Clinical trial NCT03406377
Conditions: Type 2 Diabetes Mellitus
Sponsor: OPKO Health, Inc.
Start date: 2018-04-02; Completion date: 2019-06-27
Enrollment: 113 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the effect of dose escalation of once-weekly (QW) subcutaneous (SC) OPK-8003 injections vs placebo on HbA1c absolute change from baseline at 30 weeks in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise alone, or treated with a stable dose of metformin.

Detailed description:
This clinical trial is a phase 2, double-blind dose escalation regimen of once-weekly OPK-88003 in subjects with T2DM. The trial consists of a screening/baseline (up to 2 weeks prior to first dose), treatment period consisting of a dose escalation (8 weeks) and a target dose (22 weeks), and a follow-up period (4 weeks). Subjects will be randomly assigned to volume-matched OPK-88003 or placebo administered QW.

Arms: arm 1: Water for injection, Sorbitol, L-Methionine, Sodium Acetate Trihydrate arm 2: 70 mg/vial (extractable volume 1 mL) (20mg for 4 weeks, 40 mg for 4 weeks and 70 mg for 22 weeks)
Interventions: intervention 1: OPK-88003 intervention 2: Placebo
Intervention descriptions: intervention 1: OPK-88003 subcutaneous injection intervention 2: Placebo subcutaneous injection

Protocol documents:
Prot_000.pdf: 
 
PROTOCOL: DPO-203  
  
Study Title: 
A Phase 2, Double-blind, Dose Escalation Regimen of Once-weekly 
OPK-88003 in Subjects with Type 2 Diabetes 
Study Number: 
DPO-203 
Study Phase: 
Phase 2 
Product Name: 
OPK-88003 
IND Number: 
IND 113480 
Indication: 
Type 2 Diabetes Mellitus 
Investigators: 
Multicenter 
Sponsor: 
OPKO Ireland Global Holdings Ltd. (a subsidiary of OPKO Health, 
Inc.) 
Sponsor Contact: Dr. 
,  
 Medical Development 
Transition Therapeutics Corp. ULC 
101 College St, Suite 220 
Toronto, ON  M5G 1L7 
Email: 
  
Phone: 
 
Medical 
Monitor: 
Dr. 
 
Medpace
Medical Department 
5375 Medpace Way 
Cincinnati, OH 45227 
Email: 
  
Phone: 
 ext. 
 
 
Version Number 
Date 
1 
24 Jan 2018 
2 
16 May 2018 
3 
09 October 2018 
Confidentiality Statement 
The information contained in this protocol is confidential and proprietary information of OPKO Ireland Global 
Holdings Ltd. and/or its affiliates, and intended for use by clinical investigators in connection with the clinical 
investigation of OPK-88003.  It should not be copied or distributed to persons not involved in such investigation 
unless such persons are bound by written confidentiality agreement with OPKO Ireland Global Holdings Ltd. or 
its affiliates. 
PPD
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SYNOPSIS 
Sponsor: 
OPKO Ireland Global Holdings Ltd., a subsidiary of OPKO Health, Inc. 
Name of Finished Product:  
OPK-88003  
Name of Active Ingredient: 
OPK-88003  
Study Title: 
A Phase 2, Double-blind, Dose Escalation Regimen of Once-weekly OPK-88003 in 
Subjects with Type 2 Diabetes 
Study Number:  
DPO-203 
Study Phase:  
Phase 2 
Primary Objective: 
To evaluate the effect of dose escalation of once-weekly (QW) subcutaneous (SC) OPK-
88003 vs placebo injections on HbA1c absolute change from baseline to after 30 weeks 
treatment in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled with 
diet and exercise alone, or treated with a stable dose of metformin. 
Secondary Objectives: 
1. Mean percent (%) body weight change from baseline to after 30 weeks treatment 
2. Percent (%) of subjects with 5% or greater body weight loss after 30 weeks treatment 
3. Change of fasting plasma glucose (FPG) from baseline to after 30 weeks treatment 
4. Number and percent (%) of subjects achieving HbA1c ≤6.5   
3. Percent (%) of subjects permanently discontinued from the study due to hyperglycemia  
4. Incidence and rate of gastrointestinal (GI) events, major cardiovascular (CV) events, 
hypoglycemia, injection site reactions, hypersensitivity reactions and pancreatic events. 
5. To evaluate immunogenicity of OPK-88003 
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Study Design: 
Study DPO-203 is a randomized, double-blind, dose escalation, placebo-controlled, phase 
2 multicenter trial in subjects with T2DM.  There will be up to approximately 30 
investigational sites.  The trial consists of four phases: a screening/baseline phase (up to 2 
weeks prior to first dose), a 30-week treatment period consisting of a dose escalation phase 
(8 weeks) and a target dose phase (22 weeks), and a follow-up period (4 weeks).  Subjects 
will be randomly assigned to OPK-88003 or placebo administered QW.  
 
 
 
Study Population:  
Approximately 200 subjects are expected to be screened, and 110 subjects will be 
randomized to treatment (70 subjects) and placebo (40 subjects) at a ratio 1.75:1, 
respectively.   
Inclusion criteria:   
Subjects are eligible to be included in the study only if they meet all of the following 
criteria at the indicated visit: 
1. Have T2DM for at least 6 months before entering the trial based on the disease 
diagnostic criteria (AmDA 2018), controlled with diet and exercise alone or with a 
stable dose of metformin (≥1000 mg/day) for at least 3 months prior to visit 1. 
2. Males or females 18 to 80 years of age inclusive. 
3. Females must be not of childbearing potential due to surgical sterilization. 
(hysterectomy or bilateral oophorectomy or tubal ligation) or menopause.  Women 
with an intact uterus are deemed postmenopausal if they are ≥45 years old, and 
 have not taken hormones or oral contraceptives within the last year and had 
cessation of menses for at least 1 year 
OR 
 have had at least 6 months of amenorrhea with follicle-stimulating hormone (FSH) 
levels consistent with a postmenopausal state (FSH ≥40 mIU/mL). 
4. Have an HbA1c value at screening of ≥7.0% and ≤10.5%.   
5. Have a Body Mass Index (BMI) ≥27and ≤45 kg/m2 at screening. 
6. In the investigator’s opinion, are capable and willing to: 
 administer weekly study medication injection (with assistance if necessary)  
 complete study diaries 
 follow lifestyle counseling advice  
 perform self-monitored blood glucose (SMBG) 
7. Are willing to be available for the duration of the trial, comply with the required study 
procedures and visits, and abide by the clinical research site policy. 
8. Have given written informed consent. 
Exclusion criteria:  
Subjects will be excluded if they meet any of the following criteria at visit 1, unless 
otherwise specified: 
1. Participation in any other interventional trial within 30 days.  
2. Have type 1 diabetes mellitus. 
3. Previous exposure or known allergies to OPK-88003 or its components. 
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4. Previous treatment with incretin mimetic drugs (GLP-1 agonists), excluding DPP-IV 
inhibitors.  
5. Have used insulin for diabetic control for more than 6 consecutive days within the 
prior year. 
6. Use of thiazolidinedione, or any other drugs, including investigational drugs, for 
treatment of hyperglycemia (except metformin), within the prior 3 months. 
7. Use of systemic (including nasal and inhaled) glucocorticoids within the prior month,  
or subjects likely to require systemic doses of glucocorticoids during study 
participation are also excluded.  Topical applications are permitted. 
8. Evidence of hepatitis B and/or positive hepatitis B surface antigen.  Evidence of 
hepatitis C. 
9. Evidence of human immunodeficiency virus (HIV) and/or positive HIV antibodies. 
10. Have cardiac disease with functional status that is NYHA Class III, or IV or in the last 
6 months have had any of the following: myocardial infarction (MI), unstable angina, 
acute coronary syndrome, coronary artery bypass graft (CABG), percutaneous 
coronary intervention (PCI; diagnostic angiograms are permitted), transient ischemic 
attack (TIA), cerebrovascular accident (for example, stroke) or decompensated 
congestive heart failure. 
11. Have hypertension (mean systolic blood pressure >160 mm Hg or mean diastolic blood 
pressure >100 mm Hg), malignant hypertension, renal artery stenosis, and/or evidence 
of labile blood pressure including symptomatic postural hypotension at visit 1.  If on 
treatment for hypertension, doses of antihypertensive medications must be stable for 
the prior 30 days. 
12. Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or 
an alanine transaminase (ALT) or aspartate aminotransferase (AST) levels >2.5 x 
upper limit of normal (ULN) or serum total bilirubin >2.0 mg/dL. 
13. Evidence of hypothyroidism or hyperthyroidism based on clinical evaluation and/or an 
abnormal thyroid-stimulating hormone (TSH).  Subjects on a stable dose of thyroid 
replacement therapy for at least the prior two months may be eligible if they meet the 
other criteria.  
14. Evidence of obesity induced by other endocrinologic disorders (eg. Cushing 
Syndrome). 
15. Clinically significant peripheral vascular disease in the opinion of the investigator. 
16. Active proliferative diabetic retinopathy. 
17. Known significant autonomic neuropathy as evidenced by urinary retention, resting 
tachycardia, orthostatic hypotension or diabetic diarrhea. 
18. Have an active or untreated malignancy or have been in remission from a clinically 
significant malignancy (other than basal or squamous cell skin cancer, in situ 
carcinomas of the cervix or in situ prostate cancer) for less than five years.  Have a 
personal or family history of medullary C-cell thyroid hyperplasia, focal hyperplasia, 
carcinoma (including sporadic, familial or part of Multiple Endocrine Neoplasia 
syndrome type 2A or 2B); or a serum calcitonin ≥20 pg/mL. 
19. Impaired renal function (eGFR <60 mL/min/1.73 m2). 
20. Triglycerides >600 mg/dL (6.84 mmol/L) at screening.  If subject is on lipid lowering 
therapies, doses must be stable for 30 days prior to screening.   


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21. Any subject having experienced a keto-acidotic episode requiring hospitalization in the 
prior 6 months. 
22. Have an ECG considered by the investigator indicative of active cardiac disease or 
with abnormalities that may interfere with the interpretation of changes in ECG 
intervals.  A QTcB interval greater than 450 msec in men and greater than 470 msec in 
women at visit 1 or visit 2 is specifically excluded. 
23. Personal or family history of long QT syndrome, family history of sudden death in a 
first-degree relative (parents, sibling, or children) before age 40 or personal history of 
unexplained syncope within the last year.  Use of prescription or over-the-counter 
medications known to prolong the QT or QTc interval. 
24. History or presence of CV, respiratory, hepatic, renal, GI, endocrine (other than 
diabetes), hematological, or neurological disorders capable of significantly altering the 
absorption, or metabolism or elimination of drugs or of constituting a risk when taking 
the study medication or interfering with the interpretation of data. 
25. Diagnosis of gastroparesis or bariatric surgery prior to screening, or planned bariatric 
surgery for the trial duration period. 
26. Have had more than one episode of severe hypoglycemia within 6 months prior to visit 
1, as defined by hypoglycemia associated with severe cognitive impairment requiring 
external assistance for recovery, or has a history of hypoglycemia unawareness or poor 
recognition of hypoglycemic symptoms.  Any subject that the investigator feels will 
not be able to communicate an understanding of hypoglycemic symptoms and the 
appropriate treatment of hypoglycemia should also be excluded. 
27. Have had two or more emergency room visits or hospitalizations due to poor glucose 
control within the prior 6 months. 
28. Have taken prescription or over-the-counter medications to promote weight loss within 
the prior 3 months. 
29. Have had a significant change in weight, defined as a gain or loss of more than 5% in 
the prior 3 months. 
30. Are currently taking CNS stimulants (eg, Ritalin-SR®) with the exception of 
caffeinated beverages. 
31. Have had a blood transfusion or severe blood loss within the prior 3 months or have 
known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or have a hemoglobin 
value <11 g/dL (males) or <10 g/dL (females), or any other condition known to 
interfere with HbA1c methodology. 
32. Blood donation of 450 mL or more in the prior 3 months or any blood donation within 
the prior month. 
33. Have a history of alcohol or drug dependence or abuse within the last 2 years and/or 
have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 
units per week (females) [1 unit = 12 oz. or 360 mL of beer; 5 oz. or 150 mL of wine; 
1.5 oz. or 45 mL of distilled spirits]. 
34. Have a history of atopy (severe or multiple allergic manifestations) or clinically 
significant multiple or severe drug allergies, or intolerance to topical corticosteroids, or 
severe post-treatment hypersensitivity reactions (including, but not limited to, 
erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, 
anaphylaxis, angioedema, or exfoliative dermatitis). 


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35. Have a history of acute or chronic pancreatitis or confirmed elevation in serum 
lipase/amylase (>2 x ULN). 
36. Have any other condition or psychiatric disorder that, in the opinion of the investigator, 
may preclude the subject from following and completing the protocol related 
procedures. 
37. Are unsuitable for inclusion in the study in the opinion of the investigator or sponsor.  
38. Are unable to undergo MRI procedures for any reason 
 
  
Test Product, Dose, and Mode of Administration:  
OPK-88003 and placebo are supplied for once-weekly SC injection.  OPK-88003 or 
placebo will be initially administered for 4 weeks at 20 mg QW followed by 4 weeks at 40 
mg QW followed by 70 mg QW for 22 weeks.  There are no restrictions on the time of day 
each dose is given but it is advisable to administer SC injections on the same day and time 
of the week for the full 30-week treatment period.  Study drug should not be administered 
within four days of the previous injection.   
Duration of Treatment:  
OPK-88003 or placebo will be administered for 30 weeks.  Each subject may participate in 
the study for up to 36 weeks (including screening phase and follow-up).  
Efficacy Assessments: 
The primary efficacy measure is HbA1c (absolute change from baseline).  Secondary 
efficacy measures include: body weight (mean change from baseline and % of subjects 
with > 5% loss from baseline to endpoint), FPG, number and % subjects achieving HbA1c 
≤6.5. 
Safety Assessments: 
Safety assessments include all AEs, vital signs, ECG monitoring, and development of anti-
drug antibodies (ADA). 
Statistical Methods: 
Sample size: A total of 110 subjects will be randomized at a ratio 1.75:1 to OPK-88003 
(70 subjects) and placebo (40 subjects).  48 subjects in the active arm and 27 subjects in 
the placebo arm will provide at least 90% power to detect superior glycemic control over 
placebo represented by -0.8% in HbA1c levels after 30 weeks of treatment.  This assumes 
a common standard deviation (SD) of 1.0% and a two-sided alpha of 0.05.   
Efficacy:  The primary efficacy outcome of HbA1c change from baseline to the 30-week 
endpoint will be performed on the mITT analysis set.  The primary efficacy outcome will 
be analyzed using linear contrasts from an analysis of covariance (ANCOVA) model with 
treatment arm and BMI strata as factors and the baseline HbA1c value as a covariate.  An 
additional supportive analysis of the primary efficacy outcome will be a mixed-model 
repeated-measures (MMRM).  The factors in the model will be BMI strata, treatment 
group, baseline value, visit, and the treatment group by visit interactions..  Additional 
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covariates may be added and will be detailed in the statistical analysis plan (SAP). 
The mean percent weight change from baseline at the 30 week endpoint will be analyzed 
using similar dose response models as the primary analysis.  A logistic regression analysis 
will be performed for the percent of subjects with 5% or greater body weight loss with 
treatment and HbA1c and BMI strata as fixed effects, and baseline weight as a covariate.  
Comparisons between treatment groups for the number and percent of subjects achieving 
HbA1c ≤6.5 will be performed for responses after 30 weeks treatment with LOCF based 
on a logistic regression model with a factors for treatment group and BMI strata and 
baseline HbA1c as a covariate.  
Study Duration and Dates: 
The trial is expected to commence recruitment during Q1 2018 and recruitment is expected 
to take approximately 5 months. 
Study Design for DPO-203 
EOT: end of treatment  
↓ indicates dosing 
 
 


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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................2 
TABLE OF CONTENTS ........................................................................................................8 
LIST OF IN-TEXT TABLES ...............................................................................................11 
LIST OF IN-TEXT FIGURES .............................................................................................11 
LIST OF APPENDICES .......................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................12 
1 
INTRODUCTION ..........................................................................................................14 
1.1 
Background ................................................................................................................14 
1.1.1 
Incretins ................................................................................................................14 
1.1.2 
Oxyntomodulin .....................................................................................................14 
1.1.3 
OPK-88003............................................................................................................15 
1.2 
Nonclinical Studies .....................................................................................................15 
1.3 
Previous Human Experience .....................................................................................16 
1.4 
Rationale for the Study ..............................................................................................17 
1.4.1 
Rationale for Dose Selection ...............................................................................18 
2 
STUDY OBJECTIVES ..................................................................................................19 
2.1 
Primary Objective ......................................................................................................19 
2.2 
Secondary Objectives.................................................................................................20 
2.3 
Other Objectives ........................................................................................................20 
3 
INVESTIGATIONAL PLAN ........................................................................................20 
3.1 
Overall Study Design and Plan .................................................................................20 
3.2 
Rationale for Study Design and Control Group .....................................................22 
3.3 
Study Duration and Dates .........................................................................................22 
4 
STUDY POPULATION .................................................................................................22 
4.1 
Inclusion Criteria .......................................................................................................23 
4.2 
Exclusion Criteria ......................................................................................................23 
5 
DISCONTINUATIONS .................................................................................................27 
5.1 
Discontinuation of Study Drug .................................................................................27 
5.1.1 
Temporary Discontinuation of Study Drug .......................................................27 
5.1.2 
Permanent Discontinuation of Study Drug .......................................................27 
5.2 
Discontinuation of Subjects .......................................................................................28 
5.3 
Discontinuation of Study Sites ..................................................................................29 
5.4 
Discontinuation of the Study .....................................................................................29 
6 
STUDY TREATMENT(S) .............................................................................................29 
6.1 
Randomization ...........................................................................................................29 
6.2 
Description of Treatment(s) ......................................................................................29 
6.2.1 
OPK-88003 Injection ...........................................................................................30 
6.2.2 
Placebo Injection ..................................................................................................30 
6.3 
Packaging and Labeling ............................................................................................30 
6.4 
Storage and Accountability .......................................................................................30 
6.5 
Treatments Administered .........................................................................................31 
6.6 
Materials and Supplies ..............................................................................................32 
6.6.1 
Study Drug Supplies ............................................................................................32 


