A Randomized, Placebo Controlled Clinical Trial of SOM230 (Pasireotide LAR) In Severe Polycystic Liver Disease
Phase: PHASE2
Conditions: Somatostatin Analogs, Polycystic Liver Disease, Autosomal Dominant Polycystic Kidney Disease, Autosomal Dominant Polycystic Liver Disease
Sponsor: Mayo Clinic

 
 
 
A Randomized, Placebo 
Controlled Clinical Trial of 
SOM230 (Pasireotide LAR) In 
Severe Polycystic Liver Disease. 
 
NCT#  NCT01670110 
 
October 14, 2014 

 
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Medical Affairs 
SOM230C  
Clinical Trial Protocol CSOM230XUS30T 
 
 
A Randomized, Placebo Controlled Clinical Trial of SOM230 (Pasireotide LAR) In 
Severe Polycystic Liver Disease. 
 
Principal Investigator: 
 
Marie C. Hogan, MD, PhD 
Division of Nephrology & Hypertension, Mayo Clinic, Rochester, MN 55905. USA 
 
Co-Investigators: 
 
Peter Brady, MB BCh, FRCP 
Ziad El-Zoghby, MD 
Bernard F. King, M.D. 
Tetyana Masyuk, PhD 
Vicente E. Torres, MD PhD 
 
Statisticians: 
 
Eric Bergstralh, MS 
 Walter Kremers,MS 
 
 
 
Version number / date: 
10/14/2014 
 
 

 
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Table of contents 
Table of contents .......................................................................................................................2 
List of abbreviations .................................................................................................................5 
List of tables ..............................................................................................................................6 
1 
Introduction ...............................................................................................................................7 
1.1 
Overview of Autosomal Dominant Polycystic Kidney and Liver Disease:..................7 
1.2 
Background ...................................................................................................................7 
1.2.1 
Somatostatin Analogs – the first medical therapy for PLD ..........................7 
1.2.2 
Pre-Clinical Studies with Somatostatin ........................................................7 
1.3 
Somatostatin analogs in the treatment of patients with PLD ........................................7 
1.4 
Pasireotide (SOM230)...................................................................................................8 
1.5 
Clinical experience with pasireotide .............................................................................8 
1.5.1 
Pasireotide SQ ..............................................................................................8 
1.5.2 
Pasireotide LAR .........................................................................................10 
2 
Study Rationale/Purpose .........................................................................................................15 
2.1 
Selection of doses........................................................................................................16 
2.2 
Placebo dose ................................................................................................................16 
3 
Objectives ...............................................................................................................................16 
3.1 
Primary objectives.......................................................................................................16 
3.2 
Secondary objectives...................................................................................................16 
3.3 
Tertiary objective ........................................................................................................16 
4 
Study design............................................................................................................................16 
4.1 
Treatment ....................................................................................................................17 
4.2 
Follow-up ....................................................................................................................17 
4.3 
Treatment extension ....................................................................................................17 
5 
Population ...............................................................................................................................17 
5.1 
General criteria ............................................................................................................17 
5.2 
Inclusion/exclusion criteria .........................................................................................18 
5.2.1 
Inclusion criteria .........................................................................................18 
5.2.2 
Exclusion criteria ........................................................................................18 
6 
Treatment ................................................................................................................................20 
6.1 
Investigational and control drugs ................................................................................20 
6.1.1 
SOM230C / Placebo ...................................................................................20 
6.1.2 
How supplied ..............................................................................................21 
6.1.3 
Preparation and storage ..............................................................................21 

 
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6.1.4 
Administration ............................................................................................22 
6.2 
Treatment arms ...........................................................................................................22 
6.3 
Patient numbering .......................................................................................................23 
6.4 
Treatment blinding ......................................................................................................23 
6.5 
Pasireotide LAR dose adjustment ...............................................................................24 
6.5.1 
Permitted study drug adjustments ..............................................................24 
6.6 
Pasireotide LAR / placebo dose adjustment ...............................................................24 
6.7 
Concomitant therapy ...................................................................................................27 
6.8 
Study drug discontinuation .........................................................................................27 
6.9 
Premature patient withdrawal .....................................................................................28 
6.10 
Early Termination/End of treatment ...........................................................................28 
7 
Visit schedule and assessments ..............................................................................................30 
7.1 
Information to be collected on screening failures .......................................................31 
7.2 
Patient demographics/other baseline characteristics ...................................................31 
7.3 
Treatments ...................................................................................................................32 
7.4 
Efficacy .......................................................................................................................32 
7.4.1 
Liver & total kidney volume, hepatic cyst volume, renal cyst volume ......32 
7.4.2 
Treatment/Follow-up Decisions at Patient Evaluations .............................33 
7.5 
Safety ..........................................................................................................................33 
7.5.1 
Adverse events............................................................................................34 
7.5.2 
Vital signs ...................................................................................................35 
7.5.3 
Performance status......................................................................................35 
7.5.4 
Laboratory evaluations ...............................................................................35 
7.6 
Pharmacokinetics ........................................................................................................37 
8 
Other Safety Considerations: ..................................................................................................37 
8.1.2            Novartis instructions for rapid notification of serious adverse events .......41 
Protoco
10 Data management ...................................................................................................................42 
10.1 
Data collection ............................................................................................................42 
10.2 
Statistical methods ......................................................................................................42 
11 References ...............................................................................................................................43 
12 Appendices .............................................................................................................................45 
12.1 
Appendix 1 Guidance for diarrhea management ........................................................45 
12.2 
Appendix 2 Guidance for hyperglycemia management ..............................................48 
12.3 
Appendix 3 Guideline for the treatment of QT prolongation .....................................51 
12.4 
Appendix 4 SOM230 LFT Management Algorithm (s.c. and LAR Studies) .............54 
13 Procedures and instructions ....................................................................................................54 

 
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13.1.1 
Publication of results ..................................................................................52 
13.1.2 
Disclosure and confidentiality ....................................................................55 
13.1.3 
Discontinuation of study.............................................................................55 
13.2 
Ethics and Good Clinical Practice ..............................................................................55 
13.2.1 
Institutional Review Board/Independent Ethics Committee ......................55 
13.2.2 
Informed consent ........................................................................................55 
13.2.3 
Declaration of Helsinki...............................................................................54 
 

 
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List of abbreviations 
5-HIAA 
Urinary 5-hydroxyindole acetic acid 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
b.i.d. 
bis in diem/twice a day 
BG 
Blood Glucose 
CPO 
Clinical Pharma Organization 
CRF 
Case Report/Record Form 
CRD 
Clinical Research and Development 
CRO 
Contract Research Organization 
CS&E 
Clinical Safety and Epidemiology 
CT 
Computer Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DM 
Diabetes Mellitus 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practices 
GEP 
Gastroenteropancreatic 
GH 
Glycosylated Hemoglobin 
GI 
Gastrointestinal 
GOT 
Glutamic pxaloacetic transaminase 
GPT 
Glutamic pyruvic transaminase 
HSST 
Human somatostatin receptor 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IM 
Intramuscular(ly) 
ITT 
Intent to Treat 
IV 
intravenous(ly) 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
LAR 
Long Acting Release 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
o.d. 
omnia die/once a day 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
p.o. 
per os/by mouth/orally 
PRL 
Prolactin 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
q.d. 
quaque die/every day 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SQ 
Subcutaneous 
SRIFa 
Somatotropin release-inhibiting factor analog/somatostatin analogs 
SOP 
Standard Operating Procedure 
SST 
Somatostatin  
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit Normal 
 

 
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List of tables 
Table 1 
Binding profile for octreotide and pasireotide at HSST1-5 (IC50, M) ...8 
Table 2 
Gross anatomy, cystic and fibrotic volumes, in PCK rats .....................14 
Table 3 
Gross anatomy, cystic and fibrotic volumes, in Pkd2ws25 -/- mice .....14 
Table 4 
Handling and preparation of pasireotide LAR dose ............................223 
Table 5 
Stratified randomization ......................................................................224 
Table 6 
Handling and preparation of pasireotide LAR different doses ............235 
Table 7 
Guideline for treatment of patients experiencing adverse events ........245 
Table 8 
Visit evaluation schedule for patients receiving SOM230® ..................31 
Table 9 
Core safety evaluation and frequency .................................................313 
 

 
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1 
Introduction 
1.1 
Overview of Autosomal Dominant Polycystic Kidney and Liver Disease:  
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal 
disease, affecting 1 in 400 to 1000 live births.1 ADPKD is caused by mutations in the PKD1 and 
PKD2 genes, and progresses to end-stage renal disease at a mean age of 55 years and 69 
years, respectively.1-3 Hepatic cysts are the most common extra-renal manifestation of ADPKD 
and occur in the majority of these patients.4 Cysts increase with age and may cause considera-
ble morbidity; including abdominal pain and distension, rupture, hemorrhage, dyspnea, venous 
or biliary obstruction, and ascites. Some of these individuals are incapacitated due to massive 
polycystic liver disease (PLD). With increased lifespans due to dialysis and kidney transplanta-
tion, more patients with ADPKD develop severely symptomatic PLD. There are also patients 
with PLD without kidney disease due to mutations in different genes, some who develop severe 
incapacitating liver disease.5,6 
1.2 
Background 
1.2.1 Somatostatin Analogs – the first medical therapy for PLD 
Somatostatin (SST) analogs are the first medical therapy that have been demonstrated to be ef-
fective in reducing liver volume and improving quality of life in treated individuals with PLD. SST 
may blunt cyst development by acting at multiple levels: inhibition of secretin released by the 
pancreas;7 inhibition of secretin-induced cAMP generation and fluid secretion in cholangio-
cytes;8-10 vasopressin-induced cAMP generation and water permeability in collecting ducts by its 
effects on GI protein-coupled receptors;11-14 and suppression of the expression of IGF-1, vascu-
lar endothelial growth factor, and other cystogenic growth factors and of downstream signaling 
from their receptors. 
1.2.2 Pre-Clinical Studies with Somatostatin 
We have previously tested the effect of cAMP inhibition with the SST analog octreotide in an an-
imal model of PKD, the PCK rat, and observed a reduction in liver and kidney weight, cyst vol-
ume, fibrosis & cell proliferation.15 
1.3 
Somatostatin analogs in the treatment of patients with PLD 
In clinical trials SST analogs retard progression of PLD with up to one year of treatment.16-19 
Octreotide therapy also maintained the reduction in liver volume over two years in the Oc-
treotide LAR treated group, while it did not increase significantly during Year 2 (Δ% -5.96 
±8.90%; p =0.002) in our small study.20 Furthermore, using pooled analyses of all individuals 
who received Octreotide LAR depot® (OctLAR®) for 12 months (n=40, in years one or two), the 
cumulative reduction in liver volume was -6.08% ±7.58% (p=0.001) compared to a net growth of 
0.9±8.35% in the historical placebo treated group.21 
While OctLAR stimulates distinct SST receptors – SSTr 2, 3 and 5, all five receptor subtypes 
are expressed in rat and human and mouse cholangiocytes. Pasireotide (SOM230) exhibits high 
affinity binding to four of the five known human SST (HSST) receptors (SSTr 1-5) and binds with 
a 30 to 40 fold higher affinity than octreotide to the SST1 and -5 receptor subtypes with a five-
fold higher affinity to SST3. Because of the broader SST binding profile of pasireotide, and the 

 
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known SST receptor subtype expression in liver tissue, pasireotide has the potential to be more 
effective than preferential SST2 receptor- binding SST analogs. Therefore we hypothesized that 
the pharmacological targeting of cAMP by pasiroetide will be even more effective than 
cctreotide in inhibiting cAMP levels, in decreasing the rate of cell proliferation and reducing 
hepato-renal cystogenesis. 
1.4 
Pasireotide (SOM230) 
Pasireotide is an injectable SST analog. It is a novel cyclohexapeptide with the following chemi-
cal name: (2-Aminoethyl)carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-
benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-
phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-
aminosuccinic acid] salt. 
Like natural SST and other SST analogs (SRIFa), pasireotide exerts its pharmacological activity 
via binding to SST receptors. There are five known SST receptors: SST 1, 2, 3, 4 and 5. SST 
receptors are expressed in different tissues under normal physiological conditions. SST analogs 
activate these receptors with different potencies22 and this activation results in a reduced cellu-
lar activity and inhibition of hormone secretion. Sst receptors are strongly expressed in many 
solid tumors, especially in neuroendocrine tumors where hormones are excessively secreted 
e.g. acromegaly23 GEP/NET tumors24 and Cushing’s disease. 
The SRIFs currently approved for use in the clinic (octreotide and lanreotide) have a high affinity 
to the SST subtype 2 (SST2) receptor, with moderate or no affinity to the remaining subtypes. 
Pasireotide is a novel cyclohexapeptide SST analog that exhibits a unique binding profile, bind-
ing with high affinity to four of the five known HSST receptors (Table 1). Compared to Sando-
statin® (octreotide acetate), pasireotide exhibits a binding affinity, which is 30-40 times higher for 
HSST1 and HSST5, 5 times higher for HSST3, and 2.5 times lower for HSST2 receptor. A de-
tailed summary of available preclinical data is provided in the Investigators' Brochure. 
Additionally, preclinical studies suggest anti-tumor activity of SOM230. SOM230 has been found 
to significantly reduce cell proliferation of the neuroendocrine tumor cell line NCI-H727, whereas 
the conventional analog SMS 201-995 did not.25 
Table 1 
Binding profile for octreotide and pasireotide at HSST1-5 (IC50, M) 
Compound 
SST1 
SST2 
SST3 
SST4 
SST5 
Octreotide acetate (SMS 201-995) 
2.8x10-7 3.8x10-10 7.1x10-9 >10-6 6.3x10-9 
Pasireotide (SDZ 227-230) 
9.3x10-9 1.0x10-9 
1.5x10-9 >10-6 1.6x10-10 
Ratio of IC50:octreotide acetate / pasireotide SMS/SOM230 30 
0.4 
5 
-- 
40 
1.5 
Clinical experience with pasireotide 
Pasireotide is available as a short-acting subcutaneous (SQ) formulation and a long acting re-
lease (LAR) intramuscular (IM) formulation. 
1.5.1 Pasireotide SQ 
Single dose of pasireotide SQ up to 1500 μg q.d. and 750 μg b.i.d. multiple SQ doses (7-14 
days) up to 1500 μg q.d., 750 μg b.i.d. and 2100 μg b.i.d. (up to 5 days), and continuous (7-day) 
SQ infusion by insulin pump, have been well-tolerated, with mostly mild, transient side effects 
reported. The most reported adverse events (AEs) were GI related (mild diarrhea and nausea), 
requiring no treatment or study discontinuation. The frequency of these AEs appeared to de-

