., 1995). Panetta and Patel have also studied the expression of SSTRs in 
the mRNA from secretory and clinically non-functioning adenomas, observing SSTR1 and 
SSTR2 in most of adenomas, while SSTR3, 4 and 5 were expressed in approximately half of 
the adenomas (Panetta and Patel, 1995). 
 
Another study revealed that the most expressed receptor subtype was sst3, followed by sst2 
(which is the most highly expressed receptor in GH secretory adenomas), while sst1, sst4, and 
sst5 transcripts were detected only in a few tumors (Taboada et al. 2007). 


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Somatostatin and its analogues seem to inhibit the proliferation of pituitary adenomas 
interacting with one or more of its G protein-coupled transmembrane receptors: sst 1, sst 2, sst 
3, sst 4, and sst 5 (Zatelli et al 2006). A NFPA in vitro study showed that sst 1 selective 
agonists inhibit secretory activity and cell viability, sst 2 selective agonists inhibit secretion, 
but not cell viability, and sst 5 selective agonists do not affect secretory activity, but promote 
cell viability (Zatelli et al 2004). Another study conducted using the same SSTR selective  
analogues showed a decrease in cell viability in 3 of the 10 NFPAs treated in vitro with 
SSTR1 analogue, in 4/10 NFPAs incubated with SSTR2 selective analogue, and in 4/10 
adenomas exposed to a SSTR5 agonist (Gruszka et al., 2006). 
 
Natural somatostatin (binding all ssts) and the sst3 and sst2 selective analogues inhibited 
chromogranin A (CgA) and alpha subunit concentration in vitro in cell culture medium 
(Pawlikowski et al. 2007). CgA inhibition is also correlated to sst5 expression (Pawlikowski 
et al. 2007). 
 
Padova et al. showed that SSTR2 and SSTR5 selective analogues decreased cell viability in 
8/13 and 10/13 of NFPAs exposed to these in vitro peptides, respectively. This inhibitory 
effect of a compound tested for the number of viable cells in an adenoma culture reflects a 
probable antitumoral effect of this peptide (Colao et al 2008)(Padova et al 2008). 
 
Pasireotide LAR (SOM230) is a new somatostatin analogue with properties similar to natural 
somatostatin and, specifically, high affinity and functional activity to sst 1, sst 2, sst 3, and sst 
5 (Bruns et al 2002)(Schmid et al 2004). Pasireotide has been shown to inhibit GH and 
prolactin secretion from in vitro pituitary adenomas (Hofland et al 2004)(Murray et al 2004), 
in vitro ACTH, (Batista et al 2006), and in vivo GH/IGF-1 (Weckbecker et al 2002)(Fedele et 
al 2007). Additionally, pasireotide inhibited the proliferation of cells stimulated by endothelial 
VEGF (Adams et al 2004). 
A pre-clinical trial showed that pasireotide avoids NFPA cell viability by inhibiting VEGF 
secretion, which indicates that this multireceptor SSTR agonist may be useful as medical 
therapy for NFPA (Zatelli et al 2007). 
Pasireotide LAR was tested in clinical trials in healthy volunteers [CSOM230C2101] and in 2 
populations of patients (i.e., acromegaly and carcinoid disease [CSOM230C2110]). However, 
there are no previous reports about the clinical use of pasireotide LAR for NFPAs. 
Based on these findings and on the need of a medical therapy that may be used pre-surgically 
to improve surgical results, leading to less patients with remaining tumors, or to control tumor 
growth or recurrence after surgery, avoiding the need for radiation therapy, pasireotide LAR 
may be a good medical option for treatment, both as pre-surgical therapy and in the control of 
post-surgical tumor growth. 


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3 
Objectives 
3.1 
Primary objective 
 To evaluate the efficacy of pasireotide LAR in the proportion of patients with clinically 
non-functioning pituitary adenomas (NFPAs) who responded to treatment. 
3.1.1 
Primary objective endpoint 
 Proportion of patients with NFPA reaching a decrease in tumor volume of at least 20% 
after the 24-week treatment with pasireotide LAR. 
3.2 
Secondary objectives 
 To evaluate the effect of pasireotide LAR in mean tumor volume variation between 
baseline and treatment weeks 4, 12, 24, 48, 72, and 96. 
 To evaluate the effect of pasireotide LAR in mean percent tumor volume variation 
between baseline and treatment weeks 4, 12, 24, 48, 72, and 96. 
 To evaluate the effect of pasireotide LAR in the proportion of patients reaching tumor 
volume decrease of at least ≥ 20% after 4, 12, 48, 72, and 96 weeks of treatment. 
 To evaluate the effect of pasireotide LAR on time to tumor response. 
 To evaluate the effect of pasireotide LAR on the disease-related symptoms * 
* Disease-related symptoms to be evaluated: headache, visual disorders, fatigue, decreased 
libido, erectile dysfunction (for men only), menstrual irregulatiry or interruption (only for 
non-menopausal women). 
 To evaluate the effect of pasireotide LAR on the pituitary function on weeks 4, 12, 24, 48, 
72, and 96. 
 To evaluate the effect of pasireotide LAR on the alpha subunit levels on weeks 4, 12, 24, 
48, 72, and 96. 
 To evaluate the overall safety and tolerability of pasireotide LAR. 
 For the extension phase: duration of response for patients considered as responders (i.e., 
patients reaching a tumor volume decrease of at least 20% compared to the initial tumor 
volume). 
 To evaluate the percentage of patients remaining with stable tumor volume during the 
study. 
 
3.2.1 
Secondary objective endpoints 
The secondary variables are: 
 Mean change in tumor volume evaluated by pituitary MRI between baseline and weeks 4, 
12, 24, 48, 72, and 96. 
 Percent change in tumor volume evaluated by pituitary MRI between baseline and weeks 
4, 12, 24, 48, 72, and 96. 
 Proportion of patients reaching tumor volume decrease of at least ≥ 20% after 4, 12, 48, 
72, and 96 weeks of treatment. 


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 Time to treatment response for treatment responders, defined as the time from the date of 
the first injection to the first evaluation in which the patient reached a tumor volume 
decrease of at least ≥ 20%. 
 Change in grading score of disease-related symptoms between baseline and weeks 4, 12, 
24, 48, 72, and 96. 
 Incidence of pituitary hormone dysfunction at baseline and on weeks 4, 12, 24, 48, 72, and 
96. 
 Proportion of patients reaching alpha subunit decrease of at least 50% on weeks 4, 12, 24, 
48, 72, and 96. 
 Proportion of patients reaching alpha subunit normalization on weeks 4, 12, 24, 48, 72, 
and 96. 
 Percentage of adverse events with CTC grade ≥ 3 during treatment with pasireotide LAR. 
 Percentage of patients with at least one adverse event with CTC grade ≥ 3. 
 Incidence of all adverse events, incidence of abnormal lab values, and summary of 
laboratory evaluations. 
 For the extension phase: among patients who had been considered as responders (i.e., 
patients reaching a tumor volume decrease of at least 20% compared to initial tumor 
volume), to evaluate the number and proportion of patients who remained responsive 
during the extension phase treatment (according to the magnetic resonance imaging 
evaluations on weeks 48, 72, and 96). 
 To evaluate the percentage of patients remaining with stable tumor volume during the 
study, i.e., patients who mantained tumor volume variation lower than 20% compared to 
baseline tumor volume (according to magnetic resonance imaging evaluations on weeks 
24, 48, 72, and 96). 
 If applicable, to evaluate whether there was a difference in response among patients on 40 
and 60 mg doses of pasireotide LAR. 
 
 
4 
Study design 
A phase II, open-label, single-arm, prospective, multicenter study to evaluate the efficacy and 
safety of pasireotide LAR in adult patients with NFPA. 


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Eligible patients will receive 60 mg of pasireotide LAR every 28 ± 3 days for 24 weeks, 
during the Main Phase of the study. The study is complemented by an extension. At the 
discretion of the treating physician, patients who benefit from the treatment with pasireotide 
LAR will be offered the opportunity to enter an Extension Phase, in which they will continue 
to receive pasireotide LAR 60 mg at 4-week intervals (± 3 days) for up to 2 years (Table 7-2), 
or until pasireotide or other effective therapy is commercially available, or until clinical 
benefit is no longer seen (whichever occurs first). Dose decreases until 40 mg will be allowed, 
based on safety issues (see Section 6.4.2). In case of rapid deterioration of the visual field or 
sudden visual loss, the patient will be discontinued from the study. 
During the Main Phase of the study, visits will be performed every 28 ± 3 days. There will be 
two additional safety visits: Visit 3 and Visit 6. 
The sella turcica MRI will be performed during the screening period (baseline imaging). The 
follow-up MRIs will be performed on weeks 4, 12, and 24 in the Main Phase and on weeks 
48, 72, and 96 in the Extension Phase, and must be performed within 7 days of the appropriate 
visit. Enhancement with gadolinium contrast will be used to obtain the MRI. 
 
The MRIs will be submitted to a central evaluator. In order to ensure consistency in all 
participating sites, MRIs must be performed and processed according to the guidelines of the 
central reading facility, which will be distributed to the sites before study start. 
The visual field evaluations will be performed during the screening period (they will be 
considered as baseline data) and then every 4 weeks ± 3 days thereafter. 
Symptoms and potential AEs will be evaluated on all visits. Safety-related tests will be 
performed as described on Table 7-1 and Table 7-2 (Visits and evaluations schedule for the 
Main Study). 
Alpha subunit and pituitary hormone levels will be evaluated during the screening period (and 
will be considered as baseline data), as well as on Weeks 4, 12, and 24 in the Main Phase and 
on weeks 48, 72, and 96 in the Extension Phase. 
 
 
The gallbladder ultrasound will be evaluated in the screening period and within 7 days of 
Visit 10 (Week 24). In the Extension Phase, it will be evaluated on weeks 48 and 96. 
After the Main Phase of the study (first 24 weeks of treatment), patients deriving benefit from 
pasireotide LAR will be offered the opportunity to continue receiving pasireotide LAR, based 
on the physician’s evaluation and the patient’s wishes. This will be called study Extension 
Phase. The study design and a Main Phase and Extension Phase scheme are shown on Figure 
4-1 and Figure 4-2, respectively. 


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Figure 4-1 
Scheme of NFPA Study with Pasireotide LAR: Main Phase 
 
Figure 4-2 
Scheme of NFPA Study with Pasireotide LAR: Extension Phase 
 
5 
Population 
The population for this study consists of adults diagnosed with NFPA who did not receive any 
other previous therapy (treatment-naïve) for the disease. Due to the difficulty to evaluate 
changes in tumor volume in microadenomas, and also because they can be mistakenly 
diagnosed as incidentalomas, only patients with macroadenomas (≥ 1 cm) will be enrolled in 
the study. A total of 23 patients in 10 - 13 sites will be enrolled in this single-arm open-label 
study. 
Inclusion / exclusion criteria 
The investigator or his/her designee must ensure that enrollement in the study is offered to all  
patients meeting the inclusion and exclusion criteria. 
Main Phase 
Baseline 
Day 0 to Week 24 
Weeks 
Efficacy evaluations (Weeks 48, 72, and 96) * 
Safety evaluations (Weeks 36, 48, 60, 72, 84, and 96) * 
Pasireotide LAR 60 mg IM every 28 days 
Final 
follow-up 
* For details of efficacy and safety evaluations, see Table 7-2. 
(8 weeks 
after last 
dose) 
Efficacy assessments: MRI, alpha subunit, symptoms 
Special safety assessments: visual field *, glycemia *, ECG ** 
Visit 3: 
safety 
Visit 6: 
safety 
Visit 11: 
follow-up 
If the patient enters the 
extension phase, they 
will receive injection 7 
* All visits, except 3 and 6 
** All visits 


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5.1 
Inclusion criteria 
1. Male or female patients ≥ 18 years old. 
2. Patients with clinically non-functioning pituitary macroadenomas ≥ 1 cm. 
3. Patients without previous treatment for NFPA. 
4. Patients with Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 1. 
5. Written Informed Consent Form obtained before any screening procedure. 
 
5.2 
Exclusion criteria 
1. Patients requiring surgical intervention for relief of any sign or symptom related to tumor 
compression. 
2. Previous pituitary surgery. 
3. Previous medical treatment for pituitary tumor. 
4. Patients who received pituitary radiation within 10 years before the enrollment visit (Visit 
2). 
5. Prolactin (PRL) levels > 100 ng/mL. (PRL evaluation must be performed with diluted 
samples in order to ensure prevention of the “hook effect”). 
6. Patients with optic chiasm compression, causing clinically significant acute visual field 
defects. 
7. Diabetic patients whose blood glucose is poorly controlled, as proven by HbA1C > 8%. 
Patients with known history of fasting glucose impairment or diabetes mellitus with 
HbA1c < 8% may be enrolled; however, blood glucose and antidiabetic treatment must be 
closely monitored throughout the study and adjusted as required. 
8. Patients with known gallbladder or bile duct disease, or acute or chronic pancreatitis 
(patients with asymptomatic colelithiasis and asymptomatic dilation of the bile duct may 
be enrolled). 
9. Patients with abnormal coagulation (increased PT or APTT 30% above normal limits) or 
patients who have received antiacoagulants that affect PT (prothrombin time) or APTT 
(activated partial thromboplastin time). 
10.  Patients with congestive heart failure (NYHA Class III or IV), unstable angina, persistent 
ventricular tachycardia, ventricular fibrillation, advanced cardiac block, or history of acute 
myocardial infarction within 24 weeks before the enrollment visit (Visit 2). 
11. Screening (Visit 1) or baseline (pre-dose, Visit 2) QTcF > 450 msec. 
12. Patients with history of syncope or family history of idiopathic sudden death. 


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13. Patients with persistent or clinically significant cardiac arrhythmias. 
14. Patients with Torsades de Pointes risk factors, such as uncorrected hypocalemia, 
uncorrected hypomagnesemia, heart failure, clinically significant / symptomatic 
bradycardia, or high degree AV block. 
15. Patients with concurrent disease(s) that might prolong the QT interval, such as 
autonomous neuropathy (caused by diabetes or Parkinson’s disease), HIV, cirrhosis, 
uncontrolled hypothyroidism, or heart failure. 
16. Patients on medication(s) known to prolong the QT interval. 
17. Patients with liver disease or history of liver disease, such as cirrhosis, active chronic 
hepatitis B and C, or persistent chronic hepatitis, or patients with ALT and/or AST > 2 x 
ULN, total blood bilirubin > 1.5 x ULN, and serum albumin < 0.67 x LLN. 
18. Patients with blood creatinine > 2.0 x ULN. 
19. Patients with WBC < 3 x 109/L; Hgb < 90% LLN; PLT < 100 x 109/L. 
20. Patients with any current or previous medical condition that, in the investigator’s opinion, 
might interfere in the study conduction or evaluation of the study results. 
21. Patients with history of immunological impairment, including positive result for HIV tests 
(ELISA and Western blot). HIV tests will not be required; however, previous medical 
history will be analyzed. 
22. Patients with known hypersensitivity to somatostatin analogues or any other pasireotide 
LAR compound. 
23. Patients with active malignant disease within the last five years (except for basal cell 
carcinoma or in situ cervix carcinoma). 
24. Patients with presence of uncontrolled, acute suspected, or active chronic infection. 
25. Pregnant or breastfeeding patients, or patients of childbearing potential who do not adopt a 
clinically acceptable contraceptive method. If a woman is participating in the study, then 
one contraceptive method will be sufficient (pill or diaphragm), and the partner must use 
condoms. If an oral contraceptive is used in addition to condoms, the patient must have 
adopted this method at least two months prior to enrollment in the study, and must agree 
to continue to use it throughout the study, and for three months after the end of the study. 
Sexually active male patients are required to use condoms during the study and for three 
months after the end of the study, as a precautionary measure (the available data do not 
suggest any increase in reproductive risk with the study drugs). 
26. Study participants on the investigational drug 30 days prior to the enrollment visit (Visit 
2). Patients must have recovered from all side effects from other investigational therapies. 


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27. Patients with history of non-compliance to medical regimens, or patients considered 
potentially unsafe, or any circumstance at the time of study enrollment that might prevent 
the completion of the entire study or the follow-up required. 
28. Patients with history or recurrence of undue use / abuse of alcohol or drugs within 12 
months previous to visit 1 (screening). 
29. Presence of Hepatitis B surface antigen (HBsAg). 
30. Presence of Hepatitis C antibody screen (anti-HCV). 
31. Patients who had a major surgery / surgical therapy for any cause within 4 weeks before 
randomization. 
32. Patients with confirmed hypothyroidism, hypoadrenalism and hypogonadism (except for 
physiological andropause and menopause), unless appropriately treated with stable doses 
of hormone replacement therapy for at least 3 months before study entry. 
33. Patients on growth hormone replacement therapy. 
34. Patients with uncontrolled cardiovascular, renal or metabolic disorders. 
35. Patients with severe neurological or psychiatric disorders. 
36. Patients with contraindications to MRI such as, for example, (but not limited to): brain 
aneurysm clips, internal wiring of cardiac pacemaker and temporary pacemaker, cochlear 
implants, hearing devices containing internal non-removable parts, Swan-Ganz catheter, 
aortic balloon, Endovascular Graft Zenith AAA, and other potential contraindications 
related to ferromagnetic materials identified in the patient’s interview. 
6 
Treatment 
6.1 
Investigational drug 
The study drug is pasireotide LAR (long-acting release), depot IM injection. 
Pasireotide LAR excipients include: mannitol, sodium carmellose (sodium carboxymethyl 
cellulose), poloxamer 188, and water for injection. 
6.1.1 
Known untoward effects of the study drug / treatment 
Refer to the Investigator’s Brochure for further information. 
6.1.2 
Supply 
Novartis will provide the investigational drug pasireotide LAR, as 20 and 40 mg of powder in 
vials and 2 mL of vehicle in ampoules (for reconstitution), provided in boxes. 


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The medication labels will meet the Brazilian legal requirements and will be printed in 
Portuguese. They will not contain patient information. The storage conditions of the study 
drug will be described in the medication label. 
6.1.3 
Preparation and storage 
Pasireotide LAR must be prepared as described on Table 6-1: 
Table 6-1 
Handling and preparation of pasireotide LAR dose 
Dose (mg) 
Volume to be injected 
60 mg 
1 20 mg vial + 1 40 mg vial + 2 mL of vehicle; total volume to be injected 
40 mg 
1 40 mg vial + 2 mL of vehicle: total volume to be injected 
The doses must be prepared and administered immediately after preparation. For additional 
instructions on the handling and preparation of pasireotide LAR doses, refer to [Post-Text 
Supplement 3]. 
The drug supplies must be kept in an appropriate and safe area (for example, a locked cabinet) 
and stored according to the conditions specified on the drug labels. The receipt and dispensing 
of the study drug must be recorded by an authorized person at the Investigator’s site. The 
Investigator must keep an accurate shipment and dispensing record of the study drug in a drug 
accountability log, and a copy of this form will be provided to Novartis at the end of the 
study. An accurate record of the date and amount of study drug dispensed to each subject 
must be available for inspection at any time. Unless specifically instructed by Novartis, the 
Investigator must not destroy the labels of any drug or any partially used and unused drug 
supply. Any partially used ampoule must not be reused in another injection. 
 
6.2 
Patient numbering 
Each study patient is uniquely identified by a 6-digit patient number, which is a combination 
of the 3-digit site number and the 3-digit subject number. The site number is assigned by 
Novartis to the investigational site. Upon signature of the Informed Consent Form, the 
investigator or his/her designee assigns a number to the subject. Once assigned to a patient, 
the number will not be reused. If the patient cannot start treatment for any reason, this reason 
will be entered in the Screening Record electronic Case Report Form (eCRF), and the 
patient’s demographics will be entered in the Demographics eCRF. 
The Informed Consent Form must be obtained before performing any test to determine the 
patient’s eligibility. 


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6.3 
Treatment assignment 
This is a single-arm open-label study. All patients will receive pasireotide LAR 60 mg every 
28 ± 3 days for 24 weeks. In case of problems related to drug tolerability, the treatment dose 
may be adjusted (see Section 6.6.2) or the study medication may be discontinued (see Section 
6.4.2). 
6.4 
Patient treatment 
All pasireotide LAR injections must be administered only by a medical staff or healthcare 
professional at each site. Any dose change must be recorded in the Dose Administration 
Record eCRF. The drug ampoule(s) must be retained for later evaluation by the monitor. 
Screening 
On Visit 1, no pasireotide LAR will be given to the patient. 
Main Phase Treatment 
The first pasireotide LAR 60 mg IM dose will be administered on Visit 2, after all baseline 
evaluations are completed and the eligibility to participate in the study is confirmed. 
Pasireotide LAR will be administered as a depot intragluteal IM injection. 
Pasireotide LAR 60 mg IM will be administered by the site staff every 28 (± 3) days 
throughout the Main Phase treatment period (all patients are expected to receive 6 doses of 
pasireotide LAR every 4 weeks). A dose decrease to 40 mg will be allowed for safety reasons. 
End of Study (EOS) Visit 
After the Main Phase of the study (first 24 weeks of treatment), patients benefiting from 
pasireotide LAR treatment will be offered the opportunity to continue to receive pasireotide 
LAR, based on the physician’s evaluation and the patient’s wishes. 
Patients who participate in the Extension Phase will be treated with pasireotide LAR for up to 
92 weeks or approximately 2 years (Table 7-2), or until pasireotide or other effective therapy 
becomes commercially available, or until clinical benefit is no longer seen (whichever occurs 
first). 
Extension Phase 
Patients enrolled in the Extension Phase will receive pasireotide LAR IM at Visit 10 and will 
have the first extension study visit scheduled, which will occur 28 (± 3) days after Visit 10. 
Treatment with pasireotide LAR will be administered by the site’s healthcare professional 
staff every 28 (± 3) days, during the Extension Period (see Table 7-2). 
Additional Information on the Extension Phase: 


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The dose will continue to be 60 mg. If a patient is receiving 40 mg due to tolerability issues 
and such issues are resolved, there may be a dose escalation to 60 mg, at the physician’s 
discretion. If the adverse event reoccur, the dose will be decreased to 40 mg and will be 
mantained until completion of the Extension Phase or until study discontinuation. 
Safety Follow-up 
All patients in the main and extension phases will be followed for safety for approximately 56 
(± 3) days after administration of their last dose of pasireotide LAR. 
6.4.1 
Follow-up for dose-limiting toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an AE or 
abnormal laboratory value must be followed up at least once a week for 4 weeks, and in 4-
week intervals thereafter, until resolution or stabilization of the event, whichever occurs first. 
All patients will be followed up for AEs and serious adverse events (SAEs) for 8 weeks after 
administration of the last dose of pasireotide LAR (refer to Section 6.4.4 for information on 
the discontinuation of the study drug). 
 