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6.6.2 
Laboratory Supplies ............................................................................................32 
6.7 
Selection and Timing of Dose for Each Subject ......................................................32 
6.8 
Blinding .......................................................................................................................33 
6.9 
Concomitant Therapy ................................................................................................33 
6.10 
Restrictions .................................................................................................................34 
6.11 
Evaluation and Treatment of Hyperglycemia .........................................................34 
7 
STUDY PROCEDURES ................................................................................................35 
7.1 
Medical History and Physical Examination ............................................................35 
7.2 
Height and Weight,
7.3 
Electrocardiography (ECG) ......................................................................................35 
7.4 
Vital Signs (Blood Pressure and Pulse Rate) ...........................................................36 
7.5 
Fasting Self-Monitored Blood Glucose (SMBG) Levels .........................................36 
7.6 
Lifestyle Counseling ...................................................................................................37 
7.7 
Diary Completion .......................................................................................................37 
7.7.1 
Lifestyle Diary ......................................................................................................37 
7.7.2 
Subject Diary ........................................................................................................38 
7.8 
Clinical Laboratory Tests..........................................................................................38 
7.8.1 
Laboratory Parameters .......................................................................................38 
7.8.2 
Immunogenicity....................................................................................................39 
7.8.4 
Sample Collection, Storage, and Shipping .........................................................40 
7.10 
Dispensing Study Drug ..............................................................................................40 
7.11 
Treatment Compliance ..............................................................................................40 
7.12 
Concomitant Medication Assessments .....................................................................41 
8 
SAFETY EVALUATIONS ............................................................................................41 
8.1 
DSMB ..........................................................................................................................41 
8.2 
Adverse Events ...........................................................................................................41 
8.2.1 
Severity..................................................................................................................42 
8.2.2 
Relationship ..........................................................................................................42 
8.3 
Adverse Events of Special Interest ...........................................................................43 
8.3.1 
Injection Site Reactions .......................................................................................43 
8.3.2 
Hypersensitivity Reactions ..................................................................................43 
8.3.3 
Hypoglycemia .......................................................................................................43 
8.3.4 
Nausea, Vomiting and Diarrhea .........................................................................44 
8.3.5 
Acute Pancreatitis ................................................................................................44 
8.3.6 
Cardiovascular Events.........................................................................................45 
8.3.7 
Electrocardiography (ECG) Findings ................................................................45 
8.4 
Liver Function Monitoring .......................................................................................45 
8.5 
Serum Creatine Kinase Monitoring .........................................................................45 
8.6 
Serum Calcitonin Monitoring ...................................................................................46 
8.7 
Treatment Discontinuations ......................................................................................46 
8.8 
Pregnancies .................................................................................................................47 
8.9 
Serious Adverse Events (SAEs) ................................................................................47 
8.9.1 
Reporting Serious Adverse Events .....................................................................47 
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8.9.1.1 
Initial Report ..................................................................................................47 
8.9.1.2 
Follow-up Reports ..........................................................................................48 
8.10 
Safety Monitoring ......................................................................................................48 
8.10.1 
Safety Monitoring ................................................................................................48 
8.10.2 
Assessment of Tolerability ..................................................................................49 
9 
STUDY ACTIVITIES ....................................................................................................49 
9.1 
Screening/Visit 1 (Day -14 to Day -1) .......................................................................49 
9.2 
Re-testing and Re-screening......................................................................................50 
9.2.1 
Re-testing ..............................................................................................................50 
9.2.2 
Re-screening .........................................................................................................50 
9.3 
Treatment Period - Dose Escalation (Weeks 0-7) ...................................................50 
9.3.1 
Visit 2 Baseline (Day 1) 20 mg Dose Level .........................................................50 
9.3.2 
Visit 3 (Week 1±2 Days) 20 mg Dose Level ........................................................51 
9.3.3 
Visit 4 (Week 4±2 Days) 40 mg Dose Level ........................................................51 
9.3.3.1 
Visit 4A (on any day 1 to 6 days following visit 4) ......................................52 
9.4 
Treatment Period – Target Dose Phase (Week 8 to Week 30) ...............................53 
9.4.1 
Visit 5 (Week 8 ±2 Days) Target Dose ................................................................53 
9.4.1.1 
Visit 5A (on any day 1 to 3 days following visit 5) ......................................54 
9.4.1.2 
Visit 5B (on any day 4 to 6 days following visit 5).......................................54 
9.4.2 
Visit 6 (Week 9±2 Days) Target Dose .................................................................54 
9.4.3 
Visit 7 (Week 10±2 Days) Target Dose ...............................................................54 
9.4.4 
Visit 8 (Week 11±2 Days) Target Dose ...............................................................55 
9.4.5 
Visit 9 (Week 12±2 Days) Target Dose ...............................................................55 
9.4.5.1 
Visit 9A (any day 1 to 6 days post visit 9) ....................................................56 
9.4.6 
Visit 10 (Week 16±2 Days) Target Dose .............................................................56 
9.4.7 
Visit 11 (Week 22±4 Days) Target Dose .............................................................57 
9.4.8 
Visit 12 (Week 26±4 Days) Target Dose .............................................................58 
9.4.9 
Visit 13 (Week 30±4 Days) End of Treatment ...................................................59 
9.5 
Follow-up Visit 14 (Week 34±4 Days)/Early Termination .....................................60 
10 QUALITY CONTROL AND ASSURANCE ...............................................................60 
10.1 
Data Quality Assurance .............................................................................................61 
11 STATISTICAL CONSIDERATIONS ..........................................................................62 
11.1 
Determination of Sample Size ...................................................................................62 
11.2 
Planned Statistical Methods ......................................................................................62 
11.2.1 
General Considerations .......................................................................................62 
11.2.2 
Analysis Populations ............................................................................................63 
11.2.3 
Subject Disposition...............................................................................................63 
11.2.4 
Demographics and Baseline Characteristics .....................................................64 
11.2.5 
Study Drug Exposure, Compliance, and Concomitant Therapies ..................64 
11.3 
Outcomes Analysis .....................................................................................................64 
11.3.1 
Primary Outcome Analysis .................................................................................64 
11.3.1.1 
Supportive Analysis of Primary Outcome ...................................................64 
11.3.2 
Secondary Outcome Analyses .............................................................................65 
11.3.3 
Other Outcome Analyses .....................................................................................65 
11.4 
Safety Analysis ...........................................................................................................65 


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11.4.1 
Adverse Events .....................................................................................................66 
11.4.2 
Adverse Events of Special Interest .....................................................................66 
11.4.2.1 
Hypoglycemic Episodes .................................................................................66 
11.4.2.2 
Other Adverse Events of Special Interest (AESIs) .....................................66 
11.4.3 
Vital Signs .............................................................................................................66 
11.4.4 
Laboratory Measures ..........................................................................................67 
11.4.5 
Evaluation of Immunogenicity............................................................................67 
11.4.6 
Evaluation of Electrocardiography (ECG) ........................................................67 
12 ADMINISTRATIVE CONSIDERATIONS .................................................................68 
12.1 
Study Administrative Structure ...............................................................................68 
12.2 
Ethical Conduct of the Study ....................................................................................69 
12.3 
Institutional Review Board (IRB) Approval ...........................................................69 
12.4 
Subject Information and Consent ............................................................................70 
12.5 
Confidentiality ............................................................................................................70 
12.5.1 
Subject Confidentiality ........................................................................................70 
12.5.2 
Protocol/Study Confidentiality ...........................................................................70 
12.6 
Electronic Case Report Forms (CRFs) and Study Records ...................................71 
12.7 
Protocol Deviations ....................................................................................................71 
12.8 
Retention of Data .......................................................................................................72 
12.9 
Publication and Disclosure Policy ............................................................................72 
13 REFERENCE LIST........................................................................................................72 
 
LIST OF IN-TEXT TABLES 
Table 1 
Threshold Glucose Levels..............................................................................34 
Table 2 
List of Laboratory Tests ................................................................................39 
Table 3 
Classification of Hypoglycemia .....................................................................44 
Table 4 
Third-party Designees ...................................................................................69 
Table 5 
Clinically Significant Events .........................................................................78 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design for DPO-203 ............................................................................21 
LIST OF APPENDICES 
APPENDIX 1. 
SCHEDULE OF EVENTS ......................................................................75 
APPENDIX 2. 
CLINICALLY SIGNIFICANT EVENTS .............................................78 
APPENDIX 3. 
HEPATIC MONITORING TESTS FOR TREATMENT-
EMERGENT ABNORMALITY ...................................................................................80 
APPENDIX 4. 
INVESTIGATOR’S SIGNATURE ........................................................81 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
AmDA 
American Diabetes Association 
ANCOVA 
analysis of covariance 
AP. 
acute pancreatitis 
AUC 
area under the curve 
BIW 
twice-weekly 
BMI 
body mass index 
CK 
creatine kinase 
Cmax  
maximum concentration 
CNS 
central nervous system 
CRA 
clinical research associate 
CSE 
clinically significant event(s) 
CSR 
clinical study report 
CV 
cardiovascular 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment (visit) 
ET 
early termination 
FPG 
fasting plasma glucose 
GcgR 
glucagon receptor 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GLP-1 
glucagon like peptide-1 
GLP-1R 
glucagon-like protein-1 receptor 
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HbA1c 
glycosylated hemoglobin 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LDL-C 
low density lipoprotein cholesterol 
LOCF 
last observation carried forward 
LSM 
least squares mean 
MI 
myocardial infarction 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
MRI 
magnetic resonance imaging 
NAFLD 
non-alcoholic fatty liver disease 
NOAEL 
no observed adverse effect level 
OAM 
oral antidiabetic medication 
OXM 
oxyntomodulin 
PD 
pharmacodynamics(s) 
PK 
pharmacokinetic(s) 
QW 
once-weekly 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SMBG 
self-monitored blood glucose 
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 
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1 INTRODUCTION 
1.1 
Background 
Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by insulin resistance 
and loss of β-cell function.  Obesity is a major contributor to the progression of insulin 
resistance in T2DM.  Correlations between adiposity and insulin resistance have been 
reported in both adults and children.  Thus, there is a need for the development of therapies 
that target both body weight and poor glycemic control. 
1.1.1 
Incretins 
Incretin mimetics class of glucose-lowering drugs offer an alternative approach to the 
treatment of T2DM with moderate efficacy in lowering glycosylated hemoglobin A1c 
(HbA1c) and favorable weight loss.  Glucagon-like-peptide 1 (GLP-1), an endogenous 
incretin hormone, regulates postprandial glycemia by stimulating insulin secretion, inhibiting 
glucagon secretion, promoting satiety and reducing weight gain via both peripheral and 
central activation of the glucagon-like protein-1 receptor (GLP-1R) (Campbell & Drucker 
2013).   
While fasting plasma levels of endogenous GLP-1 are normal in subjects with T2DM, they 
are diminished post-prandially (Baggio & Drucker 2007).  GLP-1 is rapidly degraded by the 
protease dipeptidyl peptidase-IV (DPP-IV) resulting in a half-life of approximately 1-2 
minutes in both healthy and subjects with T2DM (Deacon et al 1995).  Since the 
glucoregulatory actions of GLP-1 remain intact in patients with T2DM, current therapeutic 
strategies have focused on analogs with improved metabolic stability and reduced clearance. 
1.1.2 
Oxyntomodulin 
Oxyntomodulin (OXM) is a 37-amino acid peptide hormone that is released postprandially, 
along with GLP-1, from the L-cells of the small intestine in proportion to energy intake.  
OXM reduces body weight in obese patients as a result of enhanced satiety and increased 
energy expenditure (Wynne et al 2010).  The satiety-inducing effects of OXM are believed to 
be mediated through the activation of the GLP-1R, since its anorectic effects in rodents are 
blocked by co-administration of the GLP-1R antagonist exendin (9-39) and are not observed 
in Glp1r-/- mice (Baggio et al 2004, Sowden et al 2007, Wynne et al 2010).  Other effects of 
OXM, including further improvement of β-cell function and increased energy expenditure 
have been attributed to the glucagon receptor (GcgR) pathway (Kosinski et al 2012).  
Chronic infusion of OXM had superior weight loss and comparable glucose lowering to 
OXMQ3E (an OXM analog which has no significant GcgR agonist activity) in diet induced 
obese (DIO) mice (Kosinski et al 2012).  Moreover, OXM improves glucose tolerance and 
stimulates insulin secretion in mice (Maida et al 2008) further suggesting a role for OXM in 
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1.1.3 
OPK-88003 
OPK-88003 is a long-acting polyethylene-glycol (PEG)-conjugated (PEGylated) synthetic 
peptide analog of mammalian OXM.  Similar to native OXM, OPK-88003 binds and 
activates both the GLP-1R and the GcgR.  In addition to the well-documented insulin 
secretion-promoting and glucose-lowering effects of GLP-1R agonists, OPK-88003 may 
have additional benefits via its action on the GcgR, including effects on satiety and weight 
loss.  Among currently available therapies for T2DM, GLP-1 agonists are most effective in 
glycemic control with favorable effects on body weight and without the risk of 
hypoglycemia.  However, the weight loss with GLP-1 agonists is modest due to dose-
dependent gastrointestinal (GI) side effects.  OPK-88003 is designed to improve upon 
existing GLP-1 agonists by offering both non-inferior glycemic control and superior weight 
management.   
1.2 
Nonclinical Studies 
Nonclinical studies support that OPK-88003 may be safely administered to subjects with 
T2DM.  The toxicity profile of OPK-88003 has been characterized in rats and monkeys using 
sub-chronic and chronic repeat-dose toxicity, and safety pharmacology studies.  The 
nonclinical testing program has followed a standard development pathway for a chronically 
used biological product.   
Safety pharmacology evaluations including central nervous system (CNS), cardiovascular 
(CV), and respiratory assessments were performed in monkeys at doses up to 5 mg/kg.  The 
no observed adverse effect level (NOAEL) for effects on CNS, CV, and respiratory safety 
pharmacology in the monkey was 5 mg/kg.  Because OPK-88003 is a synthetic peptide, no 
genetic toxicity studies were conducted.   
OPK-88003-related changes in both rat and monkey repeat-dose toxicity studies (4 and 26 
weeks in duration) were generally consistent with, or secondary to, typical GLP-1R agonist 
pharmacology.  In the 4-week studies, OPK-88003 was injected SC twice-weekly (BIW) 
with doses of 1.5 to 15 mg/kg and 0.5 to 5 mg/kg in rats and monkeys, respectively.  
Important findings were limited to reversible pharmacodynamic (PD) reductions in food 
consumption, with secondary decreases in body weight at all doses in rats and the high-dose 
in monkeys.  The maximum tolerated dose (MTD) and NOAELs for target organ toxicity 
were 15 mg/kg and 5 mg/kg, respectively.  
In the 26-week studies, SC OPK-88003 doses of 0.3 to 3.0 mg/kg and 0.5 to 5.0 mg/kg BIW 
were evaluated in rats and monkeys, respectively.  The primary effects were dose-dependent 
decreases in food consumption with secondary decreases in body weight gain.  The NOAELs 
for target organ toxicity in chronic repeat-dose toxicity studies in rats and monkeys were 3 
mg/kg and 1.5 mg/kg, respectively. 


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1.3 
Previous Human Experience 
OPK-88003 has been investigated for the treatment of patients with T2DM and 
accompanying unhealthy body weight as a once-weekly (QW) subcutaneous (SC) 
administration.  Cumulatively, 402 subjects have received OPK-88003 to date in the clinical 
program.  Single and multiple ascending doses up to 60 mg QW were tested in a two-part, 
phase 1 double–blind, randomized, placebo-controlled, clinical pharmacology trial DPO-101.  
Doses ranging from 10 mg to 50 mg per week were tested in a 24-week double-blind (for the 
first 12 weeks), randomized, placebo- and active comparator (2 mg exenatide ER)-controlled 
phase 2 trial XNAA.  Supratherapeutic multiple SC doses of 40 mg once daily for 7 days and 
titrated doses of 15 to 60 mg over 6 days were tested in a double-blind, placebo controlled 
clinical pharmacology study XNAB. 
Clinical data from the phase 1 trial DPO-101 indicated that QW SC administration of OPK-
88003 produced an improvement in HbA1c and fasting glucose and resulted in progressive 
decrease in body weight.  Changes from baseline in body weight after 5 weeks of dosing in 
T2DM and obese non-diabetic patients ranged from -1.55 kg to -2.23 kg, compared with        
-0.81 kg in the placebo group for dose levels between 25 mg to 60 mg.  Glucose tolerance 
and fasting plasma glucose (FPG) were significantly improved in subjects with T2DM. 
In the phase 2 trial, XNAA administration of OPK-88003 at 10, 15, 30 and 50 mg doses QW 
for 6 months in subjects with T2DM resulted in dose-dependent effects on blood glucose and 
body weight reduction.  Statistically significant reduction in mean HbA1c (up to 1.43%) was 
observed for all doses at 12 and 24 weeks.  OPK-88003 significantly decreased HbA1c levels 
versus placebo and was non-inferior to 2 mg exenatide ER at the 30 mg and 50 mg doses 
(p=0.994 and 0.628, respectively).  Greater reductions in FBG with OPK-88003 resulted in 
similar 7-point self-monitored blood glucose (SMBG) profile values compared to treatment 
with exenatide ER and lower values compared to placebo.  
OPK-88003 also produced a dose-dependent weight loss of up to 3.3 kg by week 24.  In 
comparison to placebo and exenatide ER, OPK-88003 50 mg resulted in statistically 
significant percent change in body weight from baseline at 12 (p<0.001 and p=0.011, 
respectively) and 24 (p= 0.007 and p=0.05, respectively) weeks.  At least twice as many 
OPK-88003-50 mg (35.5%) subjects lost ≥5% of their body weight compared to placebo 
(11.8%) (p=0.004) and exenatide ER (18.3%) (p=0.025) by week 24.   
Safety findings were consistent with what would be expected from a GLP-1 agonist effect.  
The most frequent OPK-88003 dose-related adverse events (AEs) have been GI symptoms, 
including nausea, vomiting, diarrhea, and decreased appetite.  Most of the events were single 
episodes, mild in severity, transient and self-limited.  These events occurred most commonly 
after the first dose and the incidence then declined to near control levels by the fourth weekly 
dose.  Rates of nausea, vomiting and diarrhea were dose-dependent with moderate 
tolerability at the highest dose of 50 mg in study XNAA.   
Some injection site reactions (rash/redness) with OPK-88003 treatment were observed 
although the incidence was lower than for exenatide ER and the severity of the reactions 


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tended to be mild or moderate with very few severe reactions reported in 3.21% of subjects 
(9/280).  In addition, in almost all cases the reactions decreased in severity over time.  
Incidence of anti-drug antibodies (ADA) development was <4%.   
There was no evidence of a hypoglycemia-promoting effect of OPK-88003.  Potential 
pancreatic AEs occurred in 10 subjects with 11 events requiring adjudication.  Of these, only 
one event in the OPK-88003 treatment group was adjudicated to be an actual pancreatic 
event.   
Mean heart rate (HR) increased with OPK-88003 by approximately 5 beats per minute (bpm) 
in study XNAA compared to placebo, although the differences were not statistically 
significant.   
Additional safety parameters including SAEs, other treatment emergent adverse events 
(TEAEs), other laboratory measurements and other vital signs were not different between 
treatment groups or were modified in a favorable direction by OPK-88003 treatment (notably 
systolic and diastolic blood pressure).   
In study XNAB, an increase in supine and standing pulse rate was observed 48 and 72 hours 
following single doses, that returned to predose values at 7 days post dose.  Mean supine and 
standing pulse rate increased and then generally remained high up to at least 7 days after the 
final dose following repeated doses and returned to predose values by follow-up.  The 
increases in pulse rate for individual subjects were not associated with AEs.  There was no 
indication of prolongation of QTc interval.  No additional novel safety findings, other than 
the expected increase in rate of nausea and vomiting were observed at surpatherapeutic doses 
of OPK-88003.  
1.4 
Rationale for the Study 
Equivalent effects on HbA1c and greater weight loss effects were observed for OPK-88003 
compared to exenatide ER in the phase 2 trial XNAA.  These findings are consistent with the 
hypothesis that the additional glucagon activity associated with OPK-88003 provides 
equivalent glycemic control and superior weight loss compared to GLP-1 modulation alone.  
Since it has been demonstrated that additional weight loss can be obtained by increasing the 
dose of GLP-1 agonists (Davies et al 2015), it seems likely that increasing the dose of OPK-
88003 will demonstrate additional weight loss benefits. 
XNAA investigated the dose-response relationship of OPK-88003 versus placebo and 
positive control exenatide ER, and established that QW injections over 24 weeks could 
reduce HbA1c by up to 1.43% and weight by up to 3.3 kg.  The severity of the OPK-88003 
AE profile observed so far, including the 50 mg QW dose tested in the phase 2 trial, does not 
outweigh the anticipated favorable benefits on glucose and body weight.  Thus, the benefit-
risk balance of OPK-88003 supports additional clinical testing of OPK-88003 at doses higher 
than 50 mg QW. 


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There was also a dose-dependent increase in GI side effects with higher OPK-88003 doses in 
prior human studies, however, these effects were transient in nature.  In efforts to optimize 
OPK-88003 for glucose control and body weight reduction, it is likely that dose escalation 
could be key for reducing GI side effects through gradual up-titration of doses to target dose 
levels.  Other GLP-1 agonists, such as liraglutide QD (once daily) and semaglutide QW, 
show that when slow dose escalation is implemented, higher doses are achieved and the rates 
of patients reporting GI disorders can be significantly reduced.  In the multiple ascending 
dose portion of the phase 1 trial in diabetics DPO-101, GI tolerability of OPK-88003 was 
improved with the use of a titration regimen for 60 mg QW.  Thus, it is reasonable to 
anticipate that a slower dose-escalation regimen will exhibit improved tolerability to nausea 
and vomiting at dose levels higher than the 50 mg dose administered in the previous phase 2 
trial (XNAA).  As such, for this trial, a slow dose-titration schedule over 8 weeks will be 
employed to help mitigate the gastrointestinal AEs.  
1.4.1 
Rationale for Dose Selection 
Study DPO-203 will include OPK-88003 target dose of 70 mg administered weekly.  Based 
on data from subjects with T2DM in study XNAA, the 70 mg QW dose is anticipated to 
produce maximal reduction in fasting glucose and HbA1c and yield a greater weight loss 
than the 50 mg QW dose from the dose-range finding phase 2 trial. 
The 70 mg QW dose level will be administered using a fixed dose escalation schedule over 8 
weeks.  Plasma levels of OPK-88003 reach steady state over 5 weeks with the accumulation 
ratio for Cmax and area under the curve (AUC) up to 2.6-fold.  Thus, it is reasonable to apply 
slow dose titration with dose escalation every 4 weeks.  For the first 4 weeks of dose 
escalation subjects will receive 20 mg followed by 4 weeks of 40 mg administered QW.  
Safety and tolerability from the previous phase 2 trial support evaluation of the dose levels 
planned for the 8-week dose escalation period.  
A population PK model with a first order absorption and first order elimination, along with 
inter-individual variability for all PK parameters was used to simulate the proposed 70 mg 
QW dose.  This dose is 33% higher (for Cmax and AUC) when compared to the 50 mg dose 
that had acceptable safety and tolerability over 24 weeks.  Simulated PK exposures derived 
from XNAA modeling in conjunction with the phase 1 XNAB trial with supratherapeutic 
exposures and nonclinical safety margins support a multiple dose of 70 mg, administered 
QW, in the targeted population.  
OPK-88003 at the target level of 70 mg QW dose at steady state following dose titration 
(week 30) is predicted to have mean Cmax value of 3755 ng/mL and AUC value of 560 
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µg•h/mL based on population PK modeling of the proposed titrated dosing regimen 
(20 mg/40 mg/70 mg QW).  In the clinical pharmacology trial XNAB multiple SC doses of 
40 mg administered daily for 7 days resulted in supratherapeutic exposures.  The geometric 
mean Cmax of OPK-88003 after 7 days of dosing was 11700 ng/mL with the corresponding 
AUC of 1789 µg•h/mL.  The exposures from study XNAB were three-fold higher than the 
modelled exposures with currently proposed titrated dosing regimen, for both Cmax and AUC.  
Supratherapeutic exposures in XNAB study persisted for approximately three weeks after the 
last dose due to the long terminal half-life of OPK-88003.  The once-a-day dosing regimen 
resulted in high rates of moderately severe nausea and vomiting that required concomitant 
medication, however most events resolved within a week after the last dose.  The intensity 
and/or duration of these events is expected to be reduced by a slow dose titration in the 
current study.  In previous OPK-88003 trials, there were no safety concerns reported based 
on clinical laboratory evaluations and ECGs and no severe or serious AEs (SAEs) at 
supratherapeutic exposures. 
The safety data from the human studies confirm dose-related, monitorable AEs related to GI 
tolerability.  Most of the events were single episodes, mild in severity, transient, and self-
limited.  These events occurred most commonly after the first dose and the incidence then 
declined to near control levels by the fourth dose, consistent with a GLP-1R agonist effect.   
Furthermore, studies of molecules with similar mechanism demonstrate improved tolerability 
with slow dose titration and longer duration of dosing and have not demonstrated new, 
unexpected toxicities with longer duration of dosing. 
The toxicology program for OPK-88003 provided continuous plasma exposure in rats and 
monkeys with a BIW dosing schedule and supports the proposed dosing regimen.  The safety 
margins for the 70 mg dose based on the exposures (AUC) derived from population PK 
modeling in humans and the NOAELs for organ toxicity as determined in rats (3 mg/kg) and 
monkeys (1.5 mg/kg) after chronic dosing correspond to exposure multiples of 0.7-fold and 
10-fold, respectively.   
Taking into consideration clinical efficacy and tolerability, QW doses of 70 mg are expected 
to be tolerated with slow dose-escalation and produce glycemic control and weight loss 
benefits.  The data from this trial together with the data from the previous phase 2 trial will 
enable robust benefit-risk characterizations in T2DM and will form the basis to assess the 
effect of dose escalation on OPK-88003 efficacy, safety and tolerability, and support the 
selection of dose(s) and dose regimen to be included in phase 3 trials. 
2 STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this study is: To evaluate the effect of dose escalation of QW SC 
OPK-88003 vs placebo injections on HbA1c absolute change from baseline to after 30 weeks 
treatment in subjects with T2DM inadequately controlled with diet and exercise alone, or 
treated with a stable dose of metformin. 


