A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate Efficacy and Safety of Octreotide Capsules in Patients Who Demonstrated Biochemical Control on Injectable Somatostatin Receptor Ligands (SRL) Treatment
Phase: PHASE3
Conditions: Acromegaly
Sponsor: Chiasma, Inc.

 
Document Type: 
Study Protocol 
Official Title: 
A phase 3, randomized, double-blind, placebo-controlled, multicenter 
study to evaluate efficacy and safety of octreotide capsules in patients 
who previously tolerated and demonstrated biochemical control on 
injectable somatostatin receptor ligands (SRL) treatment 
NCT Number: 
NCT03252353 
Document Date: 
November 29, 2017 
 

 
 
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Protocol Revision History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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PROTOCOL SYNOPSIS 
Study Title 
A phase 3, randomized, double-blind, placebo-controlled, multicenter study to 
evaluate efficacy and safety of octreotide capsules in patients who previously 
tolerated and demonstrated biochemical control on injectable somatostatin receptor 
ligands (SRL) treatment 
Protocol No. 
OOC-ACM-303 
Clinical Sites 
Global, Multicenter Study (including US) 
Study Phase 
3 
Investigational 
Products  
Octreotide Capsules  
Octreotide capsule is a novel, orally-administered formulation of the well-
characterized and commercially-available parenteral drug, octreotide. It is a 
capsule filled with an oily suspension of octreotide, formulated with proprietary 
Transient Permeability Enhancer (TPE®) excipients. The TPE facilitates 
paracellular transit across the intestinal wall, primarily via transient and reversible 
opening of the tight junctions between cells, enabling intact octreotide to be 
absorbed. The capsule is enteric coated and designed to pass intact through the 
stomach and dissolve in the small intestine. 
Octreotide capsules (each capsule strength is 20 mg) should be administered twice 
daily on an empty stomach, i.e. at least 1 hour prior to a meal or at least two hours 
after a meal. 
Placebo  
Matching placebo capsules, identical in appearance to octreotide capsules, 
containing TPE® with no octreotide.  
Target 
Population  
Patients diagnosed with acromegaly who are treated with somatostatin receptor 
ligand (SRL) injections (octreotide or lanreotide) for at least 6 months, with stable 
dose for at least 3 months and are biochemically controlled, defined as an average 
insulin-like growth factor [IGF-1] of 2 assessments during the Screening period is 
≤ 1 times upper limit of normal (ULN). 
Study 
Objectives 
Primary Objective 
• 
To assess maintenance of biochemical control with octreotide 
capsules compared to placebo in patients with acromegaly, who 
previously demonstrated biochemical control on SRLs 
Secondary Objectives 
• 
To assess maintenance of biochemical control, based on GH, with 
octreotide capsules compared to placebo 
• 
To evaluate the safety profile of octreotide capsules compared to 
placebo  
Open Label Extension objectives 
• 
To assess the long-term efficacy and safety of octreotide capsules in 
acromegaly patients 

 
 
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Exclusion 
Criteria 
Any of the following will exclude a patient from participating in the study: 
1. Patients taking injections of long-acting SRLs off label (unlabeled doses or 
dosing interval. e.g. 60 or 90mg lanreotide every 8 weeks or 30 mg octreotide 
every 6 or 8 weeks).  
2. Patients who previously participated in CH-ACM-01 or OOC-ACM-302 
(MPOWERED study). 
3. Symptomatic cholelithiasis. 
4. Conventional or stereotactic radiotherapy any time in the past 
5. Undergone pituitary surgery within six months prior to screening or have 
elective pituitary surgery (or other elective surgery that may affect 
compliance with protocol or confound study outcomes), planned within the 
course of the core study. 
6. High-risk pattern3 of pituitary tumor location on pituitary MRI/Computed 
tomography (CT) as per medical history or most recent MRI/CT. 
7. History of unstable angina or acute myocardial infarction within the 12 weeks 
preceding the screening visit or other clinically significant cardiac disease at 
the time of screening as judged by the Principal Investigator. 
8. Any clinically significant uncontrolled nervous system, gastrointestinal (GI), 
renal, pulmonary, or hepatic concomitant disease that in the Investigator’s 
opinion would preclude patient participation. 
9. Evidence of active malignant disease or malignancies diagnosed within the 
previous one year (except for basal cell carcinoma and uncomplicated – up to 
stage 1 squamous cell carcinoma that has been excised and cured). 
10. Known allergy or hypersensitivity to any of the test compounds or materials. 
11. Known uncontrolled diabetes defined as having a fasting glucose 
> 150 mg/dL (8.3 mmol/L) or glycosylated hemoglobin (HbA1c) ≥ 8% 
(patients can be rescreened after diabetes is brought under adequate control, 
or in case HbA1c < 8%). 
12. Known defects in visual fields due to optic chiasmal compression or other 
neurological signs, related to the pituitary tumor mass. Patients with 
long-standing (>12 months), fixed, minor defects may be considered on a 
case-by-case basis after consultation with the medical monitor. 
13. Female patients who are pregnant or lactating or intending to become 
pregnant during the study. 
14. Known history of immunodeficiency (e.g., HIV positive). 
15. Alanine transaminase (ALT), aspartate aminotransferase (AST) or alkaline 
phosphatase (ALP) > 3 × ULN or total bilirubin >1.5 × ULN. 
                                                 
3 High risk tumor burden is defined by the presence of any of the following: 
• 
Tumor recurrence or growth of residual tumor within one year after surgery or radiation (except for tumor 
regrowth occurring if SRLs have been stopped in the past) 
• 
Tumor compression of the optic chiasm and invasion of adjacent brain structures (except for sphenoid sinus 
and cavernous sinus) 
• 
Anticipated need for surgery or radiation during the study period based on tumor growth on serial MRIs 
• 
Metastatic pituitary carcinoma or prior chemotherapy for pituitary carcinoma 

 
 
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conducted. Data will be summarized using appropriate descriptive statistics. 
Missing data will be maintained as missing, unless indicated. 
Interim Analysis 
No interim analysis is planned for the core study. 

 
 
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4.8 SPONSOR'S TERMINATION OF STUDY ........................................................................... 46 
5 
STUDY PROCEDURES AND ASSESSMENTS .............................................................. 46 
5.1 SCREENING PERIOD (≤8 WEEKS) .................................................................................. 46 
5.2 DOUBLE-BLIND PLACEBO-CONTROLLED (DPC) PERIOD (WEEK 1 TO WEEK 36) ....... 47 
5.2.1 
Baseline Visit .................................................................................................. 48 
5.2.2 
Telephone Call at Week 1 and Week 2 ........................................................... 49 
5.2.3 
DPC Clinic Visits (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 34, 36) ....................... 50 
5.3 OPEN-LABEL EXTENSION (OLE) PERIOD ..................................................................... 51 
5.4 END OF TREATMENT (EOT) VISIT ............................................................................... 52 
5.5 FOLLOW-UP PERIOD .................................................................................................... 53 
5.6 UNSCHEDULED VISIT ................................................................................................... 54 
5.7 EFFICACY ASSESSMENTS ............................................................................................. 54 
5.7.1 
IGF-1 and GH ................................................................................................. 54 
5.8 SAFETY ASSESSMENTS ................................................................................................. 54 
5.8.1 
Adverse Events................................................................................................ 55 
5.8.2 
Medical History and Concomitant Medications .............................................. 55 
5.8.3 
Vital Signs ....................................................................................................... 55 
5.8.4 
ECG Assessment ............................................................................................. 55 
5.8.5 
Physical Examination ...................................................................................... 55 
5.8.6 
Abdominal Ultrasound .................................................................................... 56 
5.8.7 
Safety Laboratory Assessments ...................................................................... 56 
6 
INVESTIGATIONAL PRODUCT .................................................................................... 57 
6.1 IDENTITY OF INVESTIGATIONAL PRODUCT .................................................................. 57 
6.1.1 
Octreotide Capsules ........................................................................................ 57 
6.1.2 
Placebo ............................................................................................................ 57 
6.2 STUDY MEDICATION ADMINISTRATION ....................................................................... 57 
6.3 METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ........................................ 58 
6.4 BLINDING AND UNBLINDING........................................................................................ 58 
6.5 MANUFACTURING OF STUDY MEDICATIONS ............................................................... 59 
6.6 PACKAGING AND LABELING OF STUDY MEDICATION ................................................. 59 
6.7 DISTRIBUTION AND RECEIPT OF STUDY MEDICATION ................................................ 60 
6.8 STORAGE OF STUDY MEDICATION ............................................................................... 60 
6.9 ACCOUNTABILITY AND COMPLIANCE OF STUDY MEDICATION ................................... 60 
6.10 PRIOR AND CONCOMITANT THERAPY .......................................................................... 61 
6.10.1 General Guidelines .......................................................................................... 61 

 
 
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6.10.2 Prohibited Prior Medications or Therapies ..................................................... 61 
6.10.3 Allowed Medications ...................................................................................... 61 
6.10.4 Prohibited Concomitant Medication ............................................................... 62 
7 
SAFETY AND PHARMACOVIGILANCE ..................................................................... 62 
7.1 ADVERSE EVENT .......................................................................................................... 62 
7.1.1 
Adverse Events of Special Interest .................................................................. 65 
7.2 SERIOUS ADVERSE EVENTS ......................................................................................... 67 
7.3 DEFINITION OF AN UNEXPECTED ADVERSE EVENT ..................................................... 67 
7.4 NOTIFICATION OF SERIOUS UNEXPECTED SUSPECTED ADVERSE EVENT .................... 68 
7.5 ANTICIPATED ADVERSE EVENTS ................................................................................. 69 
7.6 OCTREOTIDE SAFETY GUIDANCE................................................................................. 69 
8 
STATISTICAL ANALYSIS PLAN ................................................................................... 72 
8.1 SAMPLE SIZE CONSIDERATION .................................................................................... 72 
8.2 ANALYZED POPULATIONS ............................................................................................ 72 
8.2.1 
Full Analysis Set (FAS) .................................................................................. 72 
8.2.2 
Per-Protocol Analysis Set (PP) ....................................................................... 72 
8.2.3 
Safety Analysis Set ......................................................................................... 73 
8.2.4 
Open Label Extension Analysis Set ................................................................ 73 
8.3 ENDPOINTS ................................................................................................................... 73 
8.4 STATISTICAL ANALYSIS ............................................................................................... 73 
8.4.1 
General Considerations ................................................................................... 73 
8.4.2 
Demographics and Baseline ............................................................................ 74 
8.4.3 
Primary Efficacy Analysis .............................................................................. 74 
8.4.4 
Secondary Efficacy Analysis .......................................................................... 74 
8.4.5 
Descriptive Endpoint Analysis ........................................................................ 75 
8.4.6 
Exploratory Efficacy Analysis ........................................................................ 75 
8.4.7 
OLE Period...................................................................................................... 75 
8.4.8 
Safety Analysis................................................................................................ 75 
8.4.9 
Interim Analyses ............................................................................................. 77 
9 
ETHICS ................................................................................................................................ 78 
9.1 INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE ................... 78 
9.2 ETHICAL CONDUCT OF THE STUDY .............................................................................. 78 
9.3 PATIENT INFORMATION AND CONSENT ....................................................................... 78 
9.4 PATIENT INSURANCE .................................................................................................... 79 
9.5 PERSONAL DATA PROTECTION .................................................................................... 79 

 
 
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9.6 STUDY COMMITTEES .................................................................................................... 79 
9.6.1 
Steering Committee ......................................................................................... 79 
9.6.2 
Independent Data Monitoring Committee ....................................................... 79 
9.7 PROTOCOL EXCEPTIONS AND DEVIATIONS .................................................................. 80 
9.8 PROTOCOL AMENDMENTS ........................................................................................... 80 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 80 
10.1 AUDITS AND INSPECTIONS ........................................................................................... 80 
10.2 STUDY MONITORING .................................................................................................... 81 
10.3 QUALITY LABORATORY STANDARDS .......................................................................... 81 
10.4 STUDY DOCUMENTATION ............................................................................................ 82 
10.4.1 Source Document ............................................................................................ 82 
10.4.2 Recording of Data on Electronic Case Report Form (eCRF) .......................... 82 
10.4.3 Investigator Site File ....................................................................................... 83 
10.5 CLINICAL TRIAL SUPPLIES ........................................................................................... 83 
10.6 DATA MANAGEMENT ................................................................................................... 83 
11 
STUDY ADMINISTRATION ............................................................................................ 83 
11.1 PARTICIPATING CENTERS ............................................................................................. 83 
11.2 REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION ................................................ 83 
11.3 STUDY COMPLETION .................................................................................................... 84 
11.4 CLINICAL STUDY REPORT ............................................................................................ 85 
11.5 RETENTION OF STUDY RECORDS ................................................................................. 85 
11.6 CONFIDENTIALITY AND PUBLICATION OF STUDY DATA ............................................. 85 
12 
REFERENCES .................................................................................................................... 87 
13 
APPENDICES ..................................................................................................................... 89 
 
Appendix A 
Schedule of Activities ..................................................................................... 90 
Appendix B 
Acromegaly and Treatment Directed Physical Examination .......................... 93 
Appendix C 
Declaration of Helsinki (2013) ........................................................................ 94 
 
List of Tables 
Table 1 
Definition of Adverse Events Severity............................................................ 64 
Table 2 
Definition of Adverse Events Causality .......................................................... 64 
Table 3 
Dysglycemia Severity criteria ......................................................................... 66 
Table 4 
Hypertension Severity criteria ......................................................................... 66 

 
 
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Table 5 
Study Power .................................................................................................... 72 
 
 
List of Figures 
Figure 1 
Study Overview ............................................................................................... 41 
Figure 2 
Decision Tree for Abnormal Liver Function Tests ......................................... 71 
 

 
 
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GLOSSARY 
Subject and patient will be used interchangeably throughout this document. 
Abbreviation/Term 
Definition 
% 
Percent 
AACE 
American Association of Clinical Endocrinologists 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
API 
Active Pharmaceutical Ingredient 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BID 
Twice Daily; bis in die  
BL 
Baseline 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CPK 
Creatine Phosphokinase  
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
d 
Day 
DPC 
Double-blind, Placebo-Controlled period 
dL 
Deciliter 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form; any reference to recording data into the eCRF 
refers to the process of initially recording data in the patient’s medical files 
or study-specific source documents, by the relevant study personnel, 
followed by upload into the eCRF, as detailed in the Study Monitoring Plan. 
EMA 
European Medicines Agency 
EOT 
End-of-Treatment  
ESRD 
End Stage Renal Disease 
EXT-AS 
Extension Analysis Set 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
FU 
Follow-up 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 

 
 
