Conditions: Diabetes Mellitus Type 2 in Obese
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 64
Healthy volunteers: no

Brief summary:
This is a double-blind, randomized, placebo-controlled, parallel-group comparison study to evaluate the efficacy and safety of Cyclo-Z for the treatment of subjects with obese type 2 diabetes.

The study will consist of 3 phases:

* Screening phase (2 weeks)
* Treatment phase (12 weeks)
* Follow-up phase (2 weeks)

Following a 2-week screening period, subjects who meet all inclusion and exclusion criteria will be randomly assigned into one of the following treatment arms:

* Dose A: Cyclo-Z containing 23 mg zinc plus 3 mg CHP - 16 subjects
* Dose B: Cyclo-Z containing 23 mg zinc plus 9 mg CHP - 16 subjects
* Dose C: Cyclo-Z containing 23 mg zinc plus 15 mg CHP - 16 subjects
* Dose D: Placebo - 16 subjects

The assigned dose will be orally administered to subjects once a day before bedtime for 12 consecutive weeks. After the randomization at Week 0 (Visit 2), subjects will visit their respective trial sites at Weeks 2, 4, 6, 8, 10, 12, and 14 (Visits 3, 4, 5, 6, 7, 8, and 9).

Detailed description:

Arms:
arm 1: Cyclo-Z containing 23 mg zinc plus 3 mg CHP arm 2: Cyclo-Z containing 23 mg zinc plus 9 mg CHP arm 3: Cyclo-Z containing 23 mg zinc plus 15 mg CHP arm 4: Placebo

Interventions: intervention 1: Cyclo-Z intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_001.pdf: 
NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 1 of 53 
 
 
 
Clinical Study Protocol  
 
 
 
Protocol Title:  
A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Phase 2 Study to Evaluate the Efficacy and Safety of Cyclo-Z in 
Patients with Obese Type 2 Diabetes 
 
Protocol Number: 
 
NMP-CYZ-P2-001 
 
Date of Protocol/Version: 
December 9, 2016 / Ver 2.4 
 
 
 
 
 
 
(Previous: May 23, 2016 / Ver 2.3)  
 
Product: 
Cyclo-Z 
 
IND No.: 
61,897 
 
Study Phase: 
2 
 
Sponsor: 
NovMetaPharma Co., Ltd. 
 
 
 
 
 
 
 
Confidentiality Statement 
 
This document and the information contained herein or attached hereto (“Confidential Material”) are 
confidential and proprietary to NovMetaPharma Co., Ltd. (“NMP”). This Confidential Material should be 
viewed only by those individuals or companies that have been given prior authorization to do so by NMP 
(“Authorized Users”). This Confidential Material should not be made available in any form to any person 
or company, other than the Authorized Users and their respective employees or associates on a need-to-
know basis, without the prior written consent from NMP. 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 2 of 53 
Protocol Signature Page 
 
I have carefully read the attached protocol entitled “A Multicenter, Randomized, Double-blind, 
Placebo-controlled, Phase 2 Study to Evaluate the Efficacy and Safety of Cyclo-Z in Patients 
with Obese Type 2 Diabetes” dated December 9, 2016 and agree to its terms including principles of 
disclosure and confidentiality. 
 
I agree to submit this protocol to the Institutional Review Board to obtain its approval prior to initiation of 
the study. 
 
I also agree to comply with the International Conference on Harmonization (ICH) Tripartite Guidelines 
on Good Clinical Practice, and applicable regulations/guidelines set forth in the Code of Federal 
Regulations Title 21, Parts 11, 50, 54, 56, and 312. 
 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of NovMetaPharma Co., Ltd. 
 
 
 
 
Signature 
 
 
 
Name of Principal Investigator 
 
Date  
 
 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 3 of 53 
Protocol Version and Amendment Tracking 
 
Version Number/Amendment 
Approval Date 
1.0 
October 2, 2013 
2.0 
January 8, 2015 
2.1 
February 27, 2015 
2.2 
April 29, 2016 
2.3 
May 23, 2016 
2.4 
December 9, 2016 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 4 of 53 
Protocol Synopsis 
 
Name of Sponsor/Company: NovMetaPharma Co., Ltd. 
Study Product: Cyclo-Z  
Protocol Number 
NMP-CYZ-P2-001 
Indication 
Obese Type 2 Diabetes 
Protocol Title 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study to Evaluate 
the Efficacy and Safety of Cyclo-Z in Patients with Obese Type 2 Diabetes 
Study 
Development 
Phase 
2 
Planned Number of 
Subjects 
Total of 64 subjects (4 groups) 
Objectives 
The primary objective is to assess the dose-dependent efficacy of Cyclo-Z for the 
treatment of subjects with obese type 2 diabetes.  
 
The secondary objective is to assess the safety of Cyclo-Z in the treatment of subjects with 
obese type 2 diabetes. 
Clinical Endpoints 
The primary clinical efficacy variables used to evaluate the efficacy of Cyclo-Z are 1) the 
change of HbA1c level from baseline at Week 12 and 2) the change of body weight (BW) 
from baseline at Week 12.  
 
The secondary clinical efficacy variables used to evaluate the efficacy of Cyclo-Z are: 
• 
Change of fasting plasma glucose (FPG) level from baseline at Week 12 
• 
Proportion of subjects achieving HbA1c goal of <7.0% at Week 12 
• 
Proportion of subjects achieving HbA1c goal of <6.5% at Week 12 
• 
Change in waist circumference from baseline at Week 12 
• 
Change of postprandial (2 hours after dinner) blood glucose level from baseline 
at Week 12 
• 
Change of OGTT from baseline at Week 12 
• 
Change of score in Audit of Diabetes-Dependent Quality of Life (ADDQoL) 
Questionnaire from baseline at Week 12 
 
In addition to the primary and secondary endpoints, the following exploratory efficacy 
variables will be separately evaluated for the change from baseline at Week 12:   
• 
Thyroid Function Test (TSH, T3, and T4) 
• 
Serum Parameters: zinc, insulin, adiponectin, C-peptide, leptin, glucagon 
• 
Urine Parameters: zinc, glucose, microalbumin, copper 
 
The safety variables include: 
• 
Blood samples for complete laboratory evaluation 
• 
ECG evaluation  
• 
Physical examination 
• 
Vital signs 
• 
Adverse events 
• 
Episodes of hypoglycemia and hyperglycemia 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 5 of 53 
Name of Sponsor/Company: NovMetaPharma Co., Ltd. 
Study Product: Cyclo-Z  
Protocol Number 
NMP-CYZ-P2-001 
Indication 
Obese Type 2 Diabetes 
 
In a subset of subjects, Cyclic dipeptide (his-pro) (CHP) levels in blood may be measured. 
Study Design 
This is a double-blind, randomized, placebo-controlled, parallel-group comparison study 
to evaluate the efficacy and safety of Cyclo-Z for the treatment of subjects with obese type 
2 diabetes.  
 
The study will consist of 3 phases:  
• Screening phase (2 weeks)  
• Treatment phase (12 weeks) 
• Follow-up phase (2 weeks) 
 
Following a 2-week screening period, subjects who meet all inclusion and exclusion 
criteria will be randomly assigned into one of the following treatment arms: 
• Dose A: Cyclo-Z containing 23 mg zinc plus 3 mg CHP – 16 subjects 
• Dose B: Cyclo-Z containing 23 mg zinc plus 9 mg CHP – 16 subjects 
• Dose C: Cyclo-Z containing 23 mg zinc plus 15 mg CHP – 16 subjects 
• Dose D: Placebo – 16 subjects 
 
The assigned dose will be orally administered to subjects once a day before bedtime for 12 
consecutive weeks. After the randomization at Week 0 (Visit 2), subjects will visit their 
respective trial sites at Weeks 2, 4, 6, 8, 10, 12, and 14 (Visits 3, 4, 5, 6, 7, 8, and 9).  
Inclusion/ 
Exclusion  
Criteria 
Eligibility will be determined based upon medical record review, physical examination, 
questionnaire and ECG results. All study subjects must meet the eligibility criteria based 
on the following inclusion and exclusion criteria: 
 
Inclusion Criteria:  
1. Males or females aged 18 or older. 
2. Subjects diagnosed with type 2 diabetes mellitus according to the American 
Diabetes Association (ADA) criteria. 
3. Subjects treated with stable doses of insulin and/or other hypoglycemic agent(s) for 
type 2 diabetes mellitus for at least 2 months prior to randomization. 
4. Subjects whose fasting blood glucose levels are reasonably stable for at least 2 
months prior to randomization and during the 2-week screening period. Stable 
glucose levels are defined based on the fact that the study subjects did not change 
the dose and/or type of insulin injection and/or other hypoglycemic agent(s) during 
the last 2 months and during the 2-week screening period to adjust blood glucose. 
5. Subjects who have Hemoglobin A1c levels of 7.5 to 10.0 % at Screening. 
6. Subjects whose BMI is 30 or above. 
7. Subjects who can give written informed consent. 
 