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2.2 
Secondary Objectives  
The secondary objectives of this study are to determine the effect of OPK-88003 vs placebo 
on: 
1. Mean percent (%) body weight change from baseline to after 30 weeks treatment 
2. Percent (%) of subjects with 5% or greater body weight loss after 30 weeks treatment 
3. Change of FPG from baseline to after 30 weeks treatment 
4. Number and percent of subjects achieving HbA1c ≤6.5  
2.3 
Other Objectives 
3. Percent (%) of subjects permanently discontinued from the study due to hyperglycemia 
4. Incidence and rate of gastrointestinal (GI) events, major cardiovascular (CV) events, 
hypoglycemia, injection site reactions, hypersensitivity reactions and pancreatic events 
5. To evaluate immunogenicity of OPK-88003 
3  INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
Study DPO-203 is a randomized, double-blind, dose-escalation, placebo-controlled 
multicenter phase 2 trial to examine the efficacy and safety of SC OPK-88003 administered 
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at 70 mg QW compared to placebo in subjects with T2DM who have inadequate glycemic 
control with diet and exercise alone or on a stable dose of metformin.  
This trial will be conducted at up to approximately 30 investigational sites in the US.  
Approximately 200 subjects are expected to be screened and 110 subjects will be randomized 
to OPK-88003 and placebo in a 1.75:1 ratio.   
After randomization, the subjects will follow a fixed dose escalation that includes a dose 
escalation over 8 weeks.  The target dose of 70 mg QW will be reached after receiving 20 mg 
for 4 weeks followed by 4 weeks of 40 mg QW.  A safety review of the 70 mg QW dose 
level will be performed by the DSMB, after which the target level may be reduced to 60 mg 
QW.  The study duration for individual subjects will be up to 36 weeks.  Blinding will be 
maintained throughout the study.  
The design for study DPO-203 is illustrated in Figure 1. 
Figure 1 
Study Design for DPO-203 
EOT: end of treatment 
↓ indicates dosing 
Study procedure timing is outlined in the Schedule of Events (Appendix 1).  Eligibility of 
subjects will be based on the results of a screening medical history, physical examination, 
vital signs and clinical laboratory tests.  At visit 2, eligible subjects will be randomized (V2), 
receive training on study drug preparation and injection technique and conduct of routine 
SMBG, and receive their first dose of study drug.  Subjects will return for 11 study visits, 
 
during the 30-week treatment period.  A final safety follow-up visit 
occurs four weeks after the treatment period (V14).  Subjects who develop ADA will be 
asked to return to the clinic approximately four months after the last dose for an additional 
blood draw.  
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Throughout the entire study, subjects treated with metformin will remain on the same dose 
they were receiving at visit 1, unless a temporary increase in dose is needed to treat 
hyperglycemia (see section 6.11). 
3.2 
Rationale for Study Design and Control Group 
This phase 2 trial is designed to establish the effect of a dose-escalation regimen on safety, 
tolerability and efficacy of 70 mg QW OPK-88003 in subjects with T2DM, relative to  
placebo.  The study duration, target population and efficacy endpoints are typical of phase 2 
trials and are consistent with FDA guidance1.  A four-week follow-up after the treatment 
period will ensure an adequate time to assess reversibility of any clinical or laboratory 
abnormalities.  Subjects who develop ADA will have one additional follow-up assessment 
approximately four months post last dose.   
This clinical study will enroll subjects with inadequate glycemic control based on HbA1c 
values ranging from 7.0% to 10.5%, inclusive.  Similar ranges of screening HbA1c have been 
used in numerous studies of T2DM treatments. 
Subjects treated with diet and exercise alone or in combination with stable metformin 
monotherapy (≥1000 mg/day), will be enrolled.  Subjects on a second oral anti-
hyperglycemic medication (OAM) may be also be eligible if the second OAM was 
discontinued 3 months or more prior to visit 1.  Stable metformin treatment for at least 3 
months is required to minimize baseline glucose drift prior to study entry. 
3.3 
Study Duration and Dates 
The study duration for individual subjects will be up to 36 weeks and will consist of four 
phases: screening (up to 2 weeks prior to first dose), dose escalation (8 weeks), target 
dose/maintenance (22 weeks) and follow-up (4 weeks).   
The trial is expected to commence recruitment during Q1 2018.  Recruitment for this trial is 
expected to take approximately 5 months.  
4 STUDY POPULATION  
Overweight and obese T2DM subjects treated with diet and exercise alone or on a stable dose 
of metformin. 
                                                 
1   Guidance for Industry:  Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and 
Prevention.  Draft guidance February 2008 
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4.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if they meet all of the following criteria 
at the indicated visit: 
1. Have T2DM for at least 6 months before entering the trial based on the disease diagnostic 
criteria (AmDA 2018), controlled with diet and exercise alone or with a stable dose of 
metformin (≥1000 mg/day) for at least 3 months prior to visit 1. 
2. Males or females 18 to 80 years of age inclusive. 
3. Females must be not of childbearing potential due to surgical sterilization (hysterectomy 
or bilateral oophorectomy or tubal ligation) or menopause.  Women with an intact uterus 
are deemed postmenopausal if they are ≥45 years old, and 
 have not taken hormones or oral contraceptives within the last year and had cessation 
of menses for at least 1 year 
OR 
 have had at least 6 months of amenorrhea with follicle-stimulating hormone (FSH) 
levels consistent with a postmenopausal state (FSH ≥40 mIU/mL). 
4. Have an HbA1c value at screening of ≥7.0% and ≤10.5%.   
5. Have a Body Mass Index (BMI) ≥27 and ≤45 kg/m2 at screening. 
6. In the investigator’s opinion, are capable and willing to: 
 administer weekly study medication injection (with assistance if necessary)  
 complete study diaries 
 follow lifestyle counseling advice  
 perform SMBG  
7. Are willing to be available for the duration of the trial, comply with the required study 
procedures and visits, and abide by the clinical research site policy. 
8. Have given written informed consent. 
4.2 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following criteria at visit 1, unless 
otherwise specified: 
1. Participation in any other interventional trial within 30 days.  


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2. Have Type 1 diabetes mellitus. 
3. Previous exposure or known allergies to OPK-88003 or its components. 
4. Previous treatment with incretin mimetic drugs (GLP-1 agonists), excluding DPP-IV 
inhibitors.  
5. Have used insulin for diabetic control for more than 6 consecutive days within the prior 
year. 
6. Use of thiazolidinedione, or any other drugs, including investigational drugs, for 
treatment of hyperglycemia (except metformin), within the prior 3 months. 
7. Use of systemic (including nasal and inhaled) glucocorticoids within the prior month, or 
subjects likely to require systemic doses of glucocorticoids during study participation are 
also excluded.  Topical applications are permitted. 
8. Evidence of hepatitis B and/or positive hepatitis B surface antigen.  Evidence of hepatitis 
C. 
9. Evidence of human immunodeficiency virus (HIV) and/or positive HIV antibodies. 
10. Have cardiac disease with functional status that is NYHA Class III, or IV or in the last 6 
months have had any of the following: myocardial infarction (MI), unstable angina, acute 
coronary syndrome, coronary artery bypass graft (CABG), percutaneous coronary 
intervention (PCI; diagnostic angiograms are permitted), transient ischemic attack (TIA), 
cerebrovascular accident (for example, stroke) or decompensated congestive heart failure. 
11. Have hypertension (mean systolic blood pressure >160 mm Hg or mean diastolic blood 
pressure >100 mm Hg), malignant hypertension, renal artery stenosis, and/or evidence of 
labile blood pressure including symptomatic postural hypotension at visit 1.  If on 
treatment for hypertension, doses of antihypertensive medications must be stable for the 
prior 30 days. 
12. Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or an 
alanine transaminase (ALT) or aspartate aminotransferase (AST) levels >2.5 x upper 
limit of normal (ULN) or serum total bilirubin >2.0 mg/dL. 
13. Evidence of hypothyroidism or hyperthyroidism based on clinical evaluation and/or an 
abnormal thyroid-stimulating hormone (TSH).  Subjects on a stable dose of thyroid 
replacement therapy for at least the prior two months may be eligible if they meet the 
other criteria.  
14. Evidence of obesity induced by other endocrinologic disorders (eg. Cushing Syndrome). 
15. Clinically significant peripheral vascular disease in the opinion of the investigator. 


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16. Active proliferative diabetic retinopathy. 
17. Known significant autonomic neuropathy as evidenced by urinary retention, resting 
tachycardia, orthostatic hypotension or diabetic diarrhea. 
18. Have an active or untreated malignancy or have been in remission from a clinically 
significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas 
of the cervix or in situ prostate cancer) for less than five years.  Have a personal or family 
history of thyroid medullary C-cell hyperplasia, focal hyperplasia, carcinoma (including 
sporadic, familial or part of Multiple Endocrine Neoplasia syndrome type 2A or 2B), or a 
serum calcitonin ≥20 pg/mL. 
19. Impaired renal function (eGFR <60 mL/min/1.73 m2). 
20. Triglycerides >600 mg/dL (6.84 mmol/L) at screening.  If subject is on lipid lowering 
therapies doses must be stable for 30 days prior to screening.   
21. Any subject having experienced a keto-acidotic episode requiring hospitalization in the 
prior 6 months. 
22. Have an ECG considered by the investigator indicative of active cardiac disease or with 
abnormalities that may interfere with the interpretation of changes in ECG intervals.  A 
QTcB interval greater than 450 msec in men and greater than 470 msec in women at visit 
1 or visit 2 is specifically excluded. 
23. Personal or family history of long QT syndrome, family history of sudden death in a first-
degree relative (parents, sibling, or children) before age 40 or personal history of 
unexplained syncope within the last year.  Use of prescription or over-the-counter 
medications known to prolong the QT or QTc interval. 
24. History or presence of CV, respiratory, hepatic, renal, GI, endocrine (other than diabetes), 
hematological, or neurological disorders capable of significantly altering the absorption, 
or metabolism or elimination of drugs or of constituting a risk when taking the study 
medication or interfering with the interpretation of data. 
25. Diagnosis of gastroparesis or bariatric surgery prior to screening, or planned bariatric 
surgery for the trial duration period. 
26. Have had more than one episode of severe hypoglycemia within 6 months prior to visit 1, 
as defined by hypoglycemia associated with severe cognitive impairment requiring 
external assistance for recovery, or has a history of hypoglycemia unawareness or poor 
recognition of hypoglycemic symptoms.  Any subject that the investigator feels will not 
be able to communicate an understanding of hypoglycemic symptoms and the appropriate 
treatment of hypoglycemia should also be excluded. 


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27. Have had two or more emergency room visits or hospitalizations due to poor glucose 
control within the prior 6 months. 
28. Have taken prescription or over-the-counter medications to promote weight loss within 
the prior 3 months. 
29. Have had a significant change in weight, defined as a gain or loss of more than 5% in the 
prior 3 months. 
30. Are currently taking CNS stimulants (eg, Ritalin-SR®) with the exception of caffeinated 
beverages. 
31. Have had a blood transfusion or severe blood loss within the prior 3 months or have 
known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or have a hemoglobin 
value <11 g/dL (males) or <10 g/dL (females), or any other condition known to interfere 
with HbA1c methodology. 
32. Blood donation of 450 mL or more in the prior 3 months or any blood donation within 
the prior month. 
33. Have a history of alcohol or drug dependence or abuse within the last 2 years and/or have 
an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per 
week (females) [1 unit = 12 oz. or 360 mL of beer; 5 oz. or 150 mL of wine; 1.5 oz. or 45 
mL of distilled spirits]. 
34. Have a history of atopy (severe or multiple allergic manifestations) or clinically 
significant multiple or severe drug allergies, or intolerance to topical corticosteroids, or 
severe post-treatment hypersensitivity reactions (including, but not limited to, erythema 
multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, anaphylaxis, 
angioedema, or exfoliative dermatitis). 
35. Have a history of acute or chronic pancreatitis or confirmed elevation in serum 
lipase/amylase (>2 x ULN). 
36. Have any other condition or psychiatric disorder that, in the opinion of the investigator, 
may preclude the subject from following and completing the protocol related procedures. 
37. Are unsuitable for inclusion in the study in the opinion of the investigator or sponsor. 
38. Are unable to undergo MRI for any reason
 
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5 DISCONTINUATIONS 
5.1 
Discontinuation of Study Drug 
5.1.1 
Temporary Discontinuation of Study Drug 
After randomization, the investigator may decide to temporarily discontinue study drug, for 
example, due to an AE or a clinically significant laboratory value.  Every effort should be 
made by the investigator to maintain subjects in the study and to restart study drug promptly 
as soon as it is safe to do so.  The dates of study drug discontinuation and re-start will be 
documented.  If a subject misses more than four doses of study drug throughout the course of 
the study or two consecutive doses during the dose escalation phase, they should be 
discontinued from the study (see section 5.2).  
Subject noncompliance with study drug regimen should not be recorded as temporary 
discontinuation of study drug (see section 7.11). 
5.1.2 
Permanent Discontinuation of Study Drug 
Permanent discontinuation of the study drug during the dose escalation and maintenance 
phase should be considered by the investigator, after consultation with the sponsor 
designated medical monitor, when the subject meets the following conditions: 
 Abnormal liver tests: 
o Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 x ULN 
o ALT or AST >5 x ULN for more than 2 weeks 
o ALT or AST >3 x ULN and (total bilirubin level >2 x ULN or INR >1.5) 
o ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5% compared to 
baseline) 
 AEs: 
o Confirmed pancreatitis or pancreatic cancer (see section 8.3.5)  
o Estimated glomerular filtration (eGFR) <30 mL/min/1.73 m2 
o Any severe injection site reaction or two or more moderate injection site reactions 
occurring a week or more apart (see section 8.3.1) 
o Any study drug related systemic hypersensitivity reaction (see section 8.3.2) 
o Any nonfatal major CV events (see section 8.3.6) 


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o Any SAE or clinically significant event (CSE) judged to be related to study drug  A 
CSE is defined as a moderate to severe AE, abnormal clinical sign, or clinical 
laboratory finding that may pose a risk to the wellbeing of the subject.  A CSE will be 
determined by the investigator, and may include findings that do not fulfil the criteria 
for SAEs (Appendix 2).   
o Any other TEAE, SAE or clinical significant laboratory value for which the 
investigator believes that permanent study drug discontinuation is the appropriate 
measure to be taken. 
 Serum calcitonin with an absolute value of ≥50 pg/mL on repeat testing 
 The subject intentionally or repeatedly takes more than the prescribed dose of study 
medication. 
Subjects who are permanently discontinued from study drug will be discontinued from the 
study (see section 5.2).   
5.2 
Discontinuation of Subjects 
If the investigator site identifies a subject who did not meet eligibility criteria but was 
inadvertently randomized, the sponsor-designated medical monitor must be contacted.   
If the sponsor or designee identifies a subject who did not meet enrollment criteria and who 
was inadvertently randomized, the investigator site will be notified.  A discussion must occur 
between the sponsor-designated medical monitor and the investigator to determine whether 
the subject may continue in the study.  Inadvertently randomized subjects may be maintained 
in the study when the sponsor agrees with the investigator that it is medically appropriate for 
that subject.  The investigator must obtain documented approval from the sponsor to allow 
the inadvertently enrolled subject to continue in the study. 
A subject will be discontinued from the study in the following circumstances: 
 The subject requests to be withdrawn from the study. 
 The subject is permanently discontinued from study drug (see section 5.1.2).   
 The subject misses more than four doses of study drug over the course of the study, or 
misses two consecutive doses of study drug during the dose escalation phase.   
 Enrollment in any other interventional clinical trial.   
 The sponsor stops the study or stops the subject’s participation in the trial for medical, 
safety, regulatory or other reasons consistent with applicable laws, regulations and good 
clinical practice (GCP).   


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 The investigator decides it is in the best interests of the subject not to continue in the 
study.   
 The subject and/or blinded study staff become unblinded to the subject’s treatment 
assignment.   
 Any medication for weight loss is given for more than one week.   
 If the subject, for any reason requires treatment for greater than one week with another 
therapeutic agent that has been approved for treatment of diabetes.  A change in dose of 
metformin is not allowed, unless a temporary increase in dose is needed to treat 
hyperglycemia (see section 6.11).  However, a change to an equivalent dose strength of 
metformin from immediate-release to extended-release (or vice versa) formulations is 
allowed.   
Subjects discontinued from the study will be requested to complete an early termination (ET) 
visit as soon as possible (section 9.5).  Subjects will be requested to complete a follow-up  
visit (see section 9.5) four weeks after their final dose.   
5.3 
Discontinuation of Study Sites 
Study site participation may be discontinued if the sponsor or its designee, the investigator, 
or the institutional review board (IRB) of the study site judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP.   
5.4 
Discontinuation of the Study 
The study will be discontinued if the sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP.   
6 STUDY TREATMENT(S) 
6.1 
Randomization 
Subjects who meet all eligibility criteria will be randomized to treatment at visit 2 (day 1). 
via the Interactive Response Technology system (IRT).  Randomization will be stratified 
using the following variables: screening HbA1c (<8.5%, ≥8.5%) and baseline BMI (<30, ≥30 
kg/m2).  The randomization to the treatment arms will be 1.75:1 for the active and placebo 
groups, respectively.  Following randomization, study drug will be dispensed in a double-
blinded manner. 
6.2 
Description of Treatment(s) 
OPK-88003 and matching placebo are provided in single-use 2 mL glass vials with blue flip-
off lid, an aluminum seal and a rubber stopper (septum). 