6.4.2 
Allowed study drug adjustments 
For patients who cannot tolerate the administration schedule specified in the protocol, dose 
adjustments are allowed so that the patient may continue to receive the study drug. 
The study drug for this study will be pasireotide LAR 60 mg given every 28 ± 3 days for 6 
months, during the main study period. In case of tolerability issues (see Table 6-2), the 
pasireotide LAR dose may be decreased to 40 mg in the next scheduled injection. However, 
patients unable to tolerate the minimum dose of 40 mg will be discontinued from the study. 
All dose changes must be recorded in the Dose Administration Record eCRF. 
During the Extension Phase, if a patient receives 40 mg due to tolerability issues and such 
issues are resolved, there may be a dose escalation to 60 mg, at the physician’s discretion. If 
the adverse event reoccurs, the dose will be decreased to 40 mg and the patient will maintain 
this dose. 
 
Table 6-2 
Guideline for treatment of patients experiencing adverse events 
Adverse event 
Action 
CTC Grade ≤ 2 AEs 
No drug adjustment 
CTC Grade ≥ 3 AEs evaluated as related to 
the study drug  
Decrease intramuscular pasireotide LAR 
dose to 40 mg. 
If the AE does not improve to grade ≤ 2 with 
the 40 mg dose, the patient will be 
withdrawn. 
 


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The guidance above must be used for all AEs, except for changes in blood glucose and QTc 
and for liver safety monitoring. Blood glucose changes must be followed as described on 
Section 7.5.2.1. Changes in QTc interval must be followed as described on Section 7.5.2.2. 
Refer to Section 7.5.2.3 for liver safety monitoring. 
6.4.3 
Other concurrent medication 
The investigator must instruct patients to notify the study site about any new medication 
administered after starting the study drug. All medications (except the study drug) and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts treatment with the study drug must be mentioned in the 
Concurrent Medication / Significant non-drug therapy eCRF after the study drug is started. If 
possible, there may be no changes in any concurrent medication during the study until all EOS 
evaluations are completed. 
The use of anticoagulant medication should be avoided. 
6.4.4 
Discontinuation of the study drug 
Patients experiencing unacceptable toxicity (grade ≥ 3 AE, including grade ≥ 3 changes in 
laboratory values) that the investigator considers as directly ascribable to the study drugs must 
have their doses decreased (Section 6.4.2) or be withdrawn from the study. 
 Patients who permanently discontinue the study drug between Visit 2 and Visit 9 
(inclusive) must be scheduled for the End of (Main) Study Visit (Visit 10) 28 ± 3 days 
after administration of the last dose of the study medication, when all evaluations listed 
will be performed. The Safety Follow-up Visit (Visit 11) will be performed approximately 
56 ± 3 days after administration of the last dose of study medication. 
 Patients who permanently discontinue the study drug in the Extension Phase must be 
scheduled for the End of (Extension) Study Visit 28 ± 3 days after administration of the 
last dose of the study medication, when all evaluations listed will be performed. The 
safety follow-up visit for the extension phase will be performed approximately 56 ± 3 
days after administration of the last dose of the study medicaiton. 
Patients who discontinue the study drug must be considered as withdrawn from the study after 
the EOS / Safety Follow-up evaluations are performed or when it’s evident that the patient 
will not return for the EOS evaluations. 
 


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6.4.5 
Early patient discontinuation 
6.4.5.1 
End of treatment 
Patients may withdraw voluntarily from the study or be withdrawn, at the investigator’s 
discretion, at any time. They may be considered as discontinued if they declare their intention 
to discontinue, or if they do not return for visits, or if they are lost to follow-up for any other 
reason. Patients may be withdrawn from the study by the investigator for any of the following 
reasons: 
 Acute or progressive vision loss confirmed by a new evaluation of the visual field 
 Increased tumor volume defined as tumor volume growth (>20%) and confirmed in a 
second MRI performed approximately one month later 
 Pregnancy 
 Adverse event(s) 
 Uncontrolled diabetes mellitus 
 Clinically significant abnormal laboratory value(s) 
 Clinically significant abnormal result(s) of test procedures 
 Protocol violation 
 Lost to follow-up 
 Administrative problems 
 Death 
 Patients who experience: 
 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 persistent ULN for more than 2 weeks 
 ALT or AST > 8 x ULN 
If any of the discontinuation criteria is met, the study medication must be immediately 
discontinued. Additionally, appropriate safety follow-up monitoring must be performed, 
as defined on Section 7.5.2.3. Resuming the study medication after the discontinuation 
criteria are met is not allowed. 
 
6.4.5.2 
Completion of the study evaluation 
For patients considered as lost to follow-up (i.e., patients whose condition is not clear because 
they did not attend the study visits without declaring an intention to discontinue), the 
investigator must show “due diligence" by documenting the actions taken in the source-
documents in order to contact the patient, such as, for example, dates of phone calls, 
registered letters, etc. 


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7 
Visits and evaluations schedule 
Tables 7-1 and 7-2 show a list of all evaluations for the Main Phase and the Extension Phase, 
respectively, and indicate with an “X” the visits to be performed. All data obtained from these 
evaluations must be confirmed in the patient’s source-documentation. The table indicates 
which data are entered in the database (DB) or remain only on the source-documents (SD). 
The evaluations producing data for registration in the database and that are recorded in the 
eCRFs are listed using the eCRF name. 


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Table 7-1 
Visits and evaluations schedule for the Main Study  
Visit number  
1 
2 
3 
4 
V401E 
48 
5 
6 
7 
8 
9 
10 
11 
EOS3 
Follow-up 
Visit 16 
Days 1 
Day  
-28 to -1 
Day 0 
Day 20 
Day 28 
Day 48 
Day 56 
Day 76 
Day 84 
Day 112 
Day 140 
Day 168 
Day 196 
Treatment week 
  
Inclusion 
Week 3 
Week 4 
Week 7 
Week 8 
Week 11 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
  
Screening 2 Baseline/ 
Injection 1 
Safety 
Only 
Injection 
2 
Safety 
Only 
Injection 
3 
Safety 
Only 
Injection 
4 
Injection 
5 
Injection 
6 
Injection 7# 
(if the patient 
participates in 
the Extension 
Phase) 
Safety 
Follow-up 
Informed Consent Form (SD) 
X 
  
  
  
 
  
 
  
  
  
  
  
Demographics (DB) 
X 
  
  
  
 
  
 
  
  
  
  
  
Disease diagnosis and extent (DB) 
X 
  
  
  
 
  
 
  
  
  
  
  
Relevant medical history / current medical 
conditions (DB) 
X 
  
  
  
 
  
 
  
  
  
  
  
Evaluation of inclusion/exclusion criteria (SD) 
X 
 
  
  
 
  
 
  
  
  
  
  
Vital signs (DB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination (SD) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (DB) 
X 
  
  
  
 
  
  
  
  
  
  
  
Weight (DB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of symptoms / Disease-related 
symptoms 4 (DB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
ECOG Performance status (DB) 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECG (DB) 14 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Blood pregnancy test5,6 
X 
  
  
  
 
  
  
X 
  
  
X 
 
Hematology (DB) 
X 
 
  
X 
 
X 
  
X 
X 
X 
X 
 


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Visit number  
1 
2 
3 
4 
V401E 
48 
5 
6 
7 
8 
9 
10 
11 
EOS3 
Follow-up 
Visit 16 
Days 1 
Day  
-28 to -1 
Day 0 
Day 20 
Day 28 
Day 48 
Day 56 
Day 76 
Day 84 
Day 112 
Day 140 
Day 168 
Day 196 
Treatment week 
  
Inclusion 
Week 3 
Week 4 
Week 7 
Week 8 
Week 11 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
  
Screening 2 Baseline/ 
Injection 1 
Safety 
Only 
Injection 
2 
Safety 
Only 
Injection 
3 
Safety 
Only 
Injection 
4 
Injection 
5 
Injection 
6 
Injection 7# 
(if the patient 
participates in 
the Extension 
Phase) 
Safety 
Follow-up 
Coagulation parameter PT (D) 
X 
X 
X14 
X14 
X14 
X14 
X 
 
 
 
X 
 
Coagulation parameter APTT (D) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Urinalysis 6 (DB) 
X 
 
  
X 
 
X 
  
X 
X 
X 
X 
 
Fasting blood glucose, insulin 6 
X 
 
  
X 
 
X 
  
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 6 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Chemistry 6,8 (DB) 
X 
 
  
X 
 
X 
  
X 
X 
X 
X 
 
LFTs (ALT, AST, total bilirubin, albumin, ALP, 
γ-GT) (D) 
X 
X 
X14 
X14 
X14 
X14 
X 
 
 
 
X 
 
HBs-Ag and anti-HCV (D) 
X 
 
 
 
 
 
 
 
 
 
 
 
Vitamin B12, folic acid6 
X 
  
 
 
 
 
 
 
 
 
X 
 
Hormone evaluation 6,9 (DB) 
X 
  
  
X 
 
  
  
X 
  
  
X 
  
Alpha subunit evaluation 6 
X 
  
  
X 
 
  
  
X 
  
  
X 
  
Visual field evaluation 10(DB) 
X 
X10 
 
X 
 
X 
 
X 
X 
X 
X 
 
Gallbladder ultrasound (DB) 15 
X 
  
  
  
 
  
  
  
  
  
X 
  
Pituitary / Sella turcica MRI 15 
X 
  
  
X 
 
  
  
X 
  
  
X 
  
Adverse events (DB) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  


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Visit number  
1 
2 
3 
4 
V401E 
48 
5 
6 
7 
8 
9 
10 
11 
EOS3 
Follow-up 
Visit 16 
Days 1 
Day  
-28 to -1 
Day 0 
Day 20 
Day 28 
Day 48 
Day 56 
Day 76 
Day 84 
Day 112 
Day 140 
Day 168 
Day 196 
Treatment week 
  
Inclusion 
Week 3 
Week 4 
Week 7 
Week 8 
Week 11 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
  
Screening 2 Baseline/ 
Injection 1 
Safety 
Only 
Injection 
2 
Safety 
Only 
Injection 
3 
Safety 
Only 
Injection 
4 
Injection 
5 
Injection 
6 
Injection 7# 
(if the patient 
participates in 
the Extension 
Phase) 
Safety 
Follow-up 
Pasireotide LAR administration (DB) 
  
X 
 
X 
 
X 
 
X 
X 
X 
X # 
  
Previous / concurrent medication 11 (DB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Study completion 13 (DB) 
  
 
 
 
 
 
 
 
 
 
 
x13 
# The pasireotide dose in this visit will be administered to selected patients, at the physician’s discretion, if the patient is included in the Extension Phase, 
based on the response evaluated by the investigator to the benefit from the drug (Section 6.4). 
1. A ± 3 day window will be allowed for scheduled visits and evaluations, unless otherwise indicated. 
2. To be performed before administration of the study drug. 
3. To be performed if the patient discontinues early or upon completion of the study. 
4. Disease-related symptoms to be evaluated: headache, visual disorders, fatigue, decreased libido, erectile dysfunction (only for men), irregular or 
interrupted menstrual cycles (only for non-menopausal women). The investigator will also ask patients to classify symptoms according to a 5-point 
scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe). The remainder will be evaluated as absent or present. 
5. A pregnancy blood test will be performed at the final follow-up visit, if a patient reports a delay in menstruation or according to the physician’s 
opinion. 
6. Blood and urine must be collected before administration of the study drug. Patients must be fasting for 12 hours. 
7. Hematology and coagulation include: hemoglobin, hematocrit (HCT), WBC count with differential, RBC count with differential, and platelet count; PT 
and APTT. 
8. Complete chemistry includes: total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, 
calcium, phosphorus, chloride, sodium, potassium, inorganic phosphorus, creatinine, urea, uric acid, CPK, LDH, alkaline phosphatase, -GT, total 
protein, albumin, SGOT, SGPT, total bilirubin. If the total bilirubin concentration increases over 2.0 times the upper limit of normal, it must be 
differentiated in direct and indirect bilirubin at visits. 
9. Hormone evaluations (blood) — pituitary disease evaluations: testosterone (for men), estradiol (for women), prolactin, free T4, TSH, LH, FSH, GH, 
IGF-I, cortisol, ACTH. 


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10. Evaluation by Standard Automated Perimetry (SAP). The Humphrey Field Analyzer is recommended. The window to perform the SAP must not be 
more than 7 days before the scheduled visit. If the visual field evaluation at Screening is performed no more than 14 days before Visit 2, it may be 
considered as baseline data and there is no need to repeat it for Visit 2. 
11. Previous and concurrent medications comprise any therapy, including chemotherapy, radiation therapy, and surgery, or medication previously 
received, or ongoing treatment. 
12. All medications / therapies used to treat tumor or symptoms in this study, given to a patient in a ≤ 4 week period after administration of the last dose 
of the study treatment, must be recorded in the eCRF. All patients will be followed up for safety for 56 days after administration of the last dose of 
the study drug. 
13. Safety follow-up must be performed 56 ± 3 days after the patient has received the last pasireotide LAR dose. For patients who continue in the 
extension study, this visit will not be performed after the end of the main study, but 56 ± 3 days after the patient has completed the extension study. 
14. The ECG will be performed before administration of the drug. On Visit 3 (Day 20) and on Visit 6 (Day 76), the ECG will be performed regardless of 
drug administration. 
15. . 
15. The window to perform gallbladder MRI and US [ultrasound] must not be more than 7 days prior to the scheduled visit. 
16. If a patient is not assigned to the Extension Phase, the follow-up visit will be Visit 11. 


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Table 7-2 
Visits and evaluations schedule for the Extension Study  
Visit 
101 
11 
12 
402 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
EOS 
29 
Follow-up 9 
Week 
24 
28 
32 
35 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96  
Last dose + 8 
weeks 
 
Day 
168 
196 
224 
244 
252 
280 
308 
336 
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
700 
Injection 
7 
8 
9 
 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
 
 
Adverse events (DB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current medical 
conditions (DB) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital signs (DB) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Physical examination (SD) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Weight (DB) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Pituitary / Sella turcica 
MRI  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Alpha subunit 2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
ECG (DB) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Gallbladder ultrasound 
(DB) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG Performance status 
(DB) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Evaluation of symptoms / 
Disease-related 
symptoms (DB) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Blood pregnancy test 2,10 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Hematology (DB) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Coagulation parameter PT 
(D) 
XE 
XK 
XK 
 
X 
XK 
XK 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulation parameter 
APTT (D) 
XE 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis 2 (DB) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Fasting blood glucose 
and insulin 2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
HbA1c 2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Chemistry 2,4 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
LFTs (ALT, AST, total 
bilirubin, albumin, ALP, 
γ-GT) (D) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 


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Visit 
101 
11 
12 
402 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
EOS 
29 
Follow-up 9 
Week 
24 
28 
32 
35 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96  
Last dose + 8 
weeks 
 
Day 
168 
196 
224 
244 
252 
280 
308 
336 
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
700 
Injection 
7 
8 
9 
 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
 
 
Hormone evaluation 2,5 
(DB) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Evaluation of the visual 
field 6 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Vitamin B12, folic acid 2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Administration of 
Pasireotide LAR 7 (DB) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Previous / concurrent 
medication8 (DB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Completion of the study 9 
(DB) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1 Patients who, according to the opinion of the physician in charge, are deriving benefit from pasireotide LAR treatment will be invited to participate in the 
extension phase. 
2 Blood and urine must be collected before administration of the study drug. Patients must be fasting for 12 hours. 
3 Hematology and coagulation include: hemoglobin, hematocrit (HCT), WBC count with differential, RBC count with differential, platelet count, PT, and 
APTT. 
4 Complete chemistry includes: total bilirubin, total cholesterol, LDL, HDL, triglycerides, creatinine, urea, uric acid, -GT, total protein, albumin, SGOT, 
SGPT, CPK, LDH, alkaline phosphatase, sodium, potassium, inorganic phosphorus, chloride, and calcium. If total bilirubin concentration increases over 
2.0 times the upper limit of normal, total bilirubin must be differentiated in direct and indirect reagent bilirubin. 
5 Hormone evaluation (blood) — evaluations of pituitary disease: testosterone (for men), estradiol (for women), prolactin, free T4, TSH, LH, FSH, GH, 
IGF-I, cortisol, ACTH. 
6 Evaluation by Standard Automated Perimetry (SAP). The use of the Humphrey Field Analyzer is recommended. The window to perform the SAP must 
not exceed 7 days before the scheduled visit. 
7 Patients will continue to receive pasireotide LAR IM every 28 (± 3) days. Administration of the drug will be performed by a healthcare professional at the 
site. Administration of the last dose occurs on Week 92 (Visit 27). 
8 All medications / therapies used to treat the tumor and symptoms in this study, administered to a patient for 4 weeks or less after administration of the 
last dose of the study treatment, must be recorded in the eCRF. All patients will be followed up for safety for 56 ± 3 days after administration of the last 
dose of the study medication. 
9 The safety follow-up visit (Visit 29) must be performed 56 ± 3 days after the patient has received the last dose of pasireotide LAR. 
10 A blood pregnancy test will be performed at the final follow-up visit, if a patient reports delayed menstruation or according to the physician’s opinion. 
 


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7.1 
Information to be collected in case of screening failure 
Patients who do not meet eligibility requirements on Visit 1 are considered as screening 
failures. If a patient cannot start treatment for any reason, this reason must be entered in the 
Screening Record eCRF, and the patient’s demographics will be entered in the Demographics 
eCRF. 
7.2 
Demographics / other baseline patient characteristics 
Patients’ demographics and baseline characteristics will include the following: demographics, 
diagnosis and disease extent, relevant medical history / current medical conditions, previous / 
concurrent medication administered, physical examination, including vital signs, laboratory 
evaluations (including, but not limited to, fasting blood glucose and insulin), urinalysis, visual 
field and radiological evaluations, alpha subunit level, and 
, if applicable. 
Evaluations performed to determine eligibility include gallbladder imaging, MRI, ECG, 
ECOG performance status, and pregnancy blood test. Other safety tests include AEs and 
SAEs, hematology and coagulation, and chemistry evaluations. 
The data will be recorded in the applicable eCRFs. 
7.3 
Treatments 
The study medication administered during the study must be documented in the Dose 
Administration eCRF. Date and time of dose administration will be recorded in the Dose 
Administration Record. Compliance will be evaluated by the investigator and/or study staff on 
all visits. Records of study drug used, treatment administered, and intervals between visits 
will be kept throughout the study. Drug accountability will be registered by the field monitor 
during site visits and upon completion of the study. 
All drugs, including over-the-counter drugs and previous therapies for the disease, taken 
before administration of the study drug and continuing throughout this study must be 
documented in the Previous / Concurrent Medication eCRF. 
In the Main Phase, patients will receive the study drug on Visit 2 (Day 0) and then every 4 
weeks (28 ± 3 days) thereafter, i.e., on Weeks 4, 8, 12, 16, 20. Patients who enter the 
Extension Phase will receive the study drug starting on Week 24, and then every 4 weeks (28 
± 3 days) thereafter, until Week 92. 
All therapies administered to a patient within 4 weeks after administration of the last dose of 
the study medication must be documented in the Therapy Since Discontinuation eCRF. 
7.4 
Efficacy 
Tumor volume, hormone response, and relevant disease-related symptoms will be evaluated, 
as previously described in this protocol. 


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7.4.1 
Primary efficacy evaluation 
Tumor volume will be evaluated by MRI with gadolinium contrast in the Screening Phase 
(and will be considered as baseline imaging), on Weeks 4, 12, and 24 in the Main Phase, and 
on Weeks 48, 72, and 96 in the Extension Phase (see Tables 7-1 and 7-2). 
 
7.4.2 
Secondary efficacy evaluations 
Tumor volume will also be evaluated as described on Section 7.4.1. Time to response will 
also be obtained (i.e., time to reach tumor volume decrease ≥ 20%). 
 
Disease-related symptoms will be reported by patients and recorded by the medical staff, on 
all Main Phase visits and on visits 13 (week 36), 16 (week 48), 19 (week 60), 22 (week 72), 
25 (week 84), and 28 (week 96) of the Extension Phase. 
Disease-related symptoms to be evaluated: headache, visual disorders, fatigue, decreased 
libido. Only for men: erectile dysfunction. Only for non-menopausal women: irregular or 
interrupted menstrual cycles. The investigator will also ask patients to classify the symptoms 
above according to a 5-point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very 
severe). The remaider will be evaluated as absent or present. 
 