 
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crease with time in multiple-dose studies. AEs were assessed using the NCI-CTC for Adverse 
Events, version 3.0 (CTCAEv3.0, [http://ctep.cancer.gov/forms/CTCAEv3.pdf]). 
Single and multiple doses of pasireotide SQ have generally been well-tolerated by patients with 
acromegaly, metastatic carcinoid tumor, or Cushing’s disease. Pasireotide has been studied in 
phase II studies at doses of up to 600 μg b.i.d. for acromegalic patients, 900 μg b.i.d. for pa-
tients with Cushing’s disease, and 1200 μg b.i.d. for patients with carcinoid tumors, with pasire-
otide treatment periods of 4 years, 4.8 years and 1.6 years, respectively. For all these indica-
tions the most frequent AEs are similar to what have been reported in healthy volunteers, 
predominantly mild diarrhea, nausea, and abdominal pain. 
Hyperglycemia was also observed across all indications. The effect on blood glucose was more 
pronounced in patients with Cushing’s disease, a setting in which glucose metabolism is inher-
ently dysregulated. The hyperglycemic effect in healthy volunteers (phase I study) is less pro-
nounced when administered with a breakfast meal and appears to decrease after multiple doses 
indicating an attenuation of effect over time. The underlying mechanism of hyperglycemia fol-
lowing pasireotide is thought to be due to the decrease in insulin secretory capacity with no ef-
fect on insulin sensitivity; however the effect of pasireotide on glucagon level is smaller. In 
phase II studies, fasting blood glucose increase tended to occur with increasing doses and ap-
peared to be more notable in patients who had a history of hyperglycemia or diabetes mellitus, 
hypertension and hyperlipidemia prior to receiving pasireotide. Although hyperglycemia was fre-
quently reported, few grade 3 or 4 AEs or SAEs or discontinuation due to AEs related hypergly-
cemia were reported. 
Although no pre-clinical or clinical studies have revealed any specific pasireotide-related cardiac 
toxicity issues, an effect of pasireotide on QTcF interval at 1950 μg SQ b.i.d. in healthy volun-
teers was demonstrated. The QTcF change from baseline showed a peak effect at 2-hour post-
dose of pasireotide SQ was 17.5 ms versus placebo. 
1.5.1.1 
Pasireotide LAR 
A total of 85 patients were enrolled in the [CSOM230C2110] study and received at least one 
dose of pasireotide (SQ and/or LAR injection). Of these, 40 patients were diagnosed with acro-
megaly and 45 with carcinoid tumors. Patients received a single dose of 300 μg Pasireotide SQ 
followed by a washout period of at least 5 days. Patients subsequently received 3 monthly ad-
ministration of pasireotide LAR IM. 
In patients with acromegaly, the most common AE overall and by treatment group was diarrhea 
affecting 12/35 patients in total, 3/10, 3/12 and 6/13 in the pasireotide LAR 20 mg, 40 mg and 
60 mg group, respectively. Majority of the diarrhea were CTCAE grade 1 and none were seri-
ous. Frequent AEs only reported in the 40 mg and 60 mg groups included abdominal distension, 
cholelithiasis, blood glucose increased, hyperglycemia and hematuria. All events but blood glu-
cose increased in the 40 mg group (2 patients) and hyperglycemia in the 60 mg group (3 pa-
tients) were observed for one patient in each of the two groups. 
In patients with carcinoid tumors, diarrhea was the most frequent AE affecting 4 patients in each 
treatment group (4/12 in the 20 mg group, 4/14 in the 40 mg group, and 4/16 in the 60 mg 
group). Diarrhea side-effects were of CTCAE grade 1 or 2 for all patients, except for one patient 
in the pasireotide LAR 20 mg group, for which the AE was reported as grade 3. Other frequently 
reported AEs were fatigue (9/42 patients), asthenia (5/42 patients), diabetes mellitus (6/42 pa-
tients), anorexia (5/42 patients), back pain (4/42 patients) and muscle spasms (3/42 patients). 
CTCAE grade 3 or 4 that were suspected to pasireotide LAR were primary hyperglycemia and 

 
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were reported in all dose groups. CTCAE grades 3/4 elevation of blood glucose level was re-
ported in 18/42 (43%) patients. Median time to grades 3/4 elevation of blood glucose occurred 
on day 1 of cycle 1 (range 1-1131 days), approximately 6 hours (range 2-8 hours) post-dose. 
Given the observed suppression of insulin secretion associated with pasireotide administration, 
the use of insulin secretagogs and/or incretin-based therapies may be particularly suited for the 
treatment of pasireotide induced glucose dysregulation. 
1.5.1.1.1 Clinical pharmacokinetics 
Pasireotide SQ and LAR have been studied in healthy volunteers, patients with acromegaly, 
Cushing’s disease and carcinoid syndrome. Following a single IM injection of 40 mg or 60 mg in 
healthy volunteers [CSOM230C2101], pasireotide LAR demonstrated a controlled release type 
of concentration-versus-time profile, with an initial spike phase on day 1 followed by a slow-
release process for up to 42 days. The Cmax of the extended release phase was observed ap-
proximately on day 20 for both dose levels. Pasireotide LAR was also investigated in patients 
with acromegaly and carcinoid tumors [CSOM230C2110]. Following monthly (q28 days) IM in-
jections of 20, 40, or 60 mg pasireotide LAR, preliminary results showed an approximately linear 
dose-exposure proportionality and a steady state achieved following 3 injections. The PK expo-
sure to pasireotide at steady state in acromegalic patients was comparable to the simulated PK 
exposure at steady state in healthy volunteers, whereas, the PK exposure in patients with car-
cinoid tumors was roughly 2-fold that in acromegalic patients. 
1.5.1.2 
Phase II studies of pasireotide SQ in neuroendocrine tumors 
Preliminary safety data are available from a Phase II study [CSOM230B2202] in 45 patients with 
symptomatic metastatic carcinoid disease who received pasireotide SQ doses from 300 µg SQ 
b.i.d. up to 1200 µg b.i.d. for a mean of 20 weeks. Overall pasireotide SQ has been found to be 
generally well-tolerated by these patients, with the most common adverse events being mild di-
arrhea, nausea and abdominal pain. Blood glucose increases tended to occur with increasing 
dose, but were moderate and generally managed easily by adjustment in oral hypoglycemic 
medications. Weight loss was also observed in 18 patients. Maximum weight loss occurred with-
in 4-6 months on the study drug, with a stabilization of effect after approximately 6 months. 
There was no apparent relationship between the weight loss and pasireotide dose. 
Preliminary efficacy data from this study also support that pasireotide is active in patients refrac-
tory/resistant to Sandostatin LAR, as partial or complete symptom control was observed in 12 of 
44 patients (27%). Complete response was achieved in two patients at the pasireotide 600 µg 
SQ b.i.d. dose and one at the 900 µg SQ b.i.d. dose. Nine patients achieved partial response to 
treatment, three at each of the following doses: 600, 750, and 900 µg SQ b.i.d. 
1.5.2 Pasireotide LAR 
Most of the experience with pasireotide comes from healthy volunteer and patient studies eval-
uating the subcutaneous formulation of pasireotide. Pasireotide LAR is being evaluated in two 
studies, one healthy volunteer study and one study involving patients with acromegaly and car-
cinoid disease. 
1.5.2.1 
Pasireotide LAR in healthy volunteers 
Preliminary data from the healthy volunteer study found single IM doses of pasireotide LAR, at 
doses of up to 40 mg and 60 mg, respectively, to be well-tolerated. The most common AEs 

 
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were gastrointestinal. Diarrhea was experienced by most of the subjects and was sometimes 
associated with abdominal pain, flatulence, and/or nausea. The gastrointestinal events were 
mild or moderate in severity. About 38% of subjects reported mild injection site pain and about 
15% reported headaches. 
Transient elevations in liver function tests and/or pancreatic enzymes were observed in three 
subjects, all of which resolved and were not accompanied by any clinical symptoms. Mild in-
creases in fasting blood glucose were observed in some subjects during the pasireotide LAR 
treatment period. All elevations were asymptomatic, considered not clinically significant, and 
generally returned to normal within 3-4 weeks after the pasireotide LAR IM injection. 
1.5.2.1.1 Serious adverse events 
A cumulative search (data lock point 12 Oct 2011) of the Novartis safety database was per-
formed using MedDRA 14.0 on SMQ “Drug related hepatic disorders – comprehensive search.” 
This search retrieved one serious case of increased liver enzymes which meets Hy’s law criteria 
in a young female patient with Cushing’s disease who appeared jaundiced and fully recovered 
upon discontinuation of pasireotide. Nine days after the start of pasireotide the laboratory values 
were as follows: total bilirubin 94 μmol/l (3.9x ULN), ALP 157 U/L (1.4x ULN), ALT 568 U/L 
(10.3x ULN), AST 251 U/L (5.6x ULN), and lactate dehydrogenase 300 U/L (1.3x ULN). All liver 
function tests were within normal limits 45 days after discontinuation of pasireotide. This report 
was released as an Investigator notification in September 2010, with follow-up Investigator noti-
fications in October 2010 and May 2011 (PHHO2010AU13717). 
1.5.2.1.2 Liver safety analysis of studies conducted with pasireotide–phase I-III studies 
A review of the unblinded data from the clinical program with the pasireotide LAR formulation 
did not reveal cases meeting the Hy’s law criteria. Across the clinical development program with 
pasireotide SQ to date: 
654 healthy volunteers have been exposed to pasireotide SQ: 
3 (0.5%) met the biochemical criteria of Hy's law (see details above) 
16 (2.4%) subjects had an ALT/AST > 3x, < 5x ULN 
3 (0.5%) of the subjects had an ALT/AST > 5x ULN 
17 (2.6%) subjects had a total bilirubin of 2x ULN (including 7 patients with pre-existing liver 
disease and elevations of total bilirubin); 
156 patients in phase 1 and phase 2 trials have been exposed to pasireotide SQ: 
None of the patients met the biochemical criteria of Hy's law 
6 (3.8%) patients had an ALT/AST > 3x, < 5x ULN 
4 (2.6%) patients had an ALT/AST > 5x ULN 
2 (1.3%) patients had a total bilirubin of 2x ULN; 
162 patients with Cushing’s disease in phase 3 trials have been exposed to pasireotide SQ: 
None of the patients met the biochemical criteria of Hy's law 
8 (4.9%) patients had an ALT/AST > 3x, < 5x ULN 
1 (0.6%) patients had an ALT/AST > 5x ULN 

 
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None of the patients out of 162 with Cushing’s disease had a total bilirubin of 2x ULN. 
Approximately 200 patients in the compassionate use program have been exposed to pasire-
otide SQ to date. There was one serious case of a patient with Cushing's disease who met the 
biochemical criteria for Hy's law. This case (PHHO2010AU13717) is discussed above. (See In-
vestigator Notification for pasireotide [SOM230] October 31, 2011)  
 
Novartis released an Investigator Notification dated 31 Oct 2011 that provided updated infor-
mation regarding reversible liver chemistry elevations in 3 healthy volunteer subjects meeting 
the biochemical criteria for Hy’s Law in two cases and potentially meeting Hy’s Law criteria in 
one case (missing ALP value and confounding concomitant medication). All three cases were 
asymptomatic and reversible and the degree of the increase in aminotransferase levels was < 
4x ULN. The investigators did not consider the laboratory abnormalities in healthy volunteers as 
adverse events and consequently did not report them as such.  
While Novartis considers the risk-benefit ratio for SOM230 to remain positive, they are imple-
menting the following urgent safety measures by means of this communication to ensure the 
safety of patients.  
For studies with ongoing enrollment using the LAR formulation: Liver function tests (LFTs) must 
be assessed at screening, baseline, Day 22 after the first injection, Day 29, Day 50, Day 57 and 
Day 85. After Day 85, monitoring should follow the existing protocol schedule. The Day 22 and 
Day 50 LFTs must be available and assessed prior to dosing on Day 29 (2nd injection) and Day 
57 (3rd LAR injection).  For studies with ongoing enrollment using s.c. or LAR formulation: Re-
vised exclusion criteria for LFTs (Table 1).  
For all ongoing studies: Additional hepatic management (i.e. liver-directed history and physical 
examination, LFTs, hepatitis screen, abdominal ultrasound, and PK sample) is to be implement-
ed within 72 hours of awareness of abnormal liver function tests. Follow-up LFT monitoring will 
take place at 3-4 day intervals for all s.c. and LAR studies (Table 2). 
For all ongoing studies: Additional LFT discontinuation criteria are to be implemented (Table 7).  
An algorithm of LFT management for all SOM230 s.c. and LAR studies is provided in appendix 
4. 
1.5.2.2 
Pasireotide LAR in PLD patients 
Preclinical studies in the PCK rat (a recessive model of polycystic kidney and liver disease) 
showed that the SST analog octreotide reduces cAMP levels in kidney and bile ducts and slows 
the progression of hepato-renal cystogenesis.15 We previously completed a double-blinded, 
randomized, placebo-controlled clinical trial (NCT00426153) using OctLAR over 1 year in forty-
two patients with severe polycystic liver disease (PLD), due to autosomal dominant polycystic 
liver disease (ADPLD) or autosomal dominant polycystic kidney disease (ADPKD). By magnetic 
resonance imaging, the mean liver volume decreased from 5907 to 5557 ml (4.95 ±7.00%) in 
the octreotide group (n = 28) compared with 5374 to 5361 ml (0.92 ±_7.00%) in the placebo 
group (n =14). This difference (mean 4.95 versus 0.92%) was significant (P= 0.045). The self-
reported SF-36 quality of life form demonstrated a significant improvement in perception of body 
pain and physical function in octreotide-treated patients.18 Moreover, three separate prospective 
clinical trials have now shown similar positive effects of SST analogs in ADPLD and ADPKD.16-
19,26 A few other published reports relating to the use of SST analogs further substantiate these 
observations.17,26-28 All of these studies were limited by small numbers of enrolled patients with a 