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maintained at each site.  If temperature excursions occur during shipping or storage at site, 
study drug should not be dispensed, and the investigator or designee should contact the 
sponsor’s designee as soon as possible for further instruction. 
Once study drug is dispensed the subject will be instructed to transport the vials in the 
provided cool container and store refrigerated at home.  Subjects will be instructed to return 
all used and unused vials in cool bags to the study site for study drug accountability.  
The investigator or their designee(s) will maintain study drug accountability records 
throughout the course of the study from receipt of study drug until final reconciliation and 
return to the sponsor.  Specifically, the investigator or their designee will confirm that all 
study drugs and supplies are received intact and in the correct amounts per the shipping 
forms.  A study drug accountability and dispensing log will be maintained on site to record 
the study drug dispensed to subjects, including dates, quantity received and returned vial 
numbers.  The investigator should ensure that the study drug is used only in accordance with 
the protocol. 
The sponsor’s designee will routinely verify the inventory of study drug supplies throughout 
the course of the study.  All used and unused cartons/vials of study drug are to be retained at 
the site until the sponsor’s designee has performed a complete verification. 
Any discrepancies identified will be indicated with a specific explanation of each 
discrepancy.  The investigator (or designee) must return all used and unused study drug in 
accordance with the sponsor’s instructions, and a copy of the clinical supplies return 
documentation will be returned to the sponsor or designee.  Drug accountability records, 
clinical drug supply receipts, and returns must be maintained by the investigator. 
6.5 
Treatments Administered 
This trial will evaluate 20 mg and 40 mg dose escalation and 70 mg target dose of OPK-
88003 QW over a 30-week treatment period.  Treatment allocation will be assigned by the 
IRT.  The group randomized to OPK-88003 will initially receive 20 mg QW for four weeks, 
followed by 40 mg QW for four weeks.  Once eight weeks of dose escalation are complete, 
subjects will receive a target dose of 70 mg QW OPK-88003 for 22 weeks.  The control 
group will receive matched placebo SC injections QW for 30 weeks.   
Site staff will train the subject on correct storage, preparation and administration of study 
drug, aiming for subject self-administration.  The subject will administer the study drug at the 
study site visits as per schedule of events under supervision of an unblinded site personnel 
(eg, research nurse) to ensure injection technique is satisfactory.  The subject will administer 
doses QW at home, with assistance if necessary.  
Prior to injection, if the vial is frozen it should be allowed to thaw/equilibrate for a minimum 
of 1 hour and a maximum of 4 hours at room temperature.  If the vial is refrigerated it should 
be allowed to equilibrate for a minimum of 30 minutes and a maximum of 4 hours at room 
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Detailed study drug handling and dosing instructions will be provided to support subject 
dosing.  
All injections will be administered SC into the abdominal wall (or other sites if approved by 
the investigator).  Instructions for rotation of injection sites and assessment of potential 
injection site reactions will also be provided.   
The investigator or their designees are responsible for the following:  
 explaining the correct use of the study drug to the subject 
 verifying that instructions are followed properly 
 maintaining accurate records of study drug dispensing and collection, and the return of all 
used and unused medication to the sponsor or designee at the end of the study 
Subjects will be instructed to contact the investigator as soon as possible if they have any 
questions or issues concerning the injection of study drug or if they have any other study-
related concerns so the issue/question can be assessed in a timely manner to ensure subject’s 
safety. 
All subjects should be observed for allergic reaction following study drug administration for 
at least 15 minutes at visits 2, 3, 4 and 5.   
6.6 
Materials and Supplies 
6.6.1 
Study Drug Supplies 
Study drug cartons containing OPK-88003 or placebo for SC injection will be supplied to 
study sites.  Ancillary supplies including needles and syringes will be provided separately.  
Study drug vials must always be stored in a secure location with access limited to designated 
study staff members.   
6.6.2 
Laboratory Supplies 
The sponsor or assigned designee will supply vacutainers, blood collection tubes, labels, 
boxes with labels for storage of serum and plasma samples and all necessary shipping 
supplies/containers, as specified in the laboratory manual.  The investigator will supply 
centrifuge equipment.  The investigator will ensure that all biohazard wastes are disposed of 
in accordance with investigator, site standard operating procedures (SOPs) and local 
regulations. 
6.7 
Selection and Timing of Dose for Each Subject 
There are no restrictions on the time of day each dose is administered, but it is advisable to 
administer the SC injections on the same day and time of the week.  If a subject misses a 
dose on the scheduled day, then they should administer the dose as soon as possible and then 


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resume their regular schedule.  Study drug should not be administered within four days of the 
previous injection.   
6.8 
Blinding 
OPK-88003 and placebo injections are identical in appearance in order to maintain a double-
blind status.  An unblinded site staff member will be available to support subject dosing as 
needed.  Study drug will be managed using IRT.  Each user will have a unique username and 
passcode to access the system.  In case of an emergency, when knowledge of the treatment 
assignment for the subject is essential for the clinical management or welfare of the subject, 
the investigator may unblind the subject’s treatment assignment.  Prior to unblinding, the 
investigator should make every effort to contact the sponsor or designee before proceeding 
with the unblinding process, if possible.  If a subject’s treatment assignment is unblinded 
without sponsor or designee’s prior knowledge, the sponsor must be notified immediately.   
Each site will be provided with a sealed envelope containing a six-digit code that can be 
entered into the IRT to unblind a subject’s treatment assignment.  In order to preserve the 
double-blind of the study, a minimal number of sponsor personnel will have access to the 
randomization scheme and treatment assignments before the study is complete.   
6.9 
Concomitant Therapy 
Treatment with medications that are excluded in the entry criteria is not permitted.   
The only concomitant anti-hyperglycemic medication permitted during this trial is 
metformin.  Subjects treated with metformin upon entering this trial should remain on the 
same dose throughout the course of the trial, unless hyperglycemic criteria are met (see 
section 6.11).  If a subject switches from the immediate-release formulation of metformin to 
the sustained-release formulation, the change will be on a milligram per milligram basis.   
Doses of anti-hypertensive and lipid-lowering agents should remain stable during the study 
unless necessary to protect subject safety.   
Doses of other prescription medications (eg, thyroxine, estrogen or progesterone 
replacement, selective estrogen receptor modulators) for treatment of concurrent medical 
conditions should remain stable during the study whenever possible.   
Anti-emetic drugs that do not increase QTc (eg, cyclizine, meclizine) may be used to treat 
nausea and vomiting, but they should not be used prophylactically.   
Non-steroidal anti-inflammatory medications (including aspirin and acetaminophen), cough 
suppressants, antihistamines, vitamin/mineral supplements, antibiotics and topical ointments 
may be used and are not restricted by the stable dosing requirements listed above. 
If the need for additional concomitant medication arises, inclusion or continuation of the 
subject may be at the discretion of the investigator after consultation with the sponsor or their 


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designated medical monitor.  Any additional medication used during the course of the study 
must be documented.   
6.10 Restrictions 
Meals – Subjects shall fast for at least 8 hours overnight prior to each visit where fasting labs 
are drawn or 
 measurements are taken. 
Alcohol – Alcohol will not be permitted at least 8 hours prior to the study visit.  
Blood donation – Study subjects should be instructed not to donate blood or blood products 
during the study and for 8 weeks following study completion. 
Contraception – Male subjects or their female partners of child-bearing potential must use 
reliable contraception during intercourse throughout the treatment period and for three 
months after the last dose of study drug (as the risk of OPK-88003 to the unborn fetus is 
unknown).  Females must not be of childbearing potential due to surgical sterilization 
(hysterectomy, bilateral oophorectomy or tubal ligation) or menopause. 
Acceptable contraception includes male sterilization (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate), oral, injected or implanted hormonal 
methods of contraception, intrauterine device or implant, and barrier methods of 
contraception (condom or occlusive cap, diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository.  The use of barrier contraceptives should always be 
supplemented with the use of a spermicide. 
6.11 Evaluation and Treatment of Hyperglycemia 
Routine fasting (at least 8 hours) SMBGs and central laboratory FPG values will be used to 
determine the requirement for additional medication.  If any fasting SMBG value exceeds the 
specified limit (Table 1), the subject will be instructed to contact the investigational site and 
asked to perform fasting SMBG on three consecutive days (see section 7.5).   
If fasting SMBG values exceed the specified limit for three consecutive days, an unscheduled 
visit should be performed to assess FPG by the central laboratory.   
Table 1 
Threshold Glucose Levels  
Study Period 
Threshold value 
Baseline to week 8 
>270 mg/dL (15 mmol/L) 
Week 8 to week 12 
>240 mg/dL (13.3 mmol/L) 
Week 12 to week 30 
>200 mg/dL (11.1 mmol/L) 
Values must be recorded on three consecutive days 
If the SMBG values are confirmed by central laboratory FPG measurement, then an 
additional therapeutic intervention should be considered at the discretion of the investigator 
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for subjects who are fully compliant with the assigned therapeutic regimen, in the absence of 
any acute condition that raises blood glucose.  Any subject who requires additional glucose-
lowering therapy for more than one week should be discontinued (see section 5.2). 
7 STUDY PROCEDURES 
7.1 
Medical History and Physical Examination 
Physical examination will be performed by qualified personnel.  A detailed medical history 
will be obtained at screening (V1). 
7.2 
Height and Weight, 
 
Height is measured once, at screening.   
Body weight 
 will be measured on fasting (minimum 8 
hours) subjects.  Duplicate measurements of weight will be performed using digital scales 
and following emptying of any bowel/bladder contents.  Subjects will change into a light 
hospital gown for weight measurements 
.  Scales will be 
calibrated at least monthly using standard weights, and records of calibration will be kept in 
the study binder.  
 
  Detailed instructions 
will be provided in a study manual. 
7.3 
Electrocardiography (ECG) 
ECG and vital sign measurements will precede blood draws and study drug administration 
when scheduled at the same time.   
ECGs will be obtained in a quiet environment after remaining in supine rest for at least 5 
minutes.  Subjects will remain supine but awake during ECG collection.  Triplicate ECGs 
(when required) will be obtained within a 5-minute window and at approximately 1-2 minute 
intervals.  Collection of more ECGs (more replicates) than expected at a particular timepoint 
is allowed when needed to ensure high quality records.  
ECGs may be obtained at additional times when deemed clinically necessary.   
ECGs will be digitally recorded and printed on paper.  The printed paper ECG will be used 
for “real time” ECG assessment by the investigator (or designee) who will be responsible for 
the overall interpretation, determination of the clinical significance and subject eligibility 
based on the ECG findings.  ECG interpretation categories are: Normal ECG, Abnormal 
ECG – not clinically significant, Abnormal ECG – clinically significant.   
The printed ECGs will be retained in the subject’s records at the site.  All digital ECG 
records will also be submitted to the cardiovascular core lab, that will perform the digital 
ECG analysis and interpretation in this study using standard methodology.  If the central 
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reviewer identifies an abnormality, per the study alert criteria, the investigator will be 
notified to review the ECG and report any AEs as necessary.   
The following variables will be reported: HR, RR, PR, QRS, QT, QTcB, and QTcF intervals.   
Any treatment emergent clinically significant ECG finding should be reported as an AE in 
the eCRF.   
7.4 
Vital Signs (Blood Pressure and Pulse Rate) 
Vital signs will include only supine blood pressure and pulse rate (after a minimum of 5 
minutes rest), and will be assessed following 12-lead ECG (if scheduled) and prior to any 
blood draws or study drug administration.  The values for blood pressure and pulse rat at 
each time point will be the average of at least three measurements. 
7.5 
Fasting Self-Monitored Blood Glucose (SMBG) Levels 
Subjects will be provided and trained on use of a glucometer, necessary glucose testing 
supplies and study diaries at baseline visit (V2), and will be instructed on how to recognize 
symptoms of hypo- and hyperglycemia.  Subjects will be asked to demonstrate competent use 
of the glucometer at or before their first dosing visit.  Results from SMBG will be recorded in 
the subject diary (section 7.7.2). 
All subjects will be instructed to perform fasting SMBG at least three times a week using a 
portable glucometer.  Subjects will record SMBG readings in their diaries.  It will be the 
investigator’s responsibility to remind subjects during study visits to perform their routine 
fasting SMBGs.   
Subjects will be requested to perform additional SMBG measurements at any time that they 
develop symptoms suggestive of hypoglycemia.  If subjects experience hypoglycemic 
symptoms or glucose value ≤70 mg/dL (≤3.9 mmol/L) they should record the SMBG value  
and symptoms in their diary and take SMBG measurements every 15 minutes until either the 
symptoms subside or the blood glucose value reaches >70 mg/dL(>3.9 mmol/L).   
Subjects who have an out of range SMBG reading (hyperglycemia, see Table 1) will perform 
fasting SMBG prior to breakfast on three consecutive days and report the values to the 
investigator via email or phone if possible on the day each measurement was taken.  The 
investigator will review the results in a timely manner and if possible on the same day as the 
results were received from the subject.   
Subjects who develop/have persistent uncontrolled hyperglycemia or hypoglycemia should 
contact the clinic.  Subjects will be requested to visit the clinic for further testing and 
appropriate medical management at the investigator’s discretion.   


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7.6 
Lifestyle Counseling 
At visit 2, subjects will have a lifestyle counseling session (either in a group or individually) 
with a qualified diabetic educator in accordance with local standards.  Subject lifestyle 
counseling sessions will focus on diet, physical activity and behavioral strategies to achieve a 
500-700 kcal/day energy deficit (AmDA 2018 4, AmDA 2018 7).  The sessions will occur 
approximately every four weeks during the dosing period.  
The goals of the counseling session are: 
 To promote and support healthful eating patterns, emphasizing a variety of nutrient-dense 
foods in appropriate portion sizes, to improve overall health  
 To address individual nutritional needs based on personal and cultural preferences, health 
literacy and numeracy, access to healthful foods, willingness and ability to make 
behavioral changes, and barriers to change 
 To maintain the pleasure of eating by providing non-judgmental messages about food 
choices 
 To provide an individual with diabetes the practical tools for developing healthy eating 
patterns rather than focusing on individual macronutrients, micronutrients, or single 
foods.  
Subjects will be encouraged to increase their physical activity.  Activities should progress in 
intensity, frequency and/or duration to at least 150 minutes per week of moderate-intensity 
exercise.  The subject’s average daily level of physical activity will be reviewed as part of the 
lifestyle counseling. 
7.7 
Diary Completion 
Subjects will complete two separate diaries during study participation.  The diaries will be 
dispensed at visit 2 following randomization, and instructions on diary completion will be 
provided. 
7.7.1 
Lifestyle Diary 
Subjects should complete a 3-day food intake diary prior to visits 4, 5, 9, 10, 11, 12 and 13, 
when lifestyle counseling will be provided (see section 7.6).  Subjects will also document 
how much physical activity was performed. 
The days recorded in the diary should be in the week prior to the counseling visit and ideally 
include one weekend day.  Information in the lifestyle diaries will be reviewed during the 
counseling as specified in the schedule of events, and not entered into the EDC. 


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7.7.2 
Subject Diary 
Subjects should document date and volume of injection of study drug, results of SMBG, and 
hypoglycemia and ISRs experienced during the study period.  
7.8 
Clinical Laboratory Tests 
7.8.1 
Laboratory Parameters 
Clinical laboratory tests to be assessed are indicated in Table 2. 


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Table 2 
List of Laboratory Tests 
Hematology: 
- 
Hematocrit (Hct) 
- 
Hemoglobin (Hgb) 
- 
Mean corpuscular hemoglobin 
concentration (MCHC) 
- 
Mean corpuscular volume (MCV) 
- 
Platelet count 
- 
Red blood cell (RBC) count  
- 
White blood cell (WBC) count with 
differential  
 
Urinalysis:  
- 
Glucose 
- 
Urine leukocyte esterase 
- 
Occult blood 
- 
pH 
- 
Protein 
 
Serology: 
- 
Hepatitis B surface antigen 
- 
Hepatitis C antibody 
 
Serum calcitonin 
Hemoglobin A1c (HbA1c) 
Triglycerides  
Glucose (fasting) 
Serum pregnancy test (females)  
Serum FSH (females) 
Serum Chemistry: 
- 
Albumin 
- 
Alkaline phosphatase (ALP) 
- 
Alanine aminotransferase (ALT) 
- 
Aspartate aminotransferase (AST) 
- 
Blood urea nitrogen (BUN) 
- 
Calcium 
- 
Creatinine for eGFR 
- 
Creatine kinase (CK) 
- 
Potassium  
- 
Sodium  
- 
Total bilirubin 
- 
Direct bilirubin 
- 
Total protein 
- 
Uric acid 
- 
Lipase  
- 
Amylase 
 
CDC Lipid Panel (fasting): 
- 
CDC total cholesterol 
- 
CDC triglycerides 
- 
CDC HDL-C 
- 
CDC LDL-C (calculated)  
 
Immunogenicity 
- 
anti-drug antibody (ADA) 
- 
Neutralization assay 
7.8.2 
Immunogenicity 
Blood samples for immunogenicity testing will be collected to determine ADA production.  
Immunogenicity will be assessed by a validated assay designed to detect ADA in the study 
drug provided by a specialized laboratory other than the central laboratory.  Antibodies may 
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be further characterized and/or evaluated for their specificity and ability to neutralize the 
activity of the OPK-88003 at the discretion of the sponsor.   
7.8.4 
Sample Collection, Storage, and Shipping 
Collection, processing, storage and shipping procedures will be performed in accordance 
with the instructions provided by the central laboratory.  Detailed instructions will be 
provided in the laboratory manual.  Blood samples will be collected and analyzed for clinical 
laboratory
 parameters.   
Additional blood draws may be needed for unscheduled visits.  Missed samples should be 
drawn whenever possible.  The investigator will provide a temperature monitored space with 
limited access for the study drug and a -20°C or -70°C freezer space for serum and plasma 
aliquot storage.   
Laboratory samples, including antibody and bioanalytical samples, may be stored according 
to applicable laws, regulatory requirements or laboratory certification standards.   
7.10 Dispensing Study Drug 
Study drug will be dispensed to the subject in a 4-vial carton as per schedule of events.   
The investigator will be responsible for the maintenance of records of receipt and disposition 
of study drug including dates, quantities administered and availability, and subject 
assignment. 
7.11 Treatment Compliance 
Treatment compliance will be verified by investigative sites.  Subjects will be asked to return 
all their used and unused cartons with vials to the investigative site for accountability as per 
schedule of events.  
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Subjects that miss more than four doses of study drug over the course of the study, or miss 
two consecutive doses of study drug during the dose escalation phase are considered non-
compliant.  A subject will also be considered non-compliant if he or she is judged by the 
investigator to have intentionally or repeatedly taken more than the prescribed amount of 
study drug.  Subjects that are noncompliant will be discontinued from the study (see section 
5.2). 
7.12 Concomitant Medication Assessments 
Medications ongoing at the time of visit 1 as well as any new medication added during the 
course of the study will be recorded in the source document and eCRF as concomitant 
medications.   
8 SAFETY EVALUATIONS 
Investigators are responsible for monitoring the safety of subjects who have entered this trial 
and for alerting the sponsor or its designee of any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the subject. 
The investigator remains responsible for following through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the trial or that caused the 
subject to discontinue before completing the trial.  The subject should be followed until the 
event is resolved or deemed to be chronic.  Frequency of follow-up evaluation is at the 
discretion of the investigator. 
In addition to records of observations made at specific times, unexpected signs and 
symptoms and concomitant medications will be recorded in the clinical trial records 
throughout the study. 
8.1 
DSMB 
A sponsor-appointed medical monitor will oversee subject safety in this study.  An 
independent data and safety monitoring board (DSMB) consisting of one statistician and 
three clinicians with appropriate expertise will monitor the study at regular intervals, and 
may make recommendations for changes to the conduct of the trial to reflect safety concerns.  
Specific responsibilities and activities of the DSMB will be defined in the charter to be 
ratified at the organizational meeting of the DSMB.  The DSMB will also perform an 
assessment of the tolerability of the 70 mg dose level (see section 8.10.2).   
8.2 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. 