Exclusion criteria:  
1. Subjects who have any DM-related end-organ damages.  
2. Subjects who have a history of diabetic ketoacidosis or hyperosmolar non-ketotic 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 6 of 53 
Name of Sponsor/Company: NovMetaPharma Co., Ltd. 
Study Product: Cyclo-Z  
Protocol Number 
NMP-CYZ-P2-001 
Indication 
Obese Type 2 Diabetes 
coma. 
3. Subjects who have any disease likely to limit life span and/or increase risks of 
interventions such as: 
• Carotid B-mode ultrasound test results indicating clinically significant stenosis in 
the common carotid arteries requiring intervention by angioplasty or resection. 
• Cancer treatment in the past 5 years, with the exception of cancers which have 
been cured, and carry a good prognosis. 
• Infectious disease:  HIV positivity, active tuberculosis, or pneumonia. 
4. Subjects who have any of the following conditions related to cardiovascular disease: 
• Hospitalization for the treatment of heart disease in the past 12 months. 
• New York Heart Association Functional Class > 2. 
• Left Bundle branch block on ECG at Screening. 
• Third degree atrioventricular block on ECG at Screening. 
• Uncontrolled hypertension with average systolic blood pressure of > 160 mmHg 
or diastolic blood pressure > 95 mmHg at Screening and Baseline. 
• Pulse rate > 95 beats per minute at Screening and Baseline. 
• Stroke or transient ischemic attack in the past 12 months. 
5. Subjects who have any of the following conditions related to gastrointestinal 
disease: 
• Chronic hepatitis or cirrhosis. 
• Episode of alcoholic hepatitis or alcoholic pancreatitis in the past 2 months. 
• Inflammatory bowel disease requiring treatment in the past 12 months. 
• Significant abdominal surgery (e.g., gastrectomy, gastric bypass) in the past 2 
months. 
6. Subjects who have serum creatinine > 1.5 mg/dL for male or > 1.4 mg/dL for 
female. 
7. Subjects who have chronic obstructive airway disease or asthma requiring daily 
therapy or home use oxygen. 
8. Subjects who have hematocrit < 36.0% for male or < 33.0% for female. 
9. Subjects who have any of the following conditions or behaviors likely to affect the 
conduct of the study: 
• Weight loss of > 10% in the past 6 months. 
• Unable to walk without assisted device. 
• Major psychiatric disorder which would impede conduct of the research.                
• Excessive alcohol intake (i.e., more than 2 drinks/day). 
10. Subjects who take any of the following medications: 
• Psychoactive agents such as monoamine oxidase inhibitors and antidepressants 
(e.g., lithium, Prozac, Zoloft, Serzone, Paxil, Effexor). 
• Any other medications that may pose harm to the subject. 
11. Female subjects who have a positive serum pregnancy test at Screening, plan a 
pregnancy during study period, or are breast feeding.  
12. Female subjects who don’t meet any of the following criteria: 
• Surgically sterile (i.e., have had bilateral tubal ligation, hysterectomy, or 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 7 of 53 
Name of Sponsor/Company: NovMetaPharma Co., Ltd. 
Study Product: Cyclo-Z  
Protocol Number 
NMP-CYZ-P2-001 
Indication 
Obese Type 2 Diabetes 
bilateral oophorectomy) at least 6 months before randomization.  
• Post-menopausal for at least 12 months prior to Screening. 
• If sexually active, they should use oral contraceptives, double barrier 
contraception (e.g., condom with spermicide), intrauterine device, or other 
methods approved by the Sponsor.  
Statistical Analysis 
This is a Phase 2 clinical trial to evaluate safety and explore the potential efficacy of the 
study drug. Therefore, the number of subjects was not based on formal statistical power 
considerations. In this clinical trial, a total of 64 subjects was deemed sufficient and will 
be enrolled and randomly assigned to be administered with 1 of 3 dose levels of Cyclo-Z 
or placebo. 
 
The co-primary variables, the reduction in HbA1c levels from baseline at Week 12 and the 
reduction of body weight (BW) from baseline at Week 12, will be analyzed using 
(ANOVA) methods if the change is approximately normally distributed. If the change is 
markedly non-normally distributed then Wilcoxon rank sum tests will be used.  
 
The continuous secondary efficacy variables will be analyzed with ANOVA or Wilcoxon 
rank sum tests, as appropriate. The categorical secondary efficacy variables will be 
analyzed with chi-square tests or Fisher’s exact tests, as appropriate.  
 
The continuous exploratory efficacy variables will be analyzed with ANOVA or 
Wilcoxon rank sum tests, as appropriate. The categorical exploratory efficacy variables 
will be analyzed with chi-square tests or Fisher’s exact tests, as appropriate. 
 
Safety variables will be summarized descriptively, by treatment group and visit. No 
formal statistical testing will be completed on the safety variables. 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 8 of 53 
Schedule of Assessments 
 
Note: A subject needs to visit the clinical site before breakfast for all study visits except the safety follow-up visit.  
 
 
Screening 
Treatment Period  
Follow-up 
Study Visits 1) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Screen 
(Wk -2) 
Baseline 
(Wk 0) Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 
Wk 14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Demographic (including height) 
X 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
 
 
 
 
Physical Examination  
X 
X 
 
X 
 
X 
 
X 
 
Vital Signs and Body Weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
Blood Sampling for serum chemistry, 
hematology, FPG, HbA1c, hCG, TSH, T3, and 
T4 2) 
X 
X 
 
X 
 
X 
 
X 
 
Blood Sampling for zinc, insulin, adiponectin, 
C-peptide, leptin, glucagon, (CHP in a subset 
of subjects 3)) 
 
X 
 
X 
 
X 
 
X 
 
Urine Sampling for glucose, microalbumin, 
copper, and zinc  
 
X 
 
X 
 
X 
 
X 
 
Dispense and Review Daily Log 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense and Review Medications 
 
X 
X 
X 
X 
X 
X 
X 
 
Waist Circumference 
 
X 
 
X 
 
X 
 
X 
 
OGTT 4)  
 
X 
 
 
 
 
 
X 
 
ADDQoL Questionnaire 
 
X 
 
 
 
 
 
X 
 
Review of Adverse Event and Concomitant 
Medication 5) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
1)  Visits 3 to 8 have ±3 day visit window and Visit 9 has +7 day visit window. 
 
2) Serum chemistry, hematology: Weeks -2, 0, 4, 8, and 12 
 
HbA1c: Weeks -2, 0, 4, 8, and 12 
 
FPG: Weeks 0, 4, 8, and 12 
 
TSH, T3, T4: Weeks 0 and 12  
 
Serum hCG (pregnancy): Weeks -2 and 12 
 
3) CHP levels may be analyzed in a subset of subjects if residual serum and/or plasma samples are available after completion of 
protocol-required tests. 
 
4) See Appendix 1. 
 