 
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short follow-up of 6-12 months. In order to evaluate whether SST analog therapy sustains retar-
dation of liver and kidney growth beyond one year, our protocol design included a second year 
of open-label active therapy with OctLAR. We completed an open-label extension with OctLAR 
for 1 additional year, to assess safety & clinical benefits over 2 years (O→O) and examine drug 
effects in the placebo group who crossed over to OctLAR in year 2 (P→O).21 The primary end-
point was a change in total liver volume (TLV); secondary endpoints were changes in total kid-
ney volume (TKV), glomerular filtration rate (GFR), quality of life (QOL), safety, vital signs, & lab 
parameters. Forty-one of 42 patients that received OctLAR (n=28) or placebo (n=14) in year 1 
received OctLAR in year 2 (max dose 40 mg). Patients originally randomized to placebo (P→O) 
showed substantial reduction in TLV after treatment with OctLAR in year 2 (-7.66±9.69%; p= 
0.011). The initial reduction of TLV in the OctLAR group (O→O) was maintained for 2 years (-
5.96± 8.90%), although it did not change significantly during year 2 (-0.77±6.82%). OctLAR in-
hibited renal enlargement during year 1 (+0.42±7.61%), but not throughout year 2 in the O→O 
group (+6.49±7.08%); and in the P→O group in year 2 (-0.41±9.45%). Using pooled analyses of 
all individuals who received OctLAR for 12 months (n=40; in years 1 & 2), reduction in TLV was 
-6.08%±7.58% (p=0.001) compared to net growth of 0.9±8.35% in the (P→O) group. 
Changes in GFR were similar in both groups. Over 2 years OctLAR significantly reduced the 
rate of increase in TLV and possibly the rate of increase in TKV. While OctLAR inhibited renal 
enlargement within the first year of treatment, it appeared to lose effectiveness during year 2. 
Several reasons may account for the reduction of effect seen in year 2. First, SST receptors 
may undergo receptor down-regulation / desensitization (probably by endocytosis of the recep-
tor-ligand complexes) after prolonged exposure to OctLAR.29-31 Second, we did not monitor 
OctLAR levels in plasma, its metabolism, cAMP concentration, or whether levels of the effectors 
IGF, GH, or EGF were modulated by therapy. In the pre-clinical animal studies, liver and kidney 
effects were dose-dependent, therefore higher doses of SST analogs may be required.15 Third, 
OctLAR is known to bind to three out of five known SSTs (SST2, SST3 and SST5). At this point, 
we do not know what SST receptors are present in liver and kidneys of our patients, and how 
their expression is different from normal hepatic and renal epithelia. Thus, the use of more po-
tent SST analogs (e.g. SOM230, pasireotide) that bind to a broader range of SST receptors 
might be more efficient (figure 1). This treatment if successful could impact greatly on quality of 
life and decrease morbidity and mortality related to PLD in these patients. A subset of individu-
als is incapacitated due to massive PLD and the numbers of patients in this subset are steadily 
increasing, due to increased lifespan because of dialysis and kidney transplantation. This study 
will evaluate the effect of SOM230 LAR® on the liver volumes of patients with severe PLD who 
are not candidates or decline surgical treatments such as liver cyst fenestration, liver resection 
or liver transplantation and therefore have no further therapeutic options.  
1.5.2.2.1 Pre- Clinical Studies with Pasireotide in PLD 
Dr. Masyuk (Mayo Clinic) has recently completed comparative studies of octreotide and pasire-
otide and shown that pasireotide decreased hepatorenal cystic and fibrotic volumes in PCK rats 
and Pkd2ws25/- mice. She found in all experiments that the effects of pasireotide were signifi-
cantly greater compared to octreotide – see Tables 2 and 3.32 

 
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Table 2 
Gross anatomy, cystic and fibrotic volumes, in PCK rats 
In the PCK rat model of PLD, liver weight decreased by 27.7% in males and 23.9% in females 
and cyst volume decreased by 41.7% compared with controls. Renal cyst volume decreased by 
30.4% compared with controls (p 0.0001). In a second animal model Pkd2ws25/- mice (Table 
3), liver weight decreased by 26% compared with controls (p=0.05), hepatic cystic areas de-
creased by 44.1% compared with controls (p=0.0007). Hepatic fibrotic area decreased by 
35.6% compared with controls (p=0.0001). Renal cystic area decreased by 35.6% on pasire-
otide compared to controls (p=0.0001). In primary cultures of normal and rat cholangiocytes, 
pasireotide was more effective in reducing proliferation of PCK cholangiocytes and growth of 
normal cholangiocytes (p<0.05, compared with octreotide) and also in reducing cyst growth in 
primary (3D) cell culture (p<0.05 compared with octreotide) (Figure 1). Therefore these pre-
clinical data provide strong justification for further clinical evaluation of the effects of pasireotide 
in individuals with polycystic liver and kidney disease. 
Parameters 
Control 
OCT 
PAS 
OCT vs control 
PAS vs control 
OCT vs PAS 
p 
%  
change 
p 
% 
change 
p 
% 
change 
Body wt (g): 
 
Male 
 
Female 
430.3±22.9 
253.7±6.57 
411.8±8.93 
244.0±6.54 
371.6±6.11 
232.8±12.86 
NS 
NS 
-4.3 
-3.8 
0.003 
0.05 
-13.6 
-8.2 
0.006 
NS 
-9.8 
-4.6 
Liver wt (g): 
 
Male 
 
Female 
27.20±1.59 
18.63±0.42 
23.60±0.83 
16.10±0.71 
19.36±1.17 
14.17±0.54 
0.02 
0.05 
-13.2 
-13.6 
0.003 
0.009 
-27.7 
-23.9 
0.001 
0.05 
-16.6 
-12.0 
Liver wt 
(% bw): 
 
Male 
 
Female 
6.32±0.11 
7.35±0.17 
5.74±0.18 
6.59±0.18 
5.30±0.14 
6.07±0.11 
0.01 
0.03 
-9.2 
-10.4 
0.002 
0.003 
-16.2 
-17.4 
0.02 
0.04 
-7.7 
-7.8 
Kidney wt (g): 
 
Male 
 
Female 
6.27±0.16 
4.20±0.17 
5.60±0.16 
3.75±0.11 
4.82±0.11 
3.33±0.10 
0.01 
0.03 
-10.6 
-10.7 
0.001 
0.001 
-23.1 
-20.6 
0.003 
0.01 
-13.9 
-11.1 
Kidney wt 
(% bw): 
 
Male 
 
Female 
1.47±0.12 
1.66±0.05 
1.36±0.09 
1.54±0.08 
1.30±0.08 
1.44±0.05 
0.01 
0.008 
-6.6 
-7.3 
0.001 
0.04 
-11.3 
-12.8 
0.05 
0.006 
-5.0 
-5.9 
Hepatic cystic 
volume 
12.20±1.67 
9.22±1.75 
7.11±1.11 
0.0001 -24.4 
0.0001 -41.7 
0.0001 -22.9 
Hepatic fibrotic 
volume 
7.55±0.56 
6.74±0.34 
6.11±0.39 
0.05 
-10.9 
0.002 
-19.3 
0.05 
-9.4 
Renal cystic vol-
ume 
17.23±1.62 
13.48±1.33 
11.99±1.28 
0.0001 -21.7 
0.0001 -30.4 
0.0001 -11.06 
Renal fibrotic 
volume 
2.68±0.11 
2.22±0.15 
2.07±0.14 
0.001 
-17.3 
0.001 
-22.9 
0.04 
-6.7 

 
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Table 3 
Gross anatomy, cystic and fibrotic volumes, in Pkd2ws25 -/- mice 
 
 
2 
Study Rationale/Purpose 
Pasireotide (SOM230) is a novel multi-receptor-targeted analog that has high affinity for four of 
the five SST receptor subtypes (SSTr1, SSTr2, SSTr3 and SSTr5);22 33 33 it has a 40-fold higher 
affinity and 158-fold higher functional activity for the SST5 receptor than octreotide. Because of 
its broad receptor binding profile, pasireotide may be more potent in PLD than octreotide. In this 
randomized double blind placebo controlled trial we will compare SOM230 treatment to placebo 
for 12 months in patients with PLD. The primary endpoints will be assessed at 12 months and 
patients receiving placebo then crossed over to SOM230, permitting all participants to receive 
SOM230 for the subsequent two years. MRI will be used to assess liver volume – the primary 
endpoint, which will be assessed at baseline, end of years 1 and 3. This study will assess the 
efficacy and safety of SOM230 in reducing total liver volume and improving quality of life over 
12 months (we will not be assessing efficacy at 24 months. The therapy way be effective in PLD 
but also may prove to be effective for many more patients with PKD which will be evaluated us-
ing eGFR and kidney volume using MRI.  
Parameters 
Control 
OCT 
PAS 
OCT vs control 
PAS vs control 
OCT vs PAS 
p 
%  
change 
p 
% 
change 
p 
% 
change 
Body wt (g): 
31.60±3.57 
33.76±2.49 
33.92±1.53 
NS 
6.8 
NS 
7.3 
NS 
0.5 
Liver wt (g): 
3.60±0.47 
2.76±0.18 
2.65±0.12 
0.05 
-23.3 
0.05 
-26.4 
NS 
-3.9 
Liver wt (% bw): 
11.57±1.21 
8.35±0.73 
7.62±0.53 
0.02 
-27.9 
0.01 
-34.1 
NS 
-8.7 
Kidney wt (g): 
0.65±0.09 
0.56±0.04 
0.55±0.06 
NS 
-13.5 
NS 
-14.2 
NS 
-0.8 
Kidney wt (% bw): 
2.08±0.14 
1.69±0.11 
1.59±0.08 
0.03 
-18.6 
0.008 
-23.7 
NS 
-6.2 
Hepatic cystic ar-
ea 
41.55±4.73 
29.75±2.53 
23.24±1.16 
0.03 
-28.4 
0.0007 -44.1 
0.03 
-21.9 
Hepatic fibrotic 
area 
2.29±0.16 
1.77±0.12 
1.39±0.09 
0.02 
-22.5 
0.0001 -39.5 
0.003 
-21.7 
Renal cystic area 
31.83±2.85 
23.69±2.15 
20.24±1.99 
0.002 
-25.6 
0.0001 -35.6 
0.03 
-13.5 
Renal fibrotic area 
1.49±0.11 
1.23±0.04 
1.06±0.06 
0.0006 -18.0 
0.0001 -29.5 
0.003 
-14.1 
Figure 1:  Role of octreotide (OCT) 
and Pasireotide (PAS) treatment in 
hepatic cystogenesis. Our experi-
mental data suggest that expression 
of SSTR1, 2 and somatostatin level 
are decreased in cystic cholangio-
cytes that results in cAMP elevation 
and activation of the cellular pro-
cesses involved in hepatic cystogen-
esis.  However, the expression of 
SSTR3, 4 and 5 did not change. 
Thus, treatment of cystic cholangio-
cytes with OCT (binds to SSTR2, 3 
and 5) or PAS (binds to SSTR1, 2,3 
and 5) should lead to cAMP inhibition 
and decreased growth of hepatic 
cysts. 

 
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2.1 
Selection of doses 
Patients will be treated with SOM-230 (pasireotide LAR) 60mg IM once every 28 days or place-
bo year 0-1. All participants will receive pasireotide LAR years 2 and 3. Each cycle is 28 ± 2 
days. There will be no dose titration above the 60mg dose but there may be dose reduction to 
20mg if patients do not tolerate 60mg or 40mg. 
2.2 
Placebo dose 
The placebo dose will be monitored and adjusted monthly in a similar fashion.  
3 
Objectives 
3.1 
Primary objectives 
The primary objectives of this study will be to evaluate the absolute and percent changes in liver 
volume from baseline to month 12 in the treatment arm compared to the placebo arm. We will 
also evaluate the adverse events throughout the length of the study and as reported at 12 and 
36 months of treatment. 
3.2 
Secondary objectives 
Absolute and percent changes in liver volume in the placebo group before (year 1) and after 
(years 2-3) cross-over to active treatment 
Absolute and percent changes in liver volume in the treatment arm during years 2-3 compared 
to the placebo arm during year 1 
Changes in eGFR from baseline (or from month 3) at 12 and 36 months in individuals with 
ADPKD 
Changes in kidney volume from baseline at 12 and 36 months in individuals with ADPKD 
Symptoms at baseline,12 and 36 months. Changes in symptoms, measured by SF36-
questionnaire QOL-questionnaire 
Quality of Life at baseline,12 and 36 months. Changes in quality of life, measured by SF36-
questionnaire (SF-36v2™) 
Responders at 12 and 36 months. 
3.3 
Tertiary objective 
Longitudinal changes beyond 12 months in above factors, stratified by treatment sequence. 
4 
Study design 
This study will be conducted over 3 years as a randomized, double-blind control, clinical trial 
through year 1, followed by an open-label extension phase for the subsequent 2 years. Screen-
ing and randomization visits will take place at Mayo Clinic and patients will then be followed by 
Mayo Clinic for three years. We will monitor the patients with blood and urine tests on days 22, 
29, 50, 57 and 89 and then at Months 6,9, 12, 15, 18, 24, 27, 30, 33 and 36. Follow up visits will 
occur at one and three months post last dose of study drug. For patients who received placebo 
during year one, the labs on days 22,29,50,27 and 85 will be repeated as these are safety labs. 
All patients will be required to undergo MRI or CT scan imaging at the baseline, 12 month (end 

 
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of year 1) and 36 month (end of year 3) visits to fulfill the primary study endpoints. Safety moni-
toring with ECG, Hemoglobin A1C, liver function and glucose testing will be performed locally at 
the study sub-sites and monitored centrally by study staff at Mayo Clinic. 
 
Patients will be recruited during visits to the Department of Nephrology and Hypertension 
 
Patients who had participated in previous studies will also be contacted as long as they meet all 
eligibility criteria. We will also recruit through clinicaltrials.gov ( http://clinicaltrials.gov ), Mayo 
Clinic Trials website ( http://clinicaltrials.mayo.edu/ ) and PKD foundation clinical trials   ( 
http://www.pkdcure.org/Research/ClinicalTrials/ActiveRecruiting.aspx )listed on the web .  Pa-
tients who contact the study coordinator will be given information regarding the study and partic-
ipation.  The study coordinator will screen those interested and proceed with the study design 
for all patients who would like to participate. 
  