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Abbreviation/Term 
Definition 
GH 
Growth Hormone 
GHRH 
Growth Hormone-Releasing Hormone 
GI 
Gastrointestinal  
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GOT (AST) 
Glutamic Oxaloacetic Transaminase (aspartate aminotransferase) 
GPT (ALT) 
Glutamic Pyruvic Transaminase (alanine transaminase) 
HbA1c 
Glycosylated Hemoglobin 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like Growth Factor 1 
im 
Intramuscular 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio (for blood coagulation tests) 
IR 
Immediate Release 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS/IVRS 
Interactive Web / Voice Response System  
kDA 
Kilo Dalton 
kg 
Kilogram 
L 
Liter 
LAR 
Long-acting Release 
LFT 
Liver Function Test 
LOCF 
Last Observation Carried Forward 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MID 
Minimal Important Difference 
min 
Minute 
mL 
Milliliter 
mmol 
Millimole 
MRI 
Magnetic Resonance Imaging 
NDA 
New Drug Application 
ng 
Nanogram 
NI 
Non-inferiority  
OGTT 
Oral Glucose Tolerance Test 

 
 
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Abbreviation/Term 
Definition 
OLE 
Open-Label Extension 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PPI 
Proton Pump Inhibitor 
PT 
Preferred Term 
QA 
Quality Assurance 
RA 
Regulatory Authority 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set  
sc (injection) 
Subcutaneous 
SC 
Steering Committee 
SD 
Standard Deviation 
SERM 
Selective Estrogen Receptor Modulator 
SOC (treatment) 
Standard of Care 
SOC (safety) 
System Organ Class 
SOP 
Standard Operation Procedures 
SRL 
Somatostatin Receptor Ligands 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Events 
TPE 
Transient Permeability Enhancer 
TSH 
Thyroid Stimulating Hormone 
TWA 
Time Weighted Average 
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
Wk 
Week 
 
 
 
 
 
 

 
 
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1 
INTRODUCTION 
1.1 
THERAPEUTIC INDICATIONS 
Acromegaly is a rare disorder of disproportionate skeletal, tissue, and organ growth arising from 
hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). The elevated 
GH and IGF-1 levels lead also to a wide range of cardiovascular, respiratory, endocrine, and 
metabolic co-morbidities. In over 95% of cases the etiology is attributed to GH-producing benign 
pituitary adenoma (Ben-Shlomo and Melmed 2008; Melmed 2009; Melmed et al. 2009). 
The annual incidence of acromegaly is 3 to 5 cases per one million individuals, and estimated 
prevalence is 40 to 70 cases per million with men and women equally affected (Holdaway and 
Rajasoorya 1999). Owing to its insidious onset it is often diagnosed late (4 to more than 10 years 
after onset), at an average age of about 40 years. At diagnosis, patients generally exhibit coarsened 
facial features, exaggerated growth of hands and feet, and soft tissue hypertrophy. The diagnosis 
of acromegaly requires demonstration of dysregulated and enhanced GH secretion or elevated 
IGF-1 levels, reflective of peripheral tissue exposure to tonically elevated GH concentrations 
(Chanson and Salenave 2008; Melmed 2009). 
1.2 
CURRENT THERAPY 
Treatment options for acromegaly include surgical resection of the pituitary adenoma, 
radiotherapy, and drug therapy to reduce GH and IGF-1 levels to normal values. Currently, there 
are three drug classes available for the treatment of acromegaly: somatostatin receptor ligands 
(SRLs) or somatostatin analogs (octreotide, lanreotide and pasireotide), dopamine agonists 
(bromocriptine and cabergoline), and a GH receptor antagonist (pegvisomant) (Melmed et al. 
2009; Melmed et al. 2014). 
SRLs are, at present, the most widely used drugs to control acromegaly. Octreotide is an 
octapeptide, displaying a high affinity for somatostatin receptor subtypes 2 and 5, effectively 
suppressing GH hypersecretion in up to ~60% of patients with acromegaly (Colao et al. 2004; 
Chanson and Salenave 2008; Melmed 2009; Fleseriu 2014; Melmed et al. 2014). 
Octreotide has been approved as an immediate-release (IR) injectable solution by the FDA since 
1988 and in UK in 1989. Octreotide IR formulation is available under the brand name Sandostatin 
by Novartis or as a generic form sold by several different suppliers. It is administered as a three 
times a day subcutaneous (sc) injection. A long-acting depot formulation of octreotide has been 
initially approved in France in 1995 and in 1998 in the US, for the treatment of acromegaly. 
Octreotide long-acting formulation is marketed under the brand name Sandostatin LAR by 
Novartis. It is administered as monthly deep intragluteal intramuscular (im) injection. Lanreotide 
long-acting formulation is marketed under the brand name Somatuline Autogel by Ipsen. It is 
administered every four weeks (or six to eight weeks at the higher dose). 
Treatment with SRLs is routinely done by dose titration, based on individual biochemical disease 
control. 
1.3 
INVESTIGATIONAL THERAPY 
Chiasma has developed octreotide capsules, a new formulation of octreotide for oral delivery. It is 
an enteric coated capsule filled with an oily suspension of unmodified octreotide formulated with 

 
 
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of the OLE period will be conducted periodically, after completion of the DPC period. Data 
collected post DPC period (week 36) will be included in the OLE database. Details of these 
analyses will be outlined in the statistical analysis plan (SAP). 
Study duration will be as follows: 
Core study duration: Up to 44 weeks, composed of: 
Screening period 
up to 8 weeks 
Double-blind Placebo-Controlled (DPC) period  
36 weeks 
 
OLE period: at least one year (for the last patient who enter the OLE period), or until study 
medication is commercially available or Sponsor terminates the study. The Sponsor may either 
extend the OLE period (via a protocol amendment for an additional one year or until product 
marketing or study termination) or consider compassionate use (if requested by the principal 
investigator under a compassionate use protocol). 
Follow-up period:  
For patients who discontinue study medication early during DPC period: Through week 36 of the 
DCP period. 
For patients who complete the DPC period on study medication and are not eligible or do not opt 
to enter OLE or patients who early discontinue OLE period on study medications: 12 weeks 
(consisting of in-clinic visit 4 weeks ±5 days after end of treatment [EOT] and a phone call 12 
weeks after EOT). 

 
 
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Figure 1 
Study Overview  
 
 

 
 
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6. High-risk pattern1 of pituitary tumor location on pituitary magnetic resonance imaging 
(MRI)/Computed tomography (CT) as per medical history or most recent MRI/CT. 
7. History of unstable angina or acute myocardial infarction within the 12 weeks preceding 
the screening visit or other clinically significant cardiac disease at the time of screening as 
judged by the Principal Investigator. 
8. Any clinically significant uncontrolled nervous system, gastrointestinal (GI), renal, 
pulmonary, or hepatic concomitant disease that in the Investigator’s opinion would 
preclude patient participation. 
9. Evidence of active malignant disease or malignancies diagnosed within the previous one 
year (except for basal cell carcinoma and uncomplicated – up to stage 1 squamous cell 
carcinoma that has been excised and cured). 
10. Known allergy or hypersensitivity to any of the test compounds or materials. 
11. Known uncontrolled diabetes defined as having a fasting glucose > 150 mg/dL 
(8.3 mmol/L) or glycosylated hemoglobin (HbA1c) ≥ 8% (patients can be rescreened after 
diabetes is brought under adequate control, or in case HbA1c < 8%). 
12. Known defects in visual fields due to optic chiasmal compression or other neurological 
signs, related to the pituitary tumor mass. Patients with long-standing (>12 months), fixed, 
minor defects may be considered on a case-by-case basis after consultation with the 
medical monitor. 
13. Female patients who are pregnant or lactating or intending to become pregnant during the 
study. 
14. Known history of immunodeficiency (e.g., HIV positive). 
15. ALT, AST or ALP > 3 × ULN or Total Bilirubin >1.5 × ULN. 
16. Undergone major surgery/surgical therapy for any cause within four weeks prior to 
enrollment or planned procedure during the study. 
17. Known hypothyroidism or hypocortisolism not adequately treated with a stable dose of 
thyroid or steroid hormone replacement therapy for ≥ 12 weeks. 
18. Any condition that may jeopardize study participation (e.g., clinically significant 
abnormal screening clinical or laboratory finding during screening), the interpretation of 
study results or may impede the ability to obtain informed consent (e.g., mental 
condition). 
19. History of illicit drug or alcohol abuse within five years. 
20. Intake of an investigational drug within 30 days prior to initiation of study treatment. 
21. Treatment with pegvisomant within 24 weeks before the screening visit. 
                                                 
1 High risk tumor burden is defined by the presence of any of the following: 
• 
Tumor recurrence or growth of residual tumor within one year after surgery or radiation (with the exception 
of tumor regrowth occurring if SRLs have been stopped in the past) 
• 
Tumor compression of the optic chiasm and invasion of adjacent brain structures (with the exception of 
sphenoid sinus and cavernous sinus) 
• 
Anticipated need for surgery or radiation during the study period based on tumor growth on serial MRIs 
• 
Metastatic pituitary carcinoma or prior chemotherapy for pituitary carcinoma 

 
 
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22. Treatment with dopamine agonists within 12 weeks before the screening visit. 
23. Treatment with pasireotide within 24 weeks before the screening visit. 
4.3 
ELIGIBILITY CRITERIA TO OLE PERIOD 
Patients must meet the following inclusion criteria to be eligible for OLE period: 
1. Patient complying with any one of the following criteria: 
a. Completed the full 36-week duration of the DPC period on study medication 
b. Met the pre-defined withdrawal criteria during the DPC period and completed follow-
up per protocol through week 36 of DCP period 
2. Patient not currently having study medication withheld for a study medication-related AE. 
3. Patient not having a clinically significant or unstable medical or surgical condition 
detected or worsening during the study, which would preclude safe participation and 
completion of the OLE period. 
4. Patient willing and able to comply with the protocol requirements for the duration of the 
OLE period. 
5. Patient preference to continue treatment with octreotide capsules and able to understand 
and sign an additional written informed consent prior to entering the OLE period. 
4.4 
PATIENT IDENTIFICATION 
Each patient who signed informed consent will be assigned a screening number. This screening 
number will be used as the primary identification for the complete duration of the study (core and 
OLE period). 
4.5 
SCREENING FAILURES 
Patients who fail to meet the entrance criteria at any stage during the screening period are defined 
as screen failures. All screen failures will be recorded on the screening log, which documents the 
screening number, patient’s initials and reason(s) for screen failure. The screening log will be kept 
in the Investigator’s Site File. 
Patients who are considered screen failures will be withdrawn from the study and receive standard 
of care as practiced at that particular site. Screen failures will not count towards the total enrolled 
and evaluable patients. Re-assessment during the screening period will generally not be allowed, 
unless for technical reasons (e.g. inadequate sample volume, lost sample, assay failure, other). Re-
screening will be possible on a case-by-case basis following Sponsor approval. 
4.6 
REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF PATIENTS FROM THERAPY 
OR ASSESSMENT 
Patients are free to discontinue study medication and/or their participation in the study at any time 
and without prejudice to further treatment. The Investigator must discontinue study medication if 
that patient requests to be withdrawn, or if it is determined that continuing study medication would 
result in a significant safety risk to the patient. 
Patients discontinued or withdrawn from the study will not be replaced. 
A patient may discontinue treatment due to the following reasons: 

 
 
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1. Request of Investigator  
2. Patient withdrew consent 
3. AE 
4. Treatment failure 
5. Patient is lost-to-follow-up 
6. Patient is non-compliant with study procedures or study protocol 
7. Request of Sponsor or regulatory authority 
8. Pregnancy 
9. Other (to be specified in the electronic case report form; eCRF) 
4.6.1 Early Study Medication Discontinuation During DPC Period 
Patients who discontinue study medication during the DPC period due to pre-defined withdrawal 
criteria will be rescued with injectable SRL treatment used prior to Screening and continue to be 
followed-up per protocol (including all in-clinic visits and assessments as detailed in DPC 
Schedule of Activities) until week 36. Their visit schedule will be customized to correspond with 
their SRL injection schedule. At week 36, these patients will be offered to enter the OLE and 
receive octreotide capsules. Patients who do not complete the full 36-week DPC period will not 
be eligible to enter the OLE period and will not require further follow up beyond week 36. 
Patients who discontinue study medication during the DPC period for reasons other than the pre-
defined withdrawal criteria should continue to be followed per protocol (including all in-clinic 
visits and assessments as detailed in DPC Schedule of Activities), until week 36. The Sponsor 
recommends re-initiation of their prior injectable SRL treatment (as rescue or escape medication) 
upon meeting the pre-defined withdrawal criteria. These patients will not be eligible to continue 
into the OLE and will not require further follow up beyond week 36. 
4.6.2 Early Termination from OLE Period 
Patients who discontinue treatment during the OLE period for any reason will revert to their prior 
injectable SRL treatment (prior to Screening) or other treatment as determined by their physician. 
These patients will be followed-up for 12 weeks after EOT (consisting of in-clinic visit 4 weeks 
±5 days after EOT and a phone call 8 weeks ±5 days later). 
4.7 
HANDLING OF WITHDRAWALS 
Patients discontinuing study medication during DPC period will be followed-up for per protocol 
and return for all scheduled visits through Week 36. In case the patient is lost-to-follow-up or 
withdraws consent to attend the remaining study visits, all efforts should be made to invite the 
patient to attend EOT visit as soon after their last dose of study medication and to attend a follow 
up visit 36 weeks after Baseline. Patients discontinuing OLE period. will be followed for 12 weeks 
after their last octreotide capsules dose. 
Patients will be asked to agree that study assessments be performed as stated in the protocol for 
the remaining study visits, even if the patient discontinues treatment by his/her decision, or that of 
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• Informed consent signature 
• Inclusion and exclusion criteria review 
• An MRI must be completed during the Screening period unless an MRI image 
and/or report is available within 12 months prior to screening. If tumor remnants 
were not visible or were less than 5 mm on the last MRI, an MRI performed within 
2 years is also acceptable. CT scans may be done if an MRI is contraindicated. 
• Acromegaly history – date of diagnosis, Number of surgeries, first and most recent 
surgery, first pathology report findings, most recently documented MRI/CT 
findings – prior to surgery, following surgery, elevated IGF-1 following surgery1 
• Medical history; any diseases that are present prior to screening or present prior to 
but diagnosed during screening will be documented in the medical history eCRF. 
• Prior and concomitant medications recording – general use since diagnosis (list of 
prior medications for acromegaly any time in the past), medications for acromegaly 
within the last year (with start and stop dates), including the last dose of SRL 
injection and medications for other conditions – within the last 12 weeks. 
• Demographic data 
• Height and weight measurements 
• Vital signs  
• 12-lead ECG 
• Safety laboratory tests: hematology, chemistry, urinalysis, HbA1c, fasting plasma 
glucose (FPG; for diabetic patients only) and serum pregnancy test, if applicable 
(for women with childbearing potential) 
• IGF-1  
• GH: Five samples every 30 ± 5 minutes over two hours from time 0 to 2 hours  
• Complete physical examination 
• Acromegaly directed and treatment directed physical examination 
• Adverse events 
• Gall bladder ultrasound 
The following evaluations will be done at Screening visit 2: 
• IGF-1  
• Adverse events 
• Concomitant medications 
 