5) Assess hypoglycemic & hyperglycemic episodes at Visits 2 to 8 only. 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 9 of 53 
List of Abbreviations  
 
Abbreviation 
Definition 
AE 
Adverse Event 
BMI 
Body Mass Index 
BP 
BW 
Blood Pressure 
Body Weight 
cGMP 
Current Good Manufacturing Practice 
CHP 
Cyclo (His-pro) 
CRO 
 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cyclo 
Cyclic dipeptide 
DM 
Diabetes Mellitus 
DPP 
Dipeptidyl Peptidase 
DW 
Distilled Water 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FPG 
GCP 
Fasting Plasma Glucose 
Good Clinical Practice 
G-K 
GLP 
GLP-1 
Goto-Kakizaki 
Good Laboratory Practice 
Glucagon-like protein-1 
GLUT-4 
Glucose transporter-4 
GMP 
Good Manufacturing Practice 
HbA1c 
Hemoglobin A1c 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Insulin Degrading Enzyme 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
NIDDM 
OGTT 
PP 
Non-insulin-dependent Diabetes Mellitus 
Oral Glucose Tolerance Test 
Per-Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
S-D 
SEM 
SMC 
Standard Deviation 
Sprague-Dawley 
Standard Error of the Mean 
Safety Monitoring Committee 
SOP 
TAFGC 
Standard Operating Procedure 
Three-hour-area-average Above Fasting Glucose Concentration 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 10 of 53 
Table of Contents 
 
Protocol Synopsis ........................................................................................................................................ 4 
Schedule of Assessments ............................................................................................................................. 8 
List of Abbreviations ................................................................................................................................... 9 
1. 
Introduction ........................................................................................................................................ 12 
1.1 
Type 2 Diabetes / Non-insulin-dependent Diabetes Mellitus (NIDDM) ............................... 12 
1.2 
Cyclo-Z (Cyclic dipeptide (his-pro) or CHP plus zinc) ......................................................... 13 
1.3 
Rationale for Study Population .............................................................................................. 14 
2. 
Study Objective(s) .............................................................................................................................. 15 
2.1 
Primary Objective .................................................................................................................. 15 
2.2 
Secondary Objective .............................................................................................................. 15 
3. 
Study Endpoints ................................................................................................................................. 16 
3.1 
Efficacy Evaluation ................................................................................................................ 16 
3.2 
Exploratory Evaluation .......................................................................................................... 16 
3.3 
Safety Evaluation ................................................................................................................... 16 
3.4 
CHP Concentration Evaluation .............................................................................................. 16 
4. 
Investigational Plan ........................................................................................................................... 17 
4.1 
Overall Study Design ............................................................................................................. 17 
4.2 
Selection of Study Population ................................................................................................ 17 
4.2.1 
Inclusion Criteria ....................................................................................................... 17 
4.2.2 
Exclusion Criteria ...................................................................................................... 18 
4.3 
Subject Withdrawal ................................................................................................................ 19 
4.4 
Premature Termination of Study / Closure of Center ............................................................ 20 
5. 
Study Treatments ............................................................................................................................... 21 
5.1 
Treatment to be Administered ................................................................................................ 21 
5.2 
Identity of Investigational Product ......................................................................................... 21 
5.3 
Randomization ....................................................................................................................... 21 
5.4 
Selection of Doses in the Study .............................................................................................. 22 
5.5 
Choice of Controls/Comparators ............................................................................................ 22 
5.6 
Blinding .................................................................................................................................. 22 
5.7 
Prior and Concomitant Treatments ........................................................................................ 22 
5.8 
Subject Education on Hypoglycemia/Hyperglycemia and its Management .......................... 23 
5.9 
Medication Accountability and Treatment Compliance ........................................................ 23 
6. 
Study Procedures ............................................................................................................................... 25 
6.1 
Screening Period .................................................................................................................... 25 
6.2 
Treatment Period .................................................................................................................... 25 
6.2.1 
Visit 2 (Week 0): Baseline .......................................................................................... 25 
6.2.2 
Visits 3, 5, and 7 (Weeks 2, 6, and 10) ....................................................................... 26 
6.2.3 
Visits 4 and 6  (Weeks 4 and 8) .................................................................................. 26 
6.2.4 
Visit 8 (Week 12) or Early Termination Visit ............................................................ 27 
6.3 
Follow-up Period .................................................................................................................... 27 
6.4 
Other Information for Study Visits ........................................................................................ 28 
6.5 
Data Quality ........................................................................................................................... 28 
6.6 
Documentation ....................................................................................................................... 28 
7. 
Ethical and Legal Aspects ................................................................................................................. 29 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 11 of 53 
7.1 
Institutional Review Board (IRB) .......................................................................................... 29 
7.2 
Ethical Conduct of the Study ................................................................................................. 29 
7.3 
Regulatory Authority Approvals/Authorizations ................................................................... 29 
7.4 
Subject Information Consent .................................................................................................. 29 
7.5 
Insurance ................................................................................................................................ 30 
7.6 
Confidentiality ........................................................................................................................ 30 
8. 
Statistical Methods and Determination of Sample Size ................................................................. 31 
8.1 
Statistical and Analytical Plan ................................................................................................ 31 
8.1.1 
Analytical Populations ............................................................................................... 31 
8.1.2 
Treatment Group Comparability ............................................................................... 31 
8.1.3 
Primary Efficacy Analyses ......................................................................................... 31 
8.1.4 
Secondary Efficacy Analyses ..................................................................................... 32 
8.1.5 
Exploratory Efficacy Analyses ................................................................................... 32 
8.1.6 
Safety Analyses ........................................................................................................... 33 
8.1.7 
CHP Concentration Analyses .................................................................................... 33 
8.1.8 
Missing Data .............................................................................................................. 33 
8.1.9 
General Statistical Considerations ............................................................................ 33 
8.2 
Determination of Sample Size ................................................................................................ 33 
8.3 
Interim Analyses .................................................................................................................... 34 
9. 
ADVERSE EVENTS ......................................................................................................................... 35 
9.1 
Warnings / Precautions ........................................................................................................... 35 
9.2 
Adverse Event Monitoring ..................................................................................................... 35 
9.3 
Adverse Event Definitions ..................................................................................................... 35 
9.3.1 
Adverse Event (AE) .................................................................................................... 35 
9.3.2 
Serious Adverse Event (SAE) ..................................................................................... 35 
9.3.3 
Unexpected Adverse Event ......................................................................................... 36 
9.3.4 
Relationship of Adverse Event to Investigational Product ........................................ 36 
9.3.5 
Severity of Adverse Event ........................................................................................... 37 
9.3.6 
Adverse Event Documentation ................................................................................... 37 
9.4 
Reporting of Serious Adverse Events/Pregnancy .................................................................. 38 
9.5 
Procedures for Managing Hypoglycemia and Hyperglycemia .............................................. 38 
10. 
USE OF DATA AND PUBLICATION .......................................................................................... 40 
11. 
REFERENCES ................................................................................................................................. 41 
12. 
APPENDICES .................................................................................................................................. 43 
Appendix 1: Oral Glucose Tolerance Test (OGTT) ......................................................................... 43 
Appendix 2: Daily Log ..................................................................................................................... 44 
Appendix 3: Audit of Diabetes-Dependent Quality of Life (ADDQoL) Questionnaire .................. 47 
Appendix 4: Determining Hypoglycemic and Hyperglycemic Episodes ......................................... 53 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 12 of 53 
1. 
Introduction 
 
1.1 
Type 2 Diabetes / Non-insulin-dependent Diabetes Mellitus (NIDDM) 
 
Approximately 29.1 million people in the United States are afflicted with Type 2 diabetes or non-insulin-
dependent diabetes mellitus (NIDDM) as of year 2012 (Data from 2014 National Diabetes Fact Sheet 
released by Centers for Disease Control and Prevention). The major defect in patients with type 2 diabetes 
is the functional impairment of insulin action on peripheral tissues to stimulate glucose uptake, to 
decrease gluconeogenesis, and to inhibit hepatic glucose output. Although these defects are caused by 
both genetic and environmental factors, the ultimate expression of diabetes is largely induced by 
environmental factors.1 This fact implies that type 2 diabetes is preventable and curable. Understanding 
the molecular mechanisms of insulin resistance and glucose intolerance is very important in the treatment 
and prevention of diabetes. However, insulin-mediated signal transduction mechanisms are extremely 
complex, involving nearly 100 proteins and enzymes.2,3 Thus, a complete understanding of these 
molecular mechanisms is unlikely in the near future. Insulin injection or oral intake of sulfonylurea 
derivatives (to stimulate pancreatic insulin secretion), and metformin (to inhibit hepatic glucose output), 
which can be toxic to humans,4 are effective in lowering blood glucose levels but do not improve insulin 
resistance. Rosiglitazone and pioglitazone are thought to improve insulin resistance, but these agents pose 
potential risks for cardiac hypertrophy and liver damage.5,6 Patients who utilize these conventional drugs 
in general do not attain normal glucose homeostasis nor do these drugs prevent diabetes.  
 