Hormone profiles, including growth hormone (GH), insulin-like growth factor I (IGF-1), 
follicle-stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotropic hormone 
(ACTH), thyroid-stimulating hormone (TSH), prolactin (PRL), cortisol, free T4, and estradiol 
(for women) or testosterone (for men), will be evaluated in the Screening Period (and will be 
considered as baseline data) and on Weeks 4, 12, and 24 of the Main Phase. Evaluations in the 
Extension Phase will be performed on Weeks 48, 72, and 96. 
 
Alpha subunit levels will be measured in the Screening Period (and will be considered as 
baseline data), on Weeks 4, 12, and 24 in the Main Phase, and on Weeks 48, 72, and 96 in the 
Extension Phase. 
 
 


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7.5 
Safety 
7.5.1 
Adverse events 
An AE for the purposes of this protocol is the onset of (or worsening of) untoward (pre-
existing) sign(s), symptom(s), or clinical condition(s) occurring after signature of the 
Informed Consent Form, even if the event is clearly considered not related to the study 
drug(s). Refer to Section 6 for specific protocol definitions of study drug and study treatment. 
 
AEs will be evaluated according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. If there is no CTCAE classification for an adverse event, mild, 
moderate, severe, and potentially fatal severities or grades 1 to 4 will be used. CTCAE grade 
5 (death) will not be used in this study; this information will be gathered in the End of 
Treatment or Survival Information eCRF. AE monitoring must continue for at least 4 weeks 
after administration of the last dose of the study treatment. 
 
AEs occurring before the study treatment is started, and after the Informed Consent Form is 
signed, are recorded in the Medical History / Current Medical Conditions electronic Case 
Report Form. 
 
Abnormal laboratory values or abnormal test results only constitute AEs if they lead to 
clinical signs or symptoms, are considered clinically significant, or require therapy (e.g., any 
hematological abnormality requiring transfusion or treatment with cytokines), and must be 
recorded in the Adverse Events eCRF according to associated signs, symptoms, or diagnoses. 
Additionally, single abnormal laboratory values that are considered clinically significant (for 
example, causing study discontinuation or constituting, themselves, a serious adverse event) 
must be recorded in the Adverse Events eCRF. SAEs occurring after the Informed Consent 
Form is signed are recorded in the Adverse Event eCRF. 
The occurrence of AEs must be obtained by means of indirect questioning to the patient on 
every visit throughout the study. AEs may also be detected when voluntarily reported by the 
patient during or between visits or through physical examination, laboratory tests, or other 
evaluations. Whenever possible, each AE must be evaluated to determine: 
1. Severity grade (CTCAE grade 1 - 4) 
2. Relationship to pasireotide LAR (suspected / non-suspected) 
3. Duration (onset and end dates or if ongoing at the final examination) 
4. Action taken (no action taken; study drug dose adjusted / temporarily interrupted; study 
drug permanently discontinued due to this AE; concurrent medication administered; non-
drug therapy administered; hospitalization / prolonged hospitalization) 
5. If serious, a serious adverse event (SAE) is defined as an event that: 


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 Is fatal or potentially fatal 
 Results in persistent or significant disability / incapacity 
 Constitutes a congenital anomaly / birth defect 
 Requires hospitalization or prolongation of ongoing hospitalization, unless the 
hospitalization is for: 
 Routine treatment or monitoring of the indication studied; not associated to any 
condition deterioration (specify what this includes) 
 Elective or pre-planned treatment to a pre-existing condition that is not related to 
the study indication and did not worsen since the consent form was signed 
 Emergency outpatient treatment for an event that does not meet any of the SAE 
definitions provided above and does not result in hospitalization 
 Social reasons and temporary care in the absence of any deterioration of the 
general patient condition 
 Is clinically significant, i.e., defined as an event that puts the patient at risk or that 
might require medical or surgical intervention to prevent one of the results listed above 
Unlike routine safety evaluations, SAEs are continuously monitored and have special 
reporting requirements; See Section 8.1. 
All AEs must be properly treated. This treatment may include changes in treatment with the 
study drug, including possible interruption or discontinuation, start or interruption of 
concurrent treatments, changes in the frequency or nature of evaluations, hospitalization, or 
any other clinically required intervention. Once an AE is detected, it must be followed up 
until its resolution, and an evaluation must be performed on every visit (or more frequently, if 
required) regarding any change in severity, its suspected relationship to the study drug(s), any 
interventions required to treat it, and its outcome. 
The information on already known common side effects related to the investigational drug 
may be found in the Investigator’s Brochure (IB) or will be notified between IB updates as 
Investigator Notifications (INs). This information will be included in the patient’s informed 
consent form and must be discussed with the patient during the study, as required. 
 
7.5.2 
Special Safety 
7.5.2.1 
Changes in blood glucose 
The principal investigator must instruct patients about signs and symptoms of hyperglycemia, 
and evaluate the risks of hyperglycemia in all patients. It is recommended to follow the 
guidelines established by international associations specialized in diabetes, such as the 
American Diabetes Association (ADA) and the European Association for the Study of 
Diabetes (EASD) (Nathan 2009). 


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Patients with history or recent diagnosis of fasting glucose impairment, glucose tolerability 
impairment, diabetes mellitus, or at risk of developing these conditions must monitor blood 
glucose by means of a fingerstick capillary glucose test twice a day (fasting and 2 hours post-
prandial). It is recommended that patients be encouraged to keep a blood glucose diary for 
appropriate disease management throughout the study, as well as to show the data collected to 
the physician / diabetes expert for evaluation. The data will not be collected by the sponsor. 
 
It is advised that any patient experiencing fasting plasma glucose > 130 mg/dL (7.2 mmol/L), 
or 2-hour post-prandial capillary glucose (PPG) ≥ 180 mg/dL (10 mmol/L) in two consecutive 
measurements with an interval of approximately 14 days and/or HbA1c > 7% be evaluated by 
an diabetes expert for proper treatment (Position statement ADA 2010). Additionally, these 
patients must be informed on diabetes control. The start or adjustment of anti-hyperglycemic 
treatment must be considered as soon as possible, at the discretion of the diabetes expert. 
Additionally, these patients must start blood glucose monitoring by fingerstick capillary 
glucose test twice a day (fasting and 2 hour post-prandial) if it has not yet been performed. It 
is recommended that patients be encouraged to keep a blood glucose diary for appropriate 
disease management throughout the study, as well as to show the data collected to the 
physician / diabetes expert for evaluation. The data will not be collected by the sponsor. 
Patients developing symptoms of uncontrolled diabetes mellitus and/or blood glucose levels 
consistently above 275 mg/dL (15.5 mmol/L), in spite of appropriate therapeutic 
interventions, must be discontinued from the study, as well as those patients whose HbA1c 
percentage is ≥ 10%, in spite of appropriate therapeutic interventions. 
7.5.2.2 
Changes in QT interval 
If, at any visit, a QTcF > 480 msec is seen in patients receiving pasireotide LAR, the 
following actions will be taken: 
 A visit to a cardiologist must be scheduled as soon as possible, but within no more than 7 
days of the initial abnormal ECG, and the cardiologist must re-evaluate the ECG (this can 
be done by the central cardiologist, if the study has one). 
o If a QTcF > 480 msec is NOT confirmed, no action will be taken. 
o If a QTcF > 480 msec is confirmed, a cardiologist must perform a thorough 
examination (such as review of baseline ECG, concurrent medication, and 
performance of a cardiovascular examination (including, at least, one cardiac 
auscultation)) in order to evaluate the patient for cardiovascular risk factors. 
o If, based on the cardiologist’s evaluation, the investigator considers that there is an 
acute cardiovascular safety risk and that the patient should not continue to receive the 
study drug, or the patient meets any discontinuation criteria (section 6.4.5.1), he/she 
must be immediately discontinued. 


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o If, after the cardiologist’s examination, the investigator considers that there is no acute 
cardiovascular safety risk and that the patient may continue to receive the study drug, 
then, the following actions must be taken: 
 
 Scenario A (Figure 7-1): If the initial ECG was performed before the pasireotide LAR 
injection: 
A (24-hour) Holter ECG must be recorded as soon as possible, but within no more than 7 
days of the initial abnormal ECG. The cardiologist evaluates the Holter ECG and provides 
the investigator with recommendations. The investigator analyzes the results and the 
cardiologist’s recommendations. If a patient meets the discontinuation criteria (section 
6.4.5.1), he/she will be immediately discontinued. 
If a patient does not meet the discontinuation criteria, the next pasireotide LAR dose may 
be administered. A second Holter ECG must be recorded on the day of the next 
pasireotide LAR injection, and it must be started 30 min before the study drug injection. 
ECG, cardiac examination, and Holter ECG results, as well as the cardiologist’s 
recommendation, must be evaluated by the investigator in order to determine whether the 
patient may or may not continue in the study (discontinuation criteria to be followed, 
Section 6.4.4 and Section 6.4.5). 
If an abnormal ECG is seen on Visit 10 and no additional dose of pasireotide LAR is 
administered, then the follow-up is at the investigator’s discretion. 
 
 Scenario B (Figure 7-2): If the initial ECG is performed at Visit 3 (Day 20) or at Visit 6 
(Day 76): 
A (24-hour) Holter ECG must be recorded as soon as possible, but within 7 days of the 
initial abnormal ECG. The cardiologist evaluates the Holter ECG and provides the 
investigator with recommendations. The investigator analyzes the results and the 
cardiologist’s recommendations. If a patient meets the discontinuation criteria (Section 
6.4.4 and Section 6.4.5), he/she will be immediately discontinued. If the investigator 
decides that the patient may continue in the study, he/she will be invited to return to the 
next regular visit, according to the visits and evaluations schedule (Table 7-1). 


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Figure 7-1 
Scenario A: Procedure for QTcF Prolongations Occurring on the Planned 
Pasireotide LAR Dosing Visits 
 
 
Visit 10: If QTcF > 480 msec on this visit and no additional pasireotide LAR dose is administered, then the 
follow-up is at the investigator’s discretion. 
Patient is 
discontinued 
YES 
QTcF > 480 msec on visits 4, 
5, 7, 8, 9 (and 10) before the 
pasireotide LAR injection 
Consultation of the cardiologist’s 
results: 
- acute risk to cardiovascular safety 
- Patients meet discontinuation 
criteria 
NO 
Do not administer 
pasireotide LAR 
The patient receives the 24-hour 
Holter monitor according to the 
regular schedule 
The patient returns the Holter 
monitor 
The cardiologist evaluates the Holter 
monitor and makes 
recommendations to the investigator 
The investigator makes a 
decision based on the 
cardiologist’s recommendations 
Administer 
pasireotide 
LAR 
NO 
The patient meets the 
discontinuation criteria 
The patient receives the 24-hour 
Holter monitor on the next visit (5, 7, 
8, 9 (and 10)) 30 min before the 
pasireotide LAR injection 
 
The patient returns the Holter 
monitor 
The cardiologist evaluates the Holter 
monitor and makes recommendations 
to the investigator 
The investigator makes a decision 
based on the cardiologist’s 
recommendations 
The patient meets the 
discontinuation criteria 
NO 
YES 
The patient 
may continue in 
the study 
The patient is 
discontinued 
YES 


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Figure 7-2 
Scenario B: Procedure for QTcF Prolongations Occurring on visits 3 and 6 
Planned Only for Patients Receiving Pasireotide LAR 
 
 
7.5.2.3 
Liver safety monitoring 
If any of the criteria below is observed on any scheduled or unscheduled visit, the sponsor 
must be informed as soon as the occurrence is acknowledged. 
 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 
The following tests will be performed immediately within 72 hours after the abnormality is 
acknowledged: 
 Perform liver-oriented medical history and physical examination (i.e., evaluate 
occupational risks, concurrent medication, including over-the-counter medication, 
concurrent disease, etc.) 
The patient is 
discontinued 
YES 
QTcF > 480 msec on 
visit 3 or on visit 6 
Consultation of the cardiologist’s 
recommendations: 
- acute risk to cardiovascular 
safety 
- The patients meet the 
discontinuation criteria 
NO 
The patient receives the 24-hour 
Holter monitor 
The patient returns the Holter 
monitor 
The cardiologist evaluates the Holter 
monitor and makes recommendations 
to the investigator 
The investigator makes a decision 
based on the cardiologist’s 
recommendation 
The patient may 
continue in the 
study 
NO 
The patient meets the 
discontinuation criteria 
YES 
The patient is 
discontinued 


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 Liver tests: ALT, AST, total bilirubin (bilirubin fractionated in direct / indirect, if total 
bilirubin is > 2.0 x ULN), Albumin, PT (INR), ALP, and γ-GT 
 Perform hepatitis tests: anti-HAV IgM (to confirm acute Hepatitis A), HBsAg, anti-
HBc, anti-HCV (if positive, viral load PCR must be evaluated), anti-HEV, ANA 
antibodies, anti-smooth muscle antibodies, CMV and EBV 
 Perform abdominal ultrasound (liver and bile duct) 
 Collect pharmacokinetic samples and record the level and time of the last dose the 
patient received before the pharmacokinetic sample. 
Liver function tests must be monitored every 3 - 4 days until resolution or return to baseline 
level. 
Patients may need to be discontinued if the abnormal liver function criteria are met when the 
liver tests are repeated (refer to discontinuation criteria on Section 6.6.5.1). The reports of the 
course of the event must be kept until resolution or stabilization (i.e., no elevation after 2 
consecutive evaluations). 
For ALT or AST > 5 x ULN and ≤ 8 x ULN, the following must occur (in addition to the 
safety follow-up procedures listed above): 
 The study medication must be temporarily interrupted and the liver tests monitored 
every 3 - 4 days until resolution or return to baseline level. 
 If no resolution or return to baseline occurs after 2 weeks, the patient must be 
discontinued. 
 If ALT or AST return to less than 5 x ULN, the study medication may be resumed 
and the patient may continue the study according to the protocol. 
 If ALT or AST increase to over 5 x ULN at any time after the study medication is 
resumed, then the study medication must be immediately discontinued. 
If any of these criteria is met and considered as an adverse event by the investigator, the event 
must be recorded on the Adverse Event page of the case report form; if the event is considered 
severe by the investigator, then proceed to complete the SAE form. Additionally, any 
significant finding of the physical examination must be recorded in the Adverse Event page of 
the case report form. 


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Figure 7-3 
Liver Test Monitoring Algorithm 
 
 
 
7.5.2.4 
Gadolinium 
There are known adverse events after the use of Gadolinium as contrast material in MRI 
scans. Caution must be taken with patients with current and previous renal failure. 
7.5.3 
Physical examination, weight, height 
Physical examinations will be performed and weight will be measured on all visits. This may 
be performed by the Investigator or any other qualified healthcare professional. The 
information on physical examinations must be present in the source-documentation at the 
study site. Height will be registered only during the screening / baseline period. Significant 
Yes 
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 
If criteria are met 
with ALP < 2 X 
ULN 
temporarily interrupt the 
study medication 
Discontinue the 
study and 
continue safety 
follow-up 
No 
Safety Follow-up (performed in up to 72h) 
 Hepatic medical history and physical examination 
 Hepatitis screening 
 Abdominal ultrasound (liver and bile duct) 
 PK sample collection 
 Collection for liver chemistry panel 
Discontinue the 
study and 
continue safety 
follow-up 
Continue liver function test follow-up monitoring every 
3 - 4 days until resolution or return to baseline status 
ALT or AST > 5 X baseline persistent after 2 
weeks of monitoring 
Yes 
No 
Continue study medication at 
the original dose level and 
continue the study 
If ALT or AST 
increases above 5 X 
ULN at any time after 
the drug is resumed 
Discontinue the 
study and 
continue safety 
follow-up 
Discontinue the 
study and 
continue safety 
follow-up 


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findings present before the start of the study treatment must be included in the Relevant 
Medical History / Current Medical Conditions Case Report Form. Significant findings after 
the start of the study drug meeting the definition of an AE must be recorded in the Adverse 
Event Case Report Form (eCRF). 
7.5.4 
Vital signs 
Body temperature, blood pressure in supine position, and heart rate in supine position will be 
evaluated on all main phase visits and on Visits 13 (week 36), 16 (week 48), 19 (week 60), 22 
(week 72), 25 (week 84), 28 (week 96), and 29 (week 100) in the extension phase. 
7.5.5 
Performance status 
Eastern Cooperative Oncology Group (ECOG) performance status will be evaluated on each 
visit in the main phases and on Visits 13 (week 36), 16 (week 48), 19 (week 60), 22 (week 
72), 25 (week 84), 28 (week 96), and 29 (week 100) in the extension phase, using the criteria 
on Table 7-3. 
Table 7-3 
Eastern Cooperative Oncology Group (ECOG) performance status 
scale  
Grade 
ECOG 
0 
Fully active, able to carry out all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
awake for approximately more than 50% of time. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Unable to carry out any self-care. Completely confined to bed or chair. 
5 
Deceased 
7.5.6 
Laboratory evaluations 
Laboratory samples will be submitted to a local laboratory for analysis, except alpha subunit 
, which will be submitted to a central laboratory. Patients will fast overnight for 12 
hours before all blood samples are collected. Blood samples must be performed in the 
morning. Drinking water is allowed during this period. 
Details about the central laboratory, including collection and submission of samples, report of 
results, and warning procedures for extreme values, will be provided in the Investigator’s 
Binder. 


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7.5.6.1 
Hematology 
Hematology parameters will be evaluated in the Screening Period, before administration of 
the study drug, and on every Main Phase visit (except Visit 2, Visit 3 [Week 3], Visit 6 
[Week 11], and Visit 10 [Week 24]), and will include: WBC count with differential, 
hemoglobin, HCT, RBC count and platelet count, and differential. 
7.5.6.2 
Coagulation 
Coagulation parameters APTT and PT will be evaluated on visit 1 (screening), visit 2 
(baseline), visit 6, and visit 10 (completion of the study) for all patients. Coagulation 
parameter PT will also be evaluated on visit 3, visit 4, visit 401 (after 48 days), and visit 5 for 
patients randomized to the double-blind treatment arm of pasireotide LAR. Coagulation 
parameters will be collected before administration of the study drug. 
During the Extension Phase, evaluations will be performed first on visit 10 (Week 24), and 
then every 6 months thereafter (i.e., Weeks 48, 72, and 96). 
 
7.5.6.3 
Chemistry 
A complete chemistry profile will be evaluated in the screening period and before 
administration of the study drug on each visit (except on Visit 2, Visit 3, Visit 6, and Visit 11, 
the Follow-up Visit) and will include: total cholesterol, low density lipoprotein (LDL) 
cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, calcium, phosphorus, 
chloride, sodium, potassium, inorganic phosphorus, creatinine, urea, uric acid, CPK, LDH, 
alkaline phosphatase, -GT, total protein, albumin, SGOT, SGPT, total bilirubin. In the 
Extension Phase, the chemistry profiles will be evaluated on visit 10 (Week 24) and then 
every 6 months thereafter (Weeks 48, 72, and 96). 
If total bilirubin concentration increases more than 2.0 times the upper limit of normal, total 
bilirubin must be differentiated in direct and indirect reagent bilirubin on all visits. 
Fasting blood glucose, insulin, and fasting chemistry evaluations will be performed in the 
screening phase and before administration of the study drug on each visit, except on Visit 2, 
Visit 3 (Week 3), Visit 6 (Week 11), and Visit 11 (Week 28, Follow-up Visit) in the Main 
Phase; they will also be performed on Weeks 48, 72, and 96 in the Extension Phase. 
Liver function tests (ALT, AST, total bilirubin, albumin, ALP, and γ-GT) will be evaluated on 
visit 1 (screening), visit 2 (baseline), visit 6, and visit 10 for all patients. Liver function tests 
will also be evaluated on visit 3, visit 4, visit 401 (after 48 days), and visit 5. 
 
HbA1c evaluations will be performed in the screening period (these will be considered as 
baseline data), on Weeks 12 and 24 in the Main Phase, and on weeks 48, 72, and 96 in the 
Extension Phase. 


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Vitamin B12 and folic acid evaluations will be performed in the Screening Period (these will 
be considered as baseline data), on Week 24 in the Main Phase, and on weeks 48 and 96 in the 
Extension Phase. 
 
7.5.6.5 
Serology 
Hepatitis B surface antigen (HBs-Ag) and Hepatitis C antibody (anti-HCV) tests will be 
performed on visit 1 (screening). 
 
7.5.6.6 
Urinalysis 
Specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes, and blood will be 
evaluated. Urine must be collected in the Screening Phase and before administration of the 
study drug on each visit (except on Visit 2, Visit 3, Visit 6, and Visit 11 or Follow-up Visit) in 
the Main Phase and on Weeks 48, 72, and 96 in the Extension Phase. 
 
7.5.6.7 
Pregnancy test 
Blood pregnancy test is performed in the screening period, on Weeks 12 and 24 in the Main 
Phase, and on Weeks 48, 72, and 96 in the Extension Phase. It may be performed on the 
Follow-up Visit (56 ± 3 days after the last dose of the study medication) if the patient reports 
late menstruation or at the physician’s discretion. Patients considered post-menopausal 
(defined as 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous 
amenorrhea with FSH blood levels > 40 mIU/mL before or during the study) are not required 
to performed subsequent pregnancy tests. 
The study drug treatment must be withdrawn in case of pregnancy. 
In order to ensure patient safety, every pregnancy in a patient under study drug administration 
must be reported to Novartis within 24 hours after acknowledgement. Pregnancy must be 
followed to determine the outcome, including miscarriage or abortion, details about the birth 
and presence or absence of any birth defects, congenital anomalies or maternal and/or 
newborn complications. 


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For information on pregnancy reports, refer to section 8.2. 
 