4.1 
Treatment 
Forty-eight patients with severe PLD identified at a single Center, Mayo Clinic, Rochester, MN 
will be stratified with randomization in a 2:1 allocation to SOM230 or placebo in year 1, in this 
study. All participants will be offered SOM230 in years 2 and 3. Recruitment of patients is ex-
pected to occur relatively rapidly (over the first 6 months) as a result of the Mayo Clinic’s large 
referral base for patients with ADPKD and ADPLD and we have more than 140 patients who 
wish to be notified if clinical trials with SST analogs for PLD become available. 
4.2 
Follow-up 
Follow up will continue until 3 months after last injection to monitor hemoglobin A1C.  
4.3 
Treatment extension 
No further treatment extension is planned beyond the three years of this protocol. 
5 
Population 
5.1 
General criteria 
A total of 48 patients (45 + 3 to allow for dropouts) with severe PLD with either autosomal domi-
nant polycystic kidney (ADPKD) or autosomal dominant liver disease (ADPLD) will be enrolled. 
To enroll a patient, call 
. Study personnel will check patient el-
igibility and the existence of a signed consent form before treatment is begun.  
Limited Travel reimbursement  is provided. Costs of tests obtained for the sole purpose of this 
study will be defrayed from study funds. Costs of tests necessary for patient's usual evaluation 
and management will be borne by patient and his/her health coverage. Pasireotide-LAR safety 
data, the absence of other medical treatment modalities for this group of patients, and prelimi-
nary experimental and clinical observations justify such a study. Patients must meet all criteria 
listed below. The investigator or her designee must ensure that all patients who are offered en-
rollment in the study meet all of the following inclusion and exclusion criteria. This will be a sin-
gle center study at Mayo Clinic, Rochester, MN. 

 
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5.2 
Inclusion/exclusion criteria 
The investigator or her designee must ensure that all patients who are offered enrollment in the 
study meet all of the following inclusion and exclusion criteria: 
5.2.1 Inclusion criteria 
Male or female Age ≥ 18 years.  
Diagnosis of PLD associated with ADPKD (meeting the Modified Ravine’s criteria)34 or isolated 
ADPLD (defined by the criteria described by Reynolds et al)35.  
Severe PLD defined as a liver volume >4000mL or symptomatic disease due to mass effects 
from hepatic cysts (must be able to undergo MRI or CT scan to determine this).  
Not a candidate for or declining surgical intervention.  
Capable of providing informed consent. 
Life expectancy ≥12 weeks 
Patients with a known history of impaired fasting blood glucose (glucose >100 and <126) may 
be included at the discretion of the PI. These patients should be monitored closely throughout 
the trial and anti-hyperglycemic treatment adjusted as necessary. Patients that are deemed non 
eligible due to elevated glucose can be re-screened after adequate medical treatment. 
Adequate end organ function as defined by: 
Adequate bone marrow function: 
• WBC ≥ 2.5 x 109/L 
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L  
• Platelets ≥ 100 x 109/L  
• Hb ≥ 9 g/dL 
No evidence of significant liver disease:  
• Serum bilirubin ≤1.5 x ULN 
• INR < 1.3 
• ALT and AST ≤ 2 x ULN 
Estimated glomerular filtration rate (eGFR) >30 ml/min/m2 
Serum amylase and lipase ≤ 1.5 x ULN 
Alkaline phosphatase ≤ 2.5 x ULN  
Written informed consent obtained prior to any screening procedures 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and 
other study procedures 
5.2.2 Exclusion criteria 
Patients will be considered ineligible for this study if they meet any of the following criteria: 
Patients with a known hypersensitivity to SST analogs or any component of the pasireotide LAR 
or SQ formulations. 

 
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Patients with known malabsorption syndrome, short bowel or chologenic diarrhea not controlled 
by specific therapeutic means. 
Patients with abnormal coagulation (PT or a PTT elevated by 30% above normal limits). 
Patients on continuous anticoagulation therapy. Patients who were on anticoagulant therapy 
must complete a washout period of at least 10 days and have confirmed normal coagulation pa-
rameters before study inclusion. 
Patients with symptomatic cholelithiasis. 
Patients who are not biochemically euthyroid. 
Patients with known history of hypothyroidism are eligible if they are on adequate and stable re-
placement thyroid hormone therapy for at least 3 months. 
Serum magnesium ≥ ULN 
QT-related exclusion criteria: 
QTcF at screening > 470 msec  
Patients with a history of syncope or family history of idiopathic sudden death  
Patients who have sustained or clinically significant cardiac arrhythmias 
Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac failure, 
clinically significant/symptomatic bradycardia, or high-grade AV block  
Patients with concomitant disease(s) that could prolong QT such as autonomic neuropathy 
(caused by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or 
cardiac failure  
Family history of long QT syndrome 
Concomitant medications known to prolong the QT interval. 
Potassium < or = to 3.5 
Patients who have any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 
Patients who have Uncontrolled diabetes as defined by HbA1c>8%* despite adequate therapy 
Patients with the presence of active or suspected acute or chronic uncontrolled infection or with 
a history of immunodeficiency, including a positive HIV test result (ELISA and Western blot). An 
HIV test will not be required; however, previous medical history will be reviewed. 
Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by 
the treatment with this study treatment. 
Liver disease such as cirrhosis, decompensated liver disease, chronic active hepatitis or chronic 
persistent hepatitis. 
Baseline ALT or AST >3x ULN 
Patients with life-threatening autoimmune and ischemic disorders. 
Uncontrolled hypertension 
Patients who have a history of a primary malignancy, with the exception of locally excised non-
melanoma skin cancer and carcinoma in situ of uterine cervix. (Patients who have had no evi-

 
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dence of disease from primary cancer for 3 or more years are allowed to participate in the 
study.) 
History of pancreatitis 
Patients with a known history of hepatitis B or C 
Presence of Hepatitis B surface antigen (HbsAg) 
Presence of Hepatitis C antibody (anti-HCV) 
Patients with a history of, or current, alcohol misuse/abuse within the past 12 months 
Known gallbladder or bile duct disease, acute or chronic pancreatitis 
Patients who have any current or prior medical condition that may interfere with the conduct of 
the study or the evaluation of its results in the opinion of the Investigator or the Sponsor’s Medi-
cal Monitor 
Use of an investigational drug within 1 month prior to dosing 
Patients with a history of non-compliance to medical regimens or who are considered potentially 
unreliable or will not be able to complete the entire study 
Females who are pregnant or lactating, or are of childbearing potential (defined as all women 
physiologically capable of becoming pregnant) and not practicing an effective method of contra-
ception/birth control. Sexually active males must use a condom during intercourse while taking 
the drug and for 2 months after the last dose of the study drug and should not father a child in 
this period. A condom is required to be used also by vasectomized men in order to prevent de-
livery of the drug via seminal fluid. Effective contraception methods include: 
Use of oral, injected or implanted hormonal methods of contraception   
Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/ vaginal suppository  
Total abstinence or  
Patient sterilization (male or female) 
6 
Treatment 
6.1 
Investigational and control drugs  
6.1.1 SOM230C / Placebo 
Pasireotide LAR (long-acting release) IM depot injection: 
Inactive ingredients of pasireotide LAR include: mannitol, carmellose sodium (carboxymethyl-
cellulose sodium), poloxamer 188 and water for injection. Inactive ingredients of pasireotide SQ 
include: mannitol, tartaric acid, sodium hydroxide and water for injection. For detailed infor-
mation on pasireotide, please refer to Sections 1.3 and 1.4 of the Pasireotide Investigator Bro-
chure. 
Placebo:  
The placebo will have an appearance similar to SOM230. 

 
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6.1.2 How supplied 
Pasireotide LAR IM depot injections will be supplied in open-label packaging by Novartis as a 
powder in vials containing 20 mg, 40 mg and 60 mg labeled as SOM230 LAR or placebo, with 
ampoules containing 2mL of vehicle (for reconstitution). 
No syringes or needles will be provided with the pasireotide study drug supplies.  
The placebo will be supplied (as powder) for mixing with injection solution by Novartis. 
6.1.3 Preparation and storage 
Prior to reconstitution, vials should be brought to room temperature. Pasireotide LAR should 
then be prepared as shown in Table 4. 

 
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Table 4 
Handling and preparation of pasireotide LAR dose 
Doses should be prepared and administered immediately after preparation.  For additional de-
tails regarding preparation, refer to Appendix 4.  
Novartis will supply pasireotide LAR as long as the patient remains on study, shows continuous 
benefit from treatment, and there are no safety concerns. Medication labels will comply with the 
legal requirements of the U.S. and will be printed in English. The storage conditions for pasire-
otide LAR will be described on the medication label. Bottles must be stored in a safe, secure lo-
cation.  
All study medication will be supplied to Mayo by Novartis. Mayo Research Pharmacy will be re-
sponsible for storage of medication.  An accurate record of the date and amount of study drug 
dispensed to each subject must be available for inspection at any time. 
All drug supplies are to be used only for this protocol and not for any other purpose. Unless 
specifically instructed by Novartis, the investigator must not destroy any drug labels. All unused 
or damage drug will be sent to ALMAC Clinical Services. The storage condition for the study 
drug will be described on the medication label. 
6.1.4 Administration 
Pasireotide LAR/placebo will be administered IM intragluteally, every 4 weeks. The starting 
dose will be 60 mg. The reconstitution has to be performed just prior to administration of the 
suspension. A minimal standing time can be tolerated for the reconstituted suspension in the vi-
al. Prior to administration, the reconstituted suspension in the vial should be shaken again be-
fore withdrawal in the syringe. The IM injection must be given immediately after withdrawal of 
the reconstituted suspension from the vial to the syringe. 
All dosages prescribed and dispensed to the patient and dose changes during the study must 
be recorded. The investigational study drugs used in the course of this trial are pasireotide LAR 
(SOM230C)/ placebo. Novartis will supply pasireotide LAR and placebo free of charge for study 
participants. 
6.2 
Treatment arms 
There will be stratified randomization for PLD patients with ADPLD and ADPKD (see Table 5):  
All participants who receive the placebo during year one will be given the option to continue on 
study to receive active study drug for years two and three. Thus, all participants will be receiving 
SOM230 years two and three. 
Table 5 
Stratified randomization 
The initial assessment will be derived on a clinical 
basis as some individuals with ADPLD also may 
have kidney cysts. 
Dose 
Volume to be injected 
20 mg 
1 x 20 mg vial + 2 mL vehicle; whole volume to be injected 
40 mg 
1 x 40 mg vial + 2 mL vehicle: whole volume to be injected 
60 mg 
1 x 60 mg vial +  2 mL vehicle; whole volume to be injected 
Disease Group 
SOM230 
Placebo 
ADPLD 
8 
4 
ADPKD 
24 
12 
Total  
32 
16 

 
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6.3 
Patient numbering 
Randomization numbers will be provided by the study statistician to Research Pharmacy.  
The recommended blinding methods are as following: randomization data are kept strictly confi-
dential until the time of treatment un-blinding. This information will not be accessible with the fol-
lowing exceptions: pharmacist, as needed for reconstitution; an independent biostatistician, who 
will perform the analysis or database lock; the investigator and only immediately relevant study 
staff after LPLV. The identity of the treatments will be concealed by the use of study treatments 
that are all identical in packaging, labeling, schedule of administration and appearance after re-
constitution. Once the last patient completes LPLV, the database will be cleaned and an interim 
or final database lock will be placed. Subsequently, the database will be unblinded to the inves-
tigator and the sponsor. 
6.4 
Treatment blinding 
Pasireotide LAR/ placebo will be administered IM every 28 ± 2 days in the clinic only by an un-
blinded study nurse. The current recommended starting doses for pasireotide LAR is 60 mg for 
NET and 40 mg or 20 mg for acromegaly. 
Medication labels for SOM230 LAR and placebo will comply with the US legal requirements. 
There will be no information about the patient provided on the study drug label.  
Study drug, SOM230 /placebo IM depot injections will be supplied by Novartis as a powder in 
vials containing 20 mg, 40 mg and 60 mg labeled as SOM230 LAR or placebo, with ampoules 
containing 2mL of vehicle (for reconstitution). 
For this blinded study, patients, investigator, site personnel and data analysts will be blinded to 
the identity of the treatment from the time of randomization until protocol specified schedule of 
un-blinding. An unblinded pharmacist or a study nurse identified prior to start of the study are to 
be the only site personnel to reconstitute the study drug.  
Un-blinding will only occur in the case of patient emergencies, after LPLV for the investigator 
only, and after final database lock (at end of year 1, and at end of year 3). Pasireotide LAR is to 
be stored in a secure locked area while under the responsibility of the investigator. An author-
ized person at the investigational site must record receipt and dispensation of the study medica-
tions. The vials for pasireotide LAR IM depot formulation must be stored at refrigerated tem-
peratures between 2°C and 8°C (36°F-46°F) and protected from light until the time of use. The 
pasireotide LAR drug product kit should remain at room temperature for 30-60 minutes prior to 
preparation of the drug suspension. For pasireotide LAR, the reconstitution must be performed 
just prior to administration of the suspension. Doses should be administered immediately after 
preparation. For doses higher than 40 mg, contents of 2 or 3 low dosage vials will be combined 
into one or two injections. Each injection will have maximum volume of 2 ml. A maximum of 
three vials will be combined per injection and a maximum of 2 injections, at 2 separate injection 
sites of each patient, will be given to reach the dosing level. 
Table 6 
Handling and preparation of pasireotide LAR different doses 
Dose (mg) 
Volume to be injected 
20 
1 x 20 mg vial +2mL vehicle: whole volume to be injected 
40 
1 x 40 mg vial + 2mL vehicle: whole volume to be injected 
60 
1 x 60 mg vial + 2mL vehicle: whole volume to be injected 

 
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A matching placebo for the pasireotide LAR formulation will be provided by Novartis. Syringes 
will be concealed by pharmacy to maintain blinding. 
6.5 
Pasireotide LAR dose adjustment 
We will use the oncology dosing (including NETs) as already described above, pasireotide LAR 
at 60 mg every 28 days being the recommended starting dose for oncological indications If tol-
erability issues occur, the treatment dose may be reduced to pasireotide LAR at 40 mg with next 
scheduled injection. Patients requiring a dose reduction can return to the higher dose once the 
tolerability issue is resolved. However, patients not able to tolerate the minimum pasireotide 
LAR dose of 20 mg are recommended to be discontinued from study. 
All dose changes must be recorded on the Dosage Administration Record CRF. Table 7 outlines 
the dose reduction steps for pasireotide. 
Emergency un-blinding will be done at the discretion of the Principal Investigator 
 
 in cases where she feels it is necessary for the safety of the patient.   
6.5.1 Permitted study drug adjustments 
Toxicity will be assessed using the NCI-CTC for Adverse Events, version 3.0 (CTCAEv3.0, 
[http://ctep.cancer.gov/forms/CTCAEv3.pdf]). For patients who are unable to tolerate the proto-
col-specified SOM230C dosing schedule, dose-adjustment guidelines are given below. 
6.6 
Pasireotide LAR / placebo dose adjustment 
As already described above, pasireotide LAR/placebo at 60 mg every 28 days is the recom-
mended starting dose for oncological indications (including NETs). If tolerability issues occur, 
the treatment dose may be reduced to pasireotide LAR at 40 mg with next scheduled injection. 
Patients requiring a dose reduction can return to the higher dose once the tolerability issue is 
resolved. However, patients not able to tolerate the minimum pasireotide LAR dose of 20 mg 
are recommended to be discontinued from study. 
All dose changes must be recorded on the Dosage Administration Record CRF. Table 7 outlines 
the dose reduction steps for pasireotide. 
Table 7 
Guideline for treatment of patients experiencing adverse events 
 