Recently, the FDA approved glucagon-like protein-1 (GLP-1) for treating human diabetes. Although this 
agent helped to reduce HbA1c levels by 0.98% during a 16 weeks trial, there was a moderate to serious 
side effect of gastric discomfort.7 Sixteen percent of subjects dropped out from the treatment group 
compared to 2% for the placebo group. Forty percent of subjects in the GLP-1 group experienced nausea, 
and 13% experienced vomiting. Since GLP-1 required continuous infusion or multiple subcutaneous 
injections to maintain its effectiveness due to rapid degradation by dipeptidyl peptidase-4 (DPP-4), GLP-
1 was not expected to be feasible as a routine treatment for human diabetes.8 More recently, the FDA 
approved a DPP-4 inhibitor for commercialization. In a 12 week, randomized, double-blind study in 
patients with type 2 diabetes the DPP-4 inhibitor at a daily dose of 100 mg decreased Hemoglobin (Hb) 
A1c by 0.39 to 0.56% (p<0.05) and fasting plasma glucose by 11.0 to 17.2 mg/dL (p<0.05) and was well-
tolerated.9 100 mg DPP-4 inhibitor plus 2000 mg metformin treatment decreased HbA1c levels by 2.07% 
while metformin treatment alone reduced levels by 1.3 %. This meant that reduction of HbA1c by DPP-4 
inhibitor was merely 0.77% above the level that was achieved by patients who continued on metformin 
alone.10 Since there were no serious side effects with the DPP-4 inhibitor, this agent was considered a 
novel anti-diabetes agent for blood glucose control. However, DPP-4 inhibitors and GLP-1 do not 
improve insulin resistance. 
 
The prevalence of overweight and obese subjects is increasing in the US with more than 70 % of the US 
population characterized as either overweight or obese and more than one third of the population either 
obese or extremely obese with BMI > 30.11 More than 80 % of diabetic subjects are overweight or 
obese.12 A body weight gain of 11 to16 pounds more than doubled the incidence of type 2 diabetes 
compared to lean subjects while a gain of 17 to 24 pounds increased the risk three-fold.13 Extensive 
counseling for diet and exercise improved weight loss in obese adults. At the same time, these subjects 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 13 of 53 
had improved glucose metabolism, lipid levels, and blood pressure.14 Thus, weight loss and blood sugar 
control are key components to the treatment of obesity-associated diabetes. Since Cyclo-Z treatment 
significantly improved insulin sensitivity in animal models of type 2 diabetes15,16 and reduced body 
weight in obese rats,17 we plan to investigate whether Cyclo-Z treatment improves both blood glucose and 
body weight in obese diabetic subjects in combination with control of diet and exercise.      
 
 
1.2 
Cyclo-Z (Cyclic dipeptide (his-pro) or CHP plus zinc) 
 
Cyclo-Z is presented in a gel capsule form containing varying doses of CHP (3, 9 or 15 mg) and zinc (23 
mg).  
 
Combination of CHP and zinc in the treatment of diabetes via stimulation of IDE synthesis: 
 
Insulin degrading enzyme (IDE) is a zinc-containing enzyme that regulates degradation of internalized 
insulin and the maintenance of insulin sensitivity.18,19 Diabetic animals and humans are zinc deficient20,21 
due to impaired intestinal zinc absorption and hyperzincuria.22,23,24,25,26 Insulin bound to its receptor is 
transported to the endosome where it is separated from the insulin receptor. The inactive insulin is 
degraded to peptides and amino acids by IDEs. Under normal conditions, incompletely digested peptides 
in the endosome are completely digested in the lysosome. Incomplete digestion of the used insulin can 
interfere with the propagation of insulin-receptor-initiated signal transduction processes, thereby inducing 
insulin resistance (Fig. 1 below). If endosomal IDE levels are inadequate, undigested insulin will remain 
in the cytosol and prevent insulin signal transduction thereby disrupting the synthesis or translocation of 
glucose transporter-4 (GLUT-4) to the cell membrane for glucose uptake. Cyclo-Z enhances IDE 
synthesis and stimulates insulin degradation. Although Cyclo (his-pro) (CHP) or zinc alone are somewhat 
effective in the control of blood glucose metabolism, we hypothesize, based on the available literature and 
previous background studies, that the combination of CHP and zinc in Cyclo-Z work synergistically to 
ameliorate insulin resistance in diabetic and obese patients mainly by stimulating IDE synthesis.  
 
 
 
Figure 1: Degradation of Used Insulin in the Muscle and Fat Cells 
 
 
Cell Membrane
Insulin
Endosome
Zinc
Insulin Degrading
Enzyme
IRS-1 Signaling Complex
Protein Synthesis
Insulin/IGF-1 receptor
Peptides
X
Amino acids


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 14 of 53 
1.3 
Rationale for Study Population 
 
Cyclo-Z is a chemically pure agent whose uniform properties would make it more conducive to careful 
study. Thus, a formal Phase 1 clinical trial with Cyclo-Z was performed on 49 healthy volunteers. This 
double-blinded study showed no acute adverse side effects in subjects taking a one-time oral dose of 0, 2, 
4, or 8 capsules of Cyclo-Z. All subjects had normal serum chemistry data and cell numbers at the start of 
the trial (0 hours) and no significant changes in these parameters from baseline occurred during 24 hours 
(0, 2, 4, 8, and 24 hours). Subjects (n = 12) who took 8 capsules of Cyclo-Z before breakfast showed 
significantly reduced blood glucose levels at 8 hours, but their plasma glucose levels remained within 
normal range. Twenty-four hours later, the blood glucose levels returned to baseline. In our animal studies, 
the optimal acute dose of Cyclo-Z was five times the daily dose required for long term diabetes treatment. 
Thus, this dose was only 70-80% of the acute optimal dose of Cyclo-Z shown to improve TAFGC values 
in diabetic animals. Since Cyclo-Z had mild glucose lowering effects in non-diabetic subjects who may or 
may not have had insulin resistance, we expect that this Phase 2 clinical trial with obese diabetic subjects 
will be successful in demonstrating blood sugar-lowering and/or weight loss with Cyclo-Z thereby 
providing “proof of concept” data. 
 
 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 15 of 53 
2. 
Study Objective(s)  
 
2.1 
Primary Objective  
 
The primary objective is to assess the dose-dependent efficacy of Cyclo-Z for the treatment of subjects 
with obese type 2 diabetes.  
 
 
2.2 
Secondary Objective  
 
The secondary objective is to assess the safety of Cyclo-Z in the treatment of subjects with obese type 2 
diabetes. 
 
 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 16 of 53 
3. 
Study Endpoints 
 
3.1 
Efficacy Evaluation 
 
The primary clinical efficacy variables used to evaluate the efficacy of Cyclo-Z are the change of HbA1c 
level from baseline at Week 12 and the change of body weight (BW) from baseline at Week 12.  
 