5.2 
DOUBLE-BLIND PLACEBO-CONTROLLED (DPC) PERIOD (WEEK 1 TO WEEK 36) 
Patients meeting the eligibility criteria will be randomized at Baseline in 1:1 ratio to one of two 
treatment arms: Octreotide capsules or matching placebo capsules. All efforts should be made to 
                                                 
1 Including assay used and/or reference ranges  

 
 
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lipoprotein) 
• Urine pregnancy test for women of childbearing potential, Positive urine pregnancy 
test will be followed by a confirmatory serum pregnancy test. In case of positive 
urine pregnancy test subjects could not be dosed, until the results of the serum 
pregnancy test will be available. Positive serum pregnancy test will result in a 
subject being a screening failure. 
• IGF-1  
• GH: Five samples every 30 ± 5 minutes over two hours from time 0 to 2 hours 
• Acromegaly directed and treatment directed physical examination  
• Concomitant medications and AE recording 
• Randomization and dispense study medication (call IVRS/IWRS) 
• Study medication administration at the site (first dose, after the collection of blood 
samples for GH) 
• Drug administration instructions:  
− apply food habits questionnaire, and adjust study medication administration and 
timing to the patient habits. Instruct the patient how he/she should take his/her 
other concomitant drugs (thyroid hormones, anti-diabetic medications, PPIs or 
H2 blockers). 
− Instruct the patient that study medications should be taken on an empty stomach 
at least one hour prior to a meal or at least two hours after. Optional drug 
administration timing for patients: 
Morning Dose 
− Take the morning dose first thing in the morning with a glass of water and have 
your breakfast at least one hour later, or 
− Have breakfast and take your morning dose at least two hours later and at least 
one hour prior to lunch 
Evening Dose 
− Take your evening dose before going to bed, at least two hours after dinner or 
any other snack or 
− Take your evening dose at least 1 hour prior to dinner and at least two hours 
following an earlier snack/meal. 
5.2.2 Telephone Call at Week 1 and Week 2  
The following assessments and procedures will be performed on the pre-scheduled telephone calls 
at Week 1 and 2: 
• AEs recording 
• Drug administration instructions (including assessments for dose titration) 
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5.2.3 DPC Clinic Visits (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 34, 36) 
The following procedures and assessments will be conducted during DPC period visits: 
• Weight  
• Vital signs 
• Safety laboratory tests: hematology and biochemistry  
• IGF-1  
• Acromegaly directed and treatment directed physical examination  
• AEs including GI  
• Concomitant medications recording 
• Assess pre-define withdrawal criteria (based on clinical judgement, consider the 
option for an unscheduled visit in case IGF-1 levels ≥ 1.3 × ULN while treated for 
at least 2 weeks with 4 capsules a day and/or patient reports significant exacerbation 
of acromegaly symptoms) 
• Assessment of dose titration (through week 24) 
• Dispense study medication (call IVRS/IWRS)  
• Drug administration instructions  
• Study medication accountability 
• Compliance assessment (with drug administration instructions) 
 
When results of IGF-1 are available from this visit assess whether additional unscheduled visits 
are required to confirm active disease. For a patient with a single visit IGF-1 level ≥ 1.3 × ULN 
a second sample will be obtained within 2 weeks of the first assessment. for a total of 2 consecutive 
IGF-1 assessments for confirmation of disease activity. Patients who miss week 34 visit, or have 
missing IGF-1 level from week 34 visit, will be scheduled to attend an unscheduled visit to collect 
blood draw for IGF-1 levels.  
In addition to the above assessments, the following assessments will be done at Week 36: 
• Laboratory tests: urinalysis, TSH, free T4, and lipid profile (total cholesterol, 
triglycerides, high-density lipoprotein, and low-density lipoprotein) and HbA1c; 
serum pregnancy test in women of childbearing potential  
• GH1 
• Physical examination  
• ECG 
• Gall bladder ultrasound 
• Treatment Period completion form 
Patients who meet the pre-defined withdrawal criteria, IGF-1 ≥1.3×ULN AND exacerbation of 
                                                 
1 GH: Five samples collected every 30 ± 5 minutes over two hours, 2-4 hours after study medication administration in 
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acromegaly clinical signs or symptoms) for 2 consecutive visits, while the patient is treated with 
study medication for at least two weeks with 4 capsules per day, will be rescued with injectable 
SRL treatment used prior to Screening and continue to be followed-up per protocol (including all 
in-clinic visits and assessments as detailed in DPC Schedule of Activities) until week 36. 
Exacerbation of acromegaly clinical signs or symptoms are defined as new or worsening of either 
one of the following - headache, fatigue, perspiration, soft tissue swelling, arthralgia, dysglycemia 
or hypertension or other signs that in view of the Investigator are related to acromegaly that are 
recorded as Adverse Events of Special Interest. Per the Investigator discretion, new/worsening 
acromegaly clinical signs or symptoms could be medically treated (e.g. with analgesics, 
antidiabetic or antihypertensive medications) while the patient remains in the study. 
Signs/symptoms which continue to require treatment will still be considered worsening 
signs/symptoms.  
Patients who discontinue study medication, during the DPC, for reasons other than the pre-defined 
withdrawal criteria, should continue to be followed per protocol (including all in-clinic visits and 
assessments as detailed in DPC Schedule of Activities), until week 36. The Sponsor recommends 
re-initiation of their prior injectable SRL treatment (as rescue or escape medication) upon meeting 
the pre-defined withdrawal criteria described above. These patients will not be eligible to enter the 
OLE period and will not require further follow up beyond week 36. Patients completing the DPC 
period and are ineligible or not opting to continue into the OLE period will revert to their prior 
parenteral injectable SRL treatment (prior to Screening), or other treatment, as determined by their 
physician, and be followed-up for 12 weeks after EOT (see Follow-up period Section 5.5). 
5.3 
OPEN-LABEL EXTENSION (OLE) PERIOD 
All patients who complete the core study (Screening and DPC period) on study medications 
(octreotide capsules or placebo), or patients who met the pre-defined withdrawal criteria and were 
followed per protocol until week 36 on prior SRL injections (as rescue medication), will be offered 
to enter the OLE period and receive octreotide capsules until the last patient enrolled completes 
one year or until product marketing or study termination. Beyond one year, the Sponsor will either 
extend the OLE period (via protocol amendment for an additional one year or until product 
marketing or study termination) or consider compassionate (if requested by the principal 
investigator under compassionate use protocol). 
During the OLE period the initial octreotide capsules dose will be 60 mg for all patients. The dose 
can be escalated or de-escalated upon the investigator’s discretion, based on either IGF-1 and/or 
safety and tolerability (See Section 6.2). 
All patients will be contacted by phone after two weeks. The following assessments and procedures 
will be performed on the pre-scheduled telephone calls at Week 2: 
• AEs recording 
• Compliance assessment and drug administration instructions (including dose 
titrations) 
• Address any potential questions the patient may have with the new treatment  
Clinic visits will be scheduled to occur every 4 weeks (±3 days) for the initial 24 weeks, at weeks 
36, 46 and 48 and every 12 weeks (±10 days) thereafter. An additional visit at OLE week 46 will 
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The following procedures will be done on OLE visits: 
• Octreotide capsules administration at the site  
• Safety laboratory tests: hematology, biochemistry, urinalysis, TSH, free T4, and 
lipid profile (total cholesterol, triglycerides, high-density lipoprotein, and low-
density lipoprotein); HbA1c will be done every six months 
• Serum pregnancy test every six months 
• Weight  
• Vital signs 
• Acromegaly directed and treatment directed physical examination  
• AEs and concomitant medications recording 
• Dispense study medication (call IVRS/IWRS) 
• Study medication accountability 
• IGF-11 (OLE Months 3 and 6 followed by every six months, including OLE week 
46 and 48) 
• GH2 (OLE Month 6, Month 12, annually thereafter and last visit of OLE period) 
• Abdominal gall bladder (every six months) 
During the OLE, patients who meet the pre-defined withdrawal criteria [(IGF-1 levels ≥ 1.3 × ULN 
AND exacerbation of acromegaly clinical signs or symptoms), for 2 consecutive assessments, 
while treated for at least 2 weeks with 4 capsules per day, will discontinue study medication and 
will be rescued with injectable SRL treatment used prior to Screening.  
Patients who discontinued study medication, for any reason, during the OLE period, will revert to 
their parenteral SRL treatment (prior to Screening) or other treatment as determined by their 
physician and will be followed-up for 12 weeks after EOT (see Follow-up period, Section 5.5). 
After the last patient has completed the core study, the database has been locked and study results 
are available, the investigators will be informed of the treatment allocation of their participating 
patients during the DPC period. In case a patient has maintained response on the placebo arm 
throughout the DPC period, the investigator, based on his clinical discretion could discontinue 
treatment and follow-up the patient for 12 weeks after EOT. 
5.4 
END OF TREATMENT (EOT) VISIT 
End of Treatment (EOT) visit is scheduled for patients who discontinued study medication 
prematurely during DPC period and OLE period. This visit may be performed on a same day as 
originally scheduled visit or could be scheduled separately. Data collection for this visit should 
primarily be guided according to principles to protect patient safety and wellbeing. 
All efforts should be made to continue and follow up, per protocol until week 36 (including all in-
clinic visits and assessments as detailed in DPC Schedule of Assessments) all patients who early 
                                                 
1 .For a patient with a single visit IGF-1 level ≥ 1.3 × ULN, a second sample will be obtained within two weeks of the 
first assessment for a total of 2 consecutive IGF-1 assessments for confirmation of disease activity. 
2 GH: Five samples collected every 30 ± 5 minutes over two hours, 2-4 hours after study medication administration in 
the clinic, (patients to fast 4 hours prior to and the 2 hours during GH sampling) 

 
 
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discontinued study medications during the DPC period for any reason. 
The following procedures will be conducted at the EOT visit: 
• Weight  
• Vital signs 
• 12-lead ECG 
• Laboratory tests: hematology, biochemistry, urinalysis, TSH, free T4, and lipid 
profile (total cholesterol, triglycerides, high-density lipoprotein, and low-density 
lipoprotein) and HbA1c; serum pregnancy test in women of childbearing potential  
• Physical examination 
• Acromegaly directed and treatment directed physical examination  
• AEs and concomitant medications recording  
• Study medication accountability and compliance assessment 
• IGF-1 and GH1 
• Abdominal (gall bladder) ultrasound 
• Complete Early discontinuation/treatment phase completion form, if applicable 
Other procedures and evaluations will be completed as deemed necessary by the Investigator after 
consultation with the medical monitor. 
5.5 
FOLLOW-UP PERIOD  
Patients who discontinue study medication any time during the OLE period, for any reason, or 
have completed the 36-week DPC period on study medication and are ineligible or opt not to 
continue into the OLE period, will revert to their prior injectable SRL treatment (prior to Screening 
period) or other treatment as determined by their physician and will be followed-up for 12 weeks 
consisting of an in-clinic follow-up visit 4 weeks (±5 days) after EOT and a phone call 8 weeks 
later (±5 days). 
The following procedures will be performed at the in-clinic Follow-up visit: 
• Vital signs and weight 
• 12-lead ECG 
• Laboratory tests: hematology and biochemistry 
• Acromegaly directed and treatment directed physical examination 
• AEs and concomitant medications recording 
• Study medication accountability 
• IGF-1 and GH2 
• Abdominal (gall bladder) ultrasound 
                                                 
1 GH: five samples will be collected every 30 ± 5 minutes over two hours. 2-4 hours after study medication 
administration in the clinic, (patients to fast 4 hours prior to and the 2 hours during GH sampling). 
2 GH: five samples will be collected every 30 ± 5 minutes over two hours. If octreotide capsules were taken at the 
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The following procedures will be performed during the phone call 12 weeks after EOT: 
• AE 
• Concomitant medications 
5.6 
UNSCHEDULED VISIT 
Unscheduled visits will be allowed throughout the study for safety, tolerability or management of 
active disease, per the Investigator discretion. If IGF-1 ≥1.3 × ULN at any visit, or upon physician 
assessment of exacerbation of clinical symptoms, the patient should be invited to an unscheduled 
visit within two weeks of the first assessment. 
The following assessments are mandatory during an unscheduled visit: 
• AEs and concomitant medications recording 
• Vital signs 
The following assessments are required on any unscheduled visit due to inadequate biochemical 
or clinical control of acromegaly (as determined by the investigator), in addition to the measures 
listed above: 
• IGF-1 assessment 
• Acromegaly directed and treatment directed physical examination 
• Compliance assessment and drug administration instructions 
• Assessment of dose titration – during DPC period or OLE period 
• Other as deemed necessary by the study investigator 
 
5.7 
EFFICACY ASSESSMENTS  
5.7.1 IGF-1 and GH 
IGF-1 and GH levels will be assessed by a central laboratory. 
IGF-1 concentration in the blood will be assessed at all study visits (single sample). GH 
concentration in the blood will be assessed at selected study visits (as specified in Schedule of 
Assessments Appendix A). Blood samples for GH will be collected every 30±5 minutes over two 
hours (total five samples), at screening from time 0-2 hours, baseline from time 0-2 hours, and at 
all other visits (Week 36 or EOT [for patients who discontinue study medication early and 
withdraw consent], during OLE Month 6, Month 12, annually thereafter and end of OLE period), 
2-4 hours after study medication administration, if administered at the clinic, otherwise 0-2 hours. 
The mean integrated concentration will be calculated. A minimum of three GH samples are needed 
to calculate the mean integrated concentration or the data point will be considered missing. GH 
samples should be collected after at least 4 hours fast; the fast should be maintained during the 2 
hours sampling. 
5.8 
SAFETY ASSESSMENTS 
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concomitant medication use, vital signs, ECG, physical examination, abdominal (gall bladder) 
ultrasound, and laboratory assessments; these assessments will be conducted as specified in 
Schedule of Assessments (Appendix A). 
5.8.1 Adverse Events 
Adverse events (AEs) will be assessed at all study visits throughout the study from informed 
consent signing. Any AEs that occur throughout the study (including the follow up periods) will 
be recorded (Refer to Section 7). Any new AE or exacerbation of existing condition (including 
acromegaly symptoms, see Section 7.57.1 for details) that occur between scheduled visits should 
be brought to the attention of the Investigator and recorded as an AE on the appropriate eCRF 
page, as well as in the patient’s medical file. 
For list of common AEs associated with octreotide capsules, please refer to the corresponding 
Investigator’s Brochure. 
5.8.2 Medical History and Concomitant Medications 
Any diseases that are ongoing at screening and before the baseline will be documented in the 
medical history and concomitant disease section of the eCRF. The diagnosis of concomitant 
disease resulting from assessment at the screening must be also documented in the medical history.  
Use of concomitant medication will be recorded onto the eCRF from the patient’s medical file at 
each study visit throughout the study. This will include trade name (generic name), strength, unit, 
route of administration, dosage form, frequency, indication, start and stop date(s) of 
administration. Refer to Section 6.10 for prohibited and allowed medications. 
5.8.3 Vital Signs 
Vital signs will be measured at all study visits and will include blood pressure and heart rate, at 
rest as per standard practice at the investigational site. Significant findings noticed after the start 
of study medication which meet the definition of an AE must be recorded on the AE eCRF. 
5.8.4 ECG Assessment 
Twelve-lead ECG will be done as specified in Schedule of Assessments (Appendix A). Any ECG 
abnormality determined by the Investigator to be clinically significant will be noted as an AE on 
the appropriate eCRF page(s). Such abnormalities will closely be monitored up to their resolution. 
5.8.5 Physical Examination 
Complete physical examination will be conducted on as specified in Schedule of Assessments 
(Appendix A). 
Acromegaly directed and treatment directed physical examination (Appendix B), will be 
conducted as specified in Schedule of Assessments (Appendix A). It will include assessment of 
physical signs related to acromegaly (soft tissue swelling, facial features, signs and symptoms 
potentially associated with carpal tunnel syndrome, other systems -- e.g. cardiovascular, 
neurology, abdomen -- as necessary, per the investigator’s judgment). 
Significant findings made after the start of study medication which meet the definition of an AE 
must be recorded on the AE eCRF. 