Recommended dose modifications for pasireotide/ placebo 
Worst toxicity 
CTCAE Grade* (value) 
Recommended dose modification any time during a cycle of therapy 
No toxicity 
Maintain dose level 
Hematologic 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1500/mm3) 
Maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3) 
Maintain dose level 
Grade 3 (ANC < 1000 - 500/mm3) 
Omit dose until resolved to ≤ Grade 2, then  1 dose level 
• 
If resolved ≤ 7 days, then maintain dose level 
• 
If resolved > 7 days, then  1 dose level 
Grade 4 (ANC < 500/mm3) 
Omit dose until resolved to ≤ Grade 2, then  1 dose level 
• 
If resolved ≤ 7 days, then maintain dose level 
• 
If resolved > 7 days, then  1 dose level 

 
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Thrombocytopenia 
Grade 1 (PLT < LLN - 75,000/mm3) 
Maintain dose level 
Grade 2 (PLT < 75,000 - 50,000/mm3) 
Maintain dose level 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
• 
If resolved ≤ 7 days, then maintain dose level 
• 
If resolved > 7 days, then  1 dose level 
Grade 4 (PLT < 25,000/mm3) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Febrile neutropenia (ANC < 1.0 x 109/L, fever 
≥ 38.5°C) 
Omit dose until resolved, then  1 dose level 
Renal 
Serum creatinine 
 
< 2 x ULN 
Maintain dose level 
2-3 x ULN 
Omit dose until resolved to ≤ Grade 1, then  
• 
If resolved ≤ 7 days, then maintain dose level 
• 
If resolved > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 6.0 x ULN) 
Omit dose and discontinue patient from study treatment 
Grade 4 (> 6.0 x ULN) 
Omit dose and discontinue patient from study treatment 
Hepatic See also section 7.5.4.1  
Bilirubin 
 
Grade 1 (< 2 x baseline value) 
Maintain dose level 
Grade 2 (2-3 x baseline value) 
Omit dose until resolved to ≤ Grade 1, then  
• 
If resolved ≤ 7 days, then maintain dose level 
• 
If resolved > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then  
• 
If resolved ≤ 7 days, then maintain dose level 
• 
If resolved > 7 days, then  1 dose level 
Grade 4 (> 10.0 x ULN) 
Omit dose and discontinue patient from study treatment 
NOTE: If grade 3 or 4 hyperbilirubinemia is due to the indirect (unconjugat-
ed) component only, and hemolysis as the etiology has been ruled out as 
per institutional guidelines (e.g. review of peripheral blood smear and hap-
toglobin determination), then  1 dose level and continue treatment at the 
discretion of the investigator 
AST or ALT 
 
Grade 1 (> ULN - 2.5 x ULN) 
Maintain dose level 
Grade 2 (> 2.5 - 5.0 x ULN) 
Maintain dose level 
Grade 3 (> 5.0 and ≤ 8x ULN) 
For ALT or AST > 5x ULN and ≤ 8x ULN:  
• 
Study medication should be temporarily interrupted & liver chemistry 
monitored every 3-4days until resolution or return to baseline. 
• 
If resolution or return to baseline does not occur after 2 weeks, the pa-
tient should be discontinued.  
• 
If ALT or AST returns to less than 5x ULN, study drug can be resumed 
and patient can continue study per protocol  
• 
If ALT or AST rises above 5x ULN anytime after study drug is resumed, 
then study drug should be discontinued immediately. 
Grade 4 (> 20.0 x ULN) 
Omit dose and discontinue patient from study treatment 
Pancreatic 
Pancreatitis 
 
Grade 1 
Maintain dose level 

 
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Grade 2 
Maintain dose level 
Grade 3 
Omit dose and discontinue patient from study treatment 
Grade 4 
Omit dose and discontinue patient from study treatment 
Amylase and/or lipase 
 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 2.0 x ULN) 
Maintain dose level 
Grade 3 (> 2.0 - 5.0 x ULN) 
For asymptomatic:  
Omit dose until resolved to ≤ Grade 1, then  
• 
If resolved ≤ 7 days, then maintain dose level 
• 
If resolved > 7 days, then  1 dose level 
For symptomatic: 
Omit dose and discontinue patient from study treatment 
Grade 4 (> 5.0 x ULN) 
Omit dose and discontinue patient from study treatment 
A CT scan or other imaging study to assess the pancreas, liver and 
gallbladder must be performed within 1 week of the first occurrence of any 
≥ CTCAE grade 3 of amylase and/or lipase. 
Endocrine/metabolic 
Fasting plasma glucose (FPS) or 2-hour 
postprandial capillary glucose (PPG) 
 
FPG <126 mg/dL or PPG < 140 mg/dL 
Maintain dose level 
Grade 1 (> ULN – 160 mg/dL) 
appendix 2 section 12.2. 
Grade 2 (> 160 – 250 mg/dL) 
appendix 2 section 12.2. 
Grade 3 (> 250 – 500 mg/dL) 
appendix 2 section 12.2. 
Grade 4 (> 500 mg/dL) 
appendix 2 section 12.2. 
Cardiac 
Cardiac - prolonged QTc interval 
 
• 
QTcF > 480 ms and ≤ 500 ms 
If at any time a QTcF > 480 ms and ≤ 500 ms is observed a cardiology 
consultation must be sought to re-evaluate the abnormal ECG finding. 
• 
QTcF > 500 msec 
1. 
Triplicate ECGs (2-3 minutes apart) need to be taken approximately 1 
hour after the initial ECG.   
2. 
If the mean QTcF is > 500 ms, the patient must postpone study treat-
ment until a cardiologist has re-evaluated the ECG.   
3. 
The re-evaluation of ECG needs to be done as soon as practical but 
within 7 days of the initial abnormal ECG.   
4. 
If the cardiologist confirms a mean QTcF > 500 ms, the patient must 
be discontinued. 
Cardiac general 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Omit dose and discontinue patient from study treatment 
Other adverse events 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Omit dose and discontinue patient from study treatment 
Detailed treatment guidance on QT prolongation, hyperglycemia and diarrhea will be provided as appendices of the proto-
col 

 
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6.7 
Concomitant therapy 
All medications administered within 4 weeks prior to the administration of study drugs and all 
concomitant therapy administered during the study, along with the reasons for therapy, will be 
recorded.  
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug including all over-the-counter medication. All medi-
cations (other than study drug) and significant non-drug therapies (including physical therapy 
and blood transfusions) administered after the patient starts treatment with study drug must be 
listed on the Concomitant medications/Significant non-drug therapies after start of study drug 
CRF. 
The patients should also be discouraged from taking over-the-counter medications for diarrhea. 
The use of prescription medication for diarrhea is also to be avoided while patients are receiving 
study drug treatment, but exceptions may be made if the medication is to treat an adverse 
event.  
The concomitant medication CRF is to be used as an ongoing log, and must be updated as 
necessary to reflect all medications taken. 
The use of anticoagulant medication should be avoided. Patients currently receiving supple-
mental pancreatic enzymes may be enrolled, but they should not start such treatment or in-
crease the dose while on study.  
The use of concomitant medications that might lead to QT prolongation is prohibited and would 
require the discontinuation of the patient prior to starting the respective QT prolonging medica-
tion. Please check http://www.azcert.org/medical-pros/drug-lists/browse-drug-list.cfm for a list of 
QT prolonging drugs. 
6.8 
Study drug discontinuation 
Study drug must be discontinued and the subject withdrawn from the trial if the investigator de-
termines that continuing would result in significant safety risk for that subject. The following cir-
cumstances require study drug discontinuation: 
Pregnancy 
The occurrence of an adverse event or of a clinically significant laboratory change or abnormali-
ty that, in the judgment of the investigator, warrants discontinuation of treatment. 
Subjects who have fasting plasma glucose > 240 mg/dL confirmed by repeat measurement 
Any CTC grade 3 or higher abnormalities in hematology or chemistry parameters judged clini-
cally significant by the Investigator 
Any confirmed QTcF > 500 ms or confirmed increase of QTcF > 60 ms from baseline 
ALT or AST > 3x ULN and Total Bilirubin ≥ 2 x ULN and ALP > 2 x ULN 
ALT or AST > 5x ULN and ≤ 8 x ULN persistent for more than 2 weeks 
ALT or AST > 8 x ULN 

 
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6.9 
Premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. These patients will be asked to complete an Early Termination Visit. 
Patients may be withdrawn from the study if any of the following occur: 
Lack of efficacy 
Uncontrolled diabetes mellitus (DM) 
Pregnancy 
Adverse event(s) 
Abnormal laboratory value(s) 
Abnormal test procedure result(s) 
Protocol violation 
Subject withdrew consent 
Lost to follow-up 
Administrative problems 
Death 
New therapy for disease being investigated 
Disease progression 
6.10 
Overall Study Stopping Rules 
 
Stopping criteria for hyperglycemia and other side effects, e.g. related to changes in hematolo-
gy, chemistry, or cardiac test values are listed in section 6.8. Pasireotide has already demon-
strated acceptable tolerability and efficacy in several completed or ongoing clinical trials (page 
38 Investigator Brochure) and the LAR formulation is being examined in a phase 3 study for 
treatment of Acromegaly NCT00600886; Novartis data on file, and for Cushing disease (sc for-
mulation; CSOM230B2305]) recently reported (Colao, Petersenn et al. 2012). In the latter study 
hyperglycemia-related adverse events occurred in 73% of patients necessitating 6% discontinu-
ing study treatment Plasma glucose levels increased 10% from baseline compared with a 2% 
increase in placebo (P<0.02) after commencing octreotide treatment and no patient developed 
diabetes in our prior somatostatin analog study using OctLAR.  
 
Gastrointestinal problems are the most commonly reported AEs associated with the use of 
SOM230, (predominantly mild diarrhea grade 1 or 2, and nausea requiring no treatment or study 
discontinuation). In our prior somatostatin analog study in PKD, only 1/42 individuals discontin-
ued that study after one year (due to steatorrhea) and none discontinued because they devel-
oped diabetes. Based on our prior experience and others’ studies of tolerability and side effects 
associated with OctLAR (and also with lanreotide in PKD and PLD), we do not anticipate there 
will be patient discontinuation >15%, since both drugs have a similar tolerability profile (Investi-
gator brochure section 6.2). Hence, we do not anticipate we will need to stop this study in this 
patient population due to lack of study power. If there is no efficacy found after the first year 
analysis is complete then we will terminate the open label extension.  We will be monitoring 
each patient closely (table 8) for expected and unexpected drug side effects. If there are any 

 
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serious suspected adverse reactions (>1) that were unexpected these would be evaluated by 
the sponsor-investigator and the risk/benefit of study continuation would be analyzed.  Novartis 
also reserves the right to stop the study (section 13.1.3).  
 
• 
Colao, A., S. Petersenn, et al. (2012). "A 12-Month Phase 3 Study of Pasireotide in 
Cushing's Disease." New England Journal of Medicine 366(10): 914-924. 
 
 
6.11 
End of treatment 
Treatment duration will be completed per the protocol 
7 
Visit schedule and assessments  
Table 8 lists all of the assessments and indicates the visits at which they are to be performed 
with an “X”. All data obtained from these assessments must be supported in the patient’s source 
documentation. In year 2, safety assessments for patient’s crossing over from placebo to SOM 
230 will be required. These will be per the same schedule after the first SOM230 injection as 
was performed in year 1 for all patients enrolled.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 8 
Visit/Study Procedure Schedule 
 
Test / Procedure 
S 
R 
Days after 1st injec-
tion 
Months after initial visit 
Mos. 
after 
end 
22/2 29 50 57 85 6 
9 1213 15 18 21 24 27 30 33 36 / 
Early 
Term 
1 3 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History/physical 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Height,1 Weight 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
ECG2 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
Heme Group3 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
PT APTT 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Metabolic panel4 eGfr5 X 
 
X 
X 
X X X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
Hemoglobin A1C6 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
 
X 
Thyroid cascade7 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
MRI (CT) Scan  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclosporin level8 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
Microalbumin 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Fasting glucose9 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X
 
Pregnancy Test10 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
QOL SF-36v2TM 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
SOM230/Placebo11 
 
X 
 
X 
 
X X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
 
 
Concomitant meds 
X 
→ X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
 
 
Gallstone (6 mo)12 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
PK Bloods 
X 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
S= Screening 
 
R = Randomization 
 
1 
Height required only at pre-study 
2 
12 lead ECG & interpretation at screening and ½ hour after first injection. Repeat ECG on 21st day 
after injection for the first 3 months then every third month. All ECGs are faxed to the Mayo Clinic ECG 
Core lab. 
3 
Includes WBC with differential 
4 
Comprehensive fasting metabolic panel includes: albumin, total bilirubin, calcium, CO2, (bicarbonate) 
chloride, creatinine, BUN, potassium, total protein, sodium, AST, ALT, ALP,, and glucose. Liver func-
tion tests are assessed at baseline (if baseline LFTs are done within 7 days of day 1 of treatment 
they do not have to be repeated on day 1), day 22 after first injection, day 29, day 50, 57 and 85. After 
day 85 and the 4th LAR Injection, monitoring should follow the existing protocol schedule. Day 22 & 50 
LFTs must be available & assessed prior to dosing on days 29 (2nd injection) and 57 (3rd injection). 
5 
Only in patients with associated PKD. 
6 
Hemoglobin A1C is done at baseline and 3 monthly 
7 
Thyroid function is also acceptable if checked within 30 days of the screening visit 
8 
Bi-weekly cyclosporin levels will be monitored for the first month in enrolled patients who are on this 
medication (mail in test)  
9 
Plasma glucose is required 6 hours after first injection. Monitor FPG or finger stick at baseline and at 
21st day of treatment for first 3 months. Monitor FPG or finger stick monthly (or as clinically appropri-
ate), thereafter. 