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All subjects will be monitored, evaluated and queried for AEs at each visit.  Subjects may be 
asked to self-report AEs verbally during visits and they will be encouraged to self-report AEs 
in their diaries between visits.  All AEs, including SAEs occurring after the subject signs the 
ICF through the subject’s final visit will be reported and monitored.  AEs that occur 
following first administration of study drug are TEAEs.  Any clinically significant abnormal 
laboratory results, physical examination findings, ECGs, and vital signs will be reported as 
AEs.  Unless related to protocol procedures as deemed by the investigator, clinically 
significant findings reported prior to administration of first dose of study drug are 
exclusionary.  All AEs will be reported to the sponsor via eCRF.   
All AE/SAEs will be followed through to resolution or until the investigator assesses the 
AE/SAEs as resolved, chronic or irreversible.  The investigator is not obliged to follow-up 
with subjects for AEs or SAEs that begin after study completion, however if an SAE is 
reported to the investigator after a subject has completed the study, and it is ‘possibly related’ 
to the study drug, then the investigator will report it to the sponsor. 
8.2.1 
Severity 
The intensity of the AE will be rated by the investigator as mild, moderate or severe using the 
following criteria: 
 Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
 Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
 Severe: Symptoms causing inability to perform usual social and functional activities 
It should be noted that the clinical severity and seriousness of an AE are not synonymous, eg, 
a severe headache is not classified as serious until it meets the required elements as an SAE. 
The maximum severity attained for each AE reported will be recorded in the eCRFs. 
8.2.2 
Relationship 
The investigator decides whether he or she interpret the observed AEs as either related to 
disease, to the study medication, study procedure or other concomitant treatment or 
pathologies.  To assess the relationship of the AE to the study drug, the following 
terminologies are defined:  
 Related: the temporal sequence of the event relative to administration of the study drug is 
reasonable, it cannot be explained by the disease or other drugs, dechallenge (if 
performed) is positive and pharmacologically/pathologically plausible, rechallenge (if 
performed) is positive, or the event shows a pattern consistent with previous knowledge 
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 Possibly related: the temporal sequence of the event relative to administration of the 
study drug is reasonable, and is unlikely to be attributed to disease or other drugs, 
dechallenge (if performed) is positive 
 Unlikely related: the temporal sequence of the event relative to administration of the 
study drug is reasonable, the event could also be explained by disease or other drugs, 
dechallenge (if performed) is positive or uncertain, rechallenge (if performed) is negative  
 Not related: the temporal sequence of the event relative to administration of study drug 
is not reasonable, disease or other drugs provide plausible explanations, dechallenge (if 
performed) is negative or ambiguous 
All “related”, and “possibly related” AEs and SAEs will be defined as related to study drug 
in this study. 
8.3 
Adverse Events of Special Interest  
The AEs of special interest (AESIs) of varying clinical significance will be used to determine 
the tolerability of OPK-88003 doses selected for this clinical trial.  All AESIs that meet the 
definition of an SAE (section 8.9) must be reported as an SAE. 
8.3.1 
Injection Site Reactions 
Injection site reactions will be collected.  Assessment of severity, duration and relatedness to 
study drug will be recorded. 
8.3.2 
Hypersensitivity Reactions 
All hypersensitivity reactions will be collected.  Study drug should be temporarily 
discontinued in any individual suspected of having a severe or serious 
allergic/hypersensitivity reaction to study drug.  Study drug may be restarted if, in the 
opinion of the investigator, the event was not related to study drug and when/if it is safe to do 
so.    
8.3.3 
Hypoglycemia 
Fasting SMBG and central laboratory FPG values will be reviewed for hypoglycemic 
episodes as defined in the study manual.  All episodes (documented symptomatic, 
asymptomatic or probable symptomatic hypoglycemia) will be recorded as an AE; those 
falling within AmDA classification Level 3 (see Table 3) will be recorded as an SAE.  For 
each event, assessment of severity, duration and relatedness to study drug will be recorded.   


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Table 3 
Classification of Hypoglycemia 
Hypoglycemia Level 
Glycemic Criteria 
Description 
Level 1 
≤70 mg/dL (3.9 mmol/L) 
Sufficiently low for treatment with fast-acting 
carbohydrate and dose adjustment of glucose-lowering 
therapy 
Level 2 
<54 mg/dL (3.0 mmol/L) 
Sufficiently low to indicate serious, clinically 
important hypoglycemia 
Level 3 
No specific glucose 
threshold 
Hypoglycemia associated with severe cognitive 
impairment requiring external assistance for recovery 
AmDA 4 2018   
Subjects should be asked about symptomatic and asymptomatic hypoglycemia at each visit, 
and trained on treatment of hypoglycemia.   
8.3.4 
Nausea, Vomiting and Diarrhea 
Nausea, vomiting, and diarrhea events will be collected.  For each event, assessment of 
severity, duration and relatedness to study drug will be recorded.   
8.3.5 
Acute Pancreatitis  
Acute pancreatitis (AP) is an acute inflammatory process of the pancreas that may also 
involve peripancreatic tissues and/or remote organ systems.  The diagnosis of AP requires 
two of the following three features: 
 Abdominal pain, characteristic of acute pancreatitis (generally located in the epigastrium 
and radiates to the back in approximately half of the cases; the pain is often associated 
with nausea and vomiting) 
 Serum amylase and/or lipase ≥3 x ULN 
 Characteristic findings of AP on computed tomography (CT) scan or magnetic resonance 
imaging (MRI) 
If a subject experiences severe or serious abdominal pain or if acute/chronic pancreatitis is 
suspected, administration of study drug should be temporarily discontinued.  If AP is 
suspected, appropriate laboratory tests (including levels of amylase and lipase) should be 
obtained.  These laboratory tests may be obtained locally but, if possible, a serum lipase and 
amylase should also be sent to the central laboratory (for capture of data in the clinical trial 
database) at the time of presentation.  If serum amylase and/or lipase values are confirmed ≥3 
x ULN, imaging studies, such as abdominal CT scan with or without contrast, MRI, or 
abdominal ultrasound, to include pancreas and gallbladder, should be performed.  If 
diagnostic testing does not support the diagnosis of acute or chronic pancreatitis then study 
drug may be resumed as soon as it is safe to do so in the judgment of the investigator.  If 
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the subject must permanently discontinue study drug.  A review of the subject’s concomitant 
medications should be conducted to assess any potential causal relationship with pancreatitis. 
8.3.6 
Cardiovascular Events 
Deaths (CV and non-CV), nonfatal myocardial infarctions (MIs), and nonfatal strokes that 
occur during the treatment phase or follow-up phase will be reviewed by the sponsor-
designated medical monitor.  Investigative sites will also be asked to report any cases of 
transient ischemic attack (TIA) or hospitalization for unstable angina to the sponsor-
designated medical monitor, to ensure that all true stroke and MI events are captured.  CV 
event definitions will be based on the Standardized Definitions for Cardiovascular and Stroke 
Endpoint Events in Clinical Trials2 and the ESC/ACCF/AHA/WHF Expert Consensus 
Document Third Universal Definition of Myocardial Infarction3.  
8.3.7 
Electrocardiography (ECG) Findings 
Any treatment emergent clinically significant ECG finding should be reported as an AE in 
the eCRF. 
If a clinically significant increase in the QT/corrected QT (QTc) interval from baseline or 
other clinically significant quantitative or qualitative change from baseline is identified, the 
subject will be assessed by the investigator for symptoms (for example, palpitations, near 
syncope, syncope) and to determine whether the subject can continue in the trial.  The 
investigator or qualified designee is responsible for determining if any change in subject 
management is needed and must document his/her review of the ECG printed at the time of 
evaluation from at least one of the replicate ECGs from each time point.  
8.4 
Liver Function Monitoring 
If a study subject experiences elevated ALT or AST >3 x ULN or elevated total bilirubin >2 
x ULN, clinical and laboratory monitoring should be initiated by the investigator (Appendix 
3).  Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities.  To ensure subject safety and comply with regulatory guidance, 
the investigator will consult with the sponsor-designated medical monitor regarding 
collection of specific recommended clinical information and follow-up laboratory tests.   
8.5 
Serum Creatine Kinase Monitoring 
If a study subject experiences CK >5 x ULN that suggests muscle damage, the subject should 
be evaluated for any muscle-associated symptoms as well as any clinical signs of myalgia, 
                                                 
2  Hicks KA, Hung J, Mahaffey KW et al.  Draft Definition for CDISC.  Available at 
https://www.cdisc.org/system/files/all/standard/Draft%20Definitions%20for%20CDISC%20August%2020%2C
%202014.pdf 
3  Thygesen K, Alpert JS, Jaffe AS et al.  Third Universal Definition of Myocardial Infarction.  Circulation 
2012; 126:2020-2035 


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generalized weakness, or darkened urine.  Additional clinical and laboratory monitoring 
should be initiated by the investigator, in consultation with the sponsor-designated medical 
monitor.  Laboratory monitoring should include repeat CK testing as well as assessment of 
coagulation factors (prothrombin time, activated partial thromboplastin time, INR), urine 
myoglobin, cardiac troponin I, and additional testing as clinically indicated.   
8.6 
Serum Calcitonin Monitoring 
Serum calcitonin ≥20 pg/mL at screening is exclusionary (see section 4.2).  The subject will 
be referred to a thyroid specialist for futher evaluation and will be discontinued from 
screening. 
Any treatment-emergent serum calcitonin value ≥20 pg/mL will be reviewed by the DSMB 
along with relevant supplementary data (eg, demographics and medical history, concomitant 
medications, supplemental laboratory tests and relevant AE data).  The DSMB will provide 
recommendations to the investigator for individual subjects, including diagnostic procedures, 
treatment, and continuation of the study drug according to a pre-specified algorithm: 
 Calcitonin >ULN and <20 pg/mL 
The investigator shall evaluate factors potentially leading to calcitonin elevation.  
Calcitonin sampling shall be performed at intervals indicated in the protocol with no 
further action unless levels rise to ≥20 pg/mL.  If the value is the final one in the trial, the 
subject shall be referred to a thyroid specialist for further evaluation. 
 Calcitonin ≥20 pg/mL and ≤50 pg/mL 
Calcitonin sampling shall be performed at intervals indicated in the protocol with no 
further action unless levels rise to ≥50 pg/mL.  No impact on continuation of trial 
treatment.  If the value is the final one in the trial, the subject shall be referred to a 
thyroid specialist for further evaluation. 
 Calcitonin ≥50 pg/mL 
If calcitonin is confirmed to be ≥50 pg/mL, then the DSMB shall recommend the study 
investigator remove the subject from study treatment.  The subject shall be referred to a 
thyroid specialist for further evaluation. 
8.7 
Treatment Discontinuations 
If a subject’s treatment is discontinued as a result of an AE, study site personnel must clearly 
report (via eCRF) the circumstances and data leading to discontinuation of treatment. 


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8.8 
Pregnancies 
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breast-feeding will be collected for regulatory reporting 
and drug safety evaluation.  Pregnancies and female partner pregnancies will be followed 
until 6 weeks following delivery to determine the outcome. 
8.9 
Serious Adverse Events (SAEs) 
The collection of SAEs begins after the subject has signed the ICF.  SAEs occurring after the 
subject has received study drug are treatment-emergent SAEs (TESAEs). 
An SAE is defined by the investigator or sponsor as any AE resulting in any of the following 
outcomes:  
 death 
 life-threatening AE 
 in-patient hospitalization or prolongation of existing hospitalization 
 a persistent or significant disability/a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions   
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Planned surgeries should not be reported as SAEs unless the underlying medical condition 
has worsened during the course of the trial. 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not 
listed in the IB or are not listed at the specificity or severity that has been observed.  
8.9.1 
Reporting Serious Adverse Events 
8.9.1.1 
Initial Report 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to Medpace Clinical Safety within 24 hours of 
the knowledge of the occurrence (this refers to any AE that meets any of the aforementioned 
serious criteria).  All known SAEs that the investigator considers related to study drug 
occurring after the 30-day follow-up period must be reported to the sponsor.   


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To report the SAE, complete the SAE form electronically in the EDC system for the study.  
When the form is completed, Medpace Safety personnel will be notified electronically and 
will retrieve the form.   
If the event meets serious criteria and it is not possible to access the EDC system, send an 
email to Medpace Safety (email address listed below) or call the Medpace SAE hotline 
(phone number listed below), and fax the completed paper SAE form to Medpace (fax 
number listed below) within 24 hours of awareness.  When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming 
available.  
Safety Contact Information: 
Medpace SAE Reporting Phone Line: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Facsimile: +1-866-336-5320 or +1-513-570-5196 
e-mail: medpace-safetynotification@medpace.com 
The investigator is responsible for informing his or her IRB of any SAEs at that site.   
Subjects who experience one or more SAEs will receive treatment and follow-up evaluations 
by the investigator, or they will be referred to another appropriate physician for treatment and 
follow-up.  Withdrawal from the study and all therapeutic measures will be at the discretion 
of the investigator.  The investigator must continue to follow the subject until resolution or 
until the condition becomes chronic in nature, stabilizes (in the case of persistent impairment) 
or the subject is deceased.   
8.9.1.2 
Follow-up Reports 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE 
form electronically within the EDC system and submit any supporting documentation (eg, 
subject discharge summary or autopsy report) to Medpace Clinical Safety using the contacts 
listed above for initial reporting. 
8.10 Safety Monitoring 
8.10.1 
Safety Monitoring 
A study level safety review will be conducted to monitor and assess safety data collected 
during the study.  Specifically, any signs or trends indicating potential underlying safety 
issues will be identified.  The safety review will be scheduled regularly and reviewed by the 
sponsor-designated medical monitor.  More details will be provided in the safety monitoring 
plan (SMP) including the type of safety data, frequency of review, and unblinding plan if 
necessary.  
The sponsor-designated medical monitor will routinely review: 


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 trends in safety data laboratory analytes 
 serious and non-serious AEs including AESIs (see section 8.2) 
 reported pancreatitis and major CV events 
8.10.2 
Assessment of Tolerability  
The safety and tolerability of the 70 mg QW dose level will be assessed by the DSMB 
following completion of visit 7 (2 weeks of dosing) by at least 10 subjects randomized to 
OPK-88003.  If five or more of those subjects experience severe vomiting or severe nausea 
defined as an SAE, then the dose of OPK-88003 will be reduced to 60 mg for all subjects 
including those receiving 70 mg at the time of safety review.  Only members of DSMB will 
gain access to safety data.  Members of the DSMB will not have access to efficacy data for 
this assessment.  Study team and site personnel will remain blinded.   
9 STUDY ACTIVITIES 
9.1 
Screening/Visit 1 (Day -14 to Day -1) 
At this visit, the following study activities will be performed: 
 Informed consent will be reviewed and the ICF signed prior to any study-related 
activities are performed  
 Inclusion/exclusion criteria will be reviewed 
 Medical history (including diabetes and medication history), demographics and health 
habits (alcohol, tobacco use) will be reviewed 
 Physical examination will be performed, fasting weight and height will be measured 
 Single 12-lead ECG will be obtained after at least 5 minutes of supine rest 
 Vital signs will be assessed (supine blood pressure and pulse rate will be assessed 
following 12-lead ECG and prior to any blood draws) 
 Blood samples will be collected: 
o Serum chemistry 
o Serum calcitonin 
o Hematology 
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o Fasting glucose 
o HbA1c 
o Serology 
o Serum pregnancy test/FSH (females, at the investigator’s discretion) 
 Urinalysis  
9.2 
Re-testing and Re-screening 
9.2.1 
Re-testing 
Individuals that do not meet laboratory eligibility criteria are permitted one re-test of any 
analyte, except for HbA1c, during the screening period and at the discretion of the 
investigator.  In addition, if in the opinion of the investigator, an ineligible laboratory test 
result (excluding HbA1c) is due to an error or unexpected circumstance, then that analyte can 
be re-tested once.   
9.2.2 
Re-screening 
Individuals who do not meet the eligibility criteria for participation in this trial (screen 
failures) may be re-screened once at the discretion of investigator.  A new study subject 
number should be assigned and all screening procedures (including signing a new informed 
consent form) should be performed.  Re-screening should occur at least 30 days after the 
initial screening visit date.   
9.3 
Treatment Period - Dose Escalation (Weeks 0-7) 
9.3.1 
Visit 2 Baseline (Day 1) 20 mg Dose Level 
At this visit, the following study activities will be performed: 
 Fasting weight,
  
 12-lead ECG (triplicate)  
 Vital signs (supine blood pressure and pulse rate will be assessed following 12-lead ECG 
and prior to any blood draws or study drug administration) 
 Blood samples: 
o Fasting glucose 
o 
 
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o HbA1c 
o 
 
o Immunogenicity (pre-dose) 
 
 
 AE assessment  
 Concomitant medication review 
 Distribute glucometers, test strip and diary 
 Lifestyle counseling  
 Randomization 
 Injection technique training 
 SMBG training 
 The first dose will occur at the investigational site and subject will be monitored post 
injection for at least 15 minutes for safety.   
9.3.2 
Visit 3 (Week 1±2 Days) 20 mg Dose Level 
At this visit, the following study activities will be performed: 
 Concomitant medication review 
 AE assessment  
 Subject diary review  
 
 
 Distribute test strips as needed 
 The dose will occur at the investigational site and subject will be monitored post injection 
for at least 15 minutes for safety 
 Study drug dispensed to subject 
9.3.3 
Visit 4 (Week 4±2 Days) 40 mg Dose Level 
At this visit, the following will be performed: 
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 Fasting weight 
 Vital signs (prior to blood draw and IP administration) 
 Blood samples: 
o Fasting glucose 
o Serum chemistry 
o Hematology 
o 
 
o HbA1c 
o 
 
o Immunogenicity (pre-dose) 
 
 
 Urinalysis 
 AE assessment  
 Subject diary review 
 Concomitant medication review 
 Distribute test strips as needed 
 Drug accountability 
 The dose will occur at the investigational site and subject will be monitored post injection 
for at least 15 minutes for safety  
 Study drug dispensed to subject   
 Lifestyle counseling  
9.3.3.1 
Visit 4A (on any day 1 to 6 days following visit 4) 
 
  
 Concomitant medication review 
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 AE assessment 
 Distribute test strips as needed 
9.4 
Treatment Period – Target Dose Phase (Week 8 to Week 30)  
9.4.1 
Visit 5 (Week 8 ±2 Days) Target Dose  
At this visit, the following will be performed: 
 Fasting weight 
 Vital signs (prior to blood draws and IP administration) 
 Blood samples: 
o Serum chemistry 
o Hematology 
o Fasting glucose 
o 
 
o HbA1c 
o 
 
o Immunogenicity (pre-dose) 
 
  
 Urinalysis 
 AE assessment  
 Subject diary review   
 Concomitant medication review 
 Distribute test strips as needed  
 Drug accountability 
 The dose will occur at the investigational site and subject will be monitored post injection 
for at least 15 minutes for safety 
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 Lifestyle counseling 
9.4.1.1 
Visit 5A (on any day 1 to 3 days following visit 5) 
 
  
 Concomitant medication review 
 AE assessment 
 Distribute test strips as needed 
9.4.1.2 
Visit 5B (on any day 4 to 6 days following visit 5) 
 
  
 Concomitant medication review 
 AE assessment 
 Distribute test strips as needed 
9.4.2 
Visit 6 (Week 9±2 Days) Target Dose  
At this visit, the following study activities will be performed: 
 AE assessment  
 Subject diary review  
 Concomitant medication review 
 Distribute test strips as needed 
 Drug accountability 
 Dose administration   
9.4.3 
Visit 7 (Week 10±2 Days) Target Dose 
At this visit, the following will be performed: 
 Vital signs (prior to IP administration) 
 AE assessment  
 Subject diary review  
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 Concomitant medication review 
 Distribute test strips as needed 
 Drug accountability 
 Dose administration  
9.4.4 
Visit 8 (Week 11±2 Days) Target Dose  
At this visit, the following study activities will be performed: 
 AE assessment  
 Subject diary review  
 Concomitant medication review 
 Distribute test strips as needed 
 Drug accountability 
 Dose administration   
9.4.5 
Visit 9 (Week 12±2 Days) Target Dose  
At this visit, the following study activities will be performed: 
 Fasting weight, 
 
 12-lead ECG (triplicate) 
 Vital signs (supine blood pressure and pulse rate will be assessed following 12-lead ECG 
and prior to any blood draws or IP administration) 
 Blood samples: 
o Fasting glucose 
o Serum chemistry  
o Serum calcitonin 
o Hematology 
o 
 
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o HbA1c 
o 
 
o Immunogenicity (pre-dose) 
 
  
 Urinalysis 
 AE assessment  
 Subject diary review  
 Concomitant medication review 
 Distribute test strips as needed 
 Study drug dispensed to subject   
 Drug accountability 
 Dose administration  
 Lifestyle counseling  
9.4.5.1 
Visit 9A (any day 1 to 6 days post visit 9) 
 
  
 Concomitant medication review 
 AE assessment 
 Distribute test strips as needed 
9.4.6 
Visit 10 (Week 16±2 Days) Target Dose  
At this visit, the following study activities will be performed: 
 Fasting weight 
 Vital signs (prior to blood draw and study drug administration) 
 Blood draw: 
o Fasting glucose  
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 
 
 Concomitant medication review 
 AE assessment 
 Subject diary review  
 Distribute test strips as needed 
 Drug accountability 
 Study drug dispensed to subject   
 Dose administration  
 Lifestyle counseling  
9.4.7 
Visit 11 (Week 22±4 Days) Target Dose  
At this visit, the following study activities will be performed: 
 Fasting weight, 
 
 12-lead ECG (triplicate) 
 Vital signs (supine blood pressure and pulse rate will be assessed following 12-lead ECG 
and prior to any blood draws or study drug administration) 
 Blood samples: 
o Fasting glucose 
o Serum chemistry 
o Hematology 
o 
 
o HbA1c 
o 
 
 
 
 AE assessment  
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 Subject diary review 
 Concomitant medication review 
 Distribute test strips as needed 
 Drug accountability 
 Study drug dispensed to subject  
 Dose administration  
 Lifestyle counseling  
9.4.8 
 Visit 12 (Week 26±4 Days) Target Dose  
At this visit, the following study activities will be performed: 
 Fasting weight 
 Vital signs (prior to blood draw and study drug administration) 
 Blood draw: 
o Fasting glucose  
 
  
 AE assessment  
 Subject diary review  
 Concomitant medication review 
 Distribute test strips as needed 
 Drug accountability 
 Study drug dispensed to subject   
 Dose administration  
 Lifestyle counseling 
 
 
 
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9.4.9 
 Visit 13 (Week 30±4 Days) End of Treatment 
At this visit, the following study activities will be performed: 
 Fasting weight,
 