7.5.7 
Radiology tests 
A gallbladder ultrasound will be locally performed in the Screening Phase (this will be 
considered as baseline data), on Week 24 in the Main Phase, and Weeks 48 and 96 in the 
Extension Phase. Patients with history of symptomatic colelithiasis are excluded from 
participation in the study (refer to Section 5.2). Information on the presence and location of 
gallstones, gallbladder sediments, and bile dilation will be entered in the Gallbladder 
Ultrasound eCRF page. In case of abnormal liver function criteria (refer to Section 7.5.2.3), 
an abdominal ultrasound will be required (liver and bile duct). 
 
MRI Evaluation / Tumor volume measurement: 
Patients will undergo MRI evaluations in the Screening Phase (these will be considered as 
baseline data), and on Visits 4 (Week 4), 7 (Week 12), and 10 (Week 24). MRIs will be 
evaluated by a central reviewer. At least 4 MRIs are expected to be evaluated by central 
review during the Main Phase of the study. In the Extension Phase, MRI evaluations will be 
performed on Weeks 48, 72, and 96. 
Coronal and sagittal images weighted at T1 will be obtained before and after administration of 
gadolinium contrast. The minimum scanner field power will be 1.5 T. 
MRIs will be submitted for evaluation by a blinded central evaluator. In order to ensure 
consistency in all participating sites, MRIs must be performed and processed according to the 
guidelines of the central evaluator’s facility, which will be distributed to the sites before study 
start. These pituitary adenomas will be measured for analysis by a neuro-radiologist, using 
manual tracing together with the imaging analysis software. 
Total tumor volume will be derived from coronal image with gadolinium and estimated by 
multiplying each slice thickness by the area within the curve of the imaging with manual 
tracings and adding the slices’ volumes. The largest diameter at any plan will determine the 
maximum diameter of the tumor. 
A change ≥ 20% in the original volume of the tumor will be considered clinically significant. 
Smaller changes in pituitary tumor volumes may be attributed to volume measurement 
artifacts, changes in the position of the slice, or time of administration of the contrast bolus 
(Jimenez et al 2008)(Colao et al 2009). 
 


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7.5.8 
Electrocardiogram (ECG) 
All ECGs will be locally performed. An ECG will be performed in the Screening Period or 
Visit 1 (to evaluate eligibility) and then on all visits before injection of the study drug in the 
Main Phase, except for Visits 3 and 6, on which they will be performed independently of drug 
administration. In the Extension Phase, ECGs will be performed on Weeks 36, 48, 60, 72, 84, 
and 96. 
It is recommended that paper speed be programmed to 25 mm/s, and sensitivity to 10 mm/mV 
(calibration). The operator must sign and date all tracings performed. The abnormalities seen 
must be recorded in the ECG eCRF. 
 
If a clinically significant abnormality is detected, the ECG will be repeated, at the 
Investigator’s discretion, until the abnormality is resolved. More frequent ECGs may be 
performed at the Investigator’s discretion, if clinically indicated. Any abnormalities must be 
recorded in the unscheduled evaluation pages of the eCRF. 
 
Data safety records must include the following: 
• Any abnormal ECG findings (refer to Section 7.5.2.2) 
• Abnormal vital signs 
• All arrhythmias, including: Torsades de Pointes, ventricular tachycardia, ventricular 
fibrillation, and ventricular flutter 
• Syncope, near-syncope, and fainting 
• Seizures or loss of central function (sudden incontinence, dizziness, visual disorders) 
• Sudden death 
The study number must be recorded as [CSOM230D2401] at each tracing and must be kept in 
the source-documents. 
 
7.5.9 
Visual evaluations 
Visual field evaluations will be performed at screening, on Visit 2 (if the visual field 
evaluation at Screening is performed no more than 14 days before Visit 2, it may be 
considered as baseline data and there is no need to repeat it for Visit 2), on all visits in the 
Main Phase, except for Visit 3 and 6, and on Weeks 48, 72, and 96 in the Extension Phase. 
The window to perform the visual field evaluation must be of no more than 7 days before the 
scheduled visit. 
 
Standard Automated Perimetry (SAP) is the most frequently used parameter to estimate the 
severity of visual loss (Monteiro et al 2009). The use of a Humphrey Field Analyzer is 
recommended. 
 
Visual Field Test 
The visual field test will be performed using SAP. The use of a Humphrey Field Analyzer is 
recommended. The perimeter software will use the refractive correction for near vision, 
calculated according to the patient’s age (Monteiro et al 2009). 


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These test reports will determine whether the visual field is normal or abnormal. If 
abnormal, it will be classified as: 
 mild (corrected visual acuity within normal limits (better than 20/30), in addition to nasal 
visual field within normal limits and impairment of approximately one quadrant of the 
temporal visual field) or 
 severe (impaired corrected visual acuity (20/30 or worse), or impaired nasal visual field 
or impairment of more than one quadrant in the temporal visual field). 
Outcome information will also be provided in the follow-up report: Stable, improved, or 
worsened visual field. 
7.6 
Tolerability 
In addition to overall safety data, information on dose decreases will be collected. 
Furthermore, any AEs related to the study drug, e.g., gastrointestinal disorders, glucose 
metabolic disorders, cardiac dysfunctions, laboratory abnormalities, infections, and injection 
site reactions, will be summarized through the submission of counts and percentages for each 
treatment group. 
7.7 
Patient reported outcomes 
Not applicable. 
8 
Safety monitoring 
8.1 
Serious adverse event reporting 
In order to ensure patient safety, each SAE, regardless of the suspected causality, occurring 
after the beginning of any period in which the study protocol interferes with the standard 
medical care given to the patient (for example, withdrawal of treatment during washout 
period, change in treatment for a fixed dose of concurrent drug) and up to 56 days after the 
patient receives the last IM LAR injection of the study drug must be reported to Novartis 
within 24 hours after acknowledgement. Any SAE experienced after this period must be 
reported to Novartis if the investigator suspects that there is a causal relationship to the study 
drug. Recurrent episodes, complications, or progression of the initial SAE must be reported as 
a follow-up to the original episode within 24 hours of receipt of the follow-up information by 
the investigator. A SAE occurring in a different timepoint or considered as not otherwise 
related to a previously reported event, must be reported separately as a new event. 
The information about all SAEs is collected and recorded in the Serious Adverse Event 
Report Form. The investigator must evaluate and register the relationship between each SAE 
and each specific study drug (if there is more than one study drug), complete the SAE Report 
Form in English, and fax it, completed and signed, within 24 hours to the Novartis Integrated 
Medical Safety (IMS) Oncology Department. 


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The site-specific phone and fax numbers of the contact people at the local IMS department are 
indicated in the investigator’s binder provided to each site. The original copy of the SAE 
Report Form and the fax confirmation page must be kept together with the documentation of 
the case report form at the study site. 
Follow-up information is submitted to the same person as the original SAE Report Form, 
using a new SAE Report Form, indicating that this is a follow-up of a previously reported 
SAE and mentioning the date of the original report. Each recurrence, complication, or 
progression of the original event must be reported as a follow-up to that event, regardless of 
when it occurs. Follow-up information must describe whether the event resolved or continues, 
whether and how it was treated, whether there was unblinding or not, and whether the patient 
continued or discontinued his/her participation in the study. 
If the SAE is not previously documented in the Investigator’s Brochure or the Package Insert 
(new occurrence), and if it is considered related to the Novartis study drug, an associate from 
Novartis IMS Oncology Department may request emergency additional information to the 
investigator for notification of the Health Authority. Novartis may need to issue an IN to 
inform all investigators involved in any study with the same medication reported for this SAE. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
relevant authorities and ethics committees, according to Directive 2001/20/EC or according to 
the national regulatory requirements in the participating countries. 
8.2 
Pregnancy 
In order to ensure patient safety, every pregnancy in a patient under administration of the 
study drug must be reported to Novartis within 24 hours from acknowledgement of its 
occurrence. Pregnancy must be followed up in order to determine the outcome, including 
miscarriage or abortion, details about the birth, and presence or absence of any birth defect, 
congenital anomalies, or maternal and/or newborn complications. 
Pregnancy must be recorded in a Clinical Trial Pregnancy Form and reported by the 
investigator to the Local Novartis Integrated Medical Safety (IMS) Department. The 
pregnancy follow-up must be recorded in the same form and must include an evaluation of the 
possible relationship of any pregnancy outcome to the Novartis study drug. Any SAE 
experienced during pregnancy must be reported in the SAE Report Form. 
Information about pregnancy of female partners of any men receiving the study drug during 
the study must be collected. The consent to report the information about this pregnancy must 
be obtained from the mother. 


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9 
Data review and management 
9.1 
Site monitoring 
Before the study is started, in a site initiation visit or in a meeting with the investigator, the 
Novartis team (or an appointed CRO) will review the protocol and eCRFs with the 
investigators and their staff. During the study, the field monitor will visit the site regularly to 
check for correct completion of patient records, accuracy of eCRFs records, compliance with 
the protocol and Good Clinical Practice (GCP), enrollment progress, and ensure that the study 
drug is stored, dispensed, and accounted for according to specifications. The main study staff 
must be available to assist the field monitor during these visits. 
The investigator must keep the source-documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic records) containing demographics and medical 
information, laboratory data, ECGs, and results of any other tests or evaluations. All 
information contained in the eCRFs must be traceable to these source-documents in the 
patient’s file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient). 
The investigator must facilitate the monitor’s access to all relevant source-documents to 
confirm their consistency with the insertions in the eCRF. Novartis monitoring rules require 
complete verification for presence of the consent form, compliance with inclusion / exclusion 
criteria, documentation of SAEs, and recording of data that will be used for all primary and 
safety variables. Additional verifications regarding the consistency of the source-data with 
eCRFs are conducted according to the specific monitoring plan for the study. No information 
on the source-documents about the patients’ identity will be disclosed. 
9.2 
Data collection (eCRF) 
The investigator’s designated staff must enter the information required by the protocol in the 
Novartis eCRFs. Field monitors will review the eCRFs for completion and accuracy and will 
instruct the site personnel to perform any corrections or inclusions required. 
9.3 
Database management and quality control 
The data of eCRFs are entered in the study database by the CRO Data Management team after 
its own internal standard operating procedures are reviewed and approved by Novartis. 
Then, the data entered are systematically verified by the CRO Data Management team with 
the use of error messages printed from validation programs and database listings. Obvious 
errors are corrected by the CRO Data Management personnel. Other errors or omissions are 
entered in electronically created Data Query Forms. The investigator (or his/her designee) will 
answer / resolve the query directly in the system. All changes are recorded in the study audit, 
which will capture who, when, and what files were corrected / changed. Quality control 
auditing of all main safety and efficacy data in the database is performed before database lock. 


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Concurrent medication entered in the database will be coded with the use of the WHO Drug 
Reference List, which uses the Anatomical Therapeutic Chemical (ATC) classification 
system. The medical history / current medical conditions and AEs will be coded with the use 
of the terminology of the Medical Dictionary for Regulatory Activities (MedDRA). 
Laboratory samples, which will be centrally processed, will have their results submitted to the 
investigators. 
ECG readings will be locally processed and the results will be entered in the eCRF. 
The occurrence of any protocol breach will be determined. After the completion of these 
actions and after the database is declared complete and accurate, it will be locked and made 
available for data analysis. Any subsequent changes in the database may be performed only 
upon mutual written agreement between the Global Head of Biostatistics and Statistical 
Reporting and the Global Head of the Therapeutic Area. 
10 
Statistic methods and data analysis 
The following sections describe the analyses to be performed. 
For the Main Phase of the study, efficacy and safety analyses will be performed with the data 
collected when all patients enrolled complete their EOS visit. All Follow-up Visit safety data 
from patients who do not enter the Extension Study will also be included in the safety 
analyses of the Main Study. A final analysis will be performed when all Extension patients 
complete their last visit and will be reported either as an additional clinical study report or as 
an amendment to the Main Phase report. The other additional data at the end of the main study 
will be analyzed and summarized later in an additional clinical trial report or in a main study 
report. 
Novartis or the designated CRO will analyze all data using the SAS System for data analysis 
V8.0 or higher. Any data analysis performed independently by an investigator must be 
submitted to Novartis before its publication or presentation. 
Data from all participating sites in this study will be pooled so the appropriate number of 
patients is available for analysis. The statistical analysis methods described in this section will 
focus on the data analysis in the main study. Similar methods will be used in the analyses 
during the extension phase, as appropriate. 
10.1 
Analysis populations 
Full analysis set (FAS): comprises all patients successfully completing Screening and 
receiving at least one dose of the study medication. The FAS will be the primary analysis set 
for efficacy analyses. 


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Safety analysis set: comprises all patients receiving at least one dose of the study drug and 
having at least one post-baseline safety evaluation. 
It is noteworthy that the statement that a patient did not experience AEs (in the Adverse Event 
eCRF) constitutes a safety evaluation. The safety set will be used for all safety analyses. 
The analyses presented in these sections correspond to the analyses to be used for the Main 
Phase of the study. A final analysis will be performed when all Extension patients complete 
their last visit and will be reported either as an additional clinical study report or as an 
amendment to the Main Phase report. 
 
10.2 
Demographics / other baseline patient characteristics 
Demographics and other baseline data, including disease characteristics (e.g., age, gender, and 
race), will be descriptively summarized based on the FAS. Categorical data will be presented 
as frequencies and percentages. For continuous data, the mean, standard deviation, median, 
minimum, and maximum will be presented. 
10.3 
Treatments (study drug, concurrent therapies, compliance) 
Duration of exposure to the study drug, number of patients with dose adjustment (dose 
interruptions, changes), and dose intensity will be summarized for the main period and the 
study extension period. 
Significant concurrent medication and non-drug therapies administered before and after the 
beginning of the administration of the study drug will be summarized by preferred terms, 
according to ATC class of the WHO Drug Reference List. 
10.4 
Primary objective 
The primary objective is to evaluate the efficacy of pasireotide LAR on NFPA, based on 
tumor volume decrease. 
10.4.1 
Variable 
The primary efficacy variable is the proportion of patients with NFPA reaching a tumor 
volume decrease of at least 20% after treatment Week 24 with pasireotide LAR. 
10.4.2 
Statistical analysis 
The proportion of patients with a decrease of at least 20% in tumor volume will be 
summarized in terms of incidence rates and the exact 90% confidence interval at the end of 
the main study for the FAS population (week 24). 


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10.4.3 
Control of missing values / censoring / discontinuations 
A patient whose tumor volume evaluation at the beginning of the study (Screening Period, 
baseline data) is missing will not be considered for efficacy evaluations. Only patients with 
baseline evaluation and at least one later evaluation will be considered for statistical analysis. 
All analyses will be performed with the data observed, i.e. the primary analysis (Week 24) 
will only be based on data from patients with both baseline and Week 24 tumor volume 
evaluation. 
The primary endpoint analyses will be based on the cases seen, as the population is treatment-
naïve (also not having undergone surgery), and 24 weeks of treatment are expected to be 
necessary before a significant effect is evaluated. 
10.4.4 
Support Analysis 
A sensitivity analysis will be performed in the primary efficacy endpoint after the imputation 
of missing values on week 24 from the last observation carried forward (LOCF). This will be 
possible for patients with baseline data and at least one later value. 
10.5 
Secondary objectives 
Analysis population 
All secondary efficacy analyses will be based on the full analysis set (FAS). The safety 
analysis set will be used for all safety analyses. 
 
10.5.1 
Efficacy variables and analysis 
The secondary efficacy endpoints are described on section 3.3.2. 
The changes in mean and percent tumor volume variation from baseline to Weeks 4, 12, and 
24 will be presented together with the 90% confidence interval (90% CI). If the data are in a 
non-normal distribution, median CI will also be generated. The incidence rate of patients with 
tumor volume decrease ≥ 20% and its exact CI will be reported on weeks 4 and 12. 
Summary of the statistical analyses will be provided for each disease-related symptom 
(headache, visual disorders, fatigue, decreased libido, and specific symptoms for men and 
women) on each visit. Changes in baseline scores will be summarized on each visit for all 
symptoms. 
The time to response, defined as the time from the first injection to the first evaluation in 
which a patient reaches a tumor volume decrease of at least ≥ 20%, will be listed for all 
patients. If a patient did not reach tumor response, the period of his/her last evaluation will be 
used as a cutoff period. For responsive patients, average time to response will be summarized. 
Additionally, logistic and cox regression models may be used to explore the association 
between baseline characteristics and tumor response and time to tumor response. These 
analyses will be specified in the report analysis plan (RAP). 


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The frequency and percentage of patients experiencing improvement of symptoms related to 
tumor compression, pituitary hormone dysfunction, normalization of the alpha subunit level, 
 will be presented for each symptom at each period with 
the associated exact 90% CI. 
The incidence rates of pituitary hormone dysfunction, the normalization of alpha subunit 
levels, and the proportion of patients with a 50% decrease in the alpha subunit level, together 
with the exact 90% CI will be reported at baseline and on weeks 4, 12, and 24. The alpha 
subunit level analyses will be performed again with the population set according to protocol 
and for the subgroup of patients with increased alpha subunit levels at baseline. 
Hormone profiles, alpha subunit levels, 
 in each period in 
terms of frequency (N), mean, standard deviation, median, minimum, and maximum. 
10.5.3 
Safety analyses and parameters 
The safety evaluation will be based mainly on frequency of adverse events (AEs), number of 
patients with laboratory values outside the reference ranges, and number of patients with 
clinically significant changes in ECGs. Other safety data (for example, vital signs and special 
tests) will be considered when appropriate. 
10.5.3.1 Adverse events 
All AEs recorded during the study will be summarized. The incidence of treatment-emergent 
AEs (new or worsening from baseline) will be summarized by system organ class, severity 
(based on CTCAE grade), type of AE, and relationship to the study drug. Deaths that may be 
reported as SAEs and non-fatal serious adverse events will be listed by patient and organized 
in the table by type of AE. 


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10.5.3.2 Laboratory abnormalities 
All laboratory values will be converted in SI units and the severity grade will be calculated 
using the appropriate Common Toxicity Criteria (CTC). 
The frequency of laboratory abnormalities will be shown by parameter and study day. 
Considerably abnormal laboratory values (new or worsening from baseline based on CTC 
grade) will be summarized by laboratory parameter. The tables will show the comparison 
between the baseline laboratory result (CTC grade) and the worst result (expressed in CTC 
grade) during the study. Patients with abnormal laboratory values will be mentioned and 
values outside the normal range will be flagged. A separate list of CTC grade 3 or 4 
laboratory abnormalities will also be provided. 
10.5.3.3 Other safety data 
Weight, height, and vital signs will be summarized in each period, using descriptive statistics 
(N, mean, standard deviation, median, minimum, and maximum). 
Physical examination abnormalities, ECOG performance status, radiology tests, ECGs, MRIs, 
and visual evaluations will be identified and listed. 
10.5.4 
Tolerability 
Dose decreases and AEs related to the study drug, e.g., gastrointestinal disorders, glucose 
metabolic disorders, cardiac dysfunctions, laboratory abnormalities, infections, and injection 
site reactions, will be summarized by presenting counts and percentages for the safety 
population. 
10.6 
Sample Size Calculation 
This study is a proof of concept. The sample size of 19 evaluable patients was selected 
without taking statistical power into account. The response rate (proportion of patients with 
tumor volume decrease ≥ 20%) of at least 10% is considered clinically significant for this 
patient population. Table 10.1 presents the probability that there are two or more responders 
for the many assumed response rates. If the actual response rate is 10%, the probability of 
obtaining two or more responders among the 19 patients is 58%. In this study, a 90% CI will 
also be obtained. Table 10.2 presents the exact 90% CI when 2 - 6 among 19 patients respond 
to treatment. Considering that the study dropout rate is 20%, 23 patients will be enrolled in 
order to obtain the 19 evaluable patients for the final analysis. 
Table 10.1: Probability of  ≥ 2 responders in a 19 patient sample. 
assumed p  
0.05 
0.10 
0.15 
0.20 
0.25 
0.30 
P( X ≥ 2) 
25% 
58% 
80% 
92% 
97% 
99% 
X is assumed to have a binomial distribution with p probability  
 


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Table 10.2: Resulting 90% CI for different numbers of responders 
Responders / n 
Lower confidence interval  
Upper limit of the 
confidence interval   
2 / 19 
1.9% 
29.6% 
3 / 19 
4.4% 
35.9% 
4 / 19 
7.5% 
41.9% 
5 / 19 
11% 
47.6% 
6 / 19 
14.7% 
53% 
 
11 
Administrative procedures 
11.1 
Enrollment compliance 
When all inclusion / exclusion criteria are met and a patient is qualified to enter the study and 
when all information is entered into the eCRF, enrollment will be allowed. This will allow 
enrollment to be properly monitored and will ensure that the populations with each type of 
tumor are appropriately represented in the study. 
11.2 
Ethic and regulatory compliance 
This clinical study was designed and must be implemented and reported according to the 
protocol, the Harmonized Tripartite Guideline for ICH Good Clinical Practice, the applicable 
local regulations (including European Resolution 2001/20/EC and U.S. Code of Federal Rules 
Title 21), and the ethical principles established in the Declaration of Helsinki and the 
Brazilian legislation. 
11.3 
Investigator’s and REC’s responsibilities 
The protocol and the proposed informed consent form must have been reviewed and approved 
by a duly established Research Ethics Committee (REC) before the start of the study. A 
signed and dated statement that the protocol and informed consent form were approved by the 
REC must be submitted to Novartis before the start of the study. Before the start of the study, 
the investigator must sign a protocol signature page confirming his/her agreement to conduct 
the study according to these documents and all instructions and procedures found in this 
protocol, in addition to providing access to all pertaining data and records to Novartis 
monitors, auditors, Novartis Clinical Quality Assurance representatives, Novartis designees, 
RECs, and regulatory authorities, as required. 
11.4 
Informed Consent Form 
Eligible patients may only be enrolled in the study after providing the written informed 
consent (witnessed, whenever required by law or regulation), approved by the REC or, if 
unable to do it, after this consent is provided by the patient’s legally acceptable representative. 