 
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10 Women of childbearing potential only (urine pregnancy test). If CT scan is needed, a negative preg-
nancy result will need to be obtained prior to performing the CT. For women of child bearing potential 
who will be having an MRI – a pregnancy test is not required at month 12. 
11 SOM230/placebo IM injections will be given every 28 days, +/- 2 days. 
12 No gallstone assessment is needed on visits where MRI is performed, as gallstones will be detected 
on MRI if present. 
13 In year 2, safety assessments for patients crossing over from placebo to SOM 230 will be 
required. These will be per the same schedule after the first SOM230 injection as was 
performed in year 1 for all patients enrolled. 
 
At a minimum the following safety evaluations (Table 9) are to be included in all protocols. 
Table 9 
Core safety evaluation and frequency 
 
Evaluation 
Frequency 
 
ECG 
Baseline ECG prior to and 30 minutes after the first dose. 
Repeat ECG on 21st day after injection for the first 3 months 
Repeat ECG every 3 months thereafter. 
Gallstone assessment 
by CT/MRI is  part of the 
evaluation 
Baseline and every 6 months (done by ultrasound, at Mayo outside of 
baseline 12 and 36 months visits when MRI is performed) 
Fasting glucose finger 
stick 
Monitor FPG or finger stick at baseline and at 21st day of treatment for the first 
3 months. 
Monitor FPG or finger stick monthly (or as clinically appropriate), thereafter. 
Monitor of FPG 4 weeks after the end of the treatment is recommended. 
TSH/Free T4 
Baseline and at 6 months 
HbA1c* 
Baseline and every 3 months  
Monitoring HbA1c 3 months after the end of the treatment is recommended 
7.1 
Information to be collected on screening failures 
Information on all screen failures will be collected and the analysis will be performed for all pa-
tients will be included who received at least one dose of the randomized study drug.  
7.2 
Patient demographics/other baseline characteristics 
The ADPKD database at the Mayo Clinic includes 4577 patients. Approximately 500 patients 
with ADPKD or ADPLD are seen in the PKD Clinic, the Renal Transplant and Hepatobiliary Clin-
ics every year. Mayo Clinic has the largest experience in combined hepatic resection/cyst fenes-
tration for severe PLD. Ten percent of the patients undergoing renal transplantation at the Mayo 
Clinic in Rochester (~250 patients per year) have ADPKD. Pregnant women, children, prison-
ers, institutionalized individuals will not be randomized to this study. The proposed consent form 
is attached to this proposal. 

 
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7.3 
Treatments 
All current medication used to treat diabetes mellitus should be documented 
All medications, including over-the-counter medication, taken prior to study drug administration 
and which continue during the course of the study must be documented  
Compliance will be assessed by the investigator and/or study personnel at each visit. Records 
of study medication used, treatment administered, and intervals between visits will be kept dur-
ing the study. Drug accountability will be noted. Patients will be asked to return all used medica-
tion ampoules at each visit and the end of the study. 
7.4 
Efficacy 
7.4.1 Liver & total kidney volume, hepatic cyst volume, renal cyst volume 
7.4.1.1 
Primary outcome 
The primary outcome is the percent change in liver volume as assessed by MR at baseline, 12 
and 36 months follow-up. Patients will also be classified as “responders” if their liver volume de-
creases, does not change, or increases by <2% over the 12 month study period. The MR tech-
niques for imaging and interpretation of volumetric measurements established in the CRISP 
study will be employed in the present study, as early results from the CRISP study indicate that 
this MR protocol will provide an effective means for longitudinal evaluation of liver and kidney 
volume and of cyst volume and is much more sensitive in detecting cholelithiasis when com-
pared to CT, because CT cannot differentiate between the density of bile in the gallbladder and 
the more common, non-calcified gallstones. T-2 weighted images on MR can easily demon-
strate stark contrast between the bright fluid (bile) in the gallbladder from the dark gallstones 
which do not have any signal intensity on MRI. The MR Procedure comprises of the following 
(30 minutes): 
1. 
Since no gadolinium will be used in this study, patients will not have an angiocatheter 
placed at the time of their MRI. (See exception for patients undergoing CT below.) 
2. 
ECG pads will be placed over the chest. If ECG gating is not available or functioning, it may 
be replaced with a peripheral pulse gating. Hair may need to be shaved off to place the 
leads. 
3. 
Subjects will be placed supine on the MR table with their arms to their sides. 
4. 
A phased-array surface coil will be positioned with its center over the liver.   
5. 
Scout scan to locate the scan range of the entire liver.  
6. 
The field-of-view (FOV) should be kept as small as possible (30-35 cm) without producing 
wrap-around artifacts. 
7. 
Obtain breath-hold coronal Regular T2 scan (SSFSE/HASTE with fat sat) with 9mm fixed 
slice thickness, usually achievable in a single breath-hold. 
8. 
Obtain breath-hold coronal Regular T2 scan (SSFSE/HASTE with fat sat) of the liver with 
adjusted slice thickness, 3-9 mm, i.e. the slice thickness best attainable with a single 
breath-hold (the adjusted slice thickness may not remain the same in a follow-up MR scan if 
there is a change in the subject's breath-hold capacity or liver size). 
9. 
Repeat the scan over the kidneys with the same slice thickness.  
The measurements of liver, kidney and cyst volumes will be performed without knowledge of 
group assignment using the technology developed for the CRISP study.36 Liver and kidney vol-

 
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umes will be measured in T1-weighted images with a stereology method and calculated from 
the set of contiguous images by summing the products of the area measurements and slice 
thickness. A region-based threshold method will be used to calculate cyst volumes.  
In patients who are unable to undergo MRI (e.g. due to claustrophobia) a CT scan of the liver 
and kidneys will be substituted. CT scans will be performed with or without contrast, depending 
of renal function. If estimated GFR is greater that 60 iodinated IV contrast will be employed. If 
renal function is less than 60mls/min, no iodinated contrast will be used. A peripheral IV cannula 
will be inserted for patients requiring IV contrast and removed immediately after the scan is 
completed. 
7.4.1.2 
Secondary efficacy assessments 
Absolute and percent changes in liver volume in the placebo group before (year 1) and after 
(years 2-3) cross-over to active treatment will be assessed base on comparison of baseline vol-
umes as assessed by MRI/CT in each subject. The measurements will be performed in the Bio-
medical imaging core facility by blinded assessors. Similarly, absolute and percent changes in 
liver volume will be assessed in the treatment arm during years 2-3 compared to the placebo 
arm during year 1. Similarly, changes in kidney volume from baseline at 12 and 36 months in 
individuals with ADPKD will be assessed by MRI.  
Changes in eGFR, vital signs, creatinine, liver function tests, APTT, PT, glucose values from 
baseline (or from month 3) at 12 and 36 months in all individuals and treated as a continuous 
variable. Data from ADPLD patients will be excluded from the renal outcome sub-analyses.  
Measurement of Effect (Subjective Response): 
Changes in quality of life at baseline and 12 and 36 months will be measured by SF36-
questionnaire QOL-questionnaire (SF-36v2™). 
7.4.1.3 
Tertiary objectives 
We will assess longitudinal changes beyond 12 months in the above factors, stratified by treat-
ment sequence. 
7.4.2 Treatment/Follow-up Decisions at Patient Evaluations 
Response to treatment will be analyzed by measuring changes in liver volume. The study is in-
tended to provide information after 12 months of treatment. Follow-up decisions will proceed as 
follows: if the treatment is found to be definitively or possibly effective (reduction in liver volume, 
no increase or increase < 2% per year), all participants treated with will be offered Pasireotide 
LAR® Depot treatment for another 24 months. The participants treated with placebo will also be 
offered at this point treatment with Pasireotide LAR® Depot for 24 months.   
7.5 
Safety 
Safety assessments will consist of monitoring and recording all adverse events, including seri-
ous adverse events, the regular monitoring of hematology (including glycosylated hemoglobin 
and coagulation parameters), blood chemistry (including fasting glucose, thyroid function tests), 
urine for microalbumin, regular monitoring of vital signs, gallbladder by MRI/CT ultrasound, will 
be recorded from study enrollment until study completion. 
Patients with diabetes are to be instructed to check blood glucose levels via a fingerstick several 
times daily, particularly for the first few days of treatment. 

 
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7.5.1 Adverse events 
An adverse event for the purposes of this protocol is the appearance of (or worsening of any 
pre-existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after signing the 
informed consent even if the event is not considered to be related to the study drug(s). Please 
refer to the adverse event section of the protocol for the protocol-specific definitions of study 
drug and study treatment. 
Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events 
[CTCAE] version 3.0. If CTCAE grading does not exist for an adverse event, the severity of mild, 
moderate, severe, and life-threatening, or grades 1 - 4, will be used. CTCAE grade 5 (death) will 
not be used in this study; rather, this information will be collected in the End of Treatment. Ad-
verse event monitoring should be continued for at least 4 weeks following the last dose of study 
treatment. 
Adverse events (but not serious adverse events) occurring before starting study treatment but 
after signing the informed consent form are recorded on the Medical History/Current Medical 
Conditions Electronic Case Report Form. Abnormal laboratory values or test results constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically signifi-
cant or require therapy (e.g., any hematologic abnormality that requires transfusion or cytokine 
treatment); and should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them. In addition, isolated abnormal laboratory values that are con-
sidered clinically significant (e.g., cause study discontinuation or constitutes in and of itself a Se-
rious Adverse Event) should be recorded on the Adverse Events CRF. SAEs occurring after 
signing the Informed Consent are recorded on the Adverse Event CRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE grade 1-4) 
2. Its relationship to each study drug (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (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) 
5. Whether it is serious, where a serious adverse event (SAE) is defined as one which: 
• 
Is fatal or life-threatening 
• 
Results in persistent or significant disability/incapacity 
• 
Constitutes a congenital anomaly/birth defect 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, unless hos-
pitalization is for: 
• 
Routine treatment or monitoring of the studied indication, not associated with any de-
terioration in condition (specify what this includes) 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• 
Treatment on an emergency outpatient basis for an event not fulfilling any of the def-
initions of a SAE given above and not resulting in hospital admission 

 
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• 
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• 
Is medically significant, i.e., defined as an event that jeopardizes the patient or may re-
quire medical or surgical intervention to prevent one of the outcomes listed above 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements; see protocol section on Serious Adverse Event reporting. 
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping con-
comitant treatments, changes in the frequency or nature of assessments, hospitalization, or any 
other medically required intervention. Once an adverse event is detected, it should be followed 
until its resolution, an assessment should be made at each visit (or more frequently, if neces-
sary) of any changes in its severity, its suspected relationship to the study drug(s), any of the 
interventions required to treat it, and its outcome. 
Information about common side effects already known about the investigational drug can be 
found in the [Investigator’s Brochure] or will be communicated between IB updates in the form of 
Investigator Notifications. This information will be included in the patient informed consent and 
should be discussed with the patient during the study as needed. 
7.5.2 Vital signs 
Body weight, body temperature, supine blood pressure, and supine pulse rate will be assessed. 
Height will be noted during the screening/baseline period. 
7.5.3 Performance status 
SF36 quality of life form and Gastrointestinal Symptom Questionnaire will be used.  
7.5.4 Laboratory evaluations 
Patients are to fast overnight for 8 hours prior to all biochemistry samples being taken. Blood 
samples are to be taken in the morning. Water is allowed during this time. Laboratory samples 
will be analyzed locally at Mayo Clinic. Albumin, alkaline phosphatase, total bilirubin, calcium, 
chloride, creatinine with calculated eGFR, γ-GT, fasting blood glucose, potassium, total protein, 
AST, ALT, sodium, urea/BUN. If the total bilirubin concentration is increased above 1.5 times 
the upper normal limit (UNL), total bilirubin should be differentiated into the direct and indirect 
reacting bilirubin. 
7.5.4.1 
Abnormal liver function management: 
Perform within 72 hours of awareness of abnormal LFTs:  
Perform liver-directed medical history and physical examination (i.e. assess occupational haz-
ards, concomitant medications including OTC meds, intercurrent illness, etc) 
Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if total bili-
rubin is > 2.0x ULN), Alb, PT (INR), ALP, and GGT 
Perform hepatitis screen: anti-HAV, IgM (to confirm acute hepatitis A), HbsAg, Anti-HBc, anti-
HCV (if positive PCR viral load should be assessed), Anti-HEV, ANA antibodies, anti-smooth 
muscle anti-bodies, CMV, EBV 
Perform abdominal ultrasound (liver and biliary tree) 

 
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Liver chemistry tests should be monitored every 3-4 days for LAR studies until resolution or re-
turn to baseline status.   
For ALT or AST > 5x ULN and ≤ 8x ULN:  
o Study medication should be temporarily interrupted and liver chemistry tests 
monitored every 3-4 days until resolution or return to baseline  
o If resolution or return to baseline does not occur after 2 weeks, the patient should 
be discontinued.  
o If ALT or AST returns to less than 5x ULN, study drug can be resumed and pa-
tient can continue study per protocol 
o If ALT or AST rises above 5x ULN anytime after study drug is resumed, then 
study drug should be discontinued immediately.  
Resolution return to baseline does not occur after two weeks the patient should be discontinued 
If ALT or AST rises about 5X ULN anytime after study drugs resumed and study drug to be dis-
continued immediately 
Study medication should be discontinued immediately if any of the discontinuation criteria below 
are met: (see appendix 4) 
ALT or AST > 3x ULN and Total Bilirubin > 2x ULN and ALP < 2x ULN 
ALT or AST > 5x ULN and ≤ 8x ULN persistent for more than 2 weeks 
ALT or AST > 8x ULN 
Re-challenge of study medication is prohibited once discontinuation criteria are met. 
7.5.4.2 
Thyroid function tests 
Free T4 and TSH will be assessed prior to enrollment and at 6 months. 
7.5.4.3 
Urine tests: 
Serial spot urine microalbumin measurements will be followed. 
7.5.4.4 
Hormone assessments 
GH, IGF-1 and prolactin (PRL), will not be assessed.  
7.5.4.5 
Urinalysis 
Specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes and blood will be assessed. 
7.5.4.6 
Pregnancy test 
Study drug treatment should be withdrawn in the event of pregnancy. To ensure patient safety 
each pregnancy must also be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or volun-
tary termination, details of birth, and the presence or absence of any birth defects, congenital 
abnormalities or maternal and newborn complications. Any SAE experienced during pregnancy 
must be reported on the SAE Report Form. 