The secondary clinical efficacy variables used to evaluate the efficacy of Cyclo-Z are: 
• 
Change of fasting plasma glucose (FPG) level from baseline at Week 12 
• 
Proportion of subjects achieving HbA1c goal of <7.0% at Week 12 
• 
Proportion of subjects achieving HbA1c goal of <6.5% at Week 12 
• 
Change in waist circumference from baseline at Week 12 
• 
Change of postprandial (2 hours after dinner) blood glucose level from baseline at Week 12 
• 
Change of OGTT from baseline at Week 12 
• 
Change of score in Audit of Diabetes-Dependent Quality of Life (ADDQoL) Questionnaire from 
baseline at Week 12 
 
 
3.2 
Exploratory Evaluation 
 
In addition to the primary and secondary endpoints, the following exploratory efficacy variables will be 
separately evaluated for the change from baseline at Week 12:      
• 
Thyroid Function Test (TSH, T3, and T4) 
• 
Serum Parameters: zinc, insulin, adiponectin, C-peptide, leptin, glucagon 
• 
Urine Parameters: zinc, glucose, microalbumin, copper 
 
 
3.3 
Safety Evaluation 
 
The following safety parameters will be evaluated for the change from baseline assessment: 
• 
Blood samples for complete laboratory evaluation 
• 
ECG evaluation  
• 
Physical examination 
• 
Vital signs 
• 
Adverse events 
• 
Episodes of hypoglycemia and hyperglycemia 
 
3.4 
CHP Concentration Evaluation 
 
In a subset of subjects where residual serum and/or plasma are available after completion of study-
required tests, CHP levels in blood may be measured for the change from baseline.  
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 17 of 53 
4. 
Investigational Plan 
 
4.1 
Overall Study Design 
 
This is a double-blind, randomized, placebo-controlled, parallel-group comparison study to evaluate the 
efficacy and safety of Cyclo-Z vs. placebo in adult subjects with obese type 2 diabetes. Two or three 
clinical sites may be utilized in the United States so that a total of 80 subjects (a potential 20% screening 
failure rate) may be screened for total 16-week study period (2 weeks for screening, 12 weeks for 
treatment, and 2 weeks for safety follow-up).  
 
Subjects who meet preliminary inclusion and exclusion criteria at Screening will undergo a 2-week 
assessment period of record-keeping compliance. Subjects will be asked to record daily blood glucose 
values (fasting before breakfast and two hours after dinner) and study medication adherence (See 
Appendix 2).  
 
Sixty-four (64) qualified subjects will be assigned randomly to either the placebo arm or to one of the 
three treatment groups requiring the oral intake of a single gel capsule of Cyclo-Z or placebo once daily 
before bedtime for 12 consecutive weeks.  
 
Refer to the Schedule of Assessments and Section 6 for a display of all assessments to be conducted. All 
visits are to be scheduled according to their time from the randomization visit (Visit 2).  
 
 
4.2 
Selection of Study Population 
 
4.2.1 
Inclusion Criteria 
 
To be enrolled in the study, a subject must meet all of the following criteria: 
 
1. Males or females aged 18 or older. 
 
2. Subjects diagnosed with type 2 diabetes mellitus according to the American Diabetes Association 
(ADA) criteria. 
 
3. Subjects treated with stable doses of insulin and/or other hypoglycemic agent(s) for type 2 
diabetes mellitus for at least 2 months prior to randomization. 
 
4. Subjects whose fasting blood glucose levels are reasonably stable for at least 2 months prior to 
randomization and during the 2-week screening period. Stable glucose levels are defined based on 
the fact that the study subjects did not change the dose and/or type of insulin injection and/or 
other hypoglycemic agent(s) during the last 2 months and during the 2-week screening period to 
adjust blood glucose. 
 
5. Subjects who have Hemoglobin A1c levels of 7.5 to 10.0 % at Screening. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 18 of 53 
 
6. Subjects whose BMI is 30 or above. 
 
7. Subjects who can give written informed consent. 
 
4.2.2 
Exclusion Criteria 
 
A subject must not be enrolled in the study if any of the following criteria are met: 
 
1. Subjects who have any DM-related end-organ damages.  
 
2. Subjects who have a history of diabetic ketoacidosis or hyperosmolar non-ketotic coma. 
 
3. Subjects who have any disease likely to limit life span and/or increase risks of interventions such 
as: 
• Carotid B-mode ultrasound test results indicating clinically significant stenosis in the common 
carotid arteries requiring intervention by angioplasty or resection. 
• Cancer treatment in the past 5 years, with the exception of cancers which have been cured, and 
carry a good prognosis. 
• Infectious disease:  HIV positivity, active tuberculosis, or pneumonia. 
 
4. Subjects who have any of the following conditions related to cardiovascular disease: 
• Hospitalization for the treatment of heart disease in the past 12 months. 
• New York Heart Association Functional Class > 2. 
• Left Bundle branch block on ECG at Screening. 
• Third degree atrioventricular block on ECG at Screening. 
• Uncontrolled hypertension with average systolic blood pressure of > 160 mmHg or diastolic 
blood pressure > 95 mmHg at Screening and Baseline. 
• Pulse rate > 95 beats per minute at Screening and Baseline. 
• Stroke or transient ischemic attack in the past 12 months. 
 
5. Subjects who have any of the following conditions related to gastrointestinal disease: 
• Chronic hepatitis or cirrhosis. 
• Episode of alcoholic hepatitis or alcoholic pancreatitis in the past 2 months. 
• Inflammatory bowel disease requiring treatment in the past 12 months. 
• Significant abdominal surgery (e.g., gastrectomy, gastric bypass) in the past 2 months. 
 
6. Subjects who have serum creatinine > 1.5 mg/dL for male or > 1.4 mg/dL for female. 
 
7. Subjects who have chronic obstructive airway disease or asthma requiring daily therapy or home 
use oxygen. 
 
8. Subjects who have hematocrit < 36.0% for male or < 33.0% for female. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 19 of 53 
 
9. Subjects who have any of the following conditions or behaviors likely to affect the conduct of the 
study: 
• Weight loss of > 10% in the past 6 months. 
• Unable to walk without assisted device. 
• Major psychiatric disorder which would impede conduct of the research.                 
• Excessive alcohol intake (i.e., more than 2 drinks/day). 
 
10. Subjects who take any of the following medications: 
• Psychoactive agents such as monoamine oxidase inhibitors and antidepressants (e.g., lithium, 
Prozac, Zoloft, Serzone, Paxil, Effexor). 
• Any other medications that may pose harm to the subject. 
 
11. Female subjects who have a positive serum pregnancy test at Screening, plan a pregnancy during 
study period, or are breast feeding.  
 
12. Female subjects who don’t meet any of the following criteria: 
• Surgically sterile (i.e., have had bilateral tubal ligation, hysterectomy, or bilateral 
oophorectomy) at least 6 months before randomization.  
• Post-menopausal for at least 12 months prior to Screening. 
• If sexually active, they should use oral contraceptives, double barrier contraception (e.g., 
condom with spermicide), intrauterine device, or other methods approved by the Sponsor.  
 
 
4.3 
Subject Withdrawal 
 
Any subject is free to withdraw from participation in the study at any time, for any reason, specified or 
unspecified, and without prejudice to further treatment. The criteria for enrollment are to be followed 
explicitly. If a subject who does not meet enrollment criteria is inadvertently enrolled, that subject should 
be withdrawn from the study and the Sponsor/contract research organization (CRO) must be contacted. 
An exception may be granted in rare circumstances where there is a compelling reason to allow the 
subject to continue. In these rare cases, the investigator must obtain documented approval from the 
Sponsor or Sponsor designee to allow the subject to continue in the study. 
 
In addition, subjects will be withdrawn from study drug and from the study in the following 
circumstances: 
• 
The investigator decides that the subject should be withdrawn. If this decision is made because of 
an intolerable AE or a clinically significant laboratory value, if the dose of study drug has not 
been administered, it will be withheld and appropriate measures are to be taken. The Sponsor or 
Sponsor designee is to be notified immediately.  
• 
The subject is unwilling to continue in the study.  
• 
The subject is not compliant with the protocol. 
• 
The investigator or the Sponsor, for any reason, stops the study.  


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 20 of 53 
 
If a subject prematurely withdraws from the study, every effort must be made to have the subject return to 
the clinical site for a premature termination visit. In all cases, the reason for withdrawal must be recorded 
in the Electronic Case Report Form (eCRF) and in the subject’s medical records. 
 
Contact will be maintained with subjects who are removed due to an AE until it has been resolved or 
stabilized, and the information will be documented in the eCRF and in the subject’s medical records.  
 
 
4.4 
Premature Termination of Study / Closure of Center 
 
The Sponsor has the right to terminate this study, and the investigator/Sponsor has the right to close a 
clinical site, at any time, although this should occur only after consultation between involved parties; the 
IRB must be informed in any case. Should the clinical site be closed prematurely, all study materials (e.g., 
study medication) must be returned to the Sponsor. 
 