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In cases in which the patient’s representative provides the consent, the patient must be 
informed about the study as far as possible, considering his/her understanding. If the patient is 
able to understand, he/she must indicate his/her consent by personally signing and dating the 
written informed consent form or a separate consent form. The informed consent must be 
obtained before the performance of any study-specific procedures (i.e., all procedures 
described in the protocol). The process of obtaining the informed consent must be 
documented in the patient’s source-documents. 
Novartis will provide the investigators, in a separate document, with a proposed informed 
consent form following ICH GCP guidelines and regulatory requirements and considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be approved by Novartis before submission to the REC, and a copy of the 
approved version must be provided to the Novartis monitor after approval by the REC. 
Women of childbearing potential must be informed that the use of the study drug may involve 
unknown risks to the fetus in case of pregnancy during the study, and must agree that, in order 
to participate in the study, they must meet the contraceptive requirement throughout the study. 
In case of any doubt that the patient will reliably comply with the treatment, he/she must not 
be enrolled in the study. 
11.5 
Protocol amendments 
Any change or addition to the protocol may be performed only by means of a written protocol 
amendment, which must be approved by Novartis, Health Authorities, whenever required, and 
by the REC. Only amendments required for the safety of patients may be implemented before 
approval by the REC. In spite of the need for formal approval for protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
enrolled in this study, even if this action represents a protocol deviation. In such cases, 
Novartis must be notified about such action and the REC of the study site must be informed 
within 10 business days. 
11.5.1 
History of amendments 
Amendment 1 extends the treatment schedule for patients from week 24 to week 96. 
For the purpose of a reference for long-term safety and efficacy evaluation of pasireotide LAR 
treatment, patients benefiting from the treatment with this medication according to the 
evaluation by the physician in charge will be offered the opportunity to enter a 72-week 
extension period. 
 Protocol amendment 2 includes additional liver safety measurements as a result of an 
internal medical review of the pasireotide studies, on visits Core - V3 (D20), V4 
(D28), V4L (D48), and V5 (D56); 
 Extension – E2 (D28), E3 (D48), E4 (D56), E4L (D76), and E5 (D84). 
 


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Protocol No. CSOM230D2401 
 
11.6 
Discontinuation of the study 
Participation in this study is voluntary. Research subjects may withdraw their consent. The 
investigator may discontinue the participation of any research subject in this study, at any 
time, if considered as in his/her best interest. 
Novartis Biociências S. A. may discontinue the study at any time, if anything that might 
compromise the safety of research subjects is found. If this happens, the Hospital Ethics 
Committee must approve the reasons prior to discontinuation. 
11.7 
Supply and new supply, storage of the drug, and traceability / 
accountability of the study drug 
Study drugs must be received by a designee at the study site, handled and stored safely and 
appropriately, and kept in a safe place, with access restricted only to the investigator and 
his/her designees. Upon receipt, pasireotide LAR must be stored according to the instructions 
specified in the drugs labels. Clinical supplies must be dispensed only according to the 
protocol. 
Medication labels will be written in local language and will follow Brazilian legal 
requirements. These labels will include the storage conditions for the drug, but not 
information on the patient. 
The investigator must keep an accurate record of the shipment and dispensing of the study 
drug in a drug accountability log. Drug accountability will be observed by the field monitor 
during visits to the site and upon completion of the study. The site staff will be asked to return 
all unused study drug and packages at the end of the study or at the time of discontinuation of 
the study drug. 
At the end of the study and as appropriate throughout the study, the investigator will return all 
study drug, packages, drug labels used and unused, and a copy of the completed drug 
accountability log, to the Novartis monitor or to the Novartis address provided in the 
investigator’s binder at each site. 
12 
Protocol compliance 
The investigators agree to dedicate due diligence to avoid protocol deviations. The 
investigator must not, under any circumstances, contact Novartis or its representatives, if any, 
monitoring the study to request approval for a protocol deviation, as no authorized deviation 
is allowed. If the investigator considers that a protocol deviation would improve the study 
conduction, it must be considered as a protocol amendment and, unless this amendment is 
agreed upon by Novartis and approved by the REC, it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the eCSR. 
 


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13 
Publication policy 
Any formal presentation or publication of the study data will be considered as a joint 
publication by the investigator(s) and Novartis team. Authorship will be determined by 
mutual agreement, based on the number of patients enrolled. For multicenter studies, it is 
mandatory that the first publication be based on data from all sites, analyzed as established in 
the protocol by Novartis statisticians, and not by the investigators. 
The investigators participating in multicenter studies agree not to submit data from one site or 
small groups of sites before complete publication, unless formally approved by all 
investigators and Novartis. 
Novartis must receive copies of any communication before publication (at least 20 business 
days for abstracts and oral presentations and 45 business days for submission to journals). 
Novartis will review the communications for accuracy (thus avoiding potential discrepancies 
regarding the submission to health authorities), verify that confidential information is not 
unadvertedly disclosed, and provide any relevant supplementary information. 
The investigator may be asked to sign the clinical study report, if required to be used in a 
registration submission to health authorities in some countries. For multicenter studies, only 
the principal investigator appointed by Novartis at the beginning of the study must provide 
any signature required. 
 
14 
References (available upon request) 
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Neurol India, vol. 51, p. 461-465. 


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SAP_001.pdf: 
 
 
 
An Open-Label, Single Arm, Phase II Study to 
Evaluate the Efficacy and Safety of Pasireotide 
LAR on the Treatment of Patients with Clinically 
Non-Functioning Pituitary Adenomas 
 
 
STATISTICAL ANALYSIS PLAN 
Version No. 1, 14th February 2017 
 
 
 
PROTOCOL: CSOM230D2401  
STUDY DRUG: Pasireotida LAR (SOM 230) 
 
 
 
Performed by: 
 
 
 
 
 
Prepared for: 
NOVARTIS BIOCIÊNCIAS S.A. 
  
  
  
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 2 of 120 
STATISTICAL ANALYSIS PLAN (SAP) 
STUDY TITLE: An Open-Label, Single Arm, Phase II Study to Evaluate the Efficacy and Safety of 
Pasireotide LAR on the Treatment of Patients with Clinically Non-Functioning Pituitary Adenomas 
PROTOCOLO No.: CSOM230D2401 / NCT01283542 
PROTOCOL VERSION: Version No. 2.00 
PROTOCOL DATE: 26-03-2012 
SAP prepared by: 
_____________________________________ 
__________/________/___________ 
 
 dd/mmm/yyyy 
 
 
SAP reviewed by: 
_____________________________________ 
__________/________/___________ 
 
 
 dd/mmm/yyyy 
 
 
SAP reviewed and approved by: 
_____________________________________ 
__________/________/___________ 
  
 dd/mmm/yyyy 
  
NOVARTIS BIOCIÊNCIAS S.A. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 3 of 120 
 
Table of contents 
 
Table of contents .................................................................................................................................................... 3 
Index of tables ........................................................................................................................................................ 4 
1 
Objectives ....................................................................................................................................................... 6 
1.1 
Primary objective .................................................................................................................................. 6 
1.1.1 
End-point for primary objective........................................................................................................ 6 
1.2 
Secondary objectives ............................................................................................................................ 6 
1.2.1 
End-points for secondary objectives ................................................................................................ 6 
 
 7 
 
 7 
2 
Study design.................................................................................................................................................... 8 
3 
Population .................................................................................................................................................... 10 
3.1 
Inclusion/exclusion criteria ................................................................................................................. 10 
3.1.1 
Inclusion criteria ............................................................................................................................. 10 
3.1.2 
Exclusion criteria ............................................................................................................................. 10 
4 
Visit schedule and assessments .................................................................................................................... 13 
5 
Statistical methods and data analysis ........................................................................................................... 21 
5.1 
Populations for analysis ...................................................................................................................... 21 
5.2 
Patient demographics/other baseline characteristics ........................................................................ 21 
5.3 
Treatments (study drug, concomitant therapies, compliance) ........................................................... 22 
5.4 
Primary objective ................................................................................................................................ 22 
5.4.1 
Variable ........................................................................................................................................... 22 
5.4.2 
Statistical Analysis ........................................................................................................................... 22 
5.4.3 
Handling of missing values/censoring/discontinuations ................................................................ 22 
5.4.4 
Supportive analyses ........................................................................................................................ 22 
5.5 
Secondary objectives .......................................................................................................................... 23 
5.5.1 
Efficacy variables and analysis ........................................................................................................ 23 
 
 24 
5.5.3 
Safety parameters and analyses ..................................................................................................... 24 
5.5.4 
Tolerability ...................................................................................................................................... 25 
5.6 
Sample size rational ............................................................................................................................ 25 
6 
Study Results ................................................................................................................................................ 26 
7 
Clarifications to the study protocol .............................................................................................................. 27 
Appendix 1: Statistical Tables – Core study phase ............................................................................................... 28 
Appendix 2: Statistical Tables – Extension study .................................................................................................. 85 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 4 of 120 
 
Index of tables 
Table 1 – Patients’ disposition .............................................................................................................................. 28 
Table 2 – Demographics – FAS population ........................................................................................................... 29 
Table 3 – Medical history – FAS population ......................................................................................................... 30 
Table 4 – Concomitant medication ....................................................................................................................... 31 
Table 5 – HbA1c, fasting blood insulin and glucose at visit 1 – FAS population ................................................... 32 
Table 6 – Treatment – FAS population ................................................................................................................. 33 
Table 7 – Magnetic resonance imaging – FAS population .................................................................................... 34 
Table 8 – Time to response – FAS population ...................................................................................................... 35 
Table 9 – Time to response by gender – FAS population ..................................................................................... 36 
Table 10 – Disease-related symptoms – FAS population ...................................................................................... 37 
Table 11 – 
 Alpha-subunit – FAS population ....................................................................... 40 
 42 
Table 13 – Visual field – FAS population ............................................................................................................... 43 
Table 14 – Gallblader ultrasound – FAS population ............................................................................................. 45 
Table 15 – Treatment-emergent adverse events and serious adverse events – Safety population .................... 46 
Table 16 – Incidence of treatment-emergent adverse events – Safety population ............................................. 47 
Table 17 – Incidence of serious treatment-emergent adverse events – Safety population ................................. 48 
Table 18 – Incidence of treatment-emergent adverse events with suspected relationship with study drug – Safety 
population ............................................................................................................................................................ 49 
Table 19 – Incidence of serious treatment-emergent adverse events with suspected relationship with study drug 
– Safety population ............................................................................................................................................... 50 
Table 20 – treatment-emergent adverse events – Safety population .................................................................. 51 
Table 21 – Serious treatment-emergent adverse events – Safety population ..................................................... 52 
Table 22 – Treatment-emergent adverse events with suspected relationship with study drug – Safety population
 .............................................................................................................................................................................. 53 
Table 23 – Serious treatment-emergent adverse events with suspected relationship with study drug – Safety 
population ............................................................................................................................................................ 54 
Table 24 – Hematology – Safety population ......................................................................................................... 55 
Table 25 – Coagulation – Safety population ......................................................................................................... 59 
Table 26 – Urinalysis – Safety population ............................................................................................................. 61 
Table 27 – Biochemistry – Safety population ....................................................................................................... 64 
Table 28 – Tests for liver function – Safety population ........................................................................................ 71 
Table 29 – Serology – Safety population .............................................................................................................. 74 
Table 30 – Hormonal evaluation – Safety population .......................................................................................... 75 
Table 31 – Hormonal evaluation associations – FAS population .......................................................................... 79 
Table 32 – Vital signs – Safety population ............................................................................................................ 80 


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Table 33 – Physical examination – Safety population .......................................................................................... 81 
Table 34 – Eastern cooperative oncology group performance status – Safety population ................................. 82 
Table 35 – Electrocardiogram – Safety population .............................................................................................. 83 
 
 
Table B 1 – Patients’ disposition – extension study.............................................................................................. 85 
Table B 2 – Concomitant medication – extension study – FAS population .......................................................... 86 
Table B 3 – Treatment – extension study – FAS population ................................................................................. 87 
Table B 4 – Magnetic resonance imaging – FAS population ................................................................................. 88 
Table B 5 – Disease-related symptoms – FAS population..................................................................................... 89 
Table B 6 –
 Alpha-subunit – FAS population ...................................................................... 90 
Table B 7 – Visual field – FAS population .............................................................................................................. 91 
Table B 8 – Gallblader ultrasound – FAS population ............................................................................................ 92 
Table B 9 – Adverse events and serious adverse events in the extension study – Safety population ................. 93 
Table B 10 – Incidence of adverse events in the extension study – Safety population ........................................ 94 
Table B 11 – Incidence of serious adverse events in the extension study – Safety population ........................... 95 
Table B 12 – Incidence of serious adverse events with suspected relationship with study drug in the extension 
study – Safety population ..................................................................................................................................... 96 
Table B 13 – Incidence of serious adverse events with suspected relationship with study drug in the extension 
study – Safety population ..................................................................................................................................... 97 
Table B 14 – Adverse events in the extension study – Safety population ............................................................ 98 
Table B 15 – Serious adverse events in the extension study – Safety population ................................................ 99 
Table B 16 – Adverse events with suspected relationship with study drug in the extension study – Safety 
population .......................................................................................................................................................... 100 
Table B 17 – Serious adverse events with suspected relationship with study drug in the extension study – Safety 
population .......................................................................................................................................................... 101 
Table B 18 – Hematology – Safety population ................................................................................................... 102 
Table B 19 – Coagulation – Safety population .................................................................................................... 105 
Table B 20 – Urinalysis – Safety population ........................................................................................................ 106 
Table B 21 – Biochemistry – Safety population .................................................................................................. 108 
Table B 22 – Tests for liver function – Safety population ................................................................................... 112 
Table B 23 – Hormonal evaluation – Safety population ..................................................................................... 114 
Table B 24 – Vital signs – Safety population ....................................................................................................... 117 
Table B 25 – Physical examination – Safety population ..................................................................................... 118 
Table B 26 – Eastern cooperative oncology group performance status – Safety population ............................ 119 
Table B 27 – Electrocardiogram – Safety population ......................................................................................... 120 
 
 


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1 Objectives 
1.1 PRIMARY OBJECTIVE 
To evaluate the effect of pasireotide LAR on the proportion of patients with clinically non-functioning pituitary 
adenomas (NFPAs) who achieve treatment response. 
1.1.1 
End-point for primary objective 
Proportion of patients with NFPA who achieve tumor volume reduction of at least 20% after 24-week treatment 
with pasireotide LAR. 
 
1.2 SECONDARY OBJECTIVES 
 
To assess the effect of pasireotide LAR on the mean change of tumor volume from baseline to Week 4, 
12, 24, 48, 72 and 96. 
 
To assess the effect of pasireotide LAR on the percentage change of tumor volume from baseline to 
Week 4, 12, 24, 48, 72 and 96. 
 
To assess the effect of pasireotide LAR on the proportion of patients achieving tumor volume reduction 
of at least >20% after 4 and 12, 48, 72 and 96 weeks of treatment. 
 
To assess the effect of pasireotide LAR on the time to tumor response. 
 
To assess the effect of pasireotide LAR on the disease-related symptoms* 
 
*Disease-related symptoms to be evaluated: headache, visual disturbances, fatigue, decreased libido, 
erectile dysfunction (for males only), irregular or stopped menses (for not post-menopausal female 
only). 
 
 
To evaluate the effect of pasireotide LAR on pituitary function at Weeks 4, 12, 24, 48, 72 and 96. 
 
To evaluate the effect of pasireotide LAR on alpha subunit levels at Weeks 4, 12, 24, 48, 72 and 96. 
 
To evaluate the overall safety and tolerability of pasireotide LAR. 
 
For extension phase: duration of response for patients considered responsive (i.e., patients who 
achieved a tumor volume reduction of at least 20% with respect the initial tumor volume). 
 
To assess the percentage of patients that remain with tumor volume stable during the study. 
 
1.2.1 
End-points for secondary objectives 
The secondary variables are: 
 
Mean change of tumor volume assessed by pituitary MRI from baseline to Week 4, 12, 24, 48, 72 and 
96. 


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 
Percent change of tumor volume assessed by pituitary MRI from baseline to Week 4, 12, 24, 48, 72 and 
96. 
 
Proportion of patients achieving tumor volume reduction of at least > 20% after 4, 12, 48, 72 and 96 
weeks of treatment. 
 
Time to treatment response for treatment responders, defined as the time from the date of first 
injection to the first evaluation the patient achieves tumor volume reduction of at least >20%. 
 
Change from baseline to Week 4, 12, 24, 48, 72 and 96 in disease-related symptoms scores. 
 
Incidence of pituitary hormonal dysfunction at baseline and at Weeks 4, 12, 24, 48, 72 and 96. 
 
Proportion of patients achieving alpha subunit reduction of at least 50% at Weeks 4, 12, 24, 48, 72 and 
96. 
 
Proportion of patients achieving normalization of alpha subunit at Weeks 4, 12, 24, 48, 72 and 96. 
 
Percentage of CTC (≥3) adverse events during treatment with pasireotide LAR. 
 
Percentage of patients with at least one adverse event with CTC grade ≥ 3. 
 
Incidence of all adverse events, incidence of laboratory abnormal values and summary of laboratory 
assessments. 
 
For extension phase: among patients who had been considered as responsive (i.e., patients who 
achieved a reduction in tumor volume of at least 20% with respect to the initial tumor volume), assess 
the number and proportion of patients that remained responsive during the treatment period of 
extension phase (according to estimates by magnetic resonance at weeks 48, 72 and 96). 
 
To assess the percentage of patients who remained with tumor volume stable during the study, i.e. 
patients who maintained tumor volume with variation less than 20% with respect to the basal tumor 
volume (according to evaluations by magnetic resonance imaging at weeks 24, 48, 72 and 96). 
 
If applicable, assessing whether there was difference in response between patients using dose of 40 
and 60 mg of pasireotide LAR. 
 


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2 Study design 
This is a prospective, multicenter, open-label, single arm, phase II study to evaluate the efficacy and safety of 
pasireotide LAR in adult patients with NFPA. 
 
Eligible patients will receive pasireotide LAR 60 mg every 28 ± 3 days for 24 weeks, during the Core Phase of the 
study. The study is complimented by an extension. As per treating physician' discretion, patients who have 
benefited from the treatment with pasireotide LAR can enter an Extension Phase where they will continue to 
receive pasireotide LAR 60 mg at 4-week (± 3 days) intervals for up to 2 years or until pasireotide or other 
effective therapy becomes commercially available or until clinical benefit is noted (whichever comes first). Dose 
reductions to 40 mg will be permitted based on safety issues. In case of rapid deterioration of the visual field or 
sudden visual loss, the patient will be discontinued from the study. 
 
During the Core Phase of the study, visits will be performed every 28±3 days. There will be two extra visits: Visit 
3 and Visit 6. 
 
The design of the study and a schematic of the Core Phase and Extension Phase are presented in Figure 1 and 
Figure 2, respectively. 
 
Figure 1  Schematic of the Pasireotide LAR Study of NFPA: Core Phase 
 
 
 
 
 
 


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Figure 2 Schematic of the Pasireotide LAR Study of NFPA: Core Phase 
 
*Details of efficacy and safety evaluation, presented in Table A1. 
 


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3 Population 
The population for this study is adult patients with a diagnosis of NFPA who have not undergone any prior 
therapy (treatment-naïve) for the disease. As tumor volume changes are difficult to be evaluated in 
microadenomas and also because they may be misdiagnosed with incidentalomas, only patients with 
macroadenomas (≥ 1 cm) will be included. A total of 23 patients in 10-13 centers will be enrolled in this single-
arm open-label study. 
 
3.1 INCLUSION/EXCLUSION CRITERIA 
The investigator or his/her designee must ensure that all patients who meet the following inclusion and 
exclusion criteria are offered enrollment in the study. 
3.1.1 
Inclusion criteria 
1. Male or female patients ≥ 18 years. 
2. Patients with clinically non-functioning pituitary macroadenomas ≥ 1 cm. 
3. No previous treatment for NFPA. 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
5. Written informed consent obtained prior to any screening procedures. 
3.1.2 
Exclusion criteria 
1. Patients who require a surgical intervention for relief of any sign or symptom associated with tumor 
compression. 
2. Previous pituitary surgery. 
3. Previous medical treatment for pituitary tumor. 
4. Patients who have received pituitary irradiation within 10 years prior to inclusion visit (Visit 2). 
5. Prolactin (PRL) levels > 100 ng/mL. (PRL evaluation should be performed with diluted samples to make sure 
to avoid the “hook effect.”). 
6. Patients with compression of the optic chiasm causing acute clinically significant visual field defects. 
7. Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%. Diabetic patients 
whose blood glucose is poorly controlled as evidenced by HbA1C >8%. Patients with a known history of 
impaired fasting glucose or diabetes mellitus with HbA1c <8% may be included; however, blood glucose 
and anti diabetic treatment must be monitored closely throughout the trial and adjusted as necessary. 
8. Patients with known disease of the bile duct or gallbladder, acute or chronic pancreatitis (patients with 
asymptomatic cholelithiasis and asymptomatic dilatation of the bile duct may be included). 
9. Patients with abnormal coagulation (PT and/or APTT elevated by 30% above normal limits) or patients 
receiving anticoagulants that affect PT (prothrombin time) or APTT (activated partial thromboplastin time). 
10. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular 
tachycardia, ventricular fibrillation, advanced heart block or a history of acute myocardial infarction within 
the 24 weeks preceding enrolment visit (Visit 2). 