 
 
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Height will be recorded at Screening and weight measurements will be recorded as specified in 
Schedule of Assessments (Appendix A).  
 
5.8.6 Abdominal Ultrasound 
Abdominal ultrasound will be conducted to monitor gall bladder and biliary tract disease as 
specified in Schedule of Assessments (Appendix A). Abdominal ultrasound may be repeated 
during the treatment period to comply with local guidelines. Evidence of cholelithiasis, biliary 
sludge, and bile duct dilatation will be documented. 
5.8.7 Safety Laboratory Assessments  
All clinical laboratory assessments will be performed by a central laboratory (except for urine 
pregnancy test). Blood sampling will be done under fasting conditions (at least eight hours). 
Fasting conditions may be altered on a case-by-case basis, per the Investigator’s clinical discretion, 
and a documented rationale, at visits when GH assessment following octreotide/placebo capsules 
administration is assessed at the clinical site as specified in Schedule of Assessments 
(Appendix A). Laboratory tests (hematology and serum chemistry) will be done under overnight 
fasting conditions at all clinic visits except Week 36/EOT as well as selected OLE visits where 
GH is collected and only a 4-hour fast is required. 
The laboratory evaluations will include, but not limited to: 
• Hematology: red blood cell count, hemoglobin (Hb), hematocrit (Htc), white blood 
cell (WBC) count and differential, platelets 
• Serum biochemistry: glucose, total bilirubin (in case that it is found elevated direct 
and indirect bilirubin), albumin, sodium, potassium, calcium, creatinine, BUN, 
phosphorous, uric acid, GOT (AST), GPT (ALT), alkaline phosphatase (ALP), 
gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), creatine 
phosphokinase (CPK), total protein (for additional assessments in case of abnormal 
liver functions please refer to Section 7.6). 
• TSH, free T4  
• HbA1c. 
• FPG; for diabetic patients only at Screening 
• Lipid profile (total cholesterol, triglycerides, HDL, LDL)  
• Urinalysis: glucose, ketones, pH, protein, specific gravity, and routine microscopy 
observations 
• Serum pregnancy test, if applicable 
• Urine pregnancy test, if applicable 

 
 
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The unblinded study statistician or programmer will not otherwise participate in study procedures 
or data analysis prior to unblinding of the study data to all study related personnel. 
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in the 
conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. Unblinding should be discussed in advance with the medical 
monitor if possible. For emergency unblinding, study personnel will use the IWRS. Access to the 
IWRS unblinding module requires a special password that may be obtained from the medical 
monitor or other designated team member. If the investigator is not able to discuss treatment 
unblinding in advance, then he/she must notify the medical monitor as soon as possible about the 
unblinding incident without revealing the subject’s treatment assignment. The investigator or 
designee must record the date and reason for study discontinuation on the appropriate eCRF for 
that subject. In all cases that are not emergencies, the investigator must discuss the event with the 
medical monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
6.5 
MANUFACTURING OF STUDY MEDICATIONS 
Octreotide capsule and matching placebo are manufactured for Chiasma, Inc. under good 
manufacturing practices (GMP) by 
, UK. Certain manufacturing 
operations have been performed by other firms. 
6.6 
PACKAGING AND LABELING OF STUDY MEDICATION 
Octreotide capsules and matching placebo capsules will appear as enteric-coated capsules provided 
by the Sponsor in wallets containing 28 capsules. The wallets will be packaged and labeled in 
compliance with the EU GMP, Annex 13 of drugs used in clinical trials and with FDA 21 CFR 
Part 312.6 Labeling of an investigational new drug. 
All study medications (octreotide capsules and matching placebo capsules) will be labeled as 
specified in the Study Pharmacy Manual and may include at minimum: 
• Product name 
• Dose 
• Lot/batch number 
• Expiration date 
• Protocol number 
• Sponsor’s name  
• Instructions for use and storage 
• “Investigational Use Only” statement 

 
 
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6.7 
DISTRIBUTION AND RECEIPT OF STUDY MEDICATION 
For detailed information on the distribution and receipt of study medication please refer to the 
Study Pharmacy Manual. 
The study medications will be shipped under appropriate conditions with temperature monitoring 
device for supplies that need to be shipped under refrigerated conditions. Upon arrival at the 
clinical investigation site, the study pharmacist or designated team member should examine the 
study medication supplies and report any discrepancies in amounts received, damaged supplies or 
temperature excursion immediately as outlined in the Pharmacy Manual. 
Each shipment of study medication supplies for the study will be accompanied by a shipment form 
describing the contents of the shipment, acknowledgement of receipt and other appropriate 
documentation. The study staff will confirm the receipt of clinical supply and will return signed 
drug accountability logs as instructed in the Study Pharmacy Manual. 
All study supplies should arrive at the Pharmacy/Investigational site in sufficient quantity and in 
time to enable dosing as scheduled. Sites must communicate individual patient status following 
each study visit to trigger shipments of study medication in time for the subsequent visit. 
6.8 
STORAGE OF STUDY MEDICATION 
The pharmacist (or other authorized designee) is responsible for ensuring that the appropriate 
storage conditions for the investigational products are maintained in accordance with the 
requirements in the Study Pharmacy Manual. 
Wallets containing enteric-coated octreotide capsules or matching placebo capsules should be 
stored at 5 ± 3°C. Temperature monitoring should be maintained by the site staff and reviewed on 
a regular basis by the study monitor. Any significant or extended temperature excursions need to 
be reported immediately as outlined in the Study Pharmacy Manual. Minor temperature excursions 
that may occur from opening the door of the refrigerator will be recorded but are not a cause of 
concern and do not need to be reported. 
The study staff and monitors should also check the study medication supplies to ensure sufficient 
amount of study medication is on hand for active patients and that the supplies are not expired. 
All study medications must be kept in a locked area with access to the study medication limited to 
designated study personnel. Only personnel under the supervision of either the Investigator or the 
local pharmacist are authorized to dispense study medication. 
Further details and instructions will be provided in the Study Pharmacy Manual. 
6.9 
ACCOUNTABILITY AND COMPLIANCE OF STUDY MEDICATION 
The Investigator or pharmacist/designee may dispense study medication(s) only to patients 
enrolled in the study. Individual patient accountability records must be kept by the site staff. The 
patient number, the date, batch number/wallet number, and quantity of study medication used or 
returned by the patient will be recorded on the appropriate accountability forms by the site staff. 
These records and the inventory of study medication on site will be verified by the study monitor 
for accuracy and completeness on an ongoing basis throughout the study. Unused drug supplies 
will be disposed of as instructed in the Study Pharmacy Manual. 
Treatment compliance will be assessed at all visits during the study. It will be based on 

 
 
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accountability records and an inventory of used/unused supplies. Study medications compliance 
may be enhanced with regular telephone calls and other reminders. 
At the end of the study, the monitor will conduct a final drug reconciliation for all patients and the 
study site overall. All records of study medication receipt, accountability records and drug 
disposition records will be examined and reconciled by the study monitor. Further details will be 
provided in the Study Pharmacy Manual. 
6.10 
PRIOR AND CONCOMITANT THERAPY 
6.10.1 General Guidelines 
All prior treatments received by the patient, e.g. general use since diagnosis (list of prior 
medications for acromegaly any time in the past), medications for acromegaly within the last year 
(including the last dose of SRL injection) and medications for other conditions – within the last 12 
weeks of the initial Screening visit will be recorded on the patient’s eCRF including the treatment's 
name, indication and the start and stop dates. 
Any medications (including prescription, over-the-counter, herbal supplements and health store 
products) to be taken during the study must be approved by the Investigator and recorded on the 
concomitant medication eCRF page. 
All concomitant medications taken by the patient must be recorded on the eCRF, along with the 
indication and start and stop dates as well as daily dose. 
6.10.2 Prohibited Prior Medications or Therapies 
The following are prohibited prior medications or therapies: 
• Treatment with pegvisomant within 24 weeks before the first screening visit 
• Treatment with dopamine agonists within 12 weeks before the first screening visit 
• Treatment with pasireotide within 24 weeks before the first screening visit 
• Treatment with long-acting SRLs at a dosing frequency different than once monthly 
except for lanreotide 120 mg every six or eight weeks  
• Conventional or stereotactic radiotherapy any time in the past 
• New treatment with estrogens and/or selective estrogen receptor modulators 
(SERMs)  
(stable regimen of estrogens and/or SERMs will be permitted. Women who are 
treated with oral contraceptives for 21 days or who are treated with active (hormone 
containing) pills for 21 days and with non-active pills (non-hormone containing), 
during the monthly period should make all efforts to schedule all their clinical visits 
during the 21 days when active hormonal contraception is administered and 
preferably on the same week pre/post the monthly period). 
6.10.3 Allowed Medications 
Other than the investigational medicinal drugs, concomitant medications allowed to be used in this 
study are those used at screening to control existing medical condition, and/or those taken during 
the study to treat possible AEs. Per the Investigator discretion, new/worsening acromegaly clinical 

 
 
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signs or symptoms could be medically treated (e.g. with analgesics, antidiabetic or 
antihypertensive medications) while the patient remains in the study.  
Concomitant administration of octreotide capsules and thyroid hormone replacement therapy 
(HRT) is permitted on an empty stomach after an overnight fast or two hours after breakfast. PPIs 
and H2 blockers are advised to be taken at least 30-60 minutes prior to meals and at least 1 hour 
after octreotide capsule administration. Anti-acid is advised to be taken with food or just prior to 
meals. Timing of octreotide capsules intake in patients taking anti-diabetic medications should be 
discussed with the study investigator/study nurse. 
Loperamide is allowed to treat GI symptoms. 
Acute steroid use should be documented on the appropriate eCRF page. 
All concomitant medications used to treat AEs will be recorded in the patient’s medical file and 
on the appropriate eCRF page. 
If intake of a new systemic prescription drug should become necessary for any reason during the 
course of the study, the patient is required to inform the Investigator immediately, who will record 
the drug, the dose and the time of administration in the patient’s eCRF. 
6.10.4 Prohibited Concomitant Medication 
Women taking oral contraception containing levonorgestrel are advised to switch to another oral 
contraceptive or barrier method. 
Investigational therapy for the treatment of acromegaly are prohibited during the course of the 
study. 
Parenteral SRLs or dopamine agonists, GH antagonists are prohibited while the patient is treated 
with study medication (octreotide capsules/placebo). 
7 
SAFETY AND PHARMACOVIGILANCE 
7.1 
ADVERSE EVENT 
The FDA defines an AE as “Adverse event means any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related” (US Department of 
Health and Human Services Food and Drug Administration December 2012). 
An AE (also referred to as an adverse experience) can therefore be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a drug, without any judgment about causality or seriousness. An AE can arise from any use 
of the drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
An abnormal result of diagnostic procedures including abnormal laboratory findings will be 
considered an AE if it fulfills one or more of the following: 
• Results in patient's withdrawal by the Investigator 
• Is associated with clinical signs or symptoms 
• Results in change in study medication schedule or in concomitant medication 

 
 
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• Is considered by the Investigator to be of clinical significance (a laboratory 
abnormality that is not clinically significant will not be considered an AE) 
A new condition or the worsening of a pre-existing condition will be considered an AE. 
An adverse reaction means any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Suspected adverse reaction is “any AE for which there is a reasonable possibility that the drug 
caused the adverse event.” 
AEs do not include the following: 
• Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that 
are present prior to study entry and do not worsen during the study. 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is an AE if not present at 
baseline. 
• Overdose of either study medication or concomitant medication without any signs 
or symptoms unless the patient is hospitalized for observation. 
• Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred). 
• Pregnancy will not be considered an AE, but if occurs, will be reported on 
pregnancy form. 
AEs will be assessed at all study visits throughout the study from informed consent signing. AEs 
reported prior to dosing on Baseline Day will be captured and considered non-treatment emergent 
AEs. Treatment Emergent AEs (TEAEs) will be considered all AEs that occurred from Baseline 
(following study medication administration) to end of core study (i.e. end of DPC period). AEs 
reported after termination/completion of the core study, during the Follow-up period will be 
reported separately. AEs reported during the OLE period will be reported separately and together 
with the core study. The final safety analysis will be detailed in the Statistical Analysis Plan (SAP). 
The date and time of each AE occurrence will be recorded. 
All AEs, whether observed by the Investigator or designee or volunteered by the patient, should 
be recorded individually on an AE eCRF page with the following information: the specific event 
or condition, whether the event was present pre-study (and if so, should be captured in the medical 
history eCRF page), the dates and times (using the 24 hour clock, where midnight is 00:00 and 
noon is 12:00) of occurrence, duration, severity, relationship to study medication, specific 
countermeasures, outcome, and whether considered non-serious or serious, drug-related or not. 
AEs will be recorded from the time a patient has signed the informed consent form (ICF) and 
throughout the study, including the Core study, Follow-up and OLE period. Severity of the AE 
will be assessed by the Investigator in accordance with the definitions below. An SAE must fulfill 
the requirements listed in the Section 7.2. 
Three definitions only should be used by the investigating physician to describe the severity of the 
AE (Table 1). Only one severity (the worst severity) definition should be used for each AE (e.g., 
"mild/moderate" is not acceptable). 