Discontinuation of the study may be necessary for medical or administrative reasons such as: 
• 
Serious adverse events probably related to study drug administration so that the use of study drug 
may no longer be justifiable 
• 
Significant change of benefit-risk ratio for the subjects 
• 
The enrollment period has been exceeded 
• 
The Sponsor discontinues the investigation of Cyclo-Z for type 2 diabetes indication or 
determines that the doses being studied are no longer justifiable 
 
Possible reasons for closing of a clinical site include the following: 
• 
The investigator feels that the number or severity of adverse events is excessive 
• 
A change of technical, administrative, or personal circumstances occurs and the conduct of the 
study no longer meets ICH-GCP guidelines 
• 
In case of evident, significant non-compliance to protocol or poor data quality 
• 
The enrollment rate at a clinical site is unlikely to result in the recruitment of the required subject 
numbers. 
 
 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 21 of 53 
5. 
Study Treatments 
 
5.1 
Treatment to be Administered 
 
At Visits 2, 3, 4, 5, 6, and 7 (Weeks 0, 2, 4, 6, 8, and 10), each subjects will be dispensed with study drug 
supply for a 2-week period (14 capsules plus 4 extra capsules, total 18 capsules). The subjects will be 
instructed to orally administer one capsule just before bedtime each day. 
 
All subjects will be instructed to continue their current diabetes medications and all other prescribed 
drugs.  
 
 
5.2 
Identity of Investigational Product 
 
Investigational products are white-color capsules and supplied to clinical sites in HDPE bottles. Placebo 
capsules will be matched for Cyclo-Z capsules in color, shape, and size and will be indistinguishable from 
Cyclo-Z capsules. All manufacturing and packaging activities will be performed according to cGMP 
guidelines.  
 
Each bottle has a label including the following information:  
• 
Product name 
• 
Randomization number 
• 
Dosage form information 
• 
Protocol number 
• 
Lot number 
• 
Dosing instruction 
• 
Storage condition 
• 
Cautionary statement 
• 
Sponsor name and contact information 
 
All drug supplies must be stored in a secure area (e.g., locked cabinet), at controlled room temperature 
15~30 °C (59~86 °F). 
 
 
5.3 
Randomization 
 
At Visit 2 (Week 0), subjects who meet the inclusion/exclusion criteria will be randomly assigned to 
receive placebo or 1 of 3 doses of Cyclo-Z in accordance with the randomization code, which will be 
generated by the Sponsor. Specifically, the subjects will be randomly assigned in a 1:1:1:1 ratio to the 
following: 
 
• 
Dose A: Cyclo-Z containing 23 mg zinc plus 3 mg CHP – 16 subjects 
• 
Dose B: Cyclo-Z containing 23 mg zinc plus 9 mg CHP – 16 subjects 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 22 of 53 
• 
Dose C: Cyclo-Z containing 23 mg zinc plus 15 mg CHP – 16 subjects 
• 
Dose D: Placebo – 16 subjects 
 
 
5.4 
Selection of Doses in the Study 
 
The doses of Cyclo-Z were chosen on the basis of results of non-clinical efficacy and safety studies. The 
detailed results are documented in the Investigator’s Brochure.  
 
 
5.5 
Choice of Controls/Comparators 
 
This study uses an inert placebo as a negative control. The purpose of this is to reduce all potential 
influences on the actual or apparent course of the disease other than those arising from the pharmacologic 
or toxicological action of the study medication.  
 
 
5.6 
Blinding 
 
As this is a double-blind study, blinding of the drug contents from the subjects, investigator, and other 
study personnel at each site is necessary. The subject will be assigned with an identification number at 
Visit 2 which will remain with the subject throughout the study.  
 
A code-break document including the randomization code information will be retained by each site and 
can be opened, revealing the randomization information, for emergency purposes only. The investigator 
should note that the occurrence of a SAE should not routinely precipitate immediate unblinding. An 
attempt to contact the Sponsor must be made prior to unblinding. If unblinding occurs, the study 
medication for the subject must be discontinued; a written explanation on the relevant form must be 
prepared immediately.  
 
 
5.7 
Prior and Concomitant Treatments 
 
All the subjects will be instructed to continue their current diabetes medications and all other prescribed 
drugs. All prior (2 months prior to Screening) and concomitant medications must be entered into the 
electronic case report form (eCRF), including the name of the drug or treatment, dose, route of 
administration, date and time of the treatment, and indication. In the event that prior or concomitant 
medication is administered, the investigator must access the subject’s eligibility of continuing the 
participation in the study.  
 
The following medications are not allowed to be taken by subjects enrolled in this study during the trial: 
• 
Psychoactive agents such as monoamine oxidase inhibitors and antidepressive agents (e.g., 
lithium, Prozac, Zoloft, Serzone, Paxil, Effexor) 
• 
Any other medications that may pose harm to the subject  


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 23 of 53 
• 
Any investigational drug (including placebo) 
 
 
5.8 
Subject Education on Hypoglycemia/Hyperglycemia and its Management 
 
All subjects will be instructed in life style modification and asked to maintain a stable diet and daily 
exercise routine and to keep a daily record of their blood glucose level before breakfast and 2 hours after 
dinner. Hypo- or hyperglycemia are of particular concern and if either occurs, it will be handled in a 
standard fashion as outlined in Section 9.5, Procedures for Managing Hypoglycemia and Hyperglycemia. 
 
Although Cyclo-Z treatment alone does not cause hypoglycemia in human as demonstrated in the prior 
informal study, it may potentially lead to hypoglycemia when interacting with other anti-diabetic drugs. 
The interaction between Cyclo-Z and other oral anti-diabetic agents or obesity medications are not known 
at this time. However, some anti-diabetic agents such as insulin injection, sulfonyl derivatives or other 
insulin secretion stimulating agents may cause hypoglycemia regardless of Cyclo-Z treatment. Improved 
insulin resistance during the study requires reduction in the use of other insulin and insulin secretagogues. 
Thus, subjects’ blood glucose levels should be closely monitored to detect hypoglycemia in order for the 
use of other anti-diabetic agents to be appropriately reduced. For the purpose of record keeping and 
maintaining subject’s health, all subjects will be provided with their own glucometer to measure their 
blood glucose levels.  If there are subjects with a possibility of developing acute hypoglycemia while 
using their current hypoglycemic agents concomitantly with Cyclo-Z, they will be instructed to carry 
commercial glucose tablets with them to take when feeling dizzy and weak. While taking Cyclo-Z, an 
improvement in insulin sensitivity or symptoms of hypoglycemia will not develop acutely. Furthermore, 
2-week periodical examinations and subjects’ daily blood glucose measurements will keep their glucose 
levels on track and help prevent them from experiencing possible hypoglycemic episodes. 
 
At the same time, hyperglycemia will be well maintained by examining subjects bi-weekly. Taking 
Cyclo-Z may increase fasting blood glucose initially for 2 months due to the reduction in pancreatic 
insulin secretion, which could occur with improved insulin sensitivity. Subjects will be instructed to 
monitor for increased thirst, urination and blurry vision, but subjects will also be advised that the best 
method for detecting hyperglycemia is by measuring blood glucose level. 
 
 
5.9 
Medication Accountability and Treatment Compliance 
 
Subjects will return all unused study medications with the diary at Visits 3, 4, 5, 6, 7, and 8 (Weeks 2, 4, 6, 
8, 10, and 12) or at Early Termination Visit. The returned medications and diaries will be reviewed with 
the subject to evaluate the medication accountability and treatment compliance. If a subject misses 3 or 
more doses out of total 2-week doses (i.e., 14 doses), the site should contact the Sponsor for the 
discussion of potential early termination. 
 
All study medication supplies should be accounted for at the termination of the study and a written 
explanation provided for discrepancies. All unused study medication supplies and packaging materials are 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 24 of 53 
to be inventoried and returned to the Sponsor by the investigator. The investigator is not permitted to 
return or destroy unused clinical drug supplies or packaging materials unless authorized by the Sponsor. 
 
The medication doses for the diabetes treatment should not be changed during the 3-month treatment 
period.   
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 25 of 53 
6. 
Study Procedures 
 
Refer to the Schedule of Assessments for an outline of study specific procedures/assessments required at 
each visit. Additional procedures as part of standard of care may be performed whenever the investigator 
determines it is necessary.  
 