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11. Screening (Visit 1) or baseline (predose, Visit 2) QTcF > 450 msec. 
12. History of syncope or family history of idiopathic sudden death. 
13. Sustained or clinically significant cardiac arrhythmias. 
14. Risk factors for Torsades de Pointes such as uncorrected hypokalemia, uncorrected hypomagnesemia, 
cardiac failure, clinically significant/symptomatic bradycardia or high grade AV block. 
15. Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy (caused by 
diabetes or Parkinson’s disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure. 
16. Patients who are taking medication(s) known to increase the QT interval. 
17. Patients with liver disease such as cirrhosis, chronic active B or C hepatitis or chronic persistent hepatitis, 
or patients with ALT and/or AST more than 2 x ULN, serum bilirubin > 1.5 ULN, serum albumin < 0.67 x LLN. 
18. Patients with serum creatinine > 2.0 x ULN 
19. Patients with WBC <3 x 109/L; Hgb < 90% LLN; PLT <100 x 109/L. 
20. Patients with any current or prior medical condition that, in the judgment of the investigator may interfere 
with the conduct of the study or the evaluation of the study results. 
21. History of immunocompromise, including a positive HIV test result (ELISA and Western blot). A HIV test will 
not be required; however, previous medical history will be reviewed. 
22. Known hypersensitivity to somatostatin analogues or any other component of the pasireotide LAR. 
23. Patients with active malignant disease within the last five years (with the exception of basal cell carcinoma 
or carcinoma in situ of the cervix)  
24. Patients with the presence of active or suspected acute or chronic uncontrolled infection  
25. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a 
medically acceptable method of birth control. If a woman is participating in the trial then one form of 
contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is 
used in addition to condoms, the patient must have been practicing this method for at least two months 
prior to the enrollment and must agree to continue the oral contraceptive throughout the course of the 
study and for 3 months after the study has ended. Male patients who are sexually active are required to 
use condoms during the study and for three month afterwards as a precautionary measure (available data 
do not suggest any increased reproductive risk with the study drugs)  
26. Participants in investigational drug study 30 days before enrolment visit (Visit 2). Patients must have 
recovered from all side effects of other investigational therapy.  
27. History of non-compliance to medical regimens, or patient who is considered potentially unreliable, or any 
circumstance at the time of study inclusion that would preclude completion of the entire study or the 
required follow up . 
28. Patients who have a history of alcohol or drug abuse in the 12 month period prior to Visit 1 (Screening).  
29. Presence of the surface antigen of hepatitis B (HBsAg). 
30. Presence of the antibody test for hepatitis C virus (anti- HCV). 
31. Patients who have undergone major surgery/surgical therapy for any cause within 4 weeks prior to 
randomization.  
32. Patients with confirmed hypothyroidism, hypoadrenalism, and hypogonadism (except physiologic 
menopause and andropause), unless they are adequately treated with stable doses of hormone 
replacement therapy for a minimum of 3 months prior to study entry . 
33. Patients in use of growth hormone replacement . 
34. Uncontrolled cardiovascular, kidney, or metabolic disorders. 
35. Serious neurologic or psychiatric disorders. 


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36. Contraindication to MRI such as (but not limited to): cerebral aneurysm clips, cardiac pacemaker, retained 
cardiac pacemaker wire and temporary pacemaker, cochlear implants, hearing aids that contain internal 
and non-removable parts, Swan-Ganz catheter, aortic balloon, aortic prosthesis type Zenith AAA 
Endovascular Graft, other possible contraindications related to ferromagnetic material identified in the 
patient interview. 
 


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4 Visit schedule and assessments  
Table A 1 and Table A 2 list all of the assessments for the Core Phase and Extension Phase, respectively, and 
indicates with an “X” the visits when they will be performed. All data obtained from these assessments must be 
supported in the patient’s source documentation. The table indicates which data are entered into the database 
(D) or remain in source documents only (S). Assessments that generate data for database entry and which are 
recorded on eCRFs are listed using the eCRF name.   
 
 
 


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Page 14 of 120 
 
Table A 1:  Visit Schedule and Assessments for Core Study 
Visit number 
1 
2 
3 
4 
V401E 
48 
5 
6 
7 
8 
9 
10 
11 
TDE3 
FU Visit 
Days1 
Day   
-28 to -
1  
Day 0 
Day 20 
Day 28 
Day 48 
Day 56 
Day 76 
Day 84 
Day 112 
Day 140 
Day 168 
Day 196 
Week of treatment 
 
Enrolment 
 Week 3  
Week 4  
Week 7 
Week 8 
Week 11 
Week 12 
Week 16 
Week 20 
Week 24 
Week28 
 
Screening2 
Baseline/ 
Injection  1 
Safety 
only 
Injection 
2 
Safety 
only 
Injection 
3 
Safety 
only 
Injection 
4 
Injection 
5 
Injection 
6 
Injection 
7# (if 
patient will 
join 
the 
Extension 
Phase) 
Safety FU 
Informed consent (S) 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography (D) 
X 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of disease (D) 
X 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history/ current medical conditions (D) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria check (S) 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (D) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (S) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Height (D) 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight (D) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom assessment/ Disease-related symptoms 4 (D) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status (D) 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECG 14 (D) 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 5,6 
X 
 
 
 
 
 
 
X 
 
 
X 
Hematology (BD) 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Coagulation parameter PT (D) 
X 
X 
X14 
X14 
X14 
X14 
X 
 
 
 
X 
 
Coagulation parameter APTT (D) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Urinalysis 6 
(D) 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
Fasting Blood Glucose, Insulin 6 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 6 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Biochemistry 6,8 (D) 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
LFTs (ALT, AST, total bilirubin, albumin, ALP, γ-GT) (D) 
X 
X 
X14 
X14 
X14 
X14 
X 
 
 
 
X 
 
Hbs-Ag and anit-HCV (D) 
X 
 
 
 
 
 
 
 
 
 
 
 


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# Pasireotide dose on this visit will be administered to selected patients, as per physician discretion, if the patient will be included in the Extension Phase based on response 
assessed by investigator/ benefit with the drug. 
1 Will be allowed a window of ± 3 days for the planned visitsand assessments, unless otherwise specified. 
2 It will be allowed a window of ± 3 days for the planned visits and assessments, unless indicated otherwise.  
3 To be completed prior to study drug administration  
4 To be completed if the patient discontinues prematurely or at study completion.  
5 Disease related symptoms that will be evaluated: headache, visual disturbances, fatigue, decreased libido, erectile dysfunction (for males only), irregular or stopped menses 
(for not post-menopausal female only). The investigator will also ask the patient to score the symptoms according to a five-point score scale (0=absent, 1=mild, 2=moderate, 
3=severe, 4=very severe). The others will be assessed as present or absent.  
Vitamin B12, folic acid 6 
X 
 
 
 
 
 
 
 
 
 
X 
 
Hormonal evaluation 6, 9 (D) 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
Alpha subunit evaluation 6 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
Visual field (camp) evaluation 10 (D) 
X 
X10 
 
X 
 
X 
 
X 
X 
X 
X 
 
Gallbladder ultrasound (D) 15 
X 
 
 
 
 
 
 
 
 
 
X 
 
Pituitary MRI / Sella turcica15 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
Adverse events (D) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pasireotide LAR administration (D) 
 
X 
 
X 
 
X 
 
X 
X 
X 
X# 
 
Prior/Concomitant medications 11 (D)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study completion13  (D) 
 
 
 
 
 
 
 
 
 
 
 
X13 


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6 Serum pregnancy test will be performed in the final follow-up visit if patient report menstrual delay or as per physician discretion. 
7 Blood and urine to be collected prior to study drug administration. Pts should be fasting for 12 hours. 
8 Hematology and Coagulation include: Hemoglobin, hematocrit (HCT), WBC count with differential, RBC Count with differential and platelet count; PT and APTT. 
9Complete biochemistry includes: total cholesterol, low density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, calcium, phosphorus, 
chloride, sodium, potassium, inorganic phosphorus,  creatinine, urea/BUN, uric acid, CPK, LDH, alkaline phosphatase, -GT, total protein, albumin, SGOT, SGPT, total bilirubin. 
If the total bilirubin concentration is increased above 2.0 times the upper normal limit, total bilirubin should be differentiated into the direct and indirect reacting bilirubin 
at visits. 
10 Hormonal evaluation (serum)—pituitary disease assessments: testosterone (for male), estradiol (for female), prolactin, free T4, TSH, LH, FSH, GH, IGF-I, cortisol, ACTH, a-
subunit. If the evaluation of the visual field in the selection is performed within 14 days prior to Visit 2, it can be considered as the baseline and there is no need to repeat it 
for Visit 2. 
11 Assess with standard automated perimetry (SAP). It is suggested Humphrey Field Analyzer. The window to perform SAP should be no more than 7 days before the scheduled 
visit. 
12 Prior and concomitant medication cover any therapy including chemotherapy, radiotherapy and surgery or medication received in past or ongoing treatment. 
13 All medications/therapies used to treat the tumor/symptoms under this study given to a patient ≤ 4 weeks after the last dose of study treatment must be recorded in the 
e-CRF. All patients will be followed for safety for 56 days from the last dose of study medication. 
14 The safety follow-up has to be performed 56 ± 3 days after the patient received the last pasireotide LAR dose. For patients continuing into the extension study this visit will 
not be performed after the end of the main study but 56 ± 3 days after the patient has finished extension study.  
15 ECG will be performed prior to the drug administration. In Visit 3 (Day 20) and Visit 6 (Day 76), ECG will be done independent of drug administration. 
16 The window to perform MRI and gallbladder US should be no more than 7 days before the scheduled visit. 
17 If patient will not be assigned for Extension Phase, follow-up visit will be Visit 11. 
 


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Draft No.1, 23rd January 2015 
 
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Table A 2:  Visit Schedule and assessments for extension study 
Visit 
101 
11 
12 
402 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
TDE 
29 
FU9 
Week 
24 
28 
32 
35 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
Last dose + 8 weeks 
 
Day 
168 
196 
224 
244 
252 
280 
308 
336 
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
700 
Injection 
7 
8 
9 
 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
 
 
Adverse events (D) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current medical conditions (D) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital signs (D) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Physical exam (S) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Weight (D) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
MRI / sella turcica 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Alpha subunit 2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
ECG (D) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Gallbladder ultrasound (D) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG Performance status  (D) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Symptom assessment/ 
Disease related symptoms (D) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Serum pregnancy test 2,10 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Hematology (D) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Coagulation parameter PT (D) 
XE 
XK 
XK 
 
X 
XK 
XK 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulation parameter APTT 
(D) 
XE 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis2 (D) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 


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Fasting blood glucose  and 
insulin 2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
HbA1c2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Biochemestry2,4 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
LFTs (ALT, AST, total bilirubin, 
albumin, ALP, γ-GT) (D) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Hormonal evaluation2,5(D) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Visual field evaluation6 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Vitamin B12, folic acid 2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pariseotide LAR Admin7 (D) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Prior/Concomitant Meds8 (D) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study completition9 (D) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 Patients will be invited to participate in the extension phase, according to the opinion of the treating physician, if they are benefiting from treatment with pasireotide LAR 
2 Blood and urine to be collected prior to study drug administration. Patients should be fasting for 12 hours.  
3 Hematology and coagulation include: hemoglobin, hematocrit (Hct), WBC count with differential, RBC count with differential and platelet count, PT, and APTT.  
4 Complete biochemistry includes: total bilirubin, total cholesterol, LDL, HDL, triglycerides, creatinine, urea, uric acid, -GT, total protein, albumin, AST, ALT, CPK, LDH alkaline 
phosphatase , sodium, potassium , inorganic phosphorus , and calcium chloride. If the total bilirubin concentration is increased above 2.0 times the upper normal limit, total 
bilirubin should be differentiated into the direct and indirect reacting bilirubin. 
 5 Hormonal evaluation (serum)—pituitary disease assessments: testosterone (for male), estradiol (for female), prolactin, free T4, TSH, LH, FSH, GH, IGF-1, cortisol, ACTH. 
6 Assess with standard automated perimetry (SAP). It is suggested Humphrey Field Analyzer. The window to perform SAP should be no more than 7 days before the scheduled 
visit. 
7 Patients will continue to receive pasireotide LAR i.m. every 28 (± 3) days. The drug administration will be performed by a health care professional in the site. The last dose 
administration is in Week 92 (Visit 27).  
8 All medications/therapies used to treat the tumor/symptoms under this study given to a patient ≤ 4 weeks after the last dose of study treatment must be recorded in the 
eCRF. All patients will be followed for safety for 56 ± 3 days days from the last dose of study medication.  


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9 The safety follow-up visit (Visit 29) has to be performed 56 ± 3 days after the patient received the last pasireotide LAR dose.  
10 Serum pregnancy test will be performed in the final follow-up visit if patient report menstrual delay or as per physician discretion 
.


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5 Statistical methods and data analysis  
The following sections describe the analyses to be conducted.   
For the Core Period of the study, efficacy and safety analyses will be conducted on the data collected by the 
time when all the enrolled patients have completed their EOS Visit. All the formal safety follow-up data of those 
patients who did not enter the extension study will also be included in the core study safety analyses. A final 
analysis will be completed when all the patients in the Extension complete their last visit and will be reported 
in either an additional clinical study report or in an addendum to the core study report.  
Other additional data prior to the end of the Core Phase of the trial will be analyzed and then summarized in an 
additional report of clinical study or in a major study report. 
Novartis or designated CRO will analyze all data using the SAS System for data analysis 9.4 . Any data analyses 
carried out independently by an investigator should be submitted to Novartis before publication or 
presentation.  
The data from all centers participating in the trial will be combined, so that an adequate number of patients will 
be available for analysis. The statistical analysis methods described in this section will focus on the analysis of 
the data in the core study. Similar methods will be applied to the analyses in the Extension Phase as appropriate. 
 
5.1 POPULATIONS FOR ANALYSIS  
Full analysis set (FAS): consists of all patients who successfully completed the screening and have received at 
least one dose of study medication. FAS will be the primary set for all efficacy analyses. 
 
Safety analysis set: consists of all patients who received at least one dose of study drug and had at least one 
post-baseline safety assessment.  
Note the statement that a patient had no AEs (on the Adverse Event e-CRF) constitutes a safety assessment. 
The safety set will be used for all safety analyses.  
 
The analyzes presented in this section represent the analyzes that will be used for the Core Phase of the trial. A 
final analysis will be performed when all patients of Extension Phase completed their last visit and will be 
reported or as additional clinical study report or as an addendum to the Core Phase of the trial report. 
 
5.2 PATIENT DEMOGRAPHICS/OTHER BASELINE CHARACTERISTICS  
Demographic and other baseline data including disease characteristics (e.g., age, sex, and race) will be 
summarized descriptively based on FAS. Categorical data will be presented as frequencies and percentages. For 
continuous data, mean, standard deviation, median, minimum, and maximum will be presented. 


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5.3 TREATMENTS (STUDY DRUG, CONCOMITANT THERAPIES, COMPLIANCE)  
The duration of exposure to the study drug, number of patients with dose adjustment (i.e., interruptions, dose 
changes) and dose intensity will be summarized based on FAS for core and extension period of the study. 
 
Concomitant medications and significant non-drug therapies prior to and after the start of the study drug will 
be summarized by preferred terms according to the ATC class of the WHO Drug Reference List. 
 
5.4 PRIMARY OBJECTIVE  
The primary objective is to assess the efficacy of pasireotide LAR in NFPA based on tumor volume reduction.  
5.4.1 
Variable  
The primary efficacy variable is the proportion of patients with NFPA who achieve tumor volume reduction of 
at least 20% after Week 24 of treatment with pasireotide LAR.   
5.4.2 
Statistical Analysis  
Proportion of patients with at least 20% of reduction in tumor volume will be summarized in terms of incidence 
rates and exact 90% confidence interval at end of core period of the study for FAS population (Week 24).  
5.4.3 
Handling of missing values/censoring/discontinuations  
A patient whose tumor volume assessment at baseline (Visit 1) is missing will not be considered for the efficacy 
assessments. Only those patients will be considered for analysis for which baseline and at least one post baseline 
records are reflecting non missing values.  All the analysis will be performed with as observed data i.e. the 
primary analysis (Week 24) will be based on only patients that have both baseline and Week 24 tumor volume 
assessment.   
The analysis of the primary endpoint will be based on observed cases since the patients population is naive 
(including not having any surgery) and it is expected that 24 weeks of treatment is needed before meaningful 
effect are assessed.  
5.4.4 
Supportive analyses 
A sensitivity analysis will be performed on primary efficacy endpoint after imputing the week 24 missing values 
by last observed carried forward (LOCF) technique, for patients having baseline and at least one post baseline 
value.  
 


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5.5 SECONDARY OBJECTIVES  
Population for the analysis 
All secondary efficacy analyses will be based on the full analysis set (FAS). For all safety analyses, the safety 
analysis set will be used. 
5.5.1 
Efficacy variables and analysis 
The secondary efficacy endpoints are described in section 1.2.1.  
The mean and percent change in tumor volume from baseline to Week 4, 12 and 24 will be presented along 
with the 90% confidence interval (CI). If data is found to be skewed, CIs for median will also be generated. 
Incidence rates for patients with ≥ 20% reduction in tumor volume and its exact CI will be reported at Week 4 
and 12. 
 
Summary statistics will be provided for each disease related symptoms (headaches, visual disturbance, fatigue, 
symptoms specific to man and woman) at each visits. Change from baseline scores will be also summarized at 
each visit for all symptoms. 
 
Time to response, defined as time from the first injection to first evaluation where patient achieve tumor volume 
reduction of at least ≥ 20%, will be listed for all patients. If a patient has not achieved tumor response, the time 
of last assessment will be indicated as censoring time.   
Kaplan-Meier analysis will be performed for time to response aiming to compute the median time to response 
and corresponding 95% confidence interval. Cox regression exploratory analysis will be used to estimate the 
hazard ratio with corresponding 95% confidence intervals for time to tumor volume reduction of at least ≥ 20% 
as a function of baseline characteristics (duration of disease, dose at V2, dose reduction, visual field 
(abnormal/normal), 
 and α subunit at V1). 
Logistic regression will be performed to explore association between baseline characteristics and tumor 
response. 
Frequency and percentage of patients who present improvement of symptoms related to tumor compression, 
pituitary hormonal dysfunction, alpha subunit level normalization, 
 will be 
presented for each symptom at each time point with associated exact 95% CI. 
 
Incidence rates of pituitary hormonal dysfunction, normalization of alpha subunit level and proportion of 
patients with 50% reduction in alpha subunit level along with its exact 95% CI will be reported at baseline, Week 
4, 12 and 24. Analyses for alpha subunit level will be repeated with per protocol population set and for the 
subgroup of patients with elevated alpha subunit level at baseline. 
 
Hormone profiles, alpha subunit levels and 
 will be summarized at each time point in terms of 
frequency (N), mean, standard-deviation, median, minimum, and maximum.   


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5.5.3 
Safety parameters and analyses  
The assessment of safety will be based mainly on the frequency of adverse events (AEs), on the number of 
patients with laboratory values that fall outside of reference ranges and the number of patients with clinically 
notable ECG data. Other safety data (e.g vital signs, special tests) will be considered as appropriate. 
 
5.5.3.1 
Adverse events 
All AEs recorded during the study will be summarized. The incidence of treatment-emergent AEs (new or 
worsening from baseline) will be summarized by system organ class, severity (based on CTCAE grades), type of 
AE, relation to the study drug. Deaths reportable as SAEs and non-fatal serious adverse events will be listed by 
patient and tabulated by type of AE. 
Treatment-emergent adverse events (TEAEs) will include all adverse events who started between first and 28 
days after the last administration of study medication.  
 
5.5.3.2 
Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade calculated using appropriate Common 
Toxicity Criteria (CTC). 
Frequency of laboratory abnormalities will be displayed by parameter and study day. Notably abnormal 
laboratory values (new or worsening from baseline based on CTC grades) will be summarized by laboratory 
parameter. Shift tables will be presented comparing baseline laboratory result (CTC grade) with the worst result 
(expressed in CTC grade) during study. Patient with abnormal laboratory values will be listed and values outside 
the normal ranges will be flagged. A separate listing of laboratory abnormalities of CTC grade 3 or 4 will also be 
provided.  
 
5.5.3.3 
Other safety data  
Weight, height and vital signs will be summarized at each time point using descriptive statistics (N, mean, 
standard-deviation, median, minimum, and maximum). 


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Abnormalities of physical examination, ECOG performance status, radiological examinations, ECG, MRI, and 
visual evaluations will be identified and listed.  
5.5.4 
Tolerability  
Dose reductions and AEs related to study drug e.g. gastrointestinal disorders, glucose metabolism disorders, 
cardiac functions disorders, laboratory abnormalities, infections, injection site reactions will be summarized by 
presenting counts and percentages for the safety population. 
5.6 SAMPLE SIZE RATIONAL  
This is a proof of concept study. The sample size of 19 evaluable patients was selected without regard for 
statistical power. A response rate (proportion of patients with tumor volume reduction ≥ 20%) of at least 10% is 
considered clinically meaningful for this patient population. Table A 3, presents for various assumed response 
rates the probability of having two or more responders.  If the true response rate is 10%, the probability of 
getting two or more responders out of 19 patients is 58%. In this trial the 90% CI will also be obtained. Table A 
4, presents the exact 90% CI when 2-6 patients respond out of the 19 patients. Considering the dropout of 20%, 
we will enrol 23 patients to get 19 evaluable patients for final analysis.  
 