 
 
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AEs will be coded by data management using the Medical Dictionary for Regulatory Activities 
(MedDRA) AE dictionary, Version 18 or later. 
Follow-up Reports for Non-Serious AEs 
All AEs, that do not meet any of the criteria for serious, should be regarded as non-SAEs and will 
be recorded on the AE eCRF. Severity and relationship to study medication will be assigned by 
the Investigator. Follow-up of AEs that occur during the study will continue until their satisfactory 
resolution or stabilization. In outstanding cases, it may be defined as “ongoing without further 
follow-up” by the Investigator and Sponsor’s decision. 
7.1.1 Adverse Events of Special Interest  
New or worsening acromegaly signs and/or symptoms will be recorded as adverse events of special 
interest (AESI) and are headache, fatigue, perspiration, soft tissue swelling, arthralgia, 
dysglycemia or hypertension or other signs that in view of the Investigator are related to 
acromegaly. 
Worsening of symptoms will be any new sign/symptom or shift in severity (e.g. mild to moderate 
or moderate to severe). Severity will be defined according to Table 1. 
Worsening of dysglycemia is a shift in the severity criteria as defined in common terminology 
criteria for adverse events (CTCAE) v4.03 and shown in Table 3. 
Worsening of hypertension is defined as a shift in severity as defined in CTCAE v4.03 and shown 
in Table 4. 
 

 
 
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Table 3 
Dysglycemia Severity criteria 
Dysglycemia 
1 (mild) 
2 (moderate) 
3 (severe) 
4 (life threatening) 
5 
Death 
Hyperglycaemia 
Definition: A disorder characterized by 
laboratory test results that indicate an elevation 
in the concentration of blood sugar. It is usually 
an indication of diabetes mellitus or glucose 
intolerance 
Fasting glucose value: 
>ULN -160 mg/dL; 
>ULN - 8.9 mmol/L 
Fasting glucose 
value: 
>160 - 250 mg/dL; 
>8.9 - 13.9 mmol/L 
> 250 - 500 mg/dL 
> 13.9 - 27.8 mmol/L 
Hospitalization 
indicated 
> 500 mg/dL 
> 27.8 mmol/L 
life-threatening 
consequences 
Death 
 
Hypoglycaemia 
Definition: A disorder characterized by 
laboratory test results that indicate a low 
concentration of glucose in the blood 
<LLN - 55 mg/dL 
<LLN - 3.0 mmol/L 
< 55 - 40 mg/dL 
< 3.0 - 2.2 mmol/L 
< 40 - 30 mg/dL 
< 2.2 - 1.7 mmol/L 
< 30 mg/dL 
< 1.7 mmol/L 
Life-threatening 
consequences; 
seizures 
Death 
 
Table 4 
Hypertension Severity criteria 
Severity 
Hypertension 
Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure 
exceeding 140 over 90 mm Hg. 
1 (mild) 
Prehypertension (systolic BP 120 - 139 mm Hg or diastolic BP 80 - 89 mm Hg) 
2 (moderate) 
Stage 1 hypertension (systolic BP 140 - 159 mm Hg or diastolic BP 90 - 99 mm Hg); medical intervention indicated; recurrent or 
persistent (≥24 hrs); symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously WNL; monotherapy 
indicated Pediatric: recurrent or persistent (≥24 hrs) BP >ULN; monotherapy indicated 
3 (severe) 
Stage 2 hypertension (systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg); medical intervention indicated; more than one 
drug or more intensive therapy than previously used indicated.  
4 (life threatening) 
Life-threatening consequences (e.g. malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent 
intervention indicated 
5 (death) 
Death 

 
 
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7.2 
SERIOUS ADVERSE EVENTS  
An SAE is any AE occurring at any dose that suggest a significant hazard or side effect, regardless 
of the Investigator or Sponsor's opinion on the relationship to the study medication and that result 
in, but may not be limited to, any of the following outcomes: 
• Death (regardless of the cause) 
• A life-threatening AE or suspected adverse reaction  
• Inpatient hospitalization or prolongation of existing hospitalization (any inpatient 
hospital admission that includes a minimum of an overnight stay in a health care 
facility) 
• A persistent or significant disability/incapacity or a substantial disruption of the 
ability to conduct normal life functions 
• A congenital anomaly or birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be serious when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of AE, or that 
they occurred as a consequence of the event. 
Hospitalization for elective treatment of a pre-study condition that did not worsen while on study 
and optional hospitalizations not associated with a clinical AE (e.g., elective cosmetic surgery) are 
not considered SAEs. 
Important medical events are those which may not be immediately life-threatening, but may 
jeopardize the patient and may require intervention to prevent one of the other serious outcomes 
listed above. Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
resulting in an AE will normally be considered serious by this criterion. 
A life-threatening adverse drug experience is any AE that places the patient, in the view of the 
Investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a 
reaction that, had it occurred in a more severe form, might have caused death. 
7.3 
DEFINITION OF AN UNEXPECTED ADVERSE EVENT 
An unexpected adverse event is any AE, the specificity or severity of which is not consistent with 
information in the clinical protocol or current Investigator’s Brochure for an unapproved study 
medication or package insert/summary of product characteristics for an approved product (package 
inserts are available separately at the participating center). Evaluation will be assessed separately 
for each of the IMPs in the study. 
Serious Unexpected Suspected Adverse Reaction (SUSAR) is a serious adverse reaction 
assessed as unexpected by the Sponsor and that is judged by either the reporting Investigator or 
the Sponsor to have a reasonable causal relationship to a medical product. 

 
 
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7.4 
NOTIFICATION OF SERIOUS UNEXPECTED SUSPECTED ADVERSE EVENT 
The Investigator is responsible for identifying, documenting, evaluating and reporting SAEs in 
accordance with the protocol, 21CFR312.32, 21CFR312.64, International Council for 
Harmonisation (ICH) guidelines, and all other applicable regulations. 
Initial Notification 
Upon identification, all SAEs will be reported by the site within 24 hours using the Initial SAE 
Report Form. The Initial SAE Report Form should be submitted to the contract research 
organization (CRO), Pharm-Olam within 24 hours either by e-mail (preferable) or by fax using the 
contact information provided below.  
 
  
 
 
 
 
For regulatory purposes, the initial SAE reports should include: 
a) 
a suspected investigational medicinal product 
b)  
an identifiable patient (e.g., study patient code number) 
c)  
an AE with seriousness reason and the Investigator’s assessment of the relationship to study 
medication 
d)  
an identifiable reporting source (Investigator contact details) 
SAEs should also be reported to the IRB/IEC according to local regulations. 
Once reported, the SAE form and accompanying documentation should be placed in the 
Investigator’s site file. 
In addition, all AEs / SAEs / SUSARs will be reported by the Sponsor to the IDMC, IRB/IEC and 
regulatory authorities as required by local regulations and ICH-GCP guidelines. 
Follow-up of SAEs / SUSARs  
Follow-up of SAEs / SUSARs that occur during the study will continue until their satisfactory 
resolution or stabilization. In outstanding cases, it may be defined as “ongoing without further 
follow-up” by the Investigator and Sponsor’s decision. 
When supplementary information is available, a follow-up SAE Report Form must be completed 
by the site (marked as “follow-up report”). The contact report information for follow-up SAE 
reporting is the same as for initial SAE reports (see above section). 
If supplementary information on a SAE has to be sent, the SAE form has to be used marked as 
“follow-up report” and should be placed in the SAE section of the Investigator’s site file. 
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documents when applicable, should be sent as soon as they are available. 
Patients who have had an SAE during the treatment period must be followed clinically until all 
parameters (including laboratory) have either returned to normal or have stabilized or are otherwise 
explained. 
Any newly emergent SAEs after treatment is discontinued or the patient has completed the study 
that is considered to be related to the study medication or study participation should be recorded 
and reported immediately to Pharm-Olam using the contact information as described above. 
The Investigator will add the information on the SAE on the AE eCRF page and any other relevant 
eCRF. Particular attention will be made to ensure no discrepancies between the AE eCRF and the 
SAE form (i.e., outcome, severity, relationship must be consistent). 
7.5 
ANTICIPATED ADVERSE EVENTS 
Previous human experience and known AEs of octreotide are detailed in the corresponding IB. 
7.6 
OCTREOTIDE SAFETY GUIDANCE 
Below is the Sponsor’s safety guidance for using octreotide in case of common GI adverse events, 
elevated liver function tests (LFTs) and/or blood sugar disorder. These guidelines should be used 
to guide treatment, however, in any case, should not replace clinical judgment. 
Common Gastrointestinal Adverse Events 
In the previous Phase 3 Study (CH-ACM-01), GI symptoms were among the most commonly 
reported AEs. These AEs were generally transient and declined with time (median duration was 
13 days). Most were mild to moderate in intensity, and occurred during the first two months. There 
was no dose relationship and most resolved with treatment continuation. 
In patients who develop abdominal symptoms (e.g., nausea, vomiting, abdominal pain or diarrhea), 
common GI illnesses should be excluded (e.g., gastroenteritis, cholestasis, etc.), and treated 
accordingly. If symptoms are mild to moderate in intensity and patient is able to tolerate oral 
medications, consideration should be given to treating the patient symptomatically with anti-
emetics or anti-diarrheals to determine if patient’s GI symptoms will resolve on therapy. Patients 
who have severe or persistent symptoms or who cannot tolerate food/fluids should be discontinued. 
Of note, a phase 1 study showed no interaction between loperamide and oral octreotide capsules. 
Liver Dysfunction 
Somatostatin analogs including octreotide have been associated with liver function abnormalities, 
as well as sporadic post-marketing reports of acute hepatitis with or without cholestasis, jaundice 
and cholestatic jaundice. 
Octreotide inhibits secretion of cholecystokinin, resulting in reduced contractility of the 
gallbladder and an increased risk of sludge and stone formation. Biliary disease is the most 
common reasons for liver dysfunction in acromegaly patients. 
Liver function tests (ALT, AST and Bilirubin), will be monitored routinely at all scheduled visits 
during all periods of the study. Liver function tests could also be assessed at any unscheduled study 
visit, as clinically indicated. 

 
 
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Patients who develop liver function abnormalities (elevated transaminases to >3 × ULN) during 
the study should be evaluated for common causes of hepatitis such as cholestasis, alcoholic liver 
disease, non-alcoholic steatohepatitis, environmental exposures, other drug/herbal supplement 
exposures, viral or autoimmune hepatitis. The diagnostic work up of liver dysfunction should be 
guided by the patient’s medical history and physical exam, and local practice, at the investigator 
discretion. 
Patients with asymptomatic liver dysfunction (i.e., ALT or AST >3 × ULN and < 5 × ULN and 
total bilirubin < 2 × ULN), may continue to receive study drug (Figure 2). Liver function tests 
must be repeated in 7 days. In case of continued transaminase elevation, periodical follow up visits 
should be considered, per the investigator discretion up to resolution/return to baseline. Follow up 
should include monitoring of symptoms potentially associated with acute hepatitis (new 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia), or with complications of cholestasis (e.g. cholangitis). In case of symptoms 
suggestive of cholestasis, a follow up abdominal ultrasound should be considered. Local 
assessment of INR could be added to the liver function tests, based on the investigator discretion. 
All patients who develop significant liver dysfunction (ALT or AST ≥ 5 × ULN) should have study 
drug held and be followed up within 3 days and every 3-4 days thereafter up to resolution/return 
to baseline. In case ALT/AST remains above 5 × ULN, study drug should be discontinued. If 
ALT/AST has fallen to >3 × ULN and < 5 × ULN, patients should be managed as described in the 
previous paragraph. 
If liver function tests normalize or return to baseline, while study drug has been held, the decision 
to resume study drug must be discussed with the study medical monitor. 
If no alternative etiology exists study drug should be discontinued in the following scenarios: 
• ALT or AST >5 × ULN for at least 2 weeks  
• ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5 × ULN) 
• ALT or AST >3 × ULN with new appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 

 
 
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Figure 2 
Decision Tree for Abnormal Liver Function Tests 
 
Glucose Metabolism  
Because of its inhibitory action on growth hormone, glucagon, and insulin, octreotide may affect 
glucose regulation. Post-prandial glucose tolerance may be impaired and, in some instances, 
persistent hyperglycemia may be induced as a result of chronic administration. Hypoglycemia has 
also been reported. 
Insulin requirements of patients with type I diabetes mellitus therapy may be reduced by 
administration of octreotide. In non-diabetics and type II diabetics with partially intact insulin 
reserves, octreotide administration can result in post-prandial increases in glycaemia. Hence, 
serum glucose will be monitored during all scheduled study visits, and as clinically indicated at 
unscheduled visits. Diabetic patients should be advised to report any significant 
increases/decreases in their blood glucose levels, or insulin requirements. 
The management of impaired glucose metabolism associated with oral octreotide should be similar 
to other somatostatin analogs (i.e. octreotide or lanreotide), in conjunction with clinical judgment. 
As with octreotide or lanreotide, dose adjustments of insulin and antidiabetic medicinal products 
may be required with oral octreotide. 
In patients in whom somatostatin analogs therapy worsens glucose control, reduction of the 
somatostatin analogs dose, or diabetes management with glucose-lowering agents should be 
considered. 
A complete description of the options for managing impaired glucose tolerance is beyond the scope 
of the protocol. Patients who develop refractory or labile glucose metabolism should be considered 
for discontinuation from the study. 