The study duration for each subject may be up to 16 weeks. This includes a 2-week screening period, a 
12-week treatment period from randomization to the last treatment visit, and a 2-week safety follow up 
period. All visits from Visit 2 should occur within 6 days (i.e., ± 3 days) from the initial schedule for 
Visits 3 to 8 and within 7 days (i.e., + 7 days) for Visit 9, respectively.  
 
Each subject will be required to visit the clinical site, in a fasted state, before breakfast approximately 9 
times over a period of 16 weeks starting at Screening. All missed visits and any procedures that are not 
performed per protocol must be documented in the source documents and the appropriate CRF. 
 
6.1 
Screening Period 
 
A screening visit will occur at least 2 weeks prior to the randomization. 
 
A signed and dated Institutional Review Board (IRB) approved Informed Consent Form must be obtained 
before any study-specific procedures are performed. Once written informed consent has been obtained, 
the following screening procedures and assessments must be performed to determine eligibility and 
document adherence to the preliminary inclusion/exclusion criteria: 
• 
Record demographic data (i.e., date of birth, race, and height). 
• 
Record relevant medical history including diabetic history. 
• 
Record details of previous medications. 
• 
Perform a physical examination. 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Measure 12-lead ECG. 
• 
Collect blood samples for hematology, serum chemistry, HbA1c, and pregnancy test (serum 
hCG). 
• 
Dispense daily log with blood glucose monitoring devices to record daily blood glucose values 
(fasting before breakfast and two hours after dinner) and study medication adherence (See 
Appendix 2). 
 
 
6.2 
Treatment Period 
 
6.2.1 
Visit 2 (Week 0): Baseline 
 
Visit 2 will occur after the completion of 2-week assessment (+7 days). During this visit, the following 
procedures and assessments must be performed:  
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a physical examination. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 26 of 53 
• 
Collect daily logs and blood glucose monitoring devices and review daily logs with the subject. 
• 
Record any changes in concomitant medications. 
• 
Record an adverse event, if applicable.  
• 
Assess hypoglycemic and hyperglycemic episodes (See Appendix 4). 
• 
Confirm the inclusion and exclusion criteria. 
• 
Randomize the subject  
• 
Conduct the ADDQoL Questionnaire (See Appendix 3).  
• 
Perform the OGTT (See Appendix 1) 
• 
Measure waist circumference.  
• 
Collect blood samples for hematology, serum chemistry, HbA1c, FPG, and thyroid function test 
(TSH, T3, and T4). 
• 
Collect blood samples* for zinc, insulin, adiponectin, C-peptide, leptin, and glucagon.  
• 
Collect urine samples for glucose, microalbumin, copper, and zinc.  
• 
Dispense study medications to the subject with detailed instructions. 
• 
Dispense daily log with blood glucose monitoring devices to record daily blood glucose values 
(fasting before breakfast and two hours after dinner) and study medication adherence (See 
Appendix 2). 
 
*If residual plasma and/or serum are available, CHP levels may be measured. 
 
6.2.2 
Visits 3, 5, and 7 (Weeks 2, 6, and 10) 
 
Each study visit will occur 2 weeks (± 3 days) after the previous visit. During each visit, the following 
procedures and assessments must be performed:  
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Review adverse events and concomitant medications. 
• 
Assess hypoglycemic and hyperglycemic episodes (See Appendix 4). 
• 
Collect daily logs and blood glucose monitoring devices and review daily logs with the subject. 
• 
Collect unused study medications and review the medication accountability with the subject. 
• 
Dispense study medications to the subject. 
• 
Dispense daily log with blood glucose monitoring devices to record daily blood glucose values 
(fasting before breakfast and two hours after dinner) and study medication adherence (See 
Appendix 2). 
 
6.2.3 
Visits 4 and 6  (Weeks 4 and 8) 
 
Each study visit will occur 2 weeks (± 3 days) after the previous visit. During each visit, the following 
procedures and assessments must be performed:  
• 
Collect daily logs and blood glucose monitoring devices and review daily logs with the subject. 
• 
Collect unused study medications and review the medication accountability with the subject. 
• 
Review adverse events and concomitant medications. 
• 
Assess hypoglycemic and hyperglycemic episodes (See Appendix 4). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 27 of 53 
• 
Perform a physical examination. 
• 
Measure waist circumference.  
• 
Collect blood samples for hematology, serum chemistry, HbA1c, and FPG. 
• 
Collect blood samples* for zinc, insulin, adiponectin, C-peptide, leptin, and glucagon.  
• 
Collect urine samples for glucose, microalbumin, copper, and zinc.  
• 
Dispense study medications to the subject. 
• 
Dispense daily log with blood glucose monitoring devices to record daily blood glucose values 
(fasting before breakfast and two hours after dinner) and study medication adherence (See 
Appendix 2). 
 
*If residual plasma and/or serum are available, CHP levels may be measured. 
 
6.2.4 
Visit 8 (Week 12) or Early Termination Visit 
 
This study visit will occur 2 weeks (± 3 days) after Visit 7 or when the subject is early terminated due to 
any reason. During this visit, the following procedures and assessments must be performed:  
• 
Conduct the ADDQoL Questionnaire (See Appendix 3).  
• 
Collect daily logs and blood glucose monitoring devices and review daily logs with the subject. 
• 
Collect unused study medications and review the medication accountability with the subject. 
• 
Perform the OGTT (See Appendix 1) 
• 
Assess hypoglycemic and hyperglycemic episodes (See Appendix 4). 
• 
Review adverse events and concomitant medications. 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a physical examination. 
• 
Measure waist circumference.  
• 
Measure 12-lead ECG. 
• 
Collect blood samples for hematology, serum chemistry, HbA1c, FPG, thyroid function test (TSH, 
T3, and T4), and pregnancy test (serum hCG). 
• 
Collect blood samples* for zinc, insulin, adiponectin, C-peptide, leptin, and glucagon.  
• 
Collect urine samples for glucose, microalbumin, copper, and zinc.  
 
*If residual plasma and/or serum are available, CHP levels may be measured. 
 
6.3 
Follow-up Period 
 
The safety follow-up visit will occur at least 2 weeks after the last dose (+ 7 days). During this visit, the 
following procedures and assessments must be performed:  
• 
Review adverse events and concomitant medications. 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 28 of 53 
6.4 
Other Information for Study Visits 
 
Unscheduled visits and/or procedures may be required in addition to the visits and procedures detailed 
above. The additional visits or procedures are at the discretion of the investigator. The details of these 
unscheduled visits or procedures will be recorded in the source documents and entered into the eCRFs.  
  
If a subject misses a scheduled visit, the clinical site is to make every effort to have the subject visit the 
site as soon as possible. If a subject may delay 7 or more days from the scheduled date, the site should 
contact the Sponsor for the discussion of how to determine.  
 
 
6.5 
Data Quality 
 
Monitoring and auditing procedures defined/agreed by the Sponsor will be followed in compliance with 
current GCP guidelines. Each clinical site will be visited at regular intervals (about 6 weeks) by a monitor 
to ensure compliance with the study protocol, GCP guideline, and other regulatory aspects. This will 
include on-site review of the source documents and eCRFs for the completeness and clarity, consistency 
between source documents and eCRFs, and clarification of administrative matters. 
 
 
6.6 
Documentation 
 
Entries made in the eCRF must be either verifiable against source documents or have been directly 
entered into the eCRF, in which case the entry in the CRF will be considered as the source data. The 
source data parameter to be verified and the identification of the source document must be documented. 
The study file and all source data should be retained/archived until notification by the Sponsor for change 
of archive site or destruction. 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 29 of 53 
7. 
Ethical and Legal Aspects 
 
7.1 
Institutional Review Board (IRB) 
 
Documented approval from the IRB will be obtained for all participating clinical site(s) prior to study 
start, according to GCP and applicable laws and regulations. When necessary, an extension, amendment, 
or renewal of the IRB approval must be obtained and also forwarded to the Sponsor. The IRB must 
supply to the Sponsor, upon request, a list of the IRB members involved in the vote and a statement to 
confirm that the IRB is organized and operates according to GCP and applicable laws and regulations.  
 