 12-lead ECG (triplicate) 
 Vital signs (supine blood pressure and pulse rate will be assessed following 12-lead ECG 
and prior to any blood draws) 
 Blood samples: 
o Fasting glucose 
o Serum chemistry 
o Serum calcitonin  
o Hematology 
o 
 
o HbA1c 
o 
  
o Immunogenicity  
 
 
 Urinalysis 
 AE assessment  
 Subject diary review 
 Concomitant medication review 
 Distribute test strips as needed 
 Drug accountability 
 Lifestyle counseling 
 
 
 
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9.5 
Follow-up Visit 14 (Week 34±4 Days)/Early Termination 
The following assessments will be performed (as indicated): 
 Fasting weight, 
  
 12-lead ECG (single) 
 Vital signs (supine blood pressure and pulse rate will be assessed following 12-lead ECG 
and prior to any blood draws) 
 Blood samples: 
o Fasting glucose 
o Serum chemistry  
o Hematology 
o 
 
o HbA1c 
o 
 
o Immunogenicity 
 
 
 Urinalysis 
 AE assessment  
 Subject diary review 
 Concomitant medication review 
 Drug accountability (ET only) 
10 QUALITY CONTROL AND ASSURANCE 
A quality assurance audit may be performed by the sponsor and/or its designee at selected 
sites to verify that the study is conducted in accordance with the protocol, ICH/GCP 
[International Conference on Harmonisation (ICH) and GCP], and applicable SOPs and 
regulations, to ensure that the safety and welfare of subjects are addressed, and to confirm 
that problems reported by the study clinical research associates (CRAs) have been resolved.  
Verification of study documents and study activities will be conducted to confirm accuracy 
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of recorded data and its analysis.  The sponsor’s audit observations and findings will be 
documented and communicated to appropriate study personnel and management.  An 
inspection may be conducted by regulatory authorities including FDA.  The investigator must 
allow direct access to study documents during any inspection or audit.  
Routine monitoring visits will be performed to evaluate study conduct, data integrity, 
protocol, and GCP compliance.  Source documents, eCRFs, laboratory reports and any other 
additional study documents will be reviewed to ensure that they are accurate and complete. 
Each investigator is responsible for the accuracy, completeness, legibility, and timeliness of 
the data reported.  All source documents are to be completed in a neat, legible manner to 
ensure accurate interpretation of data. 
10.1 Data Quality Assurance 
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following: 
 provide instructional material to the study sites, as appropriate 
 provide study start-up training to instruct the investigators and study coordinators,  
protocol training, instructions on  eCRF completion  and study procedures 
 make periodic visits to the study site 
 be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax 
 review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection 
 conduct a quality review of the database 
In addition, the sponsor or its representatives will periodically check a sample of subject data 
recorded against source documents at the study site.  Investigators will maintain study 
records in a secure location upon completion of the study and the file archive location will be 
provided to the sponsor or its representatives.  
To ensure the safety of participants in the study, and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and subject 
medical records in the subject files as original source documents for the study.  If requested, 
the investigator will provide the sponsor, applicable regulatory agencies, and applicable IRBs 
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11 STATISTICAL CONSIDERATIONS 
11.1 Determination of Sample Size 
A total of 110 subjects will be randomized at a ratio 1.75:1 to OPK-88003 (70 subjects) and 
the corresponding placebo arm (40 subjects) in an effort to obtain 56 subjects completing in 
the active arm and 32 subjects completing in the placebo arm.  A sample size of 48 subjects 
in the active arm and 27 subjects in the placebo arm will provide at least 90% power of 
detecting superior glycemic control over placebo represented by -0.8% in HbA1c levels at 
week 30.  This assumes a common SD of 1.0% and a two-sided alpha of 0.05.  The 
assumptions are based on variability in previously obtained HbA1c results from the OPK-
88003 phase 2 trial XNAA.  
11.2 Planned Statistical Methods 
11.2.1 
General Considerations 
Statistical analysis of this trial will be the responsibility of the sponsor or its designee. 
Any change to the data analysis methods described in the protocol will require a protocol 
amendment only if the study design is modified in a way that it significantly affects the safety 
of the subjects, the scope of the investigation or scientific quality of the study.  Any other 
change to the data analysis methods described in the protocol and the justification for making 
the change will be described in the statistical analysis plan (SAP) or clinical study report 
(CSR).  Only results of exploratory analyses that are potentially relevant to subject safety 
will be reported in the final CSR.  Additional exploratory analyses of the data (eg, secondary 
endpoint efficacy) may be performed as deemed appropriate and may or may not be reported 
in the final CSR. 
A clinical SAP will be finalized prior to database lock.  The SAP will describe statistical 
methodologies, and the statistical programming specifications and will list planned tables and 
listings.  The SAP will describe study variables and population demographics, anticipated 
data transformations and manipulations and other details of the analyses not provided in the 
clinical protocol. 
Data from screen failures will not be presented.  The number of screen failures will be listed.  
Data from enrolled subjects will be presented in data listings arranged by treatment group.   
All pre-dose and post-dose assessments, including repeat assessments, will be included in the 
data listings.   
Continuous data will be presented with number of observations (n), mean, and median, 
standard deviation (SD), minimum and maximum.  Frequencies and percentages will be used 
for summarizing discrete (categorical) data.  The denominator for all percentages, unless 
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Data that are reported as missing will be presented as unknown (UNK) in the data listings 
and treated as missing in all data summaries.  No imputations for missing data will be made 
unless otherwise specified for endpoint derivation.   
Data handling, tabulation of descriptive statistics and calculation of inferential statistics will 
be performed using SAS® for clinical data 
 
 
  The versions used 
will be reported in the final CSR. 
11.2.2 
Analysis Populations  
The intent-to-treat (ITT) population is defined as all randomized subjects.  Statistical 
analyses (including the primary analysis) will be conducted on the modified ITT (mITT) 
population.  The mITT population is defined as all randomized subjects who received at least 
one dose of study drug and have at least one post-baseline measurement for the primary 
outcome.   
The safety population is defined as all randomized subjects who have received at least one 
dose of study drug.  All safety analyses will be performed on the safety population. 
Some efficacy measures will also be analyzed on the per-protocol (PP) dataset.  The per-
protocol (PP) population is defined as all randomized subjects who were compliant with 
study drug and completed the protocol and is a subset of the mITT population and include 
subjects who meet the following additional criteria:  The PP population will include all 
subjects in the mITT population who complete the 30-week, double-blind treatment period 
without any significant deviations from the protocol procedures.  The PP population will be 
used to assess robustness of the primary analysis results.  A final listing of all subjects to be 
excluded from the PP population will be completed prior to unblinding the study database. 
No adjustments for multiplicity will be performed.  All tests of treatment effects will be 
conducted at a two-sided alpha level of 0.05 and/or two- sided 95% confidence interval (CI), 
unless otherwise stated. 
The baseline value used for the analyses will be the last scheduled baseline value obtained 
for each subject prior to first IP dose administration.  Any measurements/events that occurred 
after the subject started rescue therapy will not be included in the efficacy analyses. 
11.2.3 
Subject Disposition 
Frequencies and percentages of all randomized, discontinued, and completed subjects in the 
study will be presented for each of the treatment groups.  A summary of discontinuations will 
be presented by treatment group and by visit.  The reasons for discontinuations will be 
summarized by treatment group.  Discontinuation rates will be compared among the 
treatment groups for each reason using a Fisher’s exact test. 
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11.2.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group.  
Categorical variables will be summarized by frequencies and percentages.  For categorical 
variables, comparisons between treatment groups will be assessed using a Pearson Chi-
Square test.  For continuous variables, comparisons between the treatment groups will be 
performed using a one-way Analysis of Variance (ANOVA) with treatment as the fixed 
effect. 
11.2.5 
Study Drug Exposure, Compliance, and Concomitant Therapies 
Exposure to each therapy during the treatment period of the trial will be calculated for each 
subject and summarized by treatment group. 
Listings and summary of concomitant therapies will be listed and summarized by subject. 
Treatment compliance for the mITT population will be listed and summarized.  Subjects that 
miss more than four doses of study drug over the course of the study, or miss two 
consecutive doses of study drug during the dose escalation phase are considered non-
compliant.  The frequency and percentage of subjects who are compliant will be summarized 
and analyzed by treatment group. 
11.3 Outcomes Analysis 
11.3.1 
Primary Outcome Analysis 
The primary efficacy outcome of HbA1c absolute change from baseline to the 30-week 
endpoint will be performed on the mITT analysis set.  Endpoint for each subject is defined as 
the week 30 measurement.  If the week 30 measurement is missing, the last valid post-
baseline observation (last observation carried forward [LOCF]) algorithm will be applied to 
impute the missing week 30 value.   
This change from baseline to week 30 in HbA1c will be analyzed using linear contrasts from 
an analysis of covariance (ANCOVA) model with treatment arm and BMI strata as factors 
and the baseline HbA1c value as a covariate.  The least-squares means, standard errors, and 
the 2-tailed 95% confidence intervals (CIs) for each treatment group and for comparison to 
placebo will be presented.  Additional covariates may be added and will be detailed in the 
SAP. 
The primary efficacy analysis will be repeated on the PP population. 
11.3.1.1 
Supportive Analysis of Primary Outcome 
The change from baseline in HbA1c at each scheduled visit without LOCF will be analyzed 
using a mixed-model repeated-measures (MMRM).  The factors in the model will be BMI 
strata, treatment group, baseline value, visit, and the treatment group by visit interactions.  
No imputation will be performed.  The least-squares means for change from baseline at each 


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visit will be estimated and compared between treatment groups.  Additional covariates may 
be added and will be detailed in the SAP. 
11.3.2 
Secondary Outcome Analyses 
The change from baseline of body weight and FPG will be calculated using the similar 
ANCOVA model used for the primary endpoint analysis.  The corresponding baseline will be 
used in the model instead of the baseline HbA1c levels.  The ANCOVA model will also 
include a term for the HbA1c stratification group.  
A logistic regression analysis will be performed for the percent of subjects with 5% or 
greater body weight loss with treatment and HbA1c and BMI strata as fixed effects, and 
baseline weight as a covariate.   
The number and percentage of subjects achieving HbA1c ≤6.5% will be summarized for each 
treatment group at each post-baseline visit.  Comparisons between treatment groups will be 
performed for responses at week 30 with LOCF based on a logistic regression model with 
factors for treatment group and BMI strata and baseline HbA1c as a covariate.  Odds ratios, 
95% CIs (Wald), and p-values will be presented.   
11.3.3 
Other Outcome Analyses 
The proportion of subjects who discontinued due to hyperglycemia in each group will be 
analyzed using a logistic regression analysis with fixed effects of treatment and strata.   
In addition to change from baseline in weight, 
 
will be listed and summarized. 
11.4 Safety Analysis 
The safety population will be used for safety analyses.  Safety measures will include vital 
signs, body weight, hypoglycemia episodes, AEs, laboratory measures (including ADAs), 
ECGs, injection site reactions, hypersensitivity reactions, major CV, pancreatic, and GI 
events.  Summary statistics will be presented by treatment for the safety measures.   
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Additional analysis, such as concentration-safety lab plots, may be performed if warranted 
upon review of the data.   
11.4.1 
Adverse Events 
Safety of all subjects will be monitored during the treatment period and queried at each visit 
for AEs.  AEs will be listed by subject, actual term, preferred term, severity, and relationship 
to the treatment.  AEs will be summarized as TEAEs; defined as events that are newly 
reported after randomization or reported to worsen in severity from baseline).  The incidence 
of subjects with at least one TEAE and the incidence of TEAEs by preferred term and system 
organ class will be presented by treatment group.  The frequency and percent of TEAEs will 
be presented.  The incidence of subjects with at least one TEAE assessed as related to the 
investigational drug will be summarized by treatment group, in addition to the incidence of 
these TEAEs by preferred term.  In addition, a summary of TEAEs by severity will be 
presented descriptively by treatment group.   
Reported CV and pancreatic AEs will be listed by subject, and if there are a sufficient 
number of cases they may be summarized by treatment group.   
All SAEs will be listed by subject.  If a sufficient number of SAEs are reported, incidence 
summaries similar to incidence of TEAEs will be included.   
Discontinuations due to TEAEs will be listed by subject and summarized by treatment group.    
11.4.2 
Adverse Events of Special Interest 
11.4.2.1 
Hypoglycemic Episodes 
The incidence of total hypoglycemic episodes will be presented for each visit (incidence 
between visits) and overall.  Listings of severity of hypoglycemic episodes will be presented 
by visit for each subject.   
11.4.2.2 
Other Adverse Events of Special Interest (AESIs) 
Hypersensitivity reactions, injection site reactions, pancreatitis, major CV and GI events, 
such as nausea, vomiting, and diarrhea are defined as additional AESIs.  Descriptive statistics 
for these AESIs will be presented by treatment group and visit.   
11.4.3 
Vital Signs 
All vital signs will be listed for the safety population.  Descriptive statistics for the actual 
measurements and changes from baseline for systolic and diastolic blood pressure and pulse 
rate will be presented by treatment arm and visit.  Corresponding figures may be presented.   


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11.4.4 
Laboratory Measures 
Summary statistics will be provided for laboratory measures by visit.  A listing of laboratory 
measurements for individual subjects will be presented by visit.  An additional listing will be 
presented for all laboratory measurements that are outside the normal range.   
Descriptive statistics for the laboratory analyses will be presented by treatment group and 
visit, including safety follow-up visits.   
Laboratory analyses with categorical responses will be summarized by visit and treatment 
group using frequency and percentage.   
Shift tables will be evaluated at the worst post-baseline observation (as applicable for a lab) 
will be compared to the baseline observation by examining the proportion of subjects whose 
test values are within and outside the reference ranges.   
11.4.5 
Evaluation of Immunogenicity 
The frequency of ADA will be determined by the specialized laboratory other than central 
laboratory using a validated assay.  If a neutralization assay is performed, the frequency of 
neutralizing antibodies will be determined.   
11.4.6 
Evaluation of Electrocardiography (ECG) 
A listing of the individual and averaged ECG measurements by subject will be produced.  
This listing will include the time elapsed between the onset of ventricular depolarization and 
the end of ventricular repolarization (QT) corrected values described below.   
Descriptive statistics for the absolute measurements, outliers, and changes from baseline for 
selected ECG parameters will be presented by treatment arm and visit.  These include the 
ECG heart rate, and the following intervals: QT and QT corrected for heart rate using 
Fridericia’s formula (QTcF).   
In addition, OPK-88003 concentration-response analysis of QTcF results will be performed 
as well as a categorical analyses of absolute and change from baseline QTc intervals.  Any 
additional ECG analyses will be detailed in the SAP.   
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12 ADMINISTRATIVE CONSIDERATIONS 
12.1 Study Administrative Structure 
This trial will be performed at up to approximately 30 clinical sites located in the US.   
All study personnel involved in conducting this study will be qualified by education, training, 
and experience to perform their respective task(s) as per ICH E6 GCP.  Study personnel will 
not include individuals against whom sanctions have been invoked after scientific 
misconduct or fraud (eg, loss of medical licensure, debarment).   
At screening, the subject will be offered notification of their primary care physician that he is 
participating in a clinical study.  If the subject accepts, a brief letter outlining the study and 
identifying the study drug will be sent once the subject is enrolled. 
Table 4 lists third-party designees contracted by the sponsor to conduct the study. 
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Table 4 
Third-party Designees   
Organization 
Responsibility 
Medpace  
5375 Medpace Way 
Cincinnati, OH 45227 
Clinical data monitoring (CRAs), project management, medical/safety 
monitoring, data management, statistical analysis, central laboratory, 
cardiovascular central lab 
Sherpa Clinical Package 
6166 Nancy Ridge Drive 
San Diego, CA 92121, USA 
Study drug distribution 
 
12.2 Ethical Conduct of the Study 
The study will be conducted in accordance with GCP (ICH GCP) and all applicable laws and 
regulations including the ethical principles of the Declaration of Helsinki (Edinburgh 2000, 
with Note of Clarification, Tokyo 2004) and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines. 
In accordance with applicable country-specific regulations, the sponsor will obtain approval 
from the appropriate regulatory authority(ies) prior to initiating the study in that country. 
12.3 Institutional Review Board (IRB) Approval 
The investigator will submit all required documentation and obtain IRB approval to 
implement the study prior to the conduct of any study procedures.  At a minimum, the study 
protocol, protocol amendments, ICF, Investigator’s Brochure, and subject-related 
information, relevant curricula vitae and promotional materials will be submitted. 
The sponsor or designee will approve all ICFs before they are used at investigative sites.  All 
ICFs must be compliant with the ICH guideline on GCP. 
Documentation of IRB approval of the protocol and the ICF must be provided before the 
study may begin at the investigative site(s).  If it is necessary to amend the protocol during 
the course of the study, the investigator must ensure that the IRB reviews and approves the 
amendment.  No amendments will be implemented without the agreement of the investigator 
and the sponsor as well as the IRB, where applicable. 
The investigator will comply with requirements for reporting to the IRB.   
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12.4 Subject Information and Consent 
The investigator will obtain a written informed consent form for each subject prior to 
performing any study-related procedures.  The investigator is responsible for ensuring that 
the subject fully understands the nature of the study, potential risks and benefits of 
participating, including answering any questions the subject may have throughout the study 
and sharing in a timely manner any new information that may be relevant to the subject’s 
willingness to continue participation in the study.   
The investigator will ensure that the ICF is signed and dated by each subject and that 
documentation of consent being obtained will be recorded in the subject’s medical 
record/source documents.  
 
 
As used in this protocol, the term “informed consent” includes all consent and assent given 
by subjects. 
12.5 Confidentiality 
12.5.1 
Subject Confidentiality 
Subject confidentiality will be strictly held in trust by the study investigators, their staff, the 
sponsor and their authorized representatives.  This confidentiality includes clinical 
information relating to participating subjects and their biological sample testing. 
The study protocol, documentation, data, and all other information will be held in strict 
confidence.  No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the sponsor. 
Authorized representatives of the sponsor, contract research organizations (if applicable), 
study monitors, employees of government authorities (eg, US FDA or other), and IRB 
members may inspect all study-related documents and records required to be maintained by 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the subjects in this study.  The investigator and clinical study site will 
permit access to such records. 
No information that would permit the identification of a specific individual will be provided 
for entry into the study database or study report.  Study documentation submitted to the 
sponsor will identify study participants by study code and initials.  The investigator will keep 
a separate confidential enrollment log that matches identifying study codes with the subject 
names and contact information.   
12.5.2 
Protocol/Study Confidentiality 
This protocol contains information that is confidential and proprietary to OPKO.  This 
information is being provided for the purposes of conducting a clinical trial for OPKO.  The 
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investigator may disclose the contents of this protocol to the study personnel under his/her 
supervision who need to know the contents for this purpose, as well as to the institution’s 
IRB or Ethics Committees, subject to the following condition: the contents of this protocol 
cannot be used in any other clinical trial and may not be disclosed to any other person or 
entity without prior written permission of OPKO.  The foregoing shall not apply to disclosure 
required by governmental regulations.  Prompt written notice of any such disclosure must be 
reported to OPKO.  Any supplemental information that may be added to this document is 
also confidential and proprietary to OPKO, and must be kept in confidence in the same 
manner as the contents of this protocol. 
12.6 Electronic Case Report Forms (CRFs) and Study Records 
This study will utilize an electronic data capture system for the management of clinical 
data.  Data capture and management will be consistent with applicable ICH/GCP guidelines.   
All data collected during the study for subjects will be recorded in an individual, subject-
specific electronic case report forms (eCRF) as part of an electronic data capture (EDC) 
system.  Access to the electronic system will be restricted and users will only be able to 
access the system via authorized individual accounts.  The sponsor or designee will provide 
training to the investigative site on the EDC system and eCRFs. Site staff will complete 
eCRFS promptly.  As electronic data capture will be utilized, instructions, training records, 
and a log will be maintained to identify the designated site personnel who can enter data 
and/or sign off on an eCRF.  
A subject eCRF must be completed for each subject who signs a consent form and undergoes 
randomization.   
To ensure the quality of the clinical data across all subjects and sites, a clinical data 
management review will be performed by the sponsor or designee on subject data entered or 
integrated into the EDC system.  During the review, subject data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol, and ICH/GCP.  Moreover, all data from external 
sources, eg, central laboratory and PD processing/analysis will be reconciled with subject 
eCRF data.  To resolve any questions arising from the Data Management review process, 
data queries and/or data clarification notifications will be generated via the EDC system for 
completion and resolution. 
The investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature.  These signatures will indicate that the investigator reviewed the data on 
the eCRF, the data queries, and the data clarifications and agrees with the content. 
12.7 Protocol Deviations 
Protocol deviations are any intentional or unintentional changes, divergences, or departures 
from the study design or procedures of an IRB-approved clinical protocol that have not been 
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The investigator is responsible for ensuring protocol and study compliance by all study staff 
members.  Deviations from protocol will be documented in subjects’ study records. 
The sponsor requires that all protocol deviations be reported to the IRB as per site’s 
institutional regulations.  In addition, the investigator is responsible for adhering to his/her 
IRB’s protocol deviation reporting requirements. 
12.8 Retention of Data 
The investigator/institution will maintain all CRFs and all source documents that support the 
subject data collected, and all study documents as specified in ICH/GCP Section 8, Essential 
Documents for the Conduct of a Clinical Trial.  The investigator/institution will take 
measures to prevent accidental or premature destruction of these documents. 
Essential documents must be retained until at least two years after a marketing application is 
approved for the drug; or, if an application is not approved for the drug, until two years after 
shipment and delivery of the drug for investigational use is discontinued and FDA has been 
so notified.  These documents will be retained for a longer period 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. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
study, the responsibility of keeping the study records, custody must be transferred to a person 
who will accept the responsibility.  The sponsor must be notified in writing of the name and 
address of the new custodian.  Under no circumstances shall the investigator relocate or 
dispose of any study documents before having obtained written approval from the sponsor. 
12.9 Publication and Disclosure Policy 
Data derived from the study are the exclusive property of the sponsor.  Publication rights are 
outlined in the clinical study agreement. 
13 REFERENCE LIST 
American Diabetes Association 2.  Classification and diagnosis of diabetes: Standards of 
Medical Care in Diabetes - 2018.  Diabetes Care 2018: 41 (Suppl 1):S13-S27 
American Diabetes Association 4.  Lifestyle management: Standards of Medical Care in 
Diabetes - 2018.  Diabetes Care 2018: 41 (Suppl 1):S38-S50American Diabetes Association 
6. Glycemic targets: Standards of Medical Care in diabetes - 2018.  Diabetes Care 2018; 
41(Suppl 1):S55-S64 
American Diabetes Association 7.  Obesity management for the treatment of Type 2 diabetes 
Standards of Medical Care in Diabetes - 2018.  Diabetes Care 2018: 41 (Suppl 1): S65-S72 