 
 
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8.2.3 Safety Analysis Set  
The safety set will consist of all randomized subjects who received any amount of study 
medication. Assuming no dosing errors, the safety set will be the same as the FAS. The safety set 
will be used for all safety analyses. Subjects will be assigned to a treatment group based on the 
treatment they received. Therefore, if a subject received octreotide at anytime during the DPC 
period, they will be included in the octreotide group for safety analyses. 
8.2.4 Open Label Extension Analysis Set  
For the OLE phase, a number of different analysis sets will be defined. 
1. The open label extension (OLE) set will consist of all patients enrolled into the OLE 
phase of the study who receive at least one dose of open label study drug.  
2. Octreotide capsules patients from the DPC period who enrolled into the OLE phase and 
received at least one dose of open label study drug (OLE-OCT) 
3. Octreotide capsules patients from the DPC period, who were classified as treatment 
responders based on the primary endpoint, at the end of the DPC period, and who 
enrolled into the OLE phase and received at least one dose of open label study drug 
(OLE-OCT-RESP) 
8.3 
ENDPOINTS 
For a description of the endpoints refer to Section 2.2. For a description of the assessment tools, 
refer to Sections 5.7 and 5.8. 
8.4 
STATISTICAL ANALYSIS  
8.4.1 General Considerations 
Descriptive statistics and graphical presentations will be used to provide an overview of the study 
results. For categorical parameters, the number and percentage of patients in each category will be 
presented. The denominator for percentages will be based on the number of patients appropriate 
for the purpose of analysis. For continuous parameters, descriptive statistics will generally include 
number of patients (n), mean, standard deviation (SD), median, minimum, and maximum. 
Given the small number of patients, data will be pooled across all sites for reporting purposes. 
However, the primary endpoint will also be summarized by region (US vs. non-US), age, gender 
and race. 
As there is a single primary endpoint, with a single primary hypothesis test, no adjustment for 
multiplicity is needed for the primary endpoint/hypothesis test. 
To adjust for multiplicity among the secondary endpoints, a fixed testing order will be used. The 
secondary endpoints will be tested in the pre-specified order as outlined in section 5.1.2, if the 
primary endpoint is found to statistically significant. Testing will proceed to the next endpoint if 
the preceding endpoint is found to be statistically significant at the 5% (two-sided) level. The 
moment and endpoint is found not to be significant at the 5% (two-sided) level, all remaining 
endpoints will be considered exploratory, instead of confirmatory. No adjustment for multiplicity 
will be made for the exploratory endpoints. 
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considered exploratory. 
8.4.2 Demographics and Baseline 
Demographic and baseline characteristics will be summarized by treatment group for the FAS set 
and the OLE set, by treatment group and overall, using descriptive statistics. If the FAS and 
safety set are different, then summaries will also be presented for the safety analysis set. No 
statistical hypothesis tests will be performed.  
8.4.3 Primary Efficacy Analysis 
The primary efficacy analysis will estimate the proportion of responders, based on the primary 
endpoint, at the end of the DPC period, within the octreotide capsules and placebo arms. An 
assessment of superiority will be made using an exact logistic regression model, with covariates 
for treatment, baseline SRL dose (low vs mid or high) and baseline IGF-1 level (< median vs ≥ 
median). If the two-sided p-value is < 0.05, octreotide capsules will be declared superior to 
placebo. The odds ratio and two-sided 95% confidence interval (CI) will be reported. The FAS 
will be the primary population used for this analysis, with the PP population used as a supportive 
analysis.  
To assess the impact of missing data on the primary endpoint, sensitivity analyses will be 
conducted using multiple imputation. Further details will be provided in the SAP. 
The primary endpoint analysis results will also be reported by sub-groups (region, age, gender 
and race). The same statistical methodology applied to the primary endpoint analysis will be 
used for analyzing the primary endpoint by each sub-group. 
Randomization, in theory, should provide balance of all baseline characteristics, between the two 
treatment groups. At the conclusion of the study, if there is an imbalance in any baseline 
characteristics felt to be clinically meaningful, the effect of this imbalance on the primary 
endpoint will be evaluated through inclusion of covariates for these characteristics into the 
primary model above. These analyses will be considered sensitivity analyses to investigate the 
robustness of the primary analysis. 
8.4.4 Secondary Efficacy Analysis 
The secondary endpoint defined as the proportion of patients who maintain GH response will 
utilize the same methods as outlined above for the primary endpoint. Analyses will be presented 
using both the FAS and the PP analysis set. For the analysis of the proportion of responders 
based on mean GH, only patients with a screening mean GH value of < 2.5 ng/mL will be 
included in the analysis. The time to loss of response will be summarized using the Kaplan-
Meier method, and treatment groups will be compared using a Log-Rank test. The proportion of 
patients who begin rescue treatment prior to and including week 36 will be compared using 
Fisher’s exact test. The denominator for each group will be all patients randomized to that group. 
The numerator will be those who start rescue treatment prior to and including week 36. 
After the study is completed, if there is an imbalance in any baseline characteristics felt to be 
clinically meaningful, the effect of this imbalance on the secondary endpoints will be evaluated 
through inclusion of covariates for these characteristics into the models described above. These 
analyses will be considered sensitivity analyses to investigate the robustness of the primary 
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8.4.5 Descriptive Endpoint Analysis 
The change from baseline for both GH and IGF-1 will be summarized within each treatment 
group separately, using descriptive statistics. No between group statistical testing will be 
conducted. 
 
8.4.6 Exploratory Efficacy Analysis 
The exploratory endpoints that are defined as proportions will utilize the same methods as 
outlined above for the primary endpoint. Analyses will be presented using both the FAS and the 
PP analysis set.  
To help with the interpretation of the primary outcomes, an exploratory supportive analysis will 
be conducted to examine the relationship between the duration of treatment (i.e., time to 
discontinuation) and final dropout status. Results will be presented by treatment group using 
descriptive statistics. 
An exploratory analysis will also be conducted to examine the relationship between the time 
from baseline to dose stabilization, and the patients’ final outcome status (i.e., responder, non-
responder as determined by the primary endpoint). Results will be presented by treatment group 
using descriptive statistics. 
 
8.4.7 OLE Period 
For all OLE endpoints which are defined as a proportion, the proportion and 2-sided 95% 
confidence interval (using the Wilson score method, without continuity correction) for the 
proportion will be reported.  
For OLE shift analyses, data will be tabulated using descriptive statistics only. 
For OLE endpoints defined as a relative change, the relative change from baseline will be 
analyzed on the log scale and back transformed for reporting. The relative change and 2-sided 
95% CI will be reported. 
8.4.8 Safety Analysis 
All safety analyses for data collected during the DPC period will be presented using the safety 
set. All safety analyses for data collected during the OLE will be presented using the OLE set 
(summaries by treatment group will be based on the treatment group in the DPC period). Safety 
analyses for the DPC period will only use data collected during the DPC period. Safety analyses 
for the OLE will include data collected during the OLE. No formal hypothesis testing will be 
conducted. Data will be summarized using appropriate descriptive statistics. Missing data will be 
maintained as missing, unless indicated. 
8.4.8.1 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA version 18.1 or 
higher). 

 
 
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All AEs that occur after randomization (i.e., date of onset is on or after the date of 
randomization) and on or before the end of treatment (last dose of blinded study drug) in the 
DPC period will be considered Treatment Emergent Adverse Events (TEAEs) for the purpose of 
reporting in the DPC period, and will be summarized using frequency counts and percentages. 
Summaries will be presented by final dose group and treatment group (i.e., octreotide 40, 60, 80, 
overall and placebo) and overall for the safety set.  
Summaries of TEAEs will be presented using the MedDRA level hierarchy (system organ class, 
high level group term, high level term, and preferred term) as follows: 
• Overall (i.e., regardless of intensity or relationship to treatment) 
• By intensity grade (mild, moderate, severe) 
• By relationship to study medication (potential relationship to study treatment or 
unlikely/no relationship to study treatment) 
TEAEs leading to premature discontinuation of study drug and serious TEAEs (SAEs) will also 
be summarized by treatment group and relationship. TEAEs leading to premature discontinuation 
of study drug will be defined as any TEAEs with an action taken regarding study medication 
equal to “permanently discontinued.” 
The incidence of patients reporting a new or worsening Adverse event of special interest will 
summarize overall and by intensity grade. In addition, the incidence of patients reporting a new 
or worsening AESI’s leading to premature discontinuation of study drug will also be summarized 
overall and by severity).  
AEs will be considered treatment emergent for the purpose of reporting in the OLE if they meet 
any of the following criteria: 
• AE onset date is after the end of treatment in the DPC period (i.e., date of onset 
greater than the end of treatment date in the DPC period)  
• AE is ongoing, and the severity worsens during the OLE (i.e., date of severity 
worsening is greater than the end of treatment date in the DPC period)  
All summaries will be presented by final dose group (i.e., 40, 60 or 80) and overall for the OLE 
set. 
Summaries of TEAEs overall, by relationship, leading to premature discontinuation and serious 
TEAEs will also be presented by sub-groups (region, age, gender and race) using descriptive 
statistics. .  
8.4.8.2 
Laboratory Assessments 
Descriptive summary statistics for chemistry and hematology data at each post randomization 
time point (both absolute and change) will be presented by final dose group and treatment group 
(i.e., octreotide 40, 60, 80, overall and placebo). Summaries will be provided for the DPC period 
and for the OLE period. In calculating the change from baseline for both the DPC and for the 
OLE, the baseline for the DPC period will be used. 
Shift tables, summarizing individual subject changes from baseline to end of treatment will be 
presented for each laboratory parameter, by treatment group, using the normal ranges from the 
central laboratory. Summaries will be provided for both the DPC period and OLE period. For 
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start of the DPC period. 
Subjects with clinically significant abnormalities (based on investigator’s assessment) will be 
identified in listings 
8.4.8.3 
Vital Signs and Body Weight 
Descriptive statistics of vital sign (systolic blood pressure, diastolic blood pressure, heart rate, 
body weight) data at each post randomization time point (both absolute and change) will be 
presented by final dose group and treatment group (i.e., octreotide 40, 60, 80, overall and 
placebo). Summaries will be provided for the DPC period and for the OLE period. In calculating 
the change from baseline for both the DPC and for the OLE, the baseline for the DPC period will 
be used. 
Additionally, shift tables, summarizing individual subject changes from baseline to end of 
treatment will be presented for heart rate, diastolic and systolic blood pressure, by final dose 
group and treatment group (i.e., octreotide 40, 60, 80, overall and placebo). These will be 
presented for both the DPC period and OLE period. For both the DPC period and the OLE 
period, shifts from baseline will use the baseline defined for the start of the DPC period. 
8.4.8.4 
ECG, Ultrasound  
All 12-Lead ECGs will be read by a central lab. 12-Lead ECG parameters will be summarized at 
each time point using descriptive statistics by final dose group and treatment group (i.e., 
octreotide 40, 60, 80, overall and placebo). Both absolute and change from baseline will be 
provided for each continuous 12-Lead ECG parameter. Summaries will be provided for the DPC 
period and for the OLE period. In calculating the change from baseline for both the DPC and for 
the OLE, the baseline for the DPC period will be used. Additionally, the numbers and 
percentages of patients with ECG abnormalities (as determined by the central laboratory) at each 
visit will be presented for both the DPC and for the OLE.  
Shift tables will be used to show the changes from baseline to each post baseline time point 
based on pre-defined abnormality criteria for both the DPC and for the OLE periods. For both 
the DPC period and the OLE period, shifts from baseline will use the baseline defined for the 
start of the DPC period. 
The following information will be summarized at baseline and end of treatment for the DPC 
period using shift tables, by final dose group and treatment group: 
• Ultrasound Normality (Normal=Yes reported on eCRF; Abnormal = No) 
• Biliary Sludge (Normal=No reported on eCRF; Abnormal =Yes) 
• Wall Thickening (Normal=No reported on eCRF; Abnormal =Yes) 
• Dilation of Common Bile Duct (Normal=No reported on eCRF; Abnormal =Yes) 
For the OLE period, shift tables will also be provided to show shifts from baseline of the DPC 
period to each assessment in the OLE period. 
8.4.9 Interim Analyses 
No interim analysis is planned; however, data will be periodically reviewed by the IDMC for safety 
purposes. Interim analyses of the OLE period may be conducted periodically for regulatory 
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9 
ETHICS 
9.1 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE 
Prior to initiation of the study, the Investigator will submit the study protocol and amendments, 
sample ICF, and any other documents that may be requested to the IRB/IEC for review and 
approval. The Investigator will request that the IRB/IEC provide written approval of the study and 
will keep on file records of approval of all documents pertaining to this study. The Investigator 
will not begin the study until the protocol and ICF have been approved by the IRB/IEC. The 
Investigator must agree to make any required progress reports to the IRB/IEC, as well as reports 
of SAEs, life-threatening conditions, or death. 
9.2 
ETHICAL CONDUCT OF THE STUDY 
All clinical work conducted under this protocol is subject to GCP guidelines. This includes an 
inspection by Sponsor or its designee, health authority or IRB/IEC representatives at any time. The 
Investigator must agree to the inspection of study-related records by health authority 
representatives and/or Sponsor or its designee. 
The study will be conducted in accordance with the following guidelines: 
• ICH-GCP: Consolidated Guideline (International Council for Harmonisation of 
Technical Requirements for the Registration of Pharmaceuticals for Human Use, 
May 1996). 
• Declaration of Helsinki: Brazil, 2013 (Appendix C) 
• US Code of Federal Regulations (Title 21, CFR Part 11, 50, 54, 56 and 312) and/or 
EU Directives; and/or local country regulations and guidelines. 
9.3 
PATIENT INFORMATION AND CONSENT 
Prior to screening for the study, each patient will be informed in detail about the study medications 
to be administered and the nature of the clinical investigation with its risks and discomforts to be 
expected. The basic elements of informed consent as specified by the FDA (21 CFR 50.25) and 
ICH-GCP will be followed. The patients will also be instructed that they are free to withdraw their 
consent and discontinue their participation in the study at any time without prejudice. Written 
consent will be obtained from each patient to be involved in the clinical trial by using the IRB/IEC-
approved ICF prior to the conduct of any study-related activity. Each patient will be given a copy 
of the written ICF, and each patient’s chart will include the signed ICF for study participation. The 
original patient signed and dated ICFs will be maintained by the site for as long as specified in 
ICH GCP1. 
Patients will be required to sign an additional ICF to participate in the OLE period. 
                                                 
1 Essential documents should be retained until at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the investigational product. These 
documents should be retained for a longer period however if required by the applicable regulatory requirements or 
by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to 
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9.4 
PATIENT INSURANCE 
A product liability insurance policy to cover against any injury and damages arising from the use 
of products in this project is provided by Chiasma for the total duration of the study covering the 
patients and Investigators in respect of the risks involved in conducting this study according to this 
protocol. The insurance policy will be filed in the Investigator’s site file or can be made available 
to the Investigator and to the IRB/IEC upon request. 
Where applicable, patients will be insured through contract between an insurance company and 
the Sponsor. 
9.5 
PERSONAL DATA PROTECTION 
The study will be conducted in accordance with the data protection laws that apply in a particular 
country and jurisdiction. 
Chiasma complies with the principle of patient’s right to protection against invasion of privacy. 
Throughout this trial, all patient data will be identified only by a patient identification number. The 
personal data will be blinded in all data analyses. The patient must be informed and consent as 
required that authorized personnel of Chiasma such as study monitor, auditor etc. and relevant 
health regulatory agency will have direct access to personal medical data to assure a high-quality 
standard of the study. 
At the patient's request, medical information may be given to his or her personal physician or other 
appropriate medical personnel responsible for his or her welfare. Personal physician will be 
notified by site personnel of patient participation in the study. 
9.6 
STUDY COMMITTEES 
9.6.1 Steering Committee 
A Steering Committee (SC) will act in an advisory capacity to the Sponsor to provide oversight to 
the trial conduct and to support its successful completion. The SC will also ensure transparent 
management of the study according to the protocol through recommending and approving 
modifications as circumstances require. The SC will review protocol amendments as appropriate. 
Together with the clinical trial team, the SC will also develop recommendations for publications 
of study results including authorship rules. 
9.6.2 Independent Data Monitoring Committee 
An IDMC will be assigned by the Sponsor prior to the beginning of the study. The IDMC will act 
in an advisory capacity to the Sponsor to monitor patient safety of octreotide capsules in 
acromegaly patients who participate in the study. The IDMC responsibilities are to:  
• Review the plans for data safety and monitoring 
• Evaluate the progress of the trial, study data quality, timeliness, patient recruitment, 
accrual and retention, patients’ risk versus benefit, and other factors that could 
affect the study outcome  
• Perform interim reviews of key safety and efficacy data at regular intervals during 
the course of the study 
• IDMC will review the data from the OLE period at regular intervals to ensure the 