 
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7.5.4.7 
Gallbladder Imaging  
The gallbladder will be imaged at baseline (by MRI or CT) and repeated 6 monthly until the end 
of study. Patients with a history of symptomatic cholelithiasis are excluded from participating in 
the study.  
7.5.4.8 
Electrocardiogram (ECG) 
A 12-lead electrocardiogram (ECG) and rhythm strip will be performed at baseline and 30 min-
utes after the first dose one half and 3 monthly for the first year and every 6 months in year 2. 
Repeat ECG on the 21st day after the injection, then every 3 months thereafter.  
If a clinically significant abnormality is detected, the electrocardiogram will be repeated at the 
discretion of the Investigator until the abnormality has been resolved. A cardiology consultation 
must be sought as soon as practical but within 7 days of the initial abnormal ECG and the cardi-
ologist must re-evaluate the ECG (this can be done by the central cardiologist). An echocardio-
gram may also be required. 
• 
If a QTcF > 480msec is NOT confirmed, no further action needs to be taken. 
• 
If a QTcF > 480msec is confirmed, a cardiologist must perform a thorough examination 
(such as reviewing baseline ECG, concurrent medications and performing a cardiovas-
cular examination, including at least a cardiac auscultation) to assess the patient for car-
diovascular risk factors.  
7.6 
Pharmacokinetics 
Blood levels of pasireotide will be done in this protocol.  
8 
Other Safety Considerations:  
The potential risks to patients should be limited to study drug use as no specific change in diet 
and pharmacologic treatment will be introduced throughout the study, unless deemed clinically 
appropriate to control blood pressure or limit the signs of renal or liver dysfunction. Antihyper-
tensive treatment will be adjusted in order to maintain a target systolic/diastolic blood pressure 
<130/80 mm Hg. Blood glucose levels will be carefully monitored during the study and antidia-
betic therapy adjusted if indicated. Other medications necessary for medical management or 
symptomatic treatment, including analgesics, antiemetics, antidiarrheals, and thyroxine, will be 
administered as clinically indicated. Claustrophobic patients will be provided a standing order of 
oral lorazepam 1mg 45 minutes before their MRI according to the standard Mayo Radiology 
Department Protocol.  
The NCI common toxicity criteria 3.0 will be used to classify adverse events (both patient and 
event counts) by organ system (neuro, GI, etc.), individually, by severity and, for each severity, 
by investigator-assessed relationship to study drug. Fisher’s exact test will be used to compare 
treatment groups (placebo, SOM230) regarding adverse events during year 1. Patients who re-
ceived at least one dose of the randomized study drug will be included. Adverse events in years 
2 and 3 (all subjects on SOM230) will be reported separately. A data safety committee will meet 
every six months (comprising of two physicians; 
). The 
committee will meet with the study coordinator and PI and review safety labs and monitoring 
and study conduct.  
 

 
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8.1.1.1 Adverse events 
Information about all adverse events, whether volunteered by the subject, discovered by inves-
tigator questioning, or detected through physical examination, laboratory test or other means, 
will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions / diseases present before starting the study drug are only con-
sidered AEs if they worsen after starting the study drug. Abnormal laboratory values or test re-
sults constitute adverse events only if they induce clinical signs or symptoms, are considered 
clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
• 
the severity grade (mild, moderate, severe) or (grade 1-4) 
• 
its relationship to the study drug(s) (suspected/not suspected) 
• 
its duration (start and end dates or if continuing at final exam) 
• 
action taken (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) 
• 
whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping con-
comitant treatments, changes in the frequency or nature of assessments, hospitalization, or any 
other medically required intervention. Once an adverse event is detected, it should be followed 
until its resolution, and assessment should be made at each visit (or more frequently, if neces-
sary) of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the [Investigators’ Brochure] or will be communicated between IB updates in the form of 
Investigator Notifications. This information will be included in the patient informed consent and 
should be discussed with the patient during the study as needed. 
8.1.1.1 
Serious adverse events 
Information about all serious adverse events will be collected and recorded. To ensure patient 
safety each serious adverse event must also be reported to Novartis within 24 hours of learning 
of its occurrence. A serious adverse event is an undesirable sign, symptom or medical condition 
which: 
• 
is fatal or life-threatening 
• 
results in persistent or significant disability/incapacity 

 
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• 
constitutes a congenital anomaly/birth defect 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, unless hospi-
talization is for: 
o routine treatment or monitoring of the studied indication, not associated with any de-
terioration in condition (specify what this includes) 
o elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the defi-
nitions of a SAE given above and not resulting in hospital admission 
o social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• 
is medically significant, i.e., defined as an event that jeopardizes the patient or may re-
quire medical or surgical intervention to prevent one of the outcomes listed above 
8.1.2 Novartis instructions for rapid notification of serious adverse events 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Novartis Pharmaceuticals Integrated Medical Safety (IMS). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).  
All events must be reported, by FAX 
), to Novartis Pharmaceuticals IMS De-
partment within 24 hours of learning of its occurrence. This includes serious, related, labeled 
(expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths during 
treatment or within 30 days following completion of active protocol therapy must be reported 
within 1 working day. 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the peri-
od in which the study protocol interferes with the standard medical treatment given to a patient 
(e.g. treatment withdrawal during washout period, change in treatment to a fixed dose of con-
comitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse ex-
periences will be forwarded to the product manufacturer by the investigator. 
8.1.2.1 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Novartis within 24 hours of learning of its occur-
rence. The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of birth, and the presence or absence of any birth defects, congen-
ital abnormalities or maternal and newborn complications. 

 
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9 
Protocol amendments, or changes in study conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Novartis and the investigator before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study require additional approval by the IRB at each study center.  A 
copy of the written approval of the IRB must be provided to Novartis. Examples of amendments 
requiring such approval are: 
1. increases in drug dose or duration of exposure of subjects, 
2. significant changes in the study design (e.g. addition or deletion of a control group), 
3. increases in the number of invasive procedures, 
4. addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all patients in-
cluded in the trial. If an immediate change to the protocol is felt to be necessary by the investi-
gator and is implemented for safety reasons Novartis must be notified and the IRB at the center 
must be informed immediately. Amendments affecting only administrative aspects of the study 
do not require formal protocol amendments or IRB approval but the IRB must be kept informed 
of such administrative changes. Examples of administrative changes not requiring formal proto-
col amendments and IRB approval include: 
1. changes in the staff used to monitor trials, 
2. minor changes in the packaging or labeling of study drug. 
10 
Data management 
10.1 
Data collection 
Every patient will have a study folder containing source documents, report forms; original signed 
consent, and stored in a locked area in the study coordinator’s office 
 
 Serial data entry recording the information required by the protocol from ini-
tial and subsequent visits will be entered on SDMS spreadsheets, and maintained on a pass-
word protected Nephrology secure server. Statistical methods 
10.2 
Statistical methods 
Demographics and laboratory data will be plotted (e.g. box plots) and summarized by treatment 
group. Frequency distributions will be used to describe categorical values and basic summary 
statistics (mean, standard deviation, median, and inter-quartile range) used to describe continu-
ous values. All tests will be two-sided with alpha level 0.05. For quantitative endpoints (e.g. 
change in kidney and liver volumes, renal function, and SF-36 scales) the two-group independ-
ent samples t-test will be used to test for an effect of treatment. Should the assumptions of nor-
mality and equality of variances be untenable, we will consider a data transformation or use of 
the Wilcoxon rank sum test. Both point estimates (mean) and 95% confidence intervals will be 
used to summarize treatment effects. For qualitative endpoints (e.g. presence or absence of re-
sponse) we will compare treatment groups using the chi-square or Fisher’s exact test as appro-
priate.  
Efficacy (Liver & kidney): The primary analysis of treatment efficacy will follow intent-to-treat 
principles, attempting to include all randomized patients. For the primary endpoint (change in 

 
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liver volume) we will not be able to include anyone without a 12 month MRI (kidney volumes will 
be handled in the same way). For the “response” endpoints, those without a 12 month MRI will 
be included in the analysis as non-responders. Secondary analysis – Efficacy (QOL): We will 
have up to 5 longitudinal assessments of QOL for each patient. Repeated measures analysis of 
variance will be used to compare mean QOL profiles over time between treatment groups. Also, 
within patient rates of change or slopes in QOL measures will be estimated (using simple linear 
regression) and compared between groups using the two-sample t-test.  
Secondary analysis–Kidney volume will be measured as part of the efficacy analysis: 
AEs (both patient and event counts) will be tabulated by organ system (neuro, GI, etc.), individ-
ually, by severity and, for each severity, by investigator-assessed relationship to study drug. 
Fisher’s exact test will be used to compare treatment groups regarding adverse events. Patients 
who received at least one dose of the randomized study drug will be included.  
Statistical power: The primary endpoint is one year percentage change in liver volume. Prior 
data in untreated patients suggest a growth rate (SD) of 5(±3) % per year4,37. We have planned 
a 2:1 randomization in order to allow as many patients as possible to receive SOM230. The goal 
is to detect up to a 7.3% percentage point decrease in the mean cyst growth using SOM230 
LAR® Depot. With 15 placebo and 30 SOM230 patients, the study will have 80% power (al-
pha=.05, two-sided) to detect a 7 percentage point difference. To allow for dropouts (1 placebo 
and 2 SOM230 patients without endpoint data); the study will randomize 16 placebo and 32 
SOM230 patients. For any quantitative endpoint the study is powered to detect a difference in 
treatment means of at least one standard deviation. Secondary endpoints include comparison of 
responder rates (based on liver and renal growth) and adverse event rates between the two 
groups. With 16 and 32 patients, a true placebo response (or adverse event rate) of 8 % (1 of 
13) vs. 30, 40, or 50% for SOM230 can be detected with 45%, 70%, and 88% power, respec-
tively. 
11 
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polycystic liver disease. Gut 2008;57:1338-1339. 
27. van Keimpema L, Drenth JP. Effect of octreotide on polycystic liver volume. Liver Int 2009. 
28. Peces R, Cuesta-Lopez E, Peces C, Perez-Duenas V, Vega-Cabrera C, Selgas R. 
Octreotide reduces hepatic, renal and breast cystic volume in autosomal-dominant polycystic 
kidney disease. International urology and nephrology 2010. 
29. Boehm S, Betz H. Somatostatin inhibits excitatory transmission at rat hippocampal 
synapses via presynaptic receptors. Journal of Neuroscience 1997;17:4066-4075. 
30. Koenig JA, Edwardson JM, Humphrey PPA. Somatostatin receptors in Neuro2A 
neuroblastoma cells: ligand internalization. British Journal of Pharmacology 1997;120:52-59. 
31. Bloch B, Dumartin B, Bernard V. In vivo regulation of intraneuronal trafficking of G protein-
coupled receptors for neurotransmitters. Trends in Pharmacological Sciences 1999;20:315-319. 
32. Masyuk T. Polycystic kidney and liver disease; role of Octreotide and Pasireotide in hepato-
renal cystogenesis. . Rochester: Mayo Clinic, 2011. 
33. Schmid HA. Pasireotide (SOM230): Development, mechanism of action and potential 
applications. Molecular and Cellular Endocrinology 2008;286:69-74. 
34. Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of 
ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 
1994;343:824-827. 
35. Reynolds DM, Falk CT, Li A, King BF, Kamath PS, Huston J, 3rd, Shub C, Iglesias DM, 
Martin RS, Pirson Y, Torres VE, Somlo S. Identification of a locus for autosomal dominant 
polycystic liver disease, on chromosome 19p13.2-13.1. Am J Hum Genet 2000;67:1598-1604. 
36. Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF, Jr., Wetzel 
LH, Baumgarten DA, Kenney PJ, Harris PC, Klahr S, Bennett WM, Hirschman GN, Meyers CM, 
Zhang X, Zhu F, Miller JP. Volume progression in polycystic kidney disease. N Engl J Med 
2006;354:2122-2130. 

 
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37. Everson GT. Hepatic cysts in autosomal dominant polycystic kidney disease. Mayo Clin 
Proc 1990;65:1020-1025. 
12 
Appendices 
12.1 
Appendix 1 
Guidance for diarrhea management 
General recommendations: 
• 
Stop all lactose-containing products, alcohol 
• 
Stop laxatives, bulk fiber (Metamucil, Procter & Gamble), and stool softeners (docusate 
sodium; Colace, Roberts) 
• 
Drink 8 to 10 large glasses of clear liquids per day (water, Pedialyte (Ross),Gatorade 
(Quaker), broth) 
• 
Eat frequent small meals (bananas, rice, applesauce, Ensure, toast) 
• 
Stop high-osmolar food supplements such as Ensure Plus and Jevity Plus (with fiber) 
It is recommended that patients be provided loperamide tablets. It is mandatory that patients are 
instructed on the use of loperamide in order to manage signs or symptoms of diarrhea at home. 
Patients should be instructed to start oral loperamide (initial administration of 4mg, then 2mg 
every 4 hours -maximum of 16 mg/day) at the first sign of loose stool or symptoms of abdominal 
pain. These instructions should be provided during each office visit and the site should ensure 
that the patient understood the instruction. At the beginning of treatment, each patient should be 
specifically questioned regarding any experience of diarrhea or diarrhea related symptoms. If 
symptoms were experienced, then the site should question the patient regarding the actions 
taken for these symptoms. 
Treatment of diarrhea grade 1 or 2 
Diarrhea grade 1 or 2 will be treated with standard loperamide (initial at first administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool). 
12-24 hours later: 
Diarrhea resolved 
• 
Continue instructions for dietary modification 
• 
Gradually add solid foods to diet 
• 
Discontinue loperamide after 12-hours diarrhea-free interval 
Diarrhea unresolved 
Persisting diarrhea grade 1 or 2 will be treated with addition of opium tincture or dihydrocodeine 
tartrate tablets/injections with monitoring of patients condition to rule out dehydration, sepsis, il-
eus) medical check and selected workup if patient does not need hospitalization (see section 
Diarrhea workup and additional test in the particular trial protocol). Observe patient for response 
to antidiarrheal treatment. 
Persisting diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide (ini-
tial 4 mg, then 2 mg every 2 hours) and addition of opium tincture or dihydrocodeine tartrate tab-