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Alberti KG, Zimmet PZ.  Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabetic Med. 1998; 15:539-553. 
Ambery P, Parker VE, Stumwall M et al.  MEDI0382, a GLP-1 and glucagon receptor dual 
agonist, in obese or overweight patients with type 2 diabetes: a randomized, controlled, 
double-blind, ascending dose and phase 2a study.  Lancet 2018; 391: 2607-2618 
Baggio LL, Huang Q, Brown TJ et al.  Oxyntomodulin and glucagon-like peptide-1 
differentially regulate murine food intake and energy expenditure. Gastroenterol 2004; 
127:546–558. 
Baggio LL, Drucker DJ.  Biology of incretins: GLP-1 and GIP. Gastroenterol 2007; 
132:2131-2157. 
Campbell JE, Drucker DJ.  Pharmacology, physiology and mechanisms of incretin hormone 
action.  Cell Metab 2013 17:819-837 
Dakin CL, Gunn I, Small CJ et al.  Oxyntomodulin inhibits food intake in the rat. 
Endocrinology 2001; 142: 4244–4250. 
Davies MJ, Bergenstal R, Kushner et al.  Efficacy of liraglutide for weight loss among 
patients with type 2 diabetes: The SCALE diabetes randomized clinical trial.  JAMA 2015; 
314:687-699. 
Deacon CF, Nauck MA, Toft-Nielsen M et al.  Both subcutaneously and intravenously 
administered glucagon-like peptide I are rapidly degraded from the NH2- terminus in type II 
diabetic patients and in healthy subjects. Diabetes 1995;  44:1126-1131. 
Kosinski JR, Hubert J, Carrington PE et al.  The glucagon receptor is involved in mediating 
the body weight lowering effects of oxyntomodulin. Obesity 2012; 20:1566–1571. 
Loomis AK, Kabadi S, Preiss D et al.  Body mass index and risk of non-alcoholic fatty liver 
disease: two electronic health record prospective studies.  J Clin Endocrinol Metab 2016 
101:945-952. 
Maida A, Lovshin JA, Baggio LLet al.  The glucagon-likepeptide-1 receptor agonist 
oxyntomodulin enhances b-cell function but does not inhibit gastric emptying in mice.  
Endocrinol 2008; 149:5670–5678. 
Petit J-M, Cercueil J-P, Loffroy R et al.  Effect of liraglutide therapy on liver fat content in 
patients with inadequately controlled type 2 diabetes: the Lira-NAFLD study.  J Endocrinol 
Metab 2016; 102:407-415. 
Sowden GL, Drucker DJ, Weinshenker D et al.  Oxyntomodulin increases intrinsic heart rate 
in mice independent of the glucagon-like peptide-1 receptor. Am J Physiol. Reg, Integr 
Comp. Physiol. 2007; 292: R962–R970. 


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Wynne K, Field BC,Bloom SR.  The mechanism of action for oxyntomodulin in the 
regulation of obesity. Curr Opin Investig Drugs 2010; 11:1151–1157..


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Appendix 1.  
Schedule of Events 
PHASE 
 
TREATMENT PERIOD 
FUPa 
ET 
DOSE-ESCALATION 
TARGET DOSE 
EOT 
Study Visit 
V1 
V2 
V3 
V4 
V4A 
 
V5 
V5A 
 
V5B 
 
V6 
V7 
V8 
V9 
V9A 
 
V10 
V11 
V12 
V13 
V14 
Study Week 
-2 to  
0 
0 
1 
4 
4 
8 
8 
8 
9 
10 
11 
12 
12 
16 
22 
26 
30 
34 
 
Visit Window 
(days) 
-14 
to -1 
1 
8±2 
29±2 
1 - 6 
post 
V4 
57±2 
1 - 3 
post 
V5 
4 - 6 
post 
V5b 
64±2 
71±2 
78±2 
85±2 
1 - 6 
post 
V9 
113±2 155±4 183±4 211±4 
239±4 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health habits 
(alcohol, 
tobacco) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting weightc, 
heightc 
X 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Vital signse
Serum 
chemistryf 
hematology 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Serum 
calcitoning 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Urinalysish 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Serum 
pregnancy/FSHi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (Hep 
B, Hep C) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting glucose 
X 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
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PHASE 
 
TREATMENT PERIOD 
FUPa 
ET 
DOSE-ESCALATION 
TARGET DOSE 
EOT 
Study Visit 
V1 
V2 
V3 
V4 
V4A 
 
V5 
V5A 
 
V5B 
 
V6 
V7 
V8 
V9 
V9A 
 
V10 
V11 
V12 
V13 
V14 
Study Week 
-2 to  
0 
0 
1 
4 
4 
8 
8 
8 
9 
10 
11 
12 
12 
16 
22 
26 
30 
34 
 
Visit Window 
(days) 
-14 
to -1 
1 
8±2 
29±2 
1 - 6 
post 
57±2 
1 - 3 
post 
4 - 6 
post 
b
64±2 
71±2 
78±2 
85±2 
1 - 6 
post 
113±2 155±4 183±4 211±4 
239±4 
 
Immunogenicity 
(pre-dose) 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
12-lead ECGl 
X1 
X2 
 
 
 
 
 
 
 
 
 
X2 
 
 
X2 
 
X2 
X1 
X1 
Concomitant 
med. review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Distribute 
glucometers and 
diaries 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Distribute test 
strips as needed  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Lifestyle 
counselingm 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Subject trainingn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SMBGo 
 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At-visit dosingp 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
Dispense study 
drug to subject 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
Drug 
accountability 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review diaryr 
 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
a. 
Subjects who complete an ET visit should complete a follow-up visit 4 weeks after their final dose 
b. Visit 5B must occur before visit 6. 
c. 
Body weight 
 will be measured on fasting subjects (minimum 8 hours).  Duplicate measurements of weight will be 
performed using digital scales after an overnight fast and following emptying of any bowel/bladder contents. Subject will change into a light hospital 
gown for weight measurements 
   
C
C
C
C
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d. Height is measured only at screening (V1). 
e. 
Vital signs (triplicate supine blood pressure and pulse rate, after minimum 5 minutes rest) will be assessed following 12-lead ECG and prior to any 
blood draws or study drug administration. 
f. 
Serum chemistry will include: albumin, ALP, ALT, AST, BUN, calcium, creatinine, creatine kinase, potassium, sodium, total and direct bilirubin, total 
protein, uric acid, lipase and amylase. Hematology will include: Hct, Hgb, MCHC, MCV, platelet count, RBC and WBC with differential.  
g. Subjects who do not have a screening calcitonin should be tested at their next visit 
h. Urinalysis will include glucose, leukocyte esterase, occult blood, pH and protein. 
i. 
Serum pregnancy/FSH will be tested at the investigator’s discretion. 
l. 
ECGs will be obtained in a quiet environment after at least 5 minutes in supine rest.  Subjects will remain supine but awake during ECG collection. 
Consecutive replicate ECGs will be obtained at approximately 1-2 minute intervals within a 5 minute window.  X1 single ECG; X2 triplicate ECG. 
m. Lifestyle counseling will include lifestyle diary review. Subjects will complete a 3-day lifestyle diary prior to visits.   
n. Subjects will receive training on study drug injection technique, routine SMBG and glucose testing supplies. 
o. Subjects will perform SMBG prior to breakfast at least three times a week using a portable glucometer. Subjects will perform additional SMBG as per 
section 7.5 and may be asked to attend an unscheduled visit if needed.   
p. There are no restrictions on the time of day each dose is given but it is advisable to administer SC injections on the same day and time of the week for 
the full 30 week treatment period.  All subjects should be observed for allergic reactions following study drug administration for at least 15 minutes at 
r. 
Subject study diary review will include SMBG, AEs and dosing records. 
 
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Appendix 2.  
Clinically Significant Events 
Table 5 summarizes the type and severity of symptoms, clinical signs, and clinical laboratory 
findings that may qualify as a CSE and lead to discontinuation (see section 5.1.2).  They are 
intended as a guideline to the investigator, not as a set of absolute criteria.  The underlying 
principle is to define a level of moderate-to-severe abnormality in safety findings that could 
cause harm to health, and would preclude further dosing of a subject who experiences this 
effect.  Safety parameters not included in this table may be interpreted in a similar fashion 
according to investigator judgement.   
Table 5 
Clinically Significant Events 
Parameter 
AE level 
Symptoms 
 
Severe Hypoglycemia 
One episode of severe hypoglycemia defined as low blood glucose with mental 
status impairment severe enough to require third-party assistance. 
Severe Nausea and 
Vomiting 
Requires IV hydration or emergency department visit or hospitalization, or 
prevents daily activity. 
Dizziness/Hypotension 
Orthostatic CNS symptoms (dizziness, confusion) that are not vasovagal 
responses to provocative stimuli (for example, phlebotomy, nausea, bowel or 
bladder function), and are associated with orthostatic SBP decrease >20 mm Hg 
or DBP decrease >10 mm Hg or heart rate >105 bpm, confirmed to persist for >3 
hours  
Headache/Pain 
Any focal or generalized head pain that disrupts normal activities and is not 
responsive to medical therapies 
Pruritus 
Generalised itching over >24 hours unresponsive to oral antihistamine 
Signs 
 
Systolic blood pressure 
>30 mg Hg increase from baseline values and an absolute level >190 mm Hga 
Diastolic blood pressure 
>20 mm Hg increase from baseline values and an absolute level >115 mm Hga 
Heart rate 
Resting (sitting or recumbent) HR >120 bpm 
QTc 
>500 msec or >60 msec increase from baseline valuea 
QRS morphology 
Significant prolongation of QRS interval or new onset of bundle branch block 
Clinical Laboratorya 
 
Hemoglobin 
Absolute value <10 g/dL and >2 g/dL reduction from baseline 
Neutropenia 
Absolute neutrophils <1,500/μL and >1,000 L decrease from baseline 
Lymphopenia 
Absolute lymphocyte count <800/μL and >500/L decrease from baseline 
Platelet count 
<75,000/μL and >50,000/uL decrease from baseline 
Creatinine 
>2 mg/dL and >0.5 mg/dL increase from baseline value 
BUN 
>25 mg/L and >10 mg/dL increase from baseline values 
Potassium 
<2.5 or >5.5 meq/L and >0.5 meq/L change from baseline value 


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Parameter 
AE level 
Sodium 
<130 or >150 meq/L and >10meq/L change from baseline value 
a  Must be confirmed by repeat measurement within 48 hours 
 
 


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Appendix 3. Hepatic Monitoring Tests for Treatment-emergent Abnormality 
The following hepatic monitoring tests should be considered for subjects with treatment-
emergent hepatic abnormalities to ensure safety and comply with regulatory guidance.  If the 
investigator needs to consider alternative hepatic monitoring tests, and/or strategy, he/she is 
advised to consult with the sponsor-designated medical monitor prior to testing. 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and 
may be required in follow up with subjects in consultation with the sponsor-designated 
medical monitor. 
Hepatic Hematologya:  
Hemoglobin  
Hematocrit  
Red blood cells (RBC) 
White blood cells (WBC) 
Neutrophils, segmented 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils  
Platelets 
Haptoglobina 
 
Hepatic Coagulationa 
Prothrombin Time 
Prothrombin Time, INR (international 
normalized  
ratio) 
 
Hepatic Serologiesb 
Hepatitis A antibody, total 
Hepatitis A antibody, IgM 
Hepatitis B surface antigen 
Hepatitis B Core antibody 
Hepatitis C antibody 
Hepatitis E antibody, IgG 
Hepatitis E antibody, IgM  
  
Anti-nuclear Antibodya 
 
Anti-smooth muscle Antibodya 
Hepatic Chemistrya: 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Gamma-glutamyl transferase (GGT) 
 
a can be assayed by either sponsor-designated laboratory or local laboratory  
b reflex/confirmation dependent on regulatory requirements and/or testing availability  
 
 


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Appendix 4. Investigator’s Signature 
Study Title: 
A Phase 2, Double-blind Dose Escalation Regimen of Once-
weekly OPK-88003 in Subjects with Type 2 Diabetes 
Study Number: 
DPO-203 
Final Date: 
09 October 2018 
I agree: 
 
To assume responsibility for the proper conduct of the study at this site. 
 
To conduct the study in compliance with this protocol, with any future amendments, and with any other 
written study conduct procedures provided and reviewed and approved by OPKO Ireland Global Holdings 
Ltd. or its designee(s). 
 
Not to implement any deviations from or changes to the protocol without agreement from the sponsor and 
prior review and the written approval from IRB, except where necessary to eliminate an immediate hazard 
to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory 
requirements). 
 
That I am thoroughly familiar with the appropriate use of the investigational drug, as described in this 
protocol, and any other information provided by the sponsor including, but not limited to, the following: the 
current Investigator’s Brochure or equivalent document provided by OPKO Ireland Global Holdings Ltd. 
or its designee(s). 
 
That I am aware of, and will comply with, GCP and all applicable regulatory requirements, including the 
regulations governing the use of controlled substances. 
 
To ensure that all persons assisting me with the study are adequately informed about the investigational 
drug and of their study-related duties and functions as described in the protocol. 
 
That I have been informed that certain regulatory authorities require the sponsor to obtain and supply 
details about the investigator's ownership interest in the sponsor or the study drug, and more generally 
about his/her financial ties with the sponsor.  OPKO Ireland Global Holdings Ltd. will use and disclose the 
information solely for the purpose of complying with regulatory requirements. 
Hence, I: 
 
Agree to supply OPKO Ireland Global Holdings Ltd. with any information regarding ownership interest 
and financial ties (including those of my spouse and dependent children), including with OPKO Health, 
Inc., and any of its affiliates. 
 
Agree to update this information if any relevant changes occur during the course of the study and for one 
year following completion of the study. 
 
Agree that OPKO Ireland Global Holdings Ltd. may disclose this information about such ownership 
interests and financial ties to regulatory authorities. 
 
 
Signed: 
 
 
Date:  
 
 
Printed Name:   
 


Signature Page for Protocol DPO-203 v4.0
Signature Page for RIM-CLIN-000470 v4.0
Approval
Medical
09-Oct-2018 19:53:38 GMT+0000
PPD

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
A PHASE 2, DOUBLE-BLIND, DOSE ESCALATION REGIMEN OF 
ONCE-WEEKLY OPK-88003 IN SUBJECTS WITH TYPE 2 DIABETES 
 
 
Protocol Number: 
DPO-203 
Phase:  
2 
Investigational Product: 
OPK-88003 
IND Number: 
113480 
Indication: 
Type 2 Diabetes Mellitus 
Sponsor: 
OPKO Ireland Global Holdings Ltd.  
(a subsidiary of OPKO Health, Inc.) 
Sponsor Contact: 
Dr. 
  
 Medical Development  
Transition Therapeutics Corp. ULC 
101 College St, Suite 220 
Toronto, ON  M5G 1L7  
Email: 
   
Phone: 
 
Protocol: 
V1 / January 24, 2018 
V2 / May 16, 2018  
V3 / October 9, 2018 
 
 
 
 
SAP: 
V2.0 / February 4, 2019 
 
 
 
 
Confidentiality Statement 
The information contained in this protocol is confidential and proprietary information 
of OPKO Ireland Global Holdings Ltd. and/or its affiliates, and intended for use by 
clinical investigators in connection with the clinical investigation of OPK-88003.  It 
should not be copied or distributed to persons not involved in such investigation unless 
such persons are bound by written confidentiality agreement with OPKO Ireland 
Global Holdings Ltd. or its affiliates. 
PPD
PPD
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DPO-203 Statistical Analysis Plan 
Page 3 of 21 
 
TABLE OF CONTENTS 
1 
SUMMARY OF CHANGES ........................................................................................................... 5 
2 
INTRODUCTION ........................................................................................................................... 5 
3 
STUDY OBJECTIVES .................................................................................................................... 5 
3.1 
Primary Objective .................................................................................................................. 5 
3.2 
Secondary Objectives ............................................................................................................. 5 
3.3 
Other Objectives .................................................................................................................... 6 
4 
STUDY OVERVIEW ...................................................................................................................... 6 
4.1 
Study Design .......................................................................................................................... 6 
4.2 
Randomization and Treatments .............................................................................................. 7 
5 
ANALYSIS ENDPOINTS............................................................................................................... 8 
5.1 
Primary Efficacy Endpoint ..................................................................................................... 8 
5.2 
Secondary Efficacy Endpoints ............................................................................................... 8 
5.3 
Additional Secondary Endpoints ............................................................................................ 8 
5.4 
Other Endpoints ..................................................................................................................... 8 
5.5 
Safety Endpoints .................................................................................................................... 9 
6 
STATISTICAL METHODOLOGY ................................................................................................ 9 
6.1 
Sample Size Determination .................................................................................................... 9 
6.2 
Baseline, Endpoint, and Other Statistical Considerations .................................................... 10 
6.3 
Analysis Populations ............................................................................................................ 11 
6.3.1 
ITT Population ........................................................................................................ 11 
6.3.2 
mITT Population ..................................................................................................... 11 
6.3.3 
Safety Population .................................................................................................... 11 
6.3.4 
Per-Protocol Population .......................................................................................... 12 
6.4 
Subject Disposition .............................................................................................................. 12 
6.5 
Demographic and Baseline Characteristics .......................................................................... 12 
6.6 
Medical History .................................................................................................................... 13 
6.7 
Prior and Concomitant Medications ..................................................................................... 13 
6.8 
Study Medication Exposure and Compliance ...................................................................... 13 
6.9 
Efficacy Analysis ................................................................................................................. 14 
6.9.1 
Primary Efficacy Endpoint ...................................................................................... 14 
6.9.2 
Secondary Endpoints ............................................................................................... 15 
6.9.2.1 
HbA1c/Responder Analysis ............................................................................... 15 
6.9.2.2 
Body Weight....................................................................................................... 16 
6.9.2.3 
Fasting Plasma Glucose ...................................................................................... 16 
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6.11 Safety Analysis .................................................................................................................... 18 
6.11.1 Adverse Events ........................................................................................................ 18 
6.11.2 Vital Signs ............................................................................................................... 19 
6.11.3 Clinical Laboratory Evaluations .............................................................................. 20 
6.11.4 12-Lead ECG .......................................................................................................... 20 
6.11.5 Other Safety Parameters .......................................................................................... 20 
7 
GENERAL INFORMATION ........................................................................................................ 20 
7.1 
Statistical Software............................................................................................................... 20 
8 
CHANGES FROM THE PROTOCOL PLANNED ANALYSES ................................................ 20 
8.1 
Sample Size Determination .................................................................................................. 20 
8.2 
Primary and Secondary Analyses ......................................................................................... 21 
 
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1 
SUMMARY OF CHANGES 
SAP Version History 
Version Date 
Description of Changes 
1.0 
Jan. 15, 2019 
Original signed version. 
2.0 
Feb. 4, 2019 
 
 
 
 
2 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a description of the statistical methods and 
procedures to be implemented for the analyses of efficacy and safety data from OPKO 
Ireland Global Holdings Ltd. Protocol DPO-203. Any deviations from this analysis plan will 
be substantiated by sound statistical rationale and will be documented in the final clinical 
study report. Analysis of immunogenicity 
 analysis will be addressed in 
separate reports. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
To evaluate the effect of dose escalation of once-weekly (QW) subcutaneous (SC) 
OPK-88003 versus placebo injections on HbA1c absolute change from baseline to after 30 
weeks treatment in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled 
with diet and exercise alone, or treated with a stable dose of metformin. 
3.2 
Secondary Objectives 
The secondary objectives of this study are to determine the effect of OPK-88003 vs placebo 
on:  
1. Mean percent (%) body weight change from baseline to after 30 weeks treatment, 
2. Percent (%) of subjects with 5% or greater body weight loss after 30 weeks treatment, 
3. Change of fasting plasma glucose (FPG) from baseline to after 30 weeks treatment, 
and 
4. Number and percent (%) of subjects achieving HbA1c ≤ 6.5%. 
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3.3 
Other Objectives 
Other objectives of this study are as follows: 
3. Percent (%) of subjects permanently discontinued from the study due to 
hyperglycemia; 
4. Incidence and rate of gastrointestinal (GI) events, major cardiovascular (CV) events, 
hypoglycemia, injection site reactions, hypersensitivity reactions and pancreatic 
events; 
5. To evaluate immunogenicity of OPK-88003 (a separate ADA report will be 
provided);  
4 
STUDY OVERVIEW 
4.1 
Study Design 
Study DPO-203 is a randomized, double-blind, dose escalation, placebo-controlled, phase 2 
multicenter trial in subjects with T2DM.  There will be up to approximately 30 
investigational sites.  The trial consists of four phases: a screening/baseline phase (up to 2 
weeks prior to first dose), a 30-week treatment period consisting of a dose escalation phase (8 
weeks) and a target dose phase (22 weeks), and a follow-up period (4 weeks).  Subjects will 
be randomly assigned to OPK-88003 or placebo administered QW. 
 