Table A 3: Probability of getting ≥ 2 response in a sample of 19 patients  
Assumed p  
0.05  
0.10  
0.15  
0.20  
0.25  
0.30  
P( X ≥ 2)  
25%  
58%  
80%  
92%  
97%  
99%  
X is assumed to have binomial distribution with probability p  
 
 
 
 
Table A 4: Resulting 90% CIs for various number of observed responders  
Responders/n  
Lower confidence limit  
Upper confidence limitl  
2/19  
1.9%  
29.6%  
3/19  
4.4%  
35.9%  
4/19  
7.5%  
41.9%  
5/19  
11%  
47.6%  
6/19  
14.7%  
53%  
 
 
 


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6 Study Results 
The study results are presented in Appendix 1: Statistical Tables  – Core study phase. 
 
The extension study results are presented in Appendix 2: Statistical Tables  – Extension study. 
 


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7 Clarifications to the study protocol 
The following clarifications to the study protocol were considered on this SAP: 
- 
Clarification of statistical analysis for time to response and baseline characteristics 
- 
Definition of treatment-emergent adverse events 
- 
Definition of comparative analysis of hormonal parameters  
- 
Confidence interval of 95% instead of 90% due to the standard approach in clinical epidemiology  
 
Any deviations from methodology/definitions/analysis described on this SAP should be previously accepted by 
the sponsor and documented (together with reasoning, if relevant) in the statistical analysis report.  
 


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Appendix 1: Statistical Tables – Core study phase 
 
Table 1 – Patients’ disposition 
 
Total 
(n=xx) 
 
 
 
Patients eligible for study treatment, n (%) 
 
 
Yes 
 
 
No 
 
 
   Inclusion criteria 
 
 
   Exclusion criteria 
 
 
   Other 
 
 
Total 
 
 
 
 
 
Treatment duration completed as per protocol, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Primary reason for end of treatment, n (%) 
 
 
Adverse Event(s) 
 
 
Subject withdrew consent 
 
 
Lost to follow-up 
 
 
Administrative problems. 
 
 
Death 
 
 
Disease  progression 
 
 
Subject is unable to tolerate the minimum pasireotide LAR dose of 40 mg. 
 
 
Acute or progressive vision loss confirmed by a new visual field evaluation. 
 
 
Pregnancy 
 
 
Uncontrolled diabetes mellitus. 
 
 
Clinically significant abnormal test procedure result(s). 
 
 
Clinically significant abnormal laboratory value(s) 
 
 
Protocol deviation 
 
 
Investigator’s decision 
 
 
Other 
 
 
 
 
 
Study populations, n (%) 
 
 
FAS 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2 – Demographics – FAS population 
 
Total 
(n=xx) 
 
 
 
Gender, n (%) 
 
 
Male 
 
 
Female 
 
 
   Childbearing potential 
 
 
   Non-childbearing potential 
 
 
Total 
 
 
 
 
 
Age (years) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Race, n (%) 
 
 
White  / Caucasian ancestry 
 
 
Black/ / African ancestry 
 
 
Native ancestry 
 
 
Asian ancestry 
 
 
Other 
 
 
Total 
 
 
 
 
 
Height (cm) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Weight (kg) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
BMI (Kg/m2) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
 
 
 


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Table 3 – Medical history – FAS population 
 
Total 
(n=xx) 
 
 
 
Duration of disease (years)a) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Medical history or current medical condition prior to first 
study drug administration, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
a) The difference between the initial visit and the date of diagnosis of pituitary adenocarcinoma, in years. 
 
 
 


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Table 4 – Concomitant medication 
 
Total 
(n=xx) 
 
 
 
Any medication or significant non-drug therapy, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Concomitant medication for hormone replacement, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
 
 
 
 


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Table 5 – HbA1c, fasting blood insulin and glucose at visit 1 – FAS population 
 
Total 
(n=xx) 
 
 
 
HbA1c performed, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
HbA1c (%) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Normal 
 
 
Abnormal 
 
 
    Clinically significant 
 
 
    Non-clinically significant 
 
 
 
 
 
HbA1c ≤7% 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Fasting blood insulin (ulU/mL), n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Fasting blood insulin (ulU/mL) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Normal 
 
 
Abnormal 
 
 
    Clinically significant 
 
 
    Non-clinically significant 
 
 
 
 
 
Fasting blood glucose (mg/dL), n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Fasting blood glucose (mg/dL) 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Normal 
 
 
Abnormal 
 
 
    Clinically significant 
 
 
    Non-clinically significant 
 
 
 
 
 
 
 
 
 


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Table 6 – Treatment – FAS population 
 
Total 
(n=xx) 
 
V2 
V4 
V5 
V7 
V8 
V9 
V10 
Core 
phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
medication 
administered, n 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
- 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
- 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
60 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
- 
40 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
- 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose 
adjustment, 
n 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
No 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Total 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exposure 
(days)a) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Mean 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Median 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Standard 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Minimum 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Maximum 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
administration 
dose (mg)b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Mean 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Median 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Standard 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Minimum 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
Maximum 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose reduction 
before  tumor 
volume 
reduction of at 
least 20%
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) The difference between the last administration and the first administration, in days. 
b) Cumulative dose (total dose administered) divided by number administrations. 
 
 
 
 
 


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Table 7 – Magnetic resonance imaging – FAS population 
 
Total 
(n=xx) 
 
V1 
V4 
95%CI 
V7 
95%CI 
V10 
95%CI 
Volume (cm3) 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
- 
 
 
- 
 
 
- 
Mean 
 
 
 
 
- 
 
 
- 
 
 
- 
Median 
 
 
 
 
- 
 
 
- 
 
 
- 
Standard 
 
 
 
 
- 
 
 
- 
 
 
- 
Minimum 
 
 
 
 
- 
 
 
- 
 
 
- 
Maximum 
 
 
 
 
-- 
 
 
-- 
 
 
-- 
Tumor is not 
 
 
 
 
- 
 
 
- 
 
 
- 
Missing values 
 
 
 
 
- 
 
 
- 
 
 
- 
 
 
 
 
 
 
 
 
 
 
 
 
Volume changea) 
(cm3) 
 
 
 
 
 
 
 
 
 
 
 
N 
- 
 
 
 
 
 
 
 
 
 
 
Mean 
- 
 
 
 
 
 
 
 
 
 
 
Median 
- 
 
 
 
 
 
 
 
 
 
 
Standard 
- 
 
 
 
 
 
 
 
 
 
 
Minimum 
- 
 
 
 
 
 
 
 
 
 
 
Maximum 
- 
 
 
 
 
 
 
 
 
 
 
Percentage 
change 
in 
volumea) (%) 
 
 
 
 
 
 
 
 
 
 
 
N 
- 
 
 
 
 
 
 
 
 
 
 
Mean 
- 
 
 
 
 
 
 
 
 
 
 
Median 
- 
 
 
 
 
 
 
 
 
 
 
Standard 
- 
 
 
 
 
 
 
 
 
 
 
Minimum 
- 
 
 
 
 
 
 
 
 
 
 
Maximum 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reduction of 
tumor  
volumeb), n (%) 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≥20% tumor 
volume 
reductionc), 
n 
(%) 
 
 
 
 
 
 
 
 
 
 
 
Yes 
- 
- 
 
 
 
 
 
 
 
 
 
No  
- 
- 
 
 
- 
 
 
- 
 
 
- 
Total 
- 
- 
 
 
- 
 
 
- 
 
 
- 
≥20% tumor 
volume 
reduction using 
LOCF method, n 
(%) 
 
 
 
 
 
 
 
 
 
 
 
Yes 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
 
No  
- 
- 
- 
- 
- 
- 
- 
- 
 
 
 
Total 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
95%CI: 95% confidence interval.  
a) The difference between visit i and V1. 
b) For reduction=’yes’ will be considered all patients who obtained ‘volume in visit i – volume in V1’ >0. 
c) For reduction ≥20%=’yes’ will be considered all patients who obtained ‘Percentage change in volume at visit i’ ≥20. 
 
 


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Table 8 – Time to response – FAS population 
 
Total 
(n=xx) 
 
Statistics 
95% CI 
 
 
 
Time to response 
 
 
N 
 
 
Censored 
 
 
Events (Reduction ≥20% in tumor volume) 
 
 
Mean 
 
 
Median 
 
 
25th Percentile 
 
 
75th Percentile 
 
 
Range 
 
 
 
 
 
CI95%: 95% confidence interval. 
Time between first administration and first date of reduction ≥20% in tumor volume. 
 
 
 
 
 
 
 
 
Figure 3 – Kaplan-Meier curve for time to response – FAS population 
 
 
 
 
 


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Table 9 – Time to response versus baseline characteristics– FAS population 
Time to response a) 
Total 
n=(xx) 
 
Statistics 
CI95% 
Statistics 
CI95% 
 
 
 
 
 
Visual field at baseline 
Normal 
 
Abnormal 
 
Time to response a) 
 
 
 
 
N 
 
 
 
 
Censored 
 
 
 
 
Events (progression or death) 
 
 
 
 
Mean 
 
 
 
 
Median 
 
 
 
 
25th Percentile 
 
 
 
 
75th Percentile 
 
 
 
 
Range 
 
 
 
 
 
 
 
 
 
Hazard ratio b) 
 
 
 
 
p-value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose at V2 
60 mg 
 
40mg 
 
Time to response a) 
 
 
 
 
N 
 
 
 
 
Censored 
 
 
 
 
Events (progression or death) 
 
 
 
 
Mean 
 
 
 
 
Median 
 
 
 
 
25th Percentile 
 
 
 
 
75th Percentile 
 
 
 
 
Range 
 
 
 
 
 
 
 
 
 
Hazard ratio b) 
 
 
 
 
p-value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose reduction before response 
Yes  
 
No 
 
Time to response a) 
 
 
 
 
N 
 
 
 
 
Censored 
 
 
 
 
Events (progression or death) 
 
 
 
 
Mean 
 
 
 
 
Median 
 
 
 
 
25th Percentile 
 
 
 
 
75th Percentile 
 
 
 
 
Range 
 
 
 
 
 
 
 
 
 
Hazard ratio b) 
 
 
 
 
p-value 
 
 
 
 
 
 
 
 
 
Duration of disease (years) 
 
 
 
 
Hazard ratio b) 
 
 
 
 
p-value 
 
 
 
 
 
 
 
 
 
α subunit at V1 
 
 
 
 
Hazard ratio b) 
 
 
 
 
p-value 
 
 
 
 
 
 
 
 
 
CI95%: 95% confidence interval. 
Time between first administration and first date of reduction ≥20% in tumor volume. 
a) Kaplan-Meier estimates. 
b) Cox regression estimates. 
 


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Table 10 – Disease-related symptoms – FAS population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Headachea), n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Absent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   95%CI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual disturbances a), n 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Absent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   95%CI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 10 (Cont.) – Disease-related symptoms – FAS population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Fatigue a), n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Absent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   95%CI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erectile dysfunctionb), 
n(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   95%CI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 10 (Cont.) – Disease-related symptoms – FAS population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Regular mensesc), n 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   95%CI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) For each symptom, it will considered as improvement if the severity reduce at least one point (eg.  ‘Severe’ at v1 and ‘moderate’ at vi will be considered as improvement in vi). 
b)  For patients who registered ‘No’ in V1 and  ‘Yes’ in vi it will be considered as an improvement in vi. 
c)  For patients who registered ‘No’ in V1 and  ‘Yes’ in vi it will be considered as an improvement in vi. 
 
 


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Table 11 –
 Alpha-subunit – FAS population 


Statistical Analysis Plan 
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Table 11 (Cont.) – 
 Alpha-subunit – FAS population 
 
Total 
(n=xx) 
 
V1 
V4 
V7 
95%CI 
V10 
95%CI 
 
 
 
 
 
 
 
 
 
 
 
α subunit (ng/mL) 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
- 
 
 
- 
Mean 
 
 
 
 
 
 
- 
 
 
- 
Median 
 
 
 
 
 
 
- 
 
 
- 
Standard Deviation 
 
 
 
 
 
 
- 
 
 
- 
Minimum 
 
 
 
 
 
 
- 
 
 
- 
Maximum 
 
 
 
 
 
 
- 
 
 
- 
Normal 
 
 
 
 
 
 
- 
 
 
- 
Abnormal 
 
 
 
 
 
 
- 
 
 
- 
   CS 
 
 
 
 
 
 
- 
 
 
- 
   NCS 
 
 
 
 
 
 
- 
 
 
- 
 
 
 
 
 
 
 
 
 
 
 
Reduction of α subunit ≥50%c), n (%) 
 
 
 
 
 
 
 
 
 
 
Yes 
- 
- 
 
 
 
 
 
 
 
 
No 
- 
- 
 
 
 
 
 
 
 
 
Total 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
95%CI: 95% confidence interval.  
 
 
c) For reduction ≥50%=’yes’ will be considered all patients who obtained percentage change from baseline in α subunit at visit i’ ≥50. 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 42 of 120 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 43 of 120 
 
Table 13 – Visual field – FAS population 
 
Total 
(n=xx) 
 
V1 
V2 
V4 
V5 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Right eye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal/abnormal, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Findings, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upper right quadrantanopia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upper left quadrantanopia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lower right quadrantanopia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lower left quadrantanopia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temporal hemianopsia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal hemianopsia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Evolutive information, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stable 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Worsened 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Left eye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal/abnormal, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Findings, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upper right quadrantanopia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upper left quadrantanopia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lower right quadrantanopia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lower left quadrantanopia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temporal hemianopsia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal hemianopsia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 44 of 120 
 
Table 13 (Cont.) – Visual field – FAS population 
 
Total 
(n=xx) 
 
V1 
V2 
V4 
V5 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Left eye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Evolutive information, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stable 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Worsened 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 45 of 120 
 
Table 14 – Gallblader ultrasound – FAS population 
 
Total 
(n=xx) 
 
V1 
V10 
 
 
 
 
 
Gallblader ultrasound performed, n (%) 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
If yes 
 
 
 
 
Any gallstones detected, n (%) 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
Dilatation of the intra or extra hepatic 
ductal system, n (%) 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
Location of dilatation, n (%) 
 
 
 
 
Intrahepatic ductal system 
 
 
 
 
Extrahepatic ductal system 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 46 of 120 
 
Table 15 – Treatment-emergent adverse events and serious adverse events – Safety population 
 
Total  
(n=xx) 
Patients with at least one adverse event, n (%)a) 
 
No  
 
 
Yes  
 
 
Total 
 
 
 
 
 
Patients with at least one serious adverse event, n (%)a) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Grade of adverse events, n (%)b) 
 
 
Grade 1  
 
 
Grade 2  
 
 
Grade 3  
 
 
Grade 4  
 
 
Total 
 
 
 
 
 
Grade ≥ 3 
 
 
 
 
 
Relationship of study drug, n (%)b) 
 
 
Not suspected  
 
 
Suspected 
 
 
Total 
 
 
 
 
 
Action taken for adverse event, n (%)b) 
 
 
No action taken. 
 
 
Study drug dosage adjusted / temporarily interrupted. 
 
 
Study drug permanently discontinued due to this adverse event 
 
 
Concomitant medication taken 
 
 
Non-drug therapy given 
 
 
Hospitalization / prolonged hospitalization 
 
 
 
 
 
Serious adverse events, n (%)b) 
 
 
Yes 
 
 
No 
 
 
 
 
a) Percentage calculated within the total number of patients of safety population (n=xx). 
b) Percentage calculated within the total number of adverse events reported by safety population (n=xxx). 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 47 of 120 
 
Table 16 – Incidence of treatment-emergent adverse events – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of adverse events, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 48 of 120 
 
Table 17 – Incidence of serious treatment-emergent adverse events – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of serious adverse events, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 49 of 120 
 
Table 18 – Incidence of treatment-emergent adverse events with suspected relationship with study 
drug – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of adverse events with suspected relationship with study 
drug, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 50 of 120 
 
Table 19 – Incidence of serious treatment-emergent adverse events with suspected relationship with 
study drug – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of serious adverse events with suspected relationship with 
study drug, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 51 of 120 
 
Table 20 – Treatment-emergent adverse events – Safety population 
 
Total  
(n=xx) 
 
 
Adverse events, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
Percentage calculated within the total number of adverse events reported by safety population (n=xxxx). 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 52 of 120 
 
Table 21 – Serious treatment-emergent adverse events – Safety population 
 
Total  
(n=xx) 
 
 
Serious adverse events, n (%) 
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of serious adverse events reported by safety population (n=xxxx). 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 53 of 120 
 
Table 22 – Treatment-emergent adverse events with suspected relationship with study drug – Safety 
population 
 
Total  
(n=xx) 
 
 
Adverse events with suspected relationship with study drug, n (%) 
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
Xxxxx 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of adverse events with remote, possible or probable relationship with study drug reported 
by safety population (n=xxxx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 54 of 120 
 
Table 23 – Serious treatment-emergent adverse events with suspected relationship with study drug – 
Safety population 
 
Total  
(n=xx) 
 
 
Serious adverse events with suspected relationship with study drug, 
n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of serious adverse events with remote, possible or probable relationship with study drug 
reported by safety population (n=xxxx). 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 55 of 120 
 
Table 24 – Hematology – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RBC count ((million/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin (g/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematocrit (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.    


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 56 of 120 
 
Table 24 (Cont.) – Hematology – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WBC count (/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eosinophils (/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophils total (/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.    
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 57 of 120 
 
Table 24 (Cont.) – Hematology – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocytes (/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monocytes (/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Basophils (/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.    
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 58 of 120 
 
Table 24 (Cont.) – Hematology – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Band neutrophils (/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet count (thousand/mm3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.    


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 59 of 120 
 
Table 25 – Coagulation – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT (seconds) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Mean 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Median 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Standard Deviation 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Minimum 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Maximum 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Normal 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Abnormal 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
   CS 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
   NCS 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.  
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 60 of 120 
 
Table 25 (Cont.) - Coagulation – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APTT (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APTT (seconds) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Mean 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Median 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Standard Deviation 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Minimum 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Maximum 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Normal 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Abnormal 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
   CS 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
   NCS 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.  
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 61 of 120 
 
Table 26 – Urinalysis – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
Specific gravity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucose,  n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
100 mg/dl or 5 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
250 (+)mg/dl or 15 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
500 (++)mg/dl or 30 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1000 (+++)mg/dl or 60 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2000 (++++) mg/dL or 110 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 62 of 120 
 
  Table 26 (Cont.) – Urinalysis – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protein, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trace 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
30 (+)mg/dl or 0.3 g/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
100 (++)mg/dl or 1.0 g/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
300 (+++)mg/dl or 3.0 g/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
> 2000 (++++) mg/dL or > 20 g/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Negative or 0 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Non – Hemolyzed” or 10 ca 
Cells/µL (Trace) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Hemolyzed” or “ Trace” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“ Small” (+) or 25 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Moderate” (++) or 80 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Large“ (+++) or 200 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Small ” (+) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Moderate” (++) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     “Large“ (+++) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 63 of 120 
 
 
  Table 26 (Cont.) – Urinalysis – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ketones, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Negative” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Trace” (5 mg/dl) or 0.5 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Small” (15 mg/dl) or 1.5 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Moderate” (40 mg/dl) or 4.0 
mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Large” (80 mg/dl) or 8.0 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Large” (160 mg/dl) or 16 mmol/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukocytes, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Negative or 0 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Trace” or 15 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“ Small” (+) or 70 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    “Moderate” (++) or 125 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Large” (+++) or 500 ca Cells/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 64 of 120 
 
Table 27 – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
Urea (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uric acid (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 65 of 120 
 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
CPK (U/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH (U/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total protein (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 66 of 120 
 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
Total cholesterol (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low 
density 
lipoprotein 
(LDL) 
cholesterol (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High-density 
lipoprotein 
(HDL) 
cholesterol (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 67 of 120 
 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
Triglycerides (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sodium (mEq/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Potassium (mEq/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 68 of 120 
 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
Calcium (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phosphorus (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chloride (mEq/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 69 of 120 
 
Table 27 (Cont.) – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
B12 Vitamin (pg/) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Folic acid (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 70 of 120 
 
Table 27 (Cont.) – Biochemistry – Safety population 
 
 
 
Total 
(n=xx) 
 
V1 
V4 
V5 
V7 
V8 
V9 
V10 
Fasting blood insulin (µlU/mL)) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting blood glucose (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 71 of 120 
 
Table 28 – Tests for liver function – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SGOT (U/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SGPT (U/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Mean 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Median 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Standard Deviation 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Minimum 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Maximum 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Normal 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Abnormal 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
   CS 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
   NCS 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alkaline Phosphatase (U/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.  
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 72 of 120 
 
Table 28 (Cont.) – Tests for liver function – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
y-GT (U/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Direct bilirubin (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Mean 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Median 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Standard Deviation 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Minimum 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Maximum 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Normal 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
Abnormal 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
   CS 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
   NCS 
 
 
 
 
- 
 
- 
 
- 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.  