 
7.2 
Ethical Conduct of the Study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this 
study, are designed to ensure that the Sponsor and investigator abide by GCP guidelines and under the 
guiding principles detailed in the Declaration of Helsinki. The study will also be carried out in keeping 
with applicable local laws and regulations. This may include an inspection by the Sponsor representatives 
and/or Regulatory Authority representatives at any time. The investigator must agree to the inspection of 
study-related records by the Regulatory Authority/Sponsor representatives, and must allow direct access 
to source documents to the Regulatory Authority/Sponsor representatives. 
 
Modifications to the study protocol will be implemented by the investigator only after the Sponsor’s 
approval. However, the investigator may implement a deviation form, or change of the protocol to 
eliminate any immediate hazard(s) to the trial subjects without prior IRB/Sponsor approval. The 
implemented deviation or change, the reasons for it and, if appropriate, the proposed amendment should 
be submitted to the IRB/Sponsor as soon as possible. Any deviations from the protocol must be fully 
explained and documented by the investigator. 
 
 
7.3 
Regulatory Authority Approvals/Authorizations 
 
Regulatory Authority approvals/authorizations/notifications, where required, will be in place and fully 
documented prior to the study’s start. 
 
 
7.4 
Subject Information Consent 
 
A core information and Informed Consent Form will be provided. Prior to the beginning of the study, the 
investigator must have the IRB written approval of the Informed Consent Form and any other written 
information that will be provided to the subjects. The written approval of the IRB with the approved 
Informed Consent Form must be in the study files.  
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 30 of 53 
Written informed consent must be obtained before any study specific procedure takes place. Participation 
in the study and date of informed consent given by the subject should be documented appropriately in the 
subject’s files. 
 
 
7.5 
Insurance 
 
All subjects participating in the study will have insurance coverage by the Sponsor, which is in line with 
applicable laws and/or regulations. 
 
 
7.6 
Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the applicable 
laws and/or regulations, will not be made publicly available.  
 
Subject names will not be supplied to the Sponsor. Only the subject number and subject initials will be 
recorded in the eCRF, and if the subject name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the Sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The subjects will be informed in 
writing that representatives of the Sponsor, IRB, or Regulatory Authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for inspection 
will be handled in strictest confidence and in accordance with local data protection laws. 
 
Even if the results of the study are published, the subject’s identity will remain confidential. The 
investigator will maintain a list to enable subjects’ records to be identified.  
 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 31 of 53 
8. 
Statistical Methods and Determination of Sample Size  
 
8.1 
Statistical and Analytical Plan 
 
8.1.1 
Analytical Populations 
 
Intent-to-Treat Population 
 
An intent-to-treat (ITT) population will include subjects who have administered at least one dose of study 
medication and who have baseline and any post-baseline efficacy data. This cohort will be evaluated for 
all efficacy variables. 
 
Per-Protocol Population 
 
All subjects valid for ITT who meet ALL the following criteria will be ‘valid per protocol’ (also called 
‘valid for efficacy’): 
• 
Complete at least 2 weeks of treatment after randomization. 
• 
Have both baseline and at least 2 weeks of efficacy data. 
• 
Subject did not have any significant violation after randomization. 
 
Additional criteria may be added prior to unblinding the study database.  
 
As with the ITT population, this per-protocol (PP) cohort will also be evaluated for all efficacy variables. 
 
Safety Population 
 
Any subject who administers at least one dose of study medication and has any post-randomization safety 
data collected will be included in the evaluation of safety. 
 
8.1.2 
Treatment Group Comparability 
 
Demographic variables, medical history, treatment duration, and efficacy variables at baseline will be 
summarized by treatment group for the subjects valid for potential safety analysis. Because, in theory, the 
goal of randomization is to balance out the patient characteristics, statistical tests are not planned for these 
variables. 
 
8.1.3 
Primary Efficacy Analyses 
 
The change from baseline to Week 12 in HbA1c will be compared for the experimental groups versus the 
control group using analysis of variance (ANOVA) methods if the change is approximately normally 
distributed. If the change is markedly non-normally distributed then Wilcoxon rank sum tests will be used. 
Specifically, all three experimental groups will be compared to the control group on the change: Dose A 
vs. D, B vs. D, and C vs. D. 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 32 of 53 
The change from baseline to Week 12 in BW will be compared for the experimental groups versus the 
control group using ANOVA methods if the change is approximately normally distributed. If the change 
is markedly non-normally distributed then Wilcoxon rank sum tests will be used. 
 
8.1.4 
Secondary Efficacy Analyses 
 
The change from baseline to Week 12 in FPG level will be compared for the experimental groups versus 
the control group using ANOVA methods if the change is approximately normally distributed. If the 
change is markedly non-normally distributed then Wilcoxon rank sum tests will be used.  
 
The proportion of subjects achieving HbA1c goal of <7.0% at Week 12 will be compared for the 
experimental groups versus the control group using chi-square testing methods or Fisher’s exact tests, as 
appropriate.  
The proportion of subjects achieving HbA1c goal of <6.5% at Week 12 will be compared for the 
experimental groups versus the control group using chi-square testing methods or Fisher’s exact tests, as 
appropriate.  
 
The change from baseline to Week 12 in waist circumference will be compared for the experimental 
groups versus the control group using ANOVA methods if the change is approximately normally 
distributed. If the change is markedly non-normally distributed then Wilcoxon rank sum tests will be used.   
 
The change from baseline to Week 12 in mean value of postprandial (2 hours after dinner) blood glucose 
level for 2 weeks will be compared for the experimental groups versus the control group using ANOVA 
methods if the change is approximately normally distributed. If the change is markedly non-normally 
distributed then Wilcoxon rank sum tests will be used.  
 
The change from baseline to Week 12 in OGTT will be compared for the experimental groups versus the 
control group using ANOVA methods if the change is approximately normally distributed. If the change 
is markedly non-normally distributed then Wilcoxon rank sum tests will be used.  
 
The change from baseline to Week 12 in ADDQoL questionnaire scores will be compared for the 
experimental groups versus the control group using ANOVA methods if the change is approximately 
normally distributed. If the change is markedly non-normally distributed then Wilcoxon rank sum tests 
will be used.  
 
8.1.5 
Exploratory Efficacy Analyses 
 
The change from baseline to Week 12 in thyroid function test (TSH, T3, T4), serum parameters (insulin, 
adiponectin, C-peptide, leptin, glucagon), and urine parameters (zinc, glucose, microalbumin, copper) will 
be compared for the experimental groups versus the control group using ANOVA methods if the change 
is approximately normally distributed. If the change is markedly non-normally distributed then Wilcoxon 
rank sum tests will be used.  
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 33 of 53 
8.1.6 
Safety Analyses 
 
Safety variables will be summarized with descriptive statistics, overall and by each of the four groups, 
separately. The safety variables include: Blood samples, ECG evaluation, physical examination endpoints, 
vital signs, adverse events (AEs) and episodes of hypoglycemia and hyperglycemia. Continuous safety 
variables will be summarized with means, standard deviations, medians and ranges. Categorical safety 
variables will be summarized with counts and percentages.  
 
AEs will be coded using MedDRA (Medical Dictionary for Regulatory Activities). AEs will be 
summarized by System Organ Class (SOC) and Preferred Term (PT). AEs will also be summarized by 
relationship to the study drug, seriousness and severity. 
 
A treatment-emergent AE (TEAE) will be defined as an AE that began or worsened on or after the first 
treatment dose. AEs recorded prior to the first application of study treatment will be considered non-
treatment-emergent. AEs with insufficient date or time information to determine whether or not they were 
treatment-emergent will be considered treatment-emergent. 
 
All reported AEs (treatment-emergent or not) will be listed. Only TEAEs will be summarized. 
 
Statistical tests are not planned for safety variables. 
 
8.1.7 
CHP Concentration Analyses 
 
Levels of CHP may be assessed in blood for a subset of subjects if there are residual serum and/or plasma 
after completion of protocol-required tests.  No statistical tests are planned for these data. 
 
8.1.8 
Missing Data 
 
No adjustments for