 
 
 
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Study Design for DPO-203 
 
The schedule of events for the study is provided in Protocol Appendix 1. 
4.2 
Randomization and Treatments 
Subjects who meet all eligibility criteria will be randomized to treatment at visit 2 (day 1). 
via the Interactive Response Technology system (IRT). Randomization will be stratified 
using the following variables: screening HbA1c (<8.5%, ≥8.5%) and baseline body mass 
index (BMI) (<30, ≥30 kg/m2). The randomization to the treatment arms will be 1.75:1 for 
the active and placebo groups, respectively. Following randomization, study drug will be 
dispensed in a double-blinded manner. OPK-88003 and matching placebo are provided in 
single-use 2 mL glass vials with blue flipoff lid, an aluminum seal and a rubber stopper 
(septum). 
This trial will evaluate 20 mg and 40 mg dose escalation and 70 mg target dose of 
OPK-88003 QW over a 30-week treatment period. Treatment allocation will be assigned by 
the IRT. The group randomized to OPK-88003 will initially receive 20 mg QW for four 
weeks, followed by 40 mg QW for four weeks.  Once eight weeks of dose escalation are 
complete, subjects will receive a target dose of 70 mg QW OPK-88003 for 22 weeks. The 
control group will receive matched placebo SC injections QW for 30 weeks. 


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DPO-203 Statistical Analysis Plan 
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5 
ANALYSIS ENDPOINTS  
5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is absolute change in HbA1c from baseline to Week 30. If the 
Week 30 measurement is missing, the last valid post-baseline observation (last post-baseline 
observation carried forward [LOCF]) algorithm will be applied to impute the missing 
Week 30 value only for subjects that have discontinued early due to hyperglycemia (Week 
30/LOCFH). Otherwise, no imputation will be made for the missing Week 30 values. 
5.2 
Secondary Efficacy Endpoints 
 Percent (%) change in body weight from baseline to Week 30, 
 Number and percent of subjects with 5% or greater body weight loss at Week 30 (i.e. 
percent change ≤ -5%), 
 Absolute change in FPG from baseline to Week 30/LOCFH, and  
 Number and percent of subjects achieving HbA1c ≤ 6.5% at Week 30/LOCFH. 
5.3 
Additional Secondary Endpoints 
 Absolute change in body weight from baseline to Week 30; 
 Absolute change and percent (%) change in body weight from baseline to Weeks 4, 8, 
12, 16, 22, 26, 30, and 34 without LOCF; 
 Number and percent of subjects achieving ≥ 5% weight loss at Weeks 4, 8, 12, 16, 22, 
26, 30, and 34 without LOCF; 
 Absolute change in FPG from baseline to Weeks 4, 8, 12, 16, 22, 26, 30/LOCFH, and 
34; 
 Absolute change in HbA1c from baseline to Weeks 4, 8, 12, 22, 30/LOCFH, and 34; 
 Number and percent of subjects achieving HbA1c ≤ 6.5% at Weeks 4, 8, 12, 22, 
30/LOCFH, and 34; 
 Number and percent of subjects achieving HbA1c < 7.0% at Week 30/LOCFH; and 
 Number and percent of subjects achieving HbA1c < 7.0% at Weeks 4, 8, 12, 22, 30, 
and 34 without LOCF. 
5.4 
Other Endpoints 
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 Number and percent of subjects permanently discontinued from the study due to 
hyperglycemia; 
5.5 
Safety Endpoints 
 Number and percent of subjects (including number of events) experiencing treatment-
emergent AEs (TEAEs) and serious AEs (SAEs); 
 Number and percent of subjects experiencing AEs of special interest (AESIs)  as 
defined by protocol (GI events such as nausea, vomiting, and diarrhea; major CV 
events; hypoglycemia; injection site reactions; hypersensitivity reactions; and 
pancreatic events); 
 Vital signs (blood pressure and pulse rate); 
 Safety laboratory measures (chemistry, hematology, and urinalysis); and 
 12-lead electrocardiograms (ECG). 
6 
STATISTICAL METHODOLOGY 
6.1 
Sample Size Determination 
Subjects will be randomized at an approximate ratio of 1.75:1 (OPK-88003:placebo). A 
sample size of 48 subjects in the active arm and 27 subjects in the placebo arm will provide 
at least 90% power to detect superior glycemic control over placebo represented by -0.8% in 
HbA1c levels after 30 weeks of treatment. This assumes a common standard deviation (SD) 
of 1.0% and a two-sided alpha of 0.05. The assumptions are based on variability in 
previously obtained HbA1c results from the OPK-88003 phase 2 trial XNAA.  
Approximately 110 subjects were enrolled in an effort to obtain 88 completed subjects (56 
subjects completing in the active arm and 32 subjects completing in the placebo arm).  
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event of treatment allocation errors, subjects will be analyzed for safety according to the 
treatment group they received. 
6.3.4 
Per-Protocol Population 
The Per-Protocol (PP) Population is defined as all randomized subjects who were compliant 
with study drug, completed at least 26 weeks of treatment or discontinued early due to 
hyperglycemia, and are a subset of the mITT Population. The PP Population will be used to 
assess robustness of the primary analysis results. 
The following criteria may be evaluated for major deviations prior to unblinding the study 
database. A final listing of all subjects to be excluded from the PP Population will be 
completed prior to unblinding the study database. 
 No eligibility criterion violations; 
 Did not withdrawal prior to Week 26 if the reason is other than hyperglycemia; 
 Subjects who did not miss more than 4 doses of study drug throughout the course of 
the study; 
 Subjects who did not miss 2 consecutive doses of study drug during the dose 
escalation phase; 
 Not taking any prohibited medications (treatment with medications that are excluded 
in the entry criteria is not permitted); and 
 No other substantial protocol deviations. 
6.4 
Subject Disposition 
Frequencies and percentages of all randomized, discontinued, and completed subjects in the 
study will be presented by treatment group and total.  The reasons for discontinuations will 
be summarized by treatment group.  Discontinuation rates will be compared between the 
treatment groups for each reason using a Fisher’s exact test. 
6.5 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively by treatment 
group and total for the ITT Population. If they differ from the ITT Population, summaries 
will also be provided for the mITT Population, PP Population, and Safety Population. 
Demographic and baseline characteristics include, but are not limited to, age at informed 
consent, gender, race, ethnicity, body weight, BMI, BMI stratification group (<30 or ≥30 
kg/m2), baseline HbA1c, HbA1c stratification group (<8.5% or ≥8.5%), and baseline FPG. 
The baseline is defined in Section 6.2, Baseline, Endpoint, and Other Statistical 
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For categorical variables, comparisons between treatment groups will be assessed using a 
Pearson Chi-Square test.  For continuous variables, comparisons between the treatment 
groups will be performed using a one-way Analysis of Variance (ANOVA) with treatment as 
the fixed effect. 
6.6 
Medical History 
Medical/surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.1. All medical history will be listed. 
6.7 
Prior and Concomitant Medications 
Medication start and stop dates that are recorded on the Prior & Concomitant Medications 
case report form will be used to determine whether the medications are prior or concomitant 
to the study drug. Medications ongoing at the time of first dose of study drug (Visit 2 
Week 0) as well as any new medication added during the course of the study will be 
considered concomitant medications. Prior medications are defined as those used prior to and 
stopped before the first dose of study drug. All prior and concomitant medication verbatim 
terms will be coded using the World Health Organization Drug Dictionary September 2017 
Global B3 version. The numbers and percentages of subjects taking concomitant medications 
in each treatment group and in total will be summarized by anatomic therapeutic chemical 
term and preferred term for the Safety Population. All prior and concomitant medications 
will be listed. 
6.8 
Study Medication Exposure and Compliance 
Subjects’ exposure to study drug will be summarized with descriptive statistics for the Safety 
Population. Weeks of exposure is defined as: 
(date of last dose of study drug – date of first dose + 1) ÷ 7 
The total number of injections administered will be calculated for each subject. A 
contingency table will be provided to display the number and percentage of subjects in each 
treatment group with the following number of injections: 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, 
25-30. 
Subjects that miss more than four doses of study drug over the course of study participation, 
or miss two consecutive doses of study drug during the dose escalation phase, are considered 
noncompliant. The frequency and percentage of subjects who are compliant and 
noncompliant will be summarized by treatment group. 


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6.9 
Efficacy Analysis 
6.9.1 
Primary Efficacy Endpoint 
The primary efficacy analysis is to evaluate the effect of dose escalation of OPK-88003 
versus placebo injections on HbA1c absolute change from baseline to Week 30. If the Week 
30 measurement is missing, the LOCF algorithm will be applied to impute the missing 
Week 30 value only for subjects that have early termed due to hyperglycemia (Week 
30/LOCFH). Otherwise, no imputation will be made. The primary analysis will be based on 
the mITT Population. The same analysis will be repeated on the PP Population. 
The change from baseline in HbA1c at each scheduled visit will be analyzed using a mixed-
model repeated-measures (MMRM).  The factors in the model will be BMI strata, treatment 
group, baseline HbA1c value, visit, and the treatment group by visit interactions. An 
unstructured covariance matrix will be used (TYPE=UN). No imputation will be performed 
except for subjects that early term due to hyperglycemia. The least-squares means for change 
from baseline at each visit will be estimated and compared between treatment groups, with 
Week 30 being primary, and no adjustments for multiplicity.  The sample SAS code can be 
found below:  
***********************************************************************  
Note:   
  USUBJID = unique subject identifier  
  TREATMENT = 0 (placebo), 1 (OPK-88003) 
  BMI: <30 or >=30 kg/m2 
  VISIT = visit  
  BASE = baseline value  
  CHG = change from baseline to the specified visit  
**********************************************************************;  
proc mixed;   
  class USUBJID BMI TREATMENT VISIT;   
  model CHG = BMI TREATMENT BASE VISIT TREATMENT*VISIT;   
  Repeated VISIT / TYPE=UN sub=USUBJID;   
  lsmeans VISIT*TREATMENT / cl slice=VISIT;   
run;   
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Supportive Analysis  
If the Week 30 HbA1c measurement is missing, the LOCF algorithm will be applied to 
impute the missing Week 30 value for all subjects (Week 30/LOCFAll). The change from 
baseline to Week 30/LOCFAll in HbA1c will be analyzed using linear contrasts from an 
analysis of covariance (ANCOVA) model with treatment group and BMI strata (<30, ≥30 
kg/m2) as factors and the baseline HbA1c value as a covariate. The least-squares means, 
standard errors, and the 2-tailed 95% confidence intervals (CIs) for each treatment group and 
for comparison of OPK-88003 to placebo will be presented. The 2-sided p-values testing for 
significance within treatment group change from baseline and comparison between treatment 
groups will be presented. 
The sample SAS code can be found below: 
*********************************************************************** 
Note:  
  TREATMENT = 0 (placebo), 1 (OPK-88003) 
  BASE: baseline HbA1c 
  BMI: <30 or >=30 kg/m2 
  CHG: change from baseline to Week 30/LOCF in HbA1c  
**********************************************************************; 
proc glm; 
  class TREATMENT BMI; 
  model CHG = TREATMENT BASE BMI / ss1 ss3; 
  means TREATMENT; 
  lsmeans TREATMENT / cov stderr pdiff cl; 
  estimate " OPK-88003 : Placebo" TREATMENT -1 1; 
run; 
Before this analysis is performed, the data will be inspected for normality and homogeneity 
of variance, and a non-parametric rank test will be applied if necessary. 
The appropriateness of the statistical model will be evaluated by testing the treatment group 
by baseline HbA1c interaction at a significance level of 0.10. 
 
 
 
6.9.2 
Secondary Endpoints 
6.9.2.1 
HbA1c/Responder Analysis 
The number and percentage of subjects achieving HbA1c ≤6.5% will be summarized for each 
treatment group at each scheduled visit without LOCF, Week 30/LOCFH, and Week 
30/LOCFAll. Comparisons between treatment groups will be performed for responses at each 
visit, with Week 30/ LOCFH being primary, based on a logistic regression model with 
treatment group and BMI strata as factors and baseline HbA1c as a covariate. Odds ratios, 
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95% CIs (Wald), and p-values will be presented. The same summary and analysis will be 
performed for HbA1c <7.0%. 
6.9.2.2 
Body Weight 
The change from baseline and percent change from baseline in body weight at each 
scheduled visit will be analyzed using an MMRM for the mITT Population and repeated on 
the PP Population. The factors in the model will be HbA1c strata, BMI strata, treatment 
group, baseline value, visit, and the treatment group by visit interactions.  An unstructured 
covariance matrix will be used (TYPE=UN). No imputation will be performed. The least-
squares means for change from baseline at each visit will be estimated and compared 
between treatment groups.   
As a supportive analysis, the change from baseline and percent change from baseline to 
Week 30/LOCFAll in body weight will be analyzed for the mITT Population using linear 
contrasts from an analysis of covariance (ANCOVA) model with treatment group, HbA1c 
strata (<8.5%, ≥8.5%), and BMI strata (<30, ≥30 kg/m2) as factors and the baseline body 
weight value as a covariate. The least-squares means, standard errors, and the 2-tailed 95% 
confidence intervals (CIs) for each treatment group and for comparison of OPK-88003 to 
placebo will be presented. The 2-sided p-values testing for significance within treatment 
group change from baseline and comparison between treatment groups will be presented.  
The number and percentage of subjects achieving >5% weight loss will be summarized for 
each treatment group at each scheduled visit without LOCF and Week 30/LOCFAll. 
Comparisons between treatment groups will be performed for responses at Week 30 based on 
a logistic regression model with treatment group, HbA1c strata, and BMI strata as factors and 
baseline body weight as a covariate. Odds ratios, 95% CIs (Wald), and p-values will be 
presented.  
6.9.2.3 
Fasting Plasma Glucose 
The same MMRM and ANCOVA model as for body weight above will be performed for the 
change from baseline in FPG. If Week 30 measurement is missing, the last valid post-
baseline observation (LOCF) algorithm will be applied to impute the missing Week 30 value 
only for subjects that have early termed due to hyperglycemia (Week 30/LOCFH). 
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6.11 
Safety Analysis 
All safety analyses will be conducted on the Safety Population. The evaluation of safety will 
be based primarily on discontinuation due to hyperglycemia, TEAEs, vital signs, safety 
laboratory measures, and 12-lead ECG. Other safety data will be summarized as appropriate. 
6.11.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. All AEs, including SAEs, occurring after the subject signs 
the informed consent form (ICF) through the subject’s final visit will be reported and 
monitored. All AEs will be coded using MedDRA version 20.1. 
TEAEs are defined as events that are newly reported after first dose of study drug or reported 
to worsen in severity or relationship to study drug after first dose of study drug.  
An overview of AEs will be provided by treatment group and in total for the following 
information: 
 All TEAEs, 
 Maximum severity of TEAEs, 
 Study drug-related TEAEs (defined as related or possibly related), 
 Maximum severity of drug-related TEAEs, 
 All serious adverse events (SAEs), 
 All treatment-emergent SAEs, 
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 Drug-related SAEs, 
 Death due to AEs, 
 Withdrawals due to AEs, and 
 Withdrawals due to study drug-related AEs. 
The numbers and percentages of subjects with TEAEs, including number of events, will be 
tabulated for each treatment group and in total by MedDRA system organ class and preferred 
term. Similar summaries will be provided by maximum severity. Drug-related TEAEs will be 
summarized in the same manner.  
Listings of SAEs and AEs leading to study medication discontinuation will be provided. 
Hyperglycemia 
The number and percent of subjects permanently discontinued from the study due to 
hyperglycemia will be tabulated by treatment group for the Safety Population. The 
discontinuation rates will be compared among the treatment groups using a Fisher’s exact 
test. The odds ratio will be provided. 
AEs of Special Interest 
The number and percent of subjects (including number of events) experiencing AESIs (GI 
events, major CV events, hypoglycemia, injection site reactions, hypersensitivity reactions 
and pancreatic events) will be tabulated for each treatment group and in total by category and 
preferred term. A listing will be provided of all AEs of special interest. For hypoglycemia, 
listings will be provided of all additional information such as glucose values, symptoms, 
countermeasures, etc. For injection site reactions, listings will be provided of all additional 
information such as symptoms, severity of each symptom, etc. 
If data allows, the monthly hypoglycemia rate will be calculated as the event rate per subject 
year divided by 12 months: 
(365.25 × total number of hypoglycemia TEAEs / study duration) ÷ 12 
Where study duration is the date of completion/early termination – date of first dose +1. 
Summary statistics for the monthly hypoglycemia rate will be provided by treatment group. 
6.11.2 
Vital Signs  
Systolic blood pressure, diastolic blood pressure, and pulse rate will be summarized at 
baseline and each scheduled post-baseline visit. The change from baseline will also be 
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6.11.3 
Clinical Laboratory Evaluations 
Summary statistics will be provided for safety laboratory tests at baseline and all scheduled 
post-baseline visits for chemistry, hematology, and urinalysis assessments by treatment group 
and in total. The change from baseline to post-baseline visits will also be presented.  
The number and frequency of subjects with laboratory abnormalities (worst value post first 
dose for each subject) will be summarized by treatment group and in total. Shift tables from 
baseline to worst value post first dose will be presented for ALT and AST (>1xULN to 
≤2xULN, >2xULN to ≤3xULN, >3xULN) and CK (>1xULN to ≤5xULN, >5xULN to 
≤10xULN, >10xULN). 
6.11.4 
12-Lead ECG 
Summary statistics will be provided for triplicate 12-Lead ECG assessments (vent rate, PR 
interval, QRS duration, QT interval, RR interval, QTcB, QTcF) at baseline and all scheduled 
post-baseline triplicate visits. The change from baseline to post-baseline visits will also be 
provided. The triplicate readings will be averaged prior to summarization. The single ECG 
assessments (screening and follow-up) will be summarized separately from the triplicate 
ECG assessments. The overall interpretation will be summarized by scheduled visit with 
counts and percentages by treatment group and in total. All ECG assessments will be listed. 
6.11.5 
Other Safety Parameters 
All other safety parameters such as physical examination will be listed. 
7 
GENERAL INFORMATION 
The mock-ups for SAS-generated tables/figures/listings will be prepared in a separate 
document and finalized before database lock for the study. 
7.1 
Statistical Software 
The creation of analysis datasets and all statistical analyses will be done using SAS® version 
9.4. The Medpace standard operating procedures will be followed for the validation of all 
SAS programs and outputs. 
8 
CHANGES FROM THE PROTOCOL PLANNED ANALYSES 
8.1 
Sample Size Determination 
Per Protocol V2 and V3, 88 subjects are needed to obtain at least 90% power to detect 
superior glycemic control over placebo. However, the dropout rate (assumed 20%) was 
considered twice in the derivation. Only at least 73 subjects are needed to obtain 90% power. 


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8.2 
Primary and Secondary Analyses 
In the Protocol, an ANCOVA model is specified for the primary efficacy analysis and 
MMRM is the supportive analysis of the primary outcome. However, there has been a higher 
than expected number of subjects that have discontinued early, particularly early in the study. 
Taking into consideration the early dropouts and the current approaches used to analyze data 
from diabetes trials, the primary efficacy analysis will use MMRM and ANCOVA will be a 
sensitivity analysis. Analyses of the applicable secondary 
 endpoints will also 
use MMRM. This change is made prior to database lock and treatment unblinding.  
Since MMRM will be used as the primary and secondary endpoint analyses, LOCF will not 
be applied to the Week 30 endpoints. However, it is deemed appropriate to use LOCF for 
subjects that discontinued due to hyperglycemia. 
 
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