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 73 of 120 
 
Table 28 (Cont.) – Tests for liver function – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Indirect bilirubin (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin (g/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.  
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 74 of 120 
 
Table 29 – Serology – Safety population 
 
Total 
(n=xx) 
 
V1 
 
 
 
Hbs-Ag 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Reactive 
 
 
Non-reactive 
 
 
   CS 
 
 
   NCS 
 
 
 
 
 
Anti-HCV 
 
 
N 
 
 
Mean 
 
 
Median 
 
 
Standard Deviation 
 
 
Minimum 
 
 
Maximum 
 
 
 
 
 
Reactive 
 
 
Non-reactive 
 
 
   CS 
 
 
   NCS 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 75 of 120 
 
Table 30 – Hormonal evaluation – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V7 
V10 
GH (ng/mL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
IGF-I (ng/mL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACTH (pg/mL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 76 of 120 
 
Table 30 (Cont.) – Hormonal evaluation – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V7 
V10 
Cortisol (µg/dl), for patients without intake of glucocorticoid 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
LH (mUI/mL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (mUI/mL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 77 of 120 
 
Table 30 (Cont.) – Hormonal evaluation – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V7 
V10 
Testosterone (ng/dl) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
Estradiol (pg/mL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH (µUl/mL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 78 of 120 
 
Table 30 (Cont.) – Hormonal evaluation – Safety population 
 
Total 
(n=xx) 
 
V1 
V4 
V7 
V10 
Free T4 (ng/dL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
Prolactin (ng/mL) 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant.  
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 79 of 120 
 
Table 31 – Hormonal evaluation associations – FAS population 
 
Testosterone replacement therapy 
Without testosterone replacement 
therapy 
p-value 
Testosterone (ng/dL) at V1  
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Hormone replacement therapy 
Without Hormone replacement 
therapy 
 
Estradiol (pg/mL) at V1 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
Levothyroxine 
Without Levothyroxine 
p-value 
TSH (µUl/mL) at V1  
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Free T4 (ng/dL) at V1  
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 80 of 120 
 
Table 32 – Vital signs – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
Systolic blood pressure (mmHg) 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diastolic blood pressure (mmHg) 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heart rate (bpm) 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature (ºC) 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 81 of 120 
 
Table 33 – Physical examination – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
 
 
 
 
 
N 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Mean 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Median 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Standard Deviation 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Minimum 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Maximum 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Findings, n (%) 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin and nails 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Nose and sinuses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Ears 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Mouth and pharynges 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Head and neck 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thorax and lungs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breast 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdomen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphatic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extremities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascular 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 82 of 120 
 
Table 34 – Eastern cooperative oncology group performance status – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG result, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG: Eastern Cooperative Oncology Group. 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 83 of 120 
 
Table 35 – Electrocardiogram – Safety population 
 
Total 
(n=xx) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QTcF (msec) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Result, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal without clinical 
significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal with clinical 
significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consultation with 
cardiologist to confirm 
abnormal ECG?, n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If yes, cardiologist confirm 
QTcF interval >480msec, n 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient discontinued after 
thorough cardiological 
examination, n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 84 of 120 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 85 of 120 
 
Appendix 2: Statistical Tables – Extension study 
Table B 1 – Patients’ disposition – extension study 
 
Total 
(n=xx) 
 
 
 
Patient agree to be followed for post-treatment evaluations, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Patient agree to be followed for survival, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Primary reason for end of treatment, n (%) 
 
 
Adverse Event(s) 
 
 
Subject withdrew consent 
 
 
Lost to follow-up 
 
 
Administrative problems. 
 
 
Death 
 
 
Disease  progression 
 
 
Subject is unable to tolerate the minimum pasireotide LAR dose of 40 mg. 
 
 
Acute or progressive vision loss confirmed by a new visual field evaluation. 
 
 
Pregnancy 
 
 
Uncontrolled diabetes mellitus. 
 
 
Clinically significant abnormal test procedure result(s). 
 
 
Clinically significant abnormal laboratory value(s) 
 
 
Protocol deviation 
 
 
Investigator’s decision 
 
 
Other 
 
 
 
 
 
Study populations, n (%) 
 
 
FAS 
 
 
Safety 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 86 of 120 
 
Table B 2 – Concomitant medication – extension study – FAS population 
 
Total 
(n=xx) 
 
 
 
Any medication or significant non-drug therapy, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 87 of 120 
 
Table B 3 – Treatment – extension study – FAS population 
 
Total 
(n=xx) 
 
V13 
V16 
V19 
V22 
V25 
Extension 
phase 
 
 
 
 
 
 
 
Study medication administered, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
- 
No 
 
 
 
 
 
- 
Total 
 
 
 
 
 
- 
 
 
 
 
 
 
 
Dose, n (%) 
 
 
 
 
 
 
60 mg 
 
 
 
 
 
- 
40 mg 
 
 
 
 
 
- 
Total 
 
 
 
 
 
- 
 
 
 
 
 
 
 
Exposure (days)a) 
 
 
 
 
 
 
N 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean administration dose (mg)b) 
 
 
 
 
 
 
N 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) The difference between the last administration and the first administration of extension phase, in days. 
b) Cumulative dose (total dose administered in the extension phase) divided by number administrations (extension phase). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 88 of 120 
 
Table B 4 – Magnetic resonance imaging – FAS population 
 
Total 
(n=xx) 
 
V16 
V22 
V28 
 
 
 
 
Volume (cm3) 
 
 
 
N 
 
 
- 
Mean 
 
 
- 
Median 
 
 
- 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
- 
Tumor is not visible 
 
 
- 
Missing values 
 
 
- 
 
 
 
 
Volume changea) (cm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Percentage change in volumea) (%) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Reduction of tumor volumeb), n (%) 
 
 
 
Yes 
 
 
 
No 
 
 
 
 
 
 
 
≥20% tumor volume reductionc), n (%) 
 
 
 
Yes 
 
 
 
No  
 
 
 
Total 
 
 
 
 
 
 
 
≥20% tumor volume reduction using LOCF method, n (%) 
 
 
 
Yes 
 
 
 
No  
 
 
 
Total 
 
 
 
 
 
 
 
For patients who achieved a reduction in tumor volume 
of at least 20% with respect to the initial tumor volume 
in the core phase 
 
 
 
≥20% tumor volume reductionc), n (%) 
 
 
 
Yes 
 
 
 
No  
 
 
 
Total 
 
 
 
 
 
 
 
For patients who achieved a reduction in tumor volume 
< 20% with respect to the initial tumor volume in the core 
phase 
 
 
 
≥20% tumor volume reductionc), n (%) 
 
 
 
Yes 
 
 
 
No  
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
a) The difference between visit i and V1. 
b) For reduction=’yes’ will be considered all patients who obtained ‘volume in visit i – volume in V1’ >0. 
c) For reduction ≥20%=’yes’ will be considered all patients who obtained ‘Percentage change in volume at visit i’ ≥20. 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 89 of 120 
 
Table B 5 – Disease-related symptoms – FAS population 
 
Total 
(n=xx) 
 
V13 
V16 
V19 
V22 
V25 
V28 
 
 
 
 
 
 
 
Headache, n (%) 
 
 
 
 
 
 
Absent 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
Very severe 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual disturbances, n (%) 
 
 
 
 
 
 
Absent 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
Very severe 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue, n (%) 
 
 
 
 
 
 
Absent 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
Very severe 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erectile dysfunction, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regular menses, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Improved, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) For each symptom, it will considered as improvement if the severity reduce at least one point (eg.  ‘Severe’ at v1 and ‘moderate’ at vi will 
be considered as improvement in vi). 
b)  For patients who registered ‘No’ in V1 and  ‘Yes’ in vi it will be considered as an improvement in vi. 
c)  For patients who registered ‘No’ in V1 and  ‘Yes’ in vi it will be considered as an improvement in vi. 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 90 of 120 
 
 
Table B 6 – 
 Alpha-subunit – FAS population 
 
Total 
(n=xx) 
 
V16 
V22 
V28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
α subunit (ng/mL) 
 
 
 
N 
 
- 
 
Mean 
 
- 
 
Median 
 
- 
 
Standard Deviation 
 
- 
 
Minimum 
 
- 
 
Maximum 
 
- 
 
 
 
 
 
Normal 
 
- 
 
Abnormal 
 
- 
 
   CS 
 
- 
 
   NCS 
 
- 
 
 
 
 
 
Reduction of α subunit ≥50%b), n (%) 
 
 
 
Yes 
 
- 
 
No 
 
- 
 
Total 
 
- 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 
b) For reduction ≥50%=’yes’ will be considered all patients who obtained percentage change from baseline in α subunit at visit i’ ≥50. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 91 of 120 
 
Table B 7 – Visual field – FAS population 
 
Total 
(n=xx) 
 
V16 
V22 
V28 
 
 
 
 
Right eye 
 
 
 
Normal/abnormal, n (%) 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   Mild 
 
 
 
       Severe 
 
 
 
Total 
 
 
 
Findings, n (%) 
 
 
 
Upper right quadrantanopia 
 
 
 
Upper left quadrantanopia 
 
 
 
    Lower right quadrantanopia 
 
 
 
Lower left quadrantanopia 
 
 
 
Temporal hemianopsia 
 
 
 
Nasal hemianopsia 
 
 
 
Other 
 
 
 
Evolutive information, n (%) 
 
 
 
Stable 
 
 
 
Improved 
 
 
 
    Worsened 
 
 
 
Total 
 
 
 
 
 
 
 
Left eye 
 
 
 
Normal/abnormal, n (%) 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   Mild 
 
 
 
       Severe 
 
 
 
Total 
 
 
 
Findings, n (%) 
 
 
 
Upper right quadrantanopia 
 
 
 
    Upper left quadrantanopia 
 
 
 
Lower right quadrantanopia 
 
 
 
Lower left quadrantanopia 
 
 
 
Temporal hemianopsia 
 
 
 
Nasal hemianopsia 
 
 
 
    Other 
 
 
 
 
 
 
 
Evolutive information, n (%) 
 
 
 
Stable 
 
 
 
Improved 
 
 
 
Worsened 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 92 of 120 
 
 
Table B 8 – Gallblader ultrasound – FAS population 
 
Total 
(n=xx) 
 
V16 
V28 
 
 
 
Gallblader ultrasound performed, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
If yes 
 
 
Any gallstones detected, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Any sludge detected, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Dilatation of the intra or extra hepatic ductal system, n (%) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Location of dilatation, n (%) 
 
 
Intrahepatic ductal system 
 
 
Extrahepatic ductal system 
 
 
Total 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 93 of 120 
 
Table B 9 – Adverse events and serious adverse events in the extension study – Safety population 
 
Total  
(n=xx) 
Patients with at least one adverse event, n (%)a) 
 
No  
 
 
Yes  
 
 
Total 
 
 
 
 
 
Patients with at least one serious adverse event, n (%)a) 
 
 
Yes 
 
 
No 
 
 
Total 
 
 
 
 
 
Grade of adverse events, n (%)b) 
 
 
Grade 1  
 
 
Grade 2  
 
 
Grade 3  
 
 
Grade 4  
 
 
Total 
 
 
 
 
 
Grade ≥ 3 
 
 
 
 
 
Relationship of study drug, n (%)b) 
 
 
Not suspected  
 
 
Suspected 
 
 
Total 
 
 
 
 
 
Action taken for adverse event, n (%)b) 
 
 
No action taken. 
 
 
Study drug dosage adjusted / temporarily interrupted. 
 
 
Study drug permanently discontinued due to this adverse event 
 
 
Concomitant medication taken 
 
 
Non-drug therapy given 
 
 
Hospitalization / prolonged hospitalization 
 
 
 
 
 
Serious adverse events, n (%)b) 
 
 
Yes 
 
 
No 
 
 
 
 
a) Percentage calculated within the total number of patients of safety population (n=xx). 
b) Percentage calculated within the total number of adverse events reported by safety population (n=xxx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 94 of 120 
 
Table B 10 – Incidence of adverse events in the extension study – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of adverse events, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 95 of 120 
 
Table B 11 – Incidence of serious adverse events in the extension study – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of serious adverse events, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 96 of 120 
 
Table B 12 – Incidence of serious adverse events with suspected relationship with study drug in the 
extension study – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of adverse events with suspected relationship with study 
drug, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 97 of 120 
 
Table B 13 – Incidence of serious adverse events with suspected relationship with study drug in the 
extension study – Safety population 
 
Total  
(n=xx) 
 
 
Incidence of serious adverse events with suspected relationship with 
study drug, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
a) Percentage calculated for total of patients of patients of the safety population (n=xx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 98 of 120 
 
Table B 14 – Adverse events in the extension study – Safety population 
 
Total  
(n=xx) 
 
 
Adverse events, n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
Percentage calculated within the total number of adverse events reported by safety population (n=xxxx). 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 99 of 120 
 
Table B 15 – Serious adverse events in the extension study – Safety population 
 
Total  
(n=xx) 
 
 
Serious adverse events, n (%) 
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of serious adverse events reported by safety population (n=xxxx). 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 100 of 120 
 
Table B 16 – Adverse events with suspected relationship with study drug in the extension study – 
Safety population 
 
Total  
(n=xx) 
 
 
Adverse events with suspected relationship with study drug, n (%) 
 
Xxxxx 
 
Xxxxx 
 
Xxxxx  
 
Xxxxx 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of adverse events with remote, possible or probable relationship with study drug reported 
by safety population (n=xxxx). 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 101 of 120 
 
Table B 17 – Serious adverse events with suspected relationship with study drug in the extension study 
– Safety population 
 
Total  
(n=xx) 
 
 
Serious adverse events with suspected relationship with study drug, 
n (%) 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
Xxxxx 
 
 
Xxxxx 
 
 
Xxxxx  
 
 
 
 
Percentage calculated within the total number of serious adverse events with remote, possible or probable relationship with study drug 
reported by safety population (n=xxxx). 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 102 of 120 
 
Table B 18 – Hematology – Safety population 
 
Total 
(n=xx) 
 
V16 
V22 
V28 
 
 
 
 
RBC count ((million/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Hemoglobin (g/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Hematocrit (%) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
RBC count ((million/mm3) 
 
 
 
    N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Hemoglobin (g/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 


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Hematocrit (%) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
    Standard Deviation 
 
 
 
    Minimum 
 
 
 
    Maximum 
 
 
 
 
 
 
 
    Normal 
 
 
 
    Abnormal 
 
 
 
CS 
 
 
 
NCS 
 
 
 
 
 
 
 
WBC count (/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
CS 
 
 
 
NCS 
 
 
 
 
 
 
 
Eosinophils (/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Neutrophils total (/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
CS 
 
 
 
NCS 
 
 
 
 
 
 
 
Lymphocytes (/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
CS 
 
 
 
NCS 
 
 
 
 
 
 
 
Monocytes (/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
CS 
 
 
 
NCS 
 
 
 
 
 
 
 
Basophils (/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
CS 
 
 
 
NCS 
 
 
 
 
 
 
 
Band neutrophils (/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
CS 
 
 
 
NCS 
 
 
 
 
 
 
 
Platelet count (thousand/mm3) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
CS 
 
 
 
NCS 
 
 
 
 
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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Table B 19 – Coagulation – Safety population 
 
Total 
(n=xx) 
 
V13 
V16 
V19 
V22 
V25 
V28 
V29 
 
 
 
 
 
 
 
 
PT (%) 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APTT (%) 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
   CS 
 
 
 
 
 
 
 
   NCS 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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Table B 20 – Urinalysis – Safety population 
 
Total 
(n=xx) 
 
V16 
V22 
V28 
 
 
 
 
Specific gravity 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
PH 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Glucose,  n (%) 
 
 
 
Negative 
 
 
 
100 mg/dl or 5 mmol/L 
 
 
 
250 (+)mg/dl or 15 mmol/L 
 
 
 
500 (++)mg/dl or 30 mmol/L 
 
 
 
1000 (+++)mg/dl or 60 mmol/L 
 
 
 
2000 (++++) mg/dL or 110 mmol/L 
 
 
 
Total 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
NCS 
 
 
 
 
 
 
 
Protein, n (%) 
 
 
 
Negative 
 
 
 
Trace 
 
 
 
30 (+)mg/dl or 0.3 g/L 
 
 
 
100 (++)mg/dl or 1.0 g/L 
 
 
 
300 (+++)mg/dl or 3.0 g/L 
 
 
 
> 2000 (++++) mg/dL or > 20 g/L 
 
 
 
Total 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Blood, n (%) 
 
 
 
Negative or 0 ca Cells/µL 
 
 
 
“Non – Hemolyzed” or 10 ca Cells/µL (Trace) 
 
 
 
“Hemolyzed” or “ Trace” 
 
 
 
“ Small” (+) or 25 ca Cells/µL 
 
 
 
“Moderate” (++) or 80 ca Cells/µL 
 
 
 
“Large“ (+++) or 200 ca Cells/µL 
 
 
 
Total 
 
 
 
 
 
 
 
Normal 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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Abnormal 
 
 
 
   CS 
 
 
 
NCS 
 
 
 
 
 
 
 
Bilirubin, n (%) 
 
 
 
Negative 
 
 
 
“Small ” (+) 
 
 
 
“Moderate” (++) 
 
 
 
“Large“ (+++) 
 
 
 
Total 
 
 
 
Not applicable 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Ketones, n (%) 
 
 
 
“Negative” 
 
 
 
“Trace” (5 mg/dl) or 0.5 mmol/L 
 
 
 
“Small” (15 mg/dl) or 1.5 mmol/L 
 
 
 
“Moderate” (40 mg/dl) or 4.0 mmol/L 
 
 
 
“Large” (80 mg/dl) or 8.0 mmol/L 
 
 
 
“Large” (160 mg/dl) or 16 mmol/L 
 
 
 
Total 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Leukocytes, n (%) 
 
 
 
Negative or 0 ca Cells/µL 
 
 
 
“Trace” or 15 ca Cells/µL 
 
 
 
“ Small” (+) or 70 ca Cells/µL 
 
 
 
“Moderate” (++) or 125 ca Cells/µL 
 
 
 
“Large” (+++) or 500 ca Cells/µL 
 
 
 
Total 
 
 
 
Not applicable 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
    
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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Table B 21 – Biochemistry – Safety population 
 
Total 
(n=xx) 
 
V16 
V22 
V28 
 
 
 
 
Urea (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Creatinine (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Uric acid (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
CPK (U/L) 
 
 
 
    N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
LDH (U/L) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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Total protein (mg/dL) 
 
 
 
        N 
 
 
 
Mean 
 
 
 
        Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Total cholesterol (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Low density lipoprotein (LDL) cholesterol (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
High-density lipoprotein (HDL) cholesterol (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Triglycerides (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Sodium (mEq/L) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 110 of 120 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Potassium (mEq/L) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Calcium (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Phosphorus (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Chloride (mEq/L) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
B12 Vitamin (pg/) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Folic acid (ng/mL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
HbA1c (%) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Fasting blood insulin (µlU/mL)) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Fasting blood glucose (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
    
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 112 of 120 
 
Table B 22 – Tests for liver function – Safety population 
 
Total 
(n=xx) 
 
V16 
V22 
V28 
 
 
 
 
SGOT (U/L) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
SGPT (U/L) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Alkaline Phosphatase (U/L) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
y-GT (U/L) 
 
 
 
    N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Total bilirubin (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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Direct bilirubin (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Indirect bilirubin (mg/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Albumin (g/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
    
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 114 of 120 
 
Table B 23 – Hormonal evaluation – Safety population 
 
Total 
(n=xx) 
 
V16 
V22 
V28 
 
 
 
 
GH (ng/mL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
IGF-I (ng/mL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
ACTH (pg/mL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Cortisol (µg/dl), for patients without intake of glucocorticoid 
 
 
 
    N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
LH (mUI/mL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
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FSH (mUI/mL) 
 
 
 
        N 
 
 
 
Mean 
 
 
 
        Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Testosterone (ng/dl) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Estradiol (pg/mL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
TSH (µUl/mL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Free T4 (ng/dL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
 
 
 
 
Prolactin (ng/mL) 
 
 
 
N 
 
 
 
Mean 
 
 
 
Median 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 116 of 120 
 
Standard Deviation 
 
 
 
Minimum 
 
 
 
Maximum 
 
 
 
 
 
 
 
Normal 
 
 
 
Abnormal 
 
 
 
   CS 
 
 
 
   NCS 
 
 
 
    
 
 
 
CS: Clinically significant; NCS: Not clinically significant. 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 117 of 120 
 
Table B 24 – Vital signs – Safety population 
 
Total 
(n=xx) 
 
V13 
V16 
V19 
V22 
V25 
V28 
V29 
 
 
 
 
 
 
 
 
Systolic blood pressure (mmHg) 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diastolic blood pressure (mmHg) 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heart rate (bpm) 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature (ºC) 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 118 of 120 
 
Table B 25 – Physical examination – Safety population 
 
Total 
(n=xx) 
 
V13 
V16 
V19 
V22 
V25 
V28 
V29 
 
 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Findings, n (%) 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
Skin and nails 
 
 
 
 
 
 
 
Eyes 
 
 
 
 
 
 
 
   Nose and sinuses 
 
 
 
 
 
 
 
   Ears 
 
 
 
 
 
 
 
   Mouth and pharynges 
 
 
 
 
 
 
 
Head and neck 
 
 
 
 
 
 
 
    Thorax and lungs 
 
 
 
 
 
 
 
Breast 
 
 
 
 
 
 
 
Abdomen 
 
 
 
 
 
 
 
Lymphatic 
 
 
 
 
 
 
 
Extremities 
 
 
 
 
 
 
 
Vascular 
 
 
 
 
 
 
 
Neurological 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 119 of 120 
 
 
Table B 26 – Eastern cooperative oncology group performance status – Safety population 
 
Total 
(n=xx) 
 
V13 
V16 
V19 
V22 
V25 
V28 
V29 
 
 
 
 
 
 
 
 
ECOG result, n (%) 
 
 
 
 
 
 
 
0 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG: Eastern Cooperative Oncology Group. 
 
 
 
 
 
 


Statistical Analysis Plan 
Version No.1, 14th February 2017 
Page 120 of 120 
 
Table B 27 – Electrocardiogram – Safety population 
 
Total 
(n=xx) 
 
V13 
V16 
V19 
V22 
V25 
V28 
 
 
 
 
 
 
 
QTcF (msec) 
 
 
 
 
 
 
N 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
Result, n (%) 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
Abnormal without clinical 
 
 
 
 
 
 
Abnormal with clinical 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consultation with cardiologist to 
confirm abnormal ECG?, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
If yes, cardiologist confirm QTcF 
interval >480msec, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient discontinued after 
thorough cardiological 
examination, n (%) 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total