 
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lets/injections, start of IV fluids and antibiotics as needed with monitoring of patients condition 
(to rule out dehydration, sepsis, ileus) medical check and workup (perform appropriate addition-
al testing). Observe patient for response. 
After 24 hours: 
Diarrhea resolved 
• 
Continue instructions for dietary modification 
• 
Gradually add solid foods to diet 
• 
Discontinue loperamide and/or other treatment after 12-hours diarrhea-free interval 
Diarrhea unresolved 
• 
If diarrhea still persisting (NCI CTC grades 1 and 2), after 2x 24 hours with high dose 
loperamide and opiates then admit to hospital and employ measures as for grade 3 
and 4 until diarrhea resolved 
• 
If diarrhea still persisting and progressed to NCI grades 3 and 4, employ measures 
described below. 
Treatment of diarrhea grade 3 or 4 
Severe diarrhea grade 3 or 4 may be treated with hospitalization, high dose loperamide (initial 4 
mg, then 2 mg every 2 hours and addition of opium tincture or dihydrocodeine tartrate tab-
lets/injections, start of IV fluids and antibiotics as needed with monitoring of patients condition 
(to rule out dehydration, sepsis, ileus) medical check and workup (see section Diarrhea workup 
and additional test in the particular trial protocol). Observe patient for response. 
After 24 hours: 
• 
If diarrhea persisting administer SQ Sandostatin/octreotide (100-500 µg tid) 
• 
Continue IV fluids and antibiotics as needed 
• 
If diarrhea grade 3 or 4 still persists patients should receive opium tincture or dihy-
drocodeine tartrate injections SQ or IM 
• 
If diarrhea grade 3 or 4 is still persisting SQ Sandostatin/octreotide (500-1000 µg tid) 
should be administered. 
• 
To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 
2 weeks. Treatment should be continued only when diarrhea resolved. 
Diarrhea workup 
Perform appropriate tests (Fine and Schiller 1999). 
Spot stool analysis 
• 
Collect stool separating it from urine (special containers, analysis immediately, excep-
tionally freeze samples) 
• 
Blood 

 
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• 
Fecal leukocytes (Wright's staining and microscopy) or 
• 
Clostridium difficile toxin 
• 
Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immunosuppressed pa-
tients), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic etc., 
possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water) 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is likely 
to be fragile with evidence of colitis and thus great care and caution must be exercised in under-
taking these invasive procedures. 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy 
of proximal jejunum to assess extent of inflammatory jejunitis 
• Sigmoidoscopy - reassessment of colitis 
12.2 
Appendix 2 
Guidance for hyperglycemia management 
Hyperglycemia is known to be associated with the treatment with SST analogs.  Clinical studies 
of pasireotide in healthy volunteers and in patients with Cushing’s disease, acromegaly or car-
cinoid syndrome have reported transient, asymptomatic increases in fasting and postprandial 
glucose levels.  Novartis has conducted 2 clinical studies ([SOM230B2216] and 
[SOM230B2124]) to further understand the mechanism of pasireotide-induced hyperglycemia 
and to evaluate the clinical utility of anti-diabetes agents in the management of pasireotide-
induced hyperglycemia.  Preliminary results suggest that pasireotide induces insulin suppres-
sion, particularly in the postprandial period, as being the key mechanistic driver of hyperglyce-
mia.  Based on the mechanisms of pasireotide-induced hyperglycemia and findings from the 
[SOM230B2124] study, appropriate management for the pasireotide-induced hyperglycemia in-
cludes the use of oral anti-diabetic agents for mild to moderate hyperglycemia, such as incretin 
enhancers (e.g. GLP-1analogs or DPP4 inhibitors or insulin secretagogues).  Metformin is not 
recommended.  Insulin should be used for moderate to severe hyperglycemia. Clinical monitor-
ing and self-monitoring of blood glucose level 
Finger -stick measurements: 
Fasting assessment: Patients will have these checked during follow up assessments. 
The glucose values from the will be recorded and sent to Mayo Clinic. At screening all patients 
should be informed of the signs/symptoms of hyperglycemia and educated on how to complete 
the patient glucose diary. The glucose values do not need to be entered into the database and 
should only be kept as source documentation.  
The below algorithm has been created as a general guidance tool on the management of pasir-
eotide-induced hyperglycemia during this study. The choice of therapeutic agent is primarily at 
the discretion of the treating physician. It is encouraged to follow the established guidelines from 
the ADA/EASD for the management of diabetes and consider a consultation with a diabetes ex-
pert as needed anytime during the study.  

 
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Postprandial Plasma Glucose Criteria 
The patient should be instructed on the steps to take in the event a glucose value is elevated. 
The below criteria is recommended: 
 
 
* Value confirmed on 2 separate occasions during the observation period.  
Fasting Plasma Glucose Criteria 
The patient should be instructed on the steps to take in the event a glucose value is elevated. 
 

 
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* Value confirmed on 2 separate occasions during the observation period.   
 

 
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Fasting plasma glucose or postprandial plasma glucose > 250 mg/dL (≥ CTCAE grade 3) 
 
 
12.3 
Appendix 3 
Guideline for the treatment of QT prolongation 
QT-related cardiology consultation/Holter monitoring 
If at any visit a QTcF > 500msec is observed, triplicate ECGs, each 2-3 minutes apart, need to 
be taken approximately 1 hour after the initial ECG. The mean QTcF from the triplicate ECGs 
will be determined. If the mean QTcF is > 500msec, the patient has to interrupt (SQ treatment)/ 
postpone (LAR treatment) study treatment until a cardiologist has re-evaluated the ECG (this 
will be done by the central cardiologist). The re-evaluation needs to be done as soon as practi-
cal but within 7 days of the initial abnormal ECG. If the cardiologist confirms a mean QTcF > 
500msec, the patient has to discontinue. Otherwise and if the cardiologist confirms that at least 
one ECG shows a QTcF > 480msec, the cardiac assessments described for a confirmed QTcF 
> 480msec need to be followed. 

 
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If at any visit a 480msec < QTcF/mean QTcF ≤ 500msec is observed, the following steps need 
to be taken:  
A cardiology consultation must be sought as soon as practical but within 7 days of the ini-
tial abnormal ECG and the cardiologist must re-evaluate the ECG (this can be done by 
the central cardiologist if the trial has one). 
If a QTcF > 480msec is NOT confirmed, no further action needs to be taken. 
If a QTcF > 480msec is confirmed, a cardiologist must perform a thorough examination (such as 
reviewing baseline ECG, concurrent medications and performing a cardiovascular examination, 
including at least a cardiac auscultation) to assess the patient for cardiovascular risk factors.  
• 
If based upon the assessment by the cardiologist, the investigator considers that there is 
an acute cardiovascular safety risk and that the patient should not continue with study 
medication, the patient needs to be discontinued immediately (discontinuation criteria to 
be followed). 
• 
If following the examination by the cardiologist, the investigator considers that there is 
not an acute cardiovascular safety risk and that the patient could continue to receive 
study medication, a Holter ECG (24hr or 48hr depending on the study) must be recorded 
soon as practical but within 7 days after the initial abnormal ECG / at the next pasire-
otide/octreotide LAR injection (for studies using LAR). The Holter-ECG must be started 
30min prior to an injection of study medication.  
The results of the ECGs, cardiac examination, Holter-ECGs and the recommendation by the 
cardiologist must be evaluated by the investigator to determine whether the patient should con-
tinue in the trial or not (discontinuation criteria to be followed). 
QT-related discontinuation criteria  
• 
Confirmed QTcF >480msec and discontinuation recommended by a cardiologist  
• 
Mean QTcF > 500 msec measured by triplicate ECGs  
• 
Significant arrhythmia findings from Holter monitoring such as: 
1. Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms  of he-
modynamic compromise 
2. Sustained ventricular tachycardia (>30 sec) irrespective of symptoms  
3. Recurrent non-sustained VT (≥ 3 beats) during any 24-hour monitoring period  
4. Torsades de Pointes (TdP)   
5. Cardiac arrest  
6. Pause >5 seconds 
7. Second or third degree AV block 
• 
New occurrence of clinically significant/symptomatic bradycardia  
• 
Increased risk of QT prolongation by use of QT prolonging medication 
• 
Hypokalemia (<3.5 mmol/L) or hypomagnesaemia (<0.7 mmol/L) confirmed by repeat test-
ing that is either a new finding or accompanied by vomiting or diarrhea and not corrected by 
treatment 

 
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QT prolonging medication 
The following drugs are generally recognized to have an association with QT prolongation.  This 
list is not considered to be all inclusive and any questions regarding the QT prolongation poten-
tial should be discussed with the Novartis Medical Monitor.  
Drugs that are generally accepted by the QTdrugs.org Advisory Board of the Arizona CERT to 
have a risk of causing torsade de pointes are listed below. 
 
Generic Name 
Brand Name 
Class 
Bepridil  
Vascor® 
Anti-anginal / heart pain 
Amiodarone  
Cordarone® 
Anti-arrhythmic / abnormal heart rhythm 
Amiodarone  
Pacerone® 
Anti-arrhythmic / abnormal heart rhythm 
Disopyramide  
Norpace® 
Anti-arrhythmic / abnormal heart rhythm 
Dofetilide  
Tikosyn® 
Anti-arrhythmic / abnormal heart rhythm 
Ibutilide 
Corvert® 
Anti-arrhythmic / abnormal heart rhythm 
Procainamide  
Pronestyl® 
Anti-arrhythmic / abnormal heart rhythm 
Procainamide  
Procan® 
Anti-arrhythmic / abnormal heart rhythm 
Quinidine 
Cardioquin® 
Anti-arrhythmic / abnormal heart rhythm 
Quinidine 
Quinaglute® 
Anti-arrhythmic / abnormal heart rhythm 
Sotalol  
Betapace® 
Anti-arrhythmic / abnormal heart rhythm 
Clarithromycin 
Biaxin® 
Antibiotic / bacterial infection 
Sparfloxacin  
Zagam® 
Antibiotic / bacterial infection 
Erythromycin  
Erythrocin® 
Antibiotic;GI stimulant / bacterial infection; increase GI motility 
Erythromycin  
E.E.S.® 
Antibiotic;GI stimulant / bacterial infection; increase GI motility 
Arsenic trioxide  
Trisenox® 
Anti-cancer / Leukemia 
Astemizole  
Hismanal® 
Antihistamine / Allergic rhinitis 
Terfenadine 
Seldane® 
Antihistamine / Allergic rhinitis 
Pentamidine  
Pentam® 
Anti-infective / pneumocystis pneumonia 
Pentamidine  
NebuPent® 
Anti-infective / pneumocystis pneumonia 
Probucol 
Lorelco® 
Antilipemic / Hypercholesterolemia 
Chloroquine 
Aralen® 
Anti-malarial / malaria infection 
Halofantrine  
Halfan® 
Anti-malarial / malaria infection 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Mesoridazine 
Serentil® 
Anti-psychotic / schizophrenia 
Thioridazine 
Mellaril®  
Anti-psychotic / schizophrenia 
Haloperidol  
Haldol® 
Anti-psychotic / schizophrenia, agitation 
Pimozide 
Orap®  
Anti-psychotic / Tourette's tics 
Chlorpromazine  
Thorazine® 
Anti-psychotic/ Anti-emetic / schizophrenia/ nausea 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
Levomethadyl 
Orlaam® 
Opiate agonist / pain control, narcotic dependence 
Methadone 
Dolophine® 
Opiate agonist / pain control, narcotic dependence 
Methadone 
Methadose® 
Opiate agonist / pain control, narcotic dependence 
Droperidol  
Inapsine® 
Sedative;Anti-nausea / anesthesia adjunct, nausea 
 
 
 
 
 
 

 
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12.4 
Appendix 4 
SOM230 LFT Management Algorithm (s.c. and LAR Studies) 
 
 
Revised SOM230 Abnormal liver function discontinuation criteria: 
 
 
13 
Procedures and instructions 
13.1.1 Publication of results 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and prior to any outside submission. Novartis must receive copies of any 
intended communication in advance of publication (at least fifteen working days for presenta-
tional materials and abstracts and thirty working days for manuscripts). These requirements 
acknowledge Novartis’ responsibility to provide peer input regarding the scientific content and 
conclusions of such publications or presentations. Principal Investigation/Institution shall have 
the final authority to determine the scope and content of its publications, provided such authority 

 
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shall be exercised with reasonable regard for the interests of Novartis and, in accord with the 
trial contract and shall not permit disclosure of Novartis confidential or proprietary information. 
13.1.2 Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents provid-
ed by Novartis (investigators' brochures and other material) will be stored appropriately to en-
sure their confidentiality. The information provided by Novartis to the investigator may not be 
disclosed to others without direct written authorization from Novartis, except to the extent nec-
essary to obtain informed consent from patients who wish to participate in the trial. 
13.1.3 Discontinuation of study 
Novartis reserves the right to discontinue any study under the conditions specified in the clinical 
trial agreement. 
13.2 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good Clini-
cal Practice, as described in Novartis standard operating procedures and: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 91/507/EEC, 
The Rules Governing Medicinal Products in the European Community. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 con-
cerning informed consent and IRB regulations). 
Declaration of Helsinki and amendments, concerning medical research in humans (Recommen-
dations Guiding Physicians in Biomedical Research Involving Human Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and thereby 
to adhere to the principles of Good Clinical Practice that it conforms to. 
13.2.1 Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other in-
formation to subjects, must be reviewed by a properly constituted Institutional Review Board / 
Independent Ethics Committee / Research Ethics Board (IRB / IEC / REB). A signed and dated 
statement that the protocol and informed consent have been approved by the IRB/IEC/REB 
must be given to Novartis before study initiation. Any amendments to the protocol, other than 
administrative ones, must be reviewed by Novartis approved by this committee. 
13.2.2 Informed consent 
We will explain to each subject (or legally authorized representative) the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits in-
volved and any discomfort it may entail. Each subject must be informed that participation in the 
study is voluntary and that he/she may withdraw from the study at any time and that withdrawal 
of consent will not affect his/her subsequent medical treatment or relationship with the treating 
physician. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing and 
dating it, and should be given a copy of the signed document. If the subject cannot read or sign 

 
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the documents, oral presentation may be made or signature given by the subject’s legally ap-
pointed representative, if witnessed by a person not involved in the study, mentioning that the 
patient could not read or sign the documents. No patient can enter the study before his/her in-
formed consent has been obtained. 
13.2.3 Declaration of Helsinki 
We will conduct the trial in accordance with the principles of the Declaration of Helsinki. Copies 
of the Declaration of Helsinki and amendments will be provided upon request or can be ac-
cessed via the website of the World Medical Association at http://www.wma.net/e/policy/17-
c_e.html.