 
 
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safety of participating subjects 
• Consider relevant information that may have an impact on the safety of the 
participants or the ethics of the study 
• Protect the safety of the study participants 
• Make recommendations to the Sponsor concerning continuation, termination or 
other modifications of the study based on their observations of the safety of the 
study 
For each IDMC meeting, pre-specified reports will be provided by the data management group. In 
addition, the IDMC Chair will be provided with or have access to periodical safety reports as 
specified in the IDMC charter. The IDMC Chair may share these reports with the IDMC or 
convene additional meetings of the IDMC at his/her discretion. The IDMC Chair may request 
additional data based on the review of study data. 
Further details regarding data safety monitoring guidelines will be included in the IDMC Charter, 
which is the governing document that supersedes this section of the protocol. 
9.7 
PROTOCOL EXCEPTIONS AND DEVIATIONS 
No protocol deviations are anticipated as it is expected that patients will meet all eligibility criteria. 
Departures from the protocol should be avoided, unless required for the safety of the patient. 
Protocol deviations, and if possible the reason for occurrence, will be documented by the study 
monitor. Should any protocol deviations occur, the Investigator must report the deviation to the 
Sponsor, and if required, to the IRB/IEC, in accordance with local regulations, within reasonable 
time. 
9.8 
PROTOCOL AMENDMENTS 
Changes to the protocol may be made only by the Sponsor (with or without consultation with the 
Investigator). All protocol modifications must be submitted to the site IRB/IEC in accordance with 
local requirements and, if required, to the Regulatory Authority, either as an amendment or a 
notification. Approval for amendments must be obtained before any changes can be implemented, 
except for changes necessary to eliminate an immediate hazard to study patients, or when the 
changes involve only logistical or administrative aspects of the trial. No approval is required for 
notifications. 
10 
QUALITY CONTROL AND QUALITY ASSURANCE  
The study will be conducted according to GCP as outlined by ICH Topic E6 step 5 guidelines. The 
Sponsor and/or designated CRO maintains a quality assurance system with written standard 
operating procedures (SOPs) to ensure that clinical trials are conducted and data are generated, 
documented and reported in compliance with the protocol, GCP and applicable regulatory 
requirements. 
10.1 
AUDITS AND INSPECTIONS 
The study may be audited according to the Sponsor's quality assurance (QA) inspection program. 
The purpose of the audit is to determine whether or not the study is being conducted and monitored 
in compliance with study protocol and ICH-GCP guideline. Audit visit(s) will be arranged in 
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The Investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from the Sponsor quality assurance or its designees or to 
regulatory authority inspectors after appropriate notification. The verification of the eCRF data 
must be by direct inspection of source documents. These audits or inspections may take place at 
any time, during or after the study, and are based on the national regulations, as well as ICH 
guidelines. 
10.2 
STUDY MONITORING 
Monitoring of the study is the responsibility of the Sponsor and may be delegated to a CRO or a 
contract monitor. The study monitor will advise the Investigator regarding the practical conduct of 
the study and maintaining compliance with the protocol, GCP and all applicable regulatory 
requirements. 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a CRO 
representative will review the protocol and eCRF with the Investigator and his staff. 
Throughout the course of the study, the study monitor will oversee the conduct and the progress 
of the study by frequent contacts with the Investigator. This will include telephone calls and on-
site visits. During the on-site visits, the eCRF will be reviewed for completeness with 
corresponding source documents. As part of the data audit, source documents will be made 
available for review by the study monitor. The study monitor will also perform drug accountability 
checks and will periodically request review of the Investigator study file to ensure completeness 
of documentation in all respects of clinical study conduct. 
Periodically, some or all of the facilities used in the study (e.g., local laboratory, pharmacy) may 
be reviewed. Monitoring visits will be arranged in advance with site personnel at a mutually 
acceptable time. Sufficient time must be allowed by the site personnel for the monitor to review 
eCRF and relevant source documents. The Investigator should be available to answer questions or 
resolve data clarifications. The Investigator or appointed delegate will receive the study monitor 
during these on-site visits, cooperate in providing the documents for inspection, and respond to 
inquiries. 
The Investigator will ensure that the study participants are aware of and consent that personal 
information may be scrutinized during the data verification process as part of study-related 
monitoring and auditing by properly authorized persons associated with Chiasma or inspection by 
domestic and/or foreign regulatory authority(ies). However, participation and personal 
information should be treated as strictly confidential to the extent that the applicable law permits 
and not be publicly available. 
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period. 
10.3 
QUALITY LABORATORY STANDARDS 
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the local institution laboratory and central 
laboratories. 
Before the study begins, the laboratories to be used in the study will provide a list of the reference 
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These will be held in the Investigator file and the trial master file. The methods employed for each 
assay should be available on request. Any change in the laboratory, its procedures, references, 
values, etc. during the study must be notified promptly to the Sponsor. 
10.4 
STUDY DOCUMENTATION 
Study documents will include the following: 
• Signed ICFs 
• Source documents (e.g., patient files, medical notes, study worksheets) 
• Investigator copies of the eCRFs and SAE reports 
• Investigator site file + contents 
• Study Manuals (including laboratory manual, pharmacy manual and reference 
manual) 
• Investigator meeting binder and or other training materials 
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period. 
10.4.1 Source Document 
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/IEC review and regulatory inspections providing direct access to source data documents. 
Source documents are original records in which raw data are first recorded. These may be 
office/clinic/hospital records, charts, diaries, ultrasound images, and laboratory results, ECG 
printouts, pharmacy records, care records, completed scales for each study participant and/or 
worksheets. Source documents should be kept in a secure and limited access area. All source 
documents should be accurate, clear, unambiguous, permanent and capable of being audited. They 
should be made using a permanent form of recording (ink, typing, printing, optical disc, etc.). They 
should not be obscured by correcting fluid or have temporary attachments (such as removable self-
stick notes). Study worksheets may be used to supplement study data not recorded in the patient’s 
medical record.  
Source data for patients registered to the study should indicate date ICF was signed, participation 
in clinical protocol, treatment number, evidence that inclusion/exclusion criteria have been met. 
10.4.2 Recording of Data on Electronic Case Report Form (eCRF) 
No data will be directly entered into the eCRF without source documentation. 
Only a patient identification number will be used to identify the patient in the eCRF. The 
Investigator must keep a separate log of patient names and medical record numbers (or other 
personal identifiers). 
The protocol will use an Internet-Based Electronic Case Report Form eCRF, primarily to collect 
clinical trial data at the investigational sites. The system will be used to enter, modify, maintain, 
archive, retrieve, and transmit data. The design of the eCRF computerized system complies with 
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10.4.3 Investigator Site File 
All documents required for the conduct of the study as specified in the ICH-GCP guidelines will 
be maintained by the Investigator in an orderly manner and made available for monitoring and/or 
auditing by the Sponsor and regulatory agencies. 
10.5 
CLINICAL TRIAL SUPPLIES 
The Sponsor or its vendors will be responsible for providing study supplies and for ensuring that 
they are used, managed and accounted for properly. Accurate and timely records of the disposition 
and accountability of all study drugs must be maintained by the site and reviewed by the Sponsor 
representative monitor. The supplies and inventory record must be made available for inspection 
upon request. Upon completion or termination of the study, the Investigator will keep the 
remaining clinical supplies along with a copy of the inventory record and a record of the clinical 
supplies returned. Under no circumstances will the Investigator allow the study medications 
to be used other than as directed by this protocol. 
Upon completion or termination of the study, all study supplies will be disposed of per instructions 
from the Sponsor and/or its vendors (CRO). 
Clinical trial supplies include, however, not limited to: eCRF, study worksheets, lab supplies and 
study medications. 
10.6 
DATA MANAGEMENT 
Data Management services will be provided by the CRO. After the data have been entered and 
verified, various edit checks will be performed for the purpose of ensuring the accuracy, integrity, 
and validity of the database. These edit checks may include: 
• Missing value checks 
• Range checks 
• Consistency checks 
• Sequence checks 
• Probabilistic checks 
• Protocol adherence checks 
Queries generated from these checks will be sent to the investigational site for resolution, and the 
database will be updated to reflect query resolutions as appropriate. 
For details on data management processes, please refer to the Study Data Management Plan. 
11 
STUDY ADMINISTRATION 
11.1 
PARTICIPATING CENTERS 
This will be a multicenter, worldwide study (including US sites). 
11.2 
REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION 
Prior to the release of study medication to a site, all essential study documents must be collected, 
reviewed and approved. These may include: 

 
 
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• Appropriate local health authority documentation properly signed and dated by the 
required Investigator (i.e., the submission package) 
• Signed copy (original) of the approved protocol 
• Completed and signed statement of Investigator 
• A signed Clinical Trial Agreement 
• Curriculum vitae for the Investigator and sub-Investigator (can be collected at site 
initiation visit) 
• IRB/IEC name and address; and membership list (can be collected at site initiation 
visit) 
• Letter of approval from the IRB/IEC for both protocol (identified by protocol title 
and number) and ICF (identified by protocol title and number) 
• Copy of the IRB/IEC-approved written ICF to be used in the study (that has also 
been approved by the Sponsor) 
• Provisions for direct access to source/data documents if necessary for trial-related 
monitoring, audits, IRB/IEC review, and regulatory inspection 
• Name and location of the laboratory utilized for laboratory assays, and other 
facilities conducting tests, as well as a copy of the laboratory certificate and list of 
normal laboratory values (can be collected at site initiation visit) 
In case a laboratory certification is not available, a written statement as to how the laboratory 
complies with quality assurance should be provided. 
Upon satisfactory receipt of all required regulatory documents, Sponsor will arrange that study 
medications be delivered to the study site. Supply of all other study materials will be the 
responsibility of Chiasma and/or designee. Patient entry should not begin until after the required 
regulatory documents are confirmed as received and the Investigator Meeting/Initiation visit has 
occurred. All personnel expected to be involved in the conduct of the study will undergo 
orientation to include review of study protocol, instructions for eCRF completion, AE reporting, 
and overall responsibilities including those for drug accountability and study file maintenance. 
The Investigator and/or designee (study monitor) will prepare an Investigator's site file. This file 
should be used for all trial related documents. The Investigator will be responsible for keeping the 
Investigator's site file updated and ensuring that all required documents are filed. The file will be 
inspected during monitoring visits. 
11.3 
STUDY COMPLETION 
This study is expected to end when all required patients have been enrolled and the last patient has 
completed the study and query resolution has been completed. 
Data and materials that are required before the study can be considered complete and/or terminated 
are: 
• Laboratory findings, clinical data, and all special test results from screening 
through the end of the follow-up period 
• eCRF (including correction forms) properly completed by appropriate study 
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• Completed Drug Accountability Records 
• Statement of outcome for each SAE reported 
• Copies of protocol amendments and IRB/IEC as well as relevant health authority 
approval/notification (if applicable) 
11.4 
CLINICAL STUDY REPORT 
A clinical study report will be developed by the Sponsor at completion of data analysis. This report 
will be a clinical and statistical integrated report, according to the ICH E3 guidelines. 
11.5 
RETENTION OF STUDY RECORDS 
The Investigator will retain copies of the approved protocol, completed eCRF, ICFs, relevant 
source documents, and all other supporting documentation related to the project for as long as 
specified in ICH GCP1. in a secure and safe facility with limited access If the Investigator is unable 
to retain the study documents for the required amount of time, Sponsor or designee must be 
informed of the individual who will be assuming this responsibility. 
Further retention, if required, will be negotiated at the end of this period. In that case, Chiasma 
will notify, in writing, the Investigator when the clinical study data may be discarded. The 
Investigator will take measures to prevent accidental or premature destruction of these documents. 
These files must be made available for inspection upon reasonable request by authorized 
representatives of Sponsor and/or the relevant regulatory agencies. 
11.6 
CONFIDENTIALITY AND PUBLICATION OF STUDY DATA 
All information supplied by Chiasma in association with this study and not previously published, 
is considered confidential information. This information includes, but is not limited to, the 
Investigator’s Brochure, the protocol, eCRFs, and other scientific data. Any data collected during 
the study are also considered confidential. This confidential information shall remain sole property 
of Chiasma, shall not be disclosed to others without the written consent of Chiasma, and shall not 
be used except in the performance of this study. 
Data cannot be used for publication or reporting outside of this study until the study is completed 
or discontinued by Chiasma. This is necessary since dissemination of preliminary information may 
inappropriately affect the objectivity of this study. For this reason, Chiasma, study Investigators 
or other parties will not be allowed to perform subset analyses at any point before the conclusion 
of this study. Violation of this will result in automatic expulsion from this study. 
Chiasma recognizes the importance of timely communication of medical research and scientific 
data and its obligations to patients enrolled in the study. The object of the study will be to publish 
the results of the complete study in an appropriate peer-reviewed journal after the conclusion. A 
formal publication of data collected as a result of the study is planned and will be considered a 
                                                 
1 Essential documents should be retained until at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the investigational product. These 
documents should be retained for a longer period however if required by the applicable regulatory requirements or 
by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to 
when these documents no longer need to be retained. 

 
 
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joint publication by the Investigators and the appropriate Chiasma personnel. Authorship will be 
determined by mutual agreement. In general, the Investigators who have made the most substantial 
contributions to the study will be considered lead and/or senior authors. Review and comment by 
Chiasma on draft abstracts and manuscripts is required prior to publication. Authors should submit 
draft publications to Chiasma no fewer than sixty (60) days prior to submission to any journal, 
publisher and/or third party. This requirement should not be construed as a means of restricting 
publication, but is intended solely (a) to ensure concurrence regarding data, evaluations, and 
conclusions, (b) to provide an opportunity to share with the Investigator any new or unpublished 
information of which he or she may be unaware and (c) to ensure that no Chiasma confidential 
information has been included. If the Sponsor believes that such publication or disclosure contains 
confidential information, the Investigator/author agrees to remove such confidential information 
from the proposed publication or disclosure. 
The information developed during the conduct of this study is also considered confidential, and 
will used by Chiasma. This information may be disclosed as deemed necessary by Chiasma. To 
allow the use of this information derived from this study, the Investigator is obliged to provide 
Chiasma with complete test results and all data collected and developed in this study. 

 
 
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12 
REFERENCES 
Ben-Shlomo, A. and S. Melmed (2008). "Acromegaly." Endocrinol Metab Clin North Am 37(1): 
101-122, viii. 
Caron, P., A. Beckers, et al. (2002). "Efficacy of the new long-acting formulation of lanreotide 
(lanreotide Autogel) in the management of acromegaly." The Journal of clinical 
endocrinology and metabolism 87(1): 99-104. 
Chanson, P. and S. Salenave (2008). "Acromegaly." Orphanet J Rare Dis 3: 17. 
Chieffo, C., D. Cook, et al. (2013). "Efficacy and safety of an octreotide implant in the treatment 
of patients with acromegaly." The Journal of clinical endocrinology and metabolism 
98(10): 4047-4054. 
Colao, A., M. D. Bronstein, et al. (2014). "Pasireotide versus octreotide in acromegaly: a head-to-
head superiority study." The Journal of clinical endocrinology and metabolism 99(3): 791-
799. 
Colao, A., D. Ferone, et al. (2004). "Systemic Complications of Acromegaly: Epidemiology, 
Pathogenesis, and Management." Endocr Rev 25(1): 102-152. 
Fleseriu, M. (2014). "Advances in the pharmacotherapy of patients with acromegaly." Discovery 
medicine 17(96): 329-338. 
Giustina, A., P. Chanson, et al. (2014). "Expert consensus document: A consensus on the medical 
treatment of acromegaly." Nature reviews. Endocrinology 10(4): 243-248. 
Holdaway, I. M. and C. Rajasoorya (1999). "Epidemiology of acromegaly." Pituitary 2(1): 29-41. 
Katznelson, L., J. L. Atkinson, et al. (2011). "American Association of Clinical Endocrinologists 
Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly-
-2011 update: executive summary." Endocrine practice : official journal of the American 
College of Endocrinology and the American Association of Clinical Endocrinologists 
17(4): 636-646. 
Lancranjan, I. and A. B. Atkinson (1999). "Results of a European multicentre study with 
Sandostatin LAR in acromegalic patients. Sandostatin LAR Group." Pituitary 1(2): 105-
114. 
Lorcy, Y., S. Dejager, et al. (2000). "Time course of GH and IGF-1 levels following withdrawal 
of long-acting octreotide in acromegaly." Pituitary 3(3): 193-197. 
Melmed, S. (2009). "Acromegaly pathogenesis and treatment." J Clin Invest 119(11): 3189-3202. 
Melmed, S., A. Colao, et al. (2009). "Guidelines for acromegaly management: an update." J Clin 
Endocrinol Metab 94(5): 1509-1517. 
Melmed, S., D. L. Kleinberg, et al. (2014). "Acromegaly: assessing the disorder and navigating 
therapeutic options for treatment." Endocrine practice : official journal of the American 
College of Endocrinology and the American Association of Clinical Endocrinologists 20 
Suppl 1: 7-17; quiz 18-20. 
Milani, D., J. D. Carmichael, et al. (2004). "Variability and reliability of single serum IGF-I 

 
 
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measurements: impact on determining predictability of risk ratios in disease development." 
The Journal of clinical endocrinology and metabolism 89(5): 2271-2274. 
Novartis (2012). Sandostatin (octreotide acetate) for Injection – US Prescribing Information. 
Petersenn, S., A. J. Farrall, et al. (2014). "Long-term efficacy and safety of subcutaneous 
pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension 
study." Pituitary 17(2): 132-140. 
Petersenn, S., J. Schopohl, et al. (2010). "Pasireotide (SOM230) demonstrates efficacy and safety 
in patients with acromegaly: a randomized, multicenter, phase II trial." The Journal of 
clinical endocrinology and metabolism 95(6): 2781-2789. 
Ramirez, C., G. Vargas, et al. (2012). "Discontinuation of octreotide LAR after long term, 
successful treatment of patients with acromegaly: is it worth trying?" European journal of 
endocrinology / European Federation of Endocrine Societies 166(1): 21-26. 
Ronchi, C. L., E. Rizzo, et al. (2008). "Preliminary data on biochemical remission of acromegaly 
after somatostatin analogs withdrawal." European journal of endocrinology / European 
Federation of Endocrine Societies 158(1): 19-25. 
Stewart, P. M., S. E. Stewart, et al. (1999). "Clinical and biochemical response following 
withdrawal of a long-acting, depot injection form of octreotide (Sandostatin-LAR)." 
Clinical endocrinology 50(3): 295-299. 
Trainer, P. J., W. M. Drake, et al. (2000). "Treatment of acromegaly with the growth hormone-
receptor antagonist pegvisomant." The New England journal of medicine 342(16): 1171-
1177. 
US Department of Health and Human Services Food and Drug Administration. Center for Drug 
Evaluation and Research (CDER). Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE Studies (draft guidance) (December 2012) 
Vilar, L., M. Fleseriu, et al. (2014). "Can we predict long-term remission after somatostatin analog 
withdrawal in patients with acromegaly? Results from a multicenter prospective trial." 
Endocrine 46(3): 577-584. 
 
 

 
 
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13 APPENDICES 
Appendix A 
Schedule of Activities ..................................................................................... 90 
Appendix B 
Acromegaly and Treatment Directed Physical Examination .......................... 93 
Appendix C 
Declaration of Helsinki (2013) ........................................................................ 94 
 
 
 
 

 
 
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Appendix A 
Schedule of Activities 
Assessment 
Screening 
Double-Blind Placebo-Controlled (DPC) Period1 
 
Open-label Extension 
(OLE) Period2 
End of Study 
Treatment 
(EOT)3 
Follow-up4 
S1 
S25  
 
Week 
Week 
 
 
Weeks 
after last 
dose 
Study Week/Month ≤ -8 weeks Baseline6 1 
 
2 
 4 8 12 16 20 24 28 32 34 36 OLE 2  
 
 
 
4 
12  
Visit Window (days) 
± 3 days 
± 3 days 
 
 
± 5 days 
 
 
 
 
 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X13 
 
 
 
 
 
Magnetic Resonance Imaging (MRI) 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & acromegaly history/demographics and 
height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
X X X X X X X X X 
X 
 
X 
X 
X 
 
Hematology8 and chemistry9 
X 
 
X 
 
 
X X X X X X X X X 
X 
 
X 
X 
 
 
Fasting Plasma Glucose (FPG)10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin A1c (HbA1c)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Every 6 M 
X 
 
 
Thyroid-stimulating hormone (TSH), free T4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Lipid profile11  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy for women with childbearing 
potential 
X 
 
X12 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Every 6 M 
X 
 
 
                                                 
1 Patients who discontinue study medication early during DPC, will be asked to continue to be followed-up per protocol through week 36; patients meeting the pre-defined withdrawal criteria will be 
rescued with injectable SRL treatment used prior to Screening). 
2 OLE scheduled to occur every 4 weeks (±5 days) for the initial 24 weeks, at weeks 36, 46 and 48 and every 12 weeks (±10 days) thereafter; the first OLE visit is also DPC Week 36. 
3 EOT is applicable for patients who discontinue study medication during DPC and/or OLE.  Every effort will be made to follow-up patients in DPC per protocol through week 36. 
4 Relevant only for patients who complete the DPC period on study medication and are ineligible or do not opt to enter the OLE period or patients who early discontinue OLE period on study medications  
5 Screening 2 should be scheduled within 2 weeks prior to randomization to determine baseline IGF-1 levels for efficacy analyses. 
6 Baseline visit (first dose), should be scheduled within ± 3 days of the intended routine dosing interval following the last injection 
7 MRI available within 12 months prior to screening is acceptable. If remnants are not visible or less than 5 mm at last MRI, MRI done within 2 years is also acceptable. A CT can be done in 
place of an MRI if the MRI is contraindicated. 
8 Hematology: RBC, Hb, Htc, platelets, WBC and differential count 
9 Chemistry: glucose, total bilirubin (in case total bilirubin is elevated, perform direct and indirect bilirubin), albumin, Na, K, Ca, creatinine, BUN, phosphorus, uric acid, GOT, GPT, ALP, GGT, 
LDH, CPK, total protein; in case of abnormal liver function additional safety assessment may be done. Blood sampling will be done under overnight fasting conditions at all visits except week 
36/EOT and at months 6, 12, every 12 months and the last visit of the OLE Period where only a four-hour fast is required. 
10 For diabetic patients only must be collected under fasting conditions. 
11 Lipid profile = total cholesterol, triglycerides, HDL and LDL 
12 Serum pregnancy is only applicable for women patients with positive urine pregnancy test at Baseline. 

 
 
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Assessment 
Screening 
Double-Blind Placebo-Controlled (DPC) Period1 
 
Open-label Extension 
(OLE) Period2 
End of Study 
Treatment 
(EOT)3 
Follow-up4 
S1 
S25  
 
Week 
Week 
 
 
Weeks 
after last 
dose 
Study Week/Month ≤ -8 weeks Baseline6 1 
 
2 
 4 8 12 16 20 24 28 32 34 36 OLE 2  
 
 
 
4 
12  
Urine pregnancy test for women with childbearing 
potential 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Growth Hormone (GH, mean integrated)13 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Months 6, 12, 
every 12 M & 
last visit 
X 
X 
 
Insulin-like growth factor 1 (IGF-1) 
X 
X 
X 
 
 
X X X X X X X X X 
X 
 
Months 3, 6  
and every 6 M 
and Week 46 
X 
X 
 
Assess IGF-1 levels and schedule an unscheduled 
visit if IGF-1 ≥1.3×ULN 
 
 
X 
 
 
X X X X X X X X X 
X 
 
X 
 
 
 
Assess Loss of Biochemical Control / Pre-defined 
withdrawal criteria14 
 
 
 
 
 
X X X X X X X X X 
X 
 
 
 
 
 
Abdominal (gall bladder) ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Every 6 M15 
X 
X 
 
Complete physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Acromegaly and treatment directed physical 
examination 
X 
 
X 
 
 
X X X X X X X X X 
X 
 
 
X 
 
 
Vital signs  
X 
 
X 
 
 
X X X X X X X X X 
X 
 
 
X 
 
 
12-lead electrocardiogram (ECG)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Concomitant medication 
X 
X 
X 
 
 
X X X X X X X X X 
X 
X 
X 
X 
 
X 
Adverse events (AE) and AEs of special interest 
X 
X 
X 
X 
X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
Randomization (call IVRS/IWRS) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study medication (call IVRS/IWRS) 
 
X 
 
 
X X X X X X X X 
 
X16 
 
X 
 
 
 
Study medication administration at the site 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Months 6, 12, 
every 12 M & 
last visit   
 
 
 
                                                 
13 GH: Five samples collected every 30 ± 5 minutes over two hours. At the first screening visit from time 0-2 hours (prior to SOC SRL administration, if planned), at baseline from time 0-2 hours 
(prior to study medication), at Week 36/EOT and at all other visits in OLE, 2-4 hours after study medication administration. GH assessment should be done under fasting conditions (patients 
to fast 4 hours prior to and throughout the 2 hours of GH sampling) 
14 Loss of biochemical control is defined IGF-1 increased by at least 30% compared to Baseline (average of 2 assessments within 2 weeks prior to randomization) to a level > 1× ULN, for 2 
consecutive visits, at least 1 week apart after the patient is treated for at least 2 weeks with 4 capsules per day; pre-defined withdrawal criteria is defined as IGF-1 ≥1.3×ULN AND exacerbation 
of acromegaly clinical signs or symptoms) for 2 consecutive visits, while the patient is treated for at least two weeks with 4 capsules per day of study medication 
15 Abdominal (gall bladder) ultrasound will be done every 6 months to week 48 and annually thereafter or as clinically indicated. 
16  For patients entering the OLE period 

 
 
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Assessment 
Screening 
Double-Blind Placebo-Controlled (DPC) Period1 
 
Open-label Extension 
(OLE) Period2 
End of Study 
Treatment 
(EOT)3 
Follow-up4 
S1 
S25  
 
Week 
Week 
 
 
Weeks 
after last 
dose 
Study Week/Month ≤ -8 weeks Baseline6 1 
 
2 
 4 8 12 16 20 24 28 32 34 36 OLE 2  
 
 
 
4 
12  
Dose titration17 
 
 
X 
X X X X X X X 
 
 
 
 
X 
X 
 
 
 
Study administration instructions 
 
 
X 
X 
X X X X X X X X X 
 
X12 
X 
X 
 
 
 
Compliance assessment 
 
 
X 
 
 
X X X X X X X X 
 
X 
 
X 
 
 
 
Study medication accountability 
 
 
 
 
X X X X X X X X 
 
X 
 
X 
X 
 
 
DPC Period Completion form 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
                                                 
17 Assess the need to escalate dose cased on pre-defined criteria of biochemical response and symptomatic control  
 

 
 
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Appendix C 
Declaration of Helsinki (2013) 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.  
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2.  
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles. 
General Principles 
3.  
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics declares 
that, “A physician shall act in the patient's best interest when providing medical care.” 
4.  
It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5.  
Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
7.  
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8.  
While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 

 
 
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9. 
It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information 
of research subjects. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professionals and never with the research subjects, even 
though they have given consent. 
10.  
Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11.  
Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.  
Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. 
13.  
Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14.  
Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the research 
study will not adversely affect the health of the patients who serve as research subjects. 
15.  
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits  
16.  
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.  
All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18.  
Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19.  
Some groups and individuals are particularly vulnerable and may have an increased 

 
 
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likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20.  
Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research. 
Scientific Requirements and Research Protocols  
21.  
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
22.  
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23.  
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee must 
be transparent in its functioning, must be independent of the researcher, the sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. 
No amendment to the protocol may be made without consideration and approval by the committee. 
After the end of the study, the researchers must submit a final report to the committee containing 
a summary of the study’s findings and conclusions. 
Privacy and Confidentiality  
24.  
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent  
25.  
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a research 
study unless he or she freely agrees. 

 
 
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26.  
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right to refuse to 
participate in the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27.  
When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28.  
For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals must not 
be included in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the group represented by the potential subject, the research cannot instead 
be performed with persons capable of providing informed consent, and the research entails only 
minimal risk and minimal burden. 
29.  
When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that assent 
in addition to the consent of the legally authorised representative. The potential subject’s dissent 
should be respected. 
30.  
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent to 
remain in the research must be obtained as soon as possible from the subject or a legally authorised 
representative. 
31.  
The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-physician relationship. 
32.  
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 

 
 
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consent for its collection, storage and/or reuse. There may be exceptional situations where consent 
would be impossible or impracticable to obtain for such research. In such situations the research 
may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33.  
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention  
and the patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of 
not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.  
In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention identified 
as beneficial in the trial. This information must also be disclosed to participants during the 
informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.  
Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.  
In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an unproven 
intervention if in the physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 
© World Medical Association, Inc. – All Rights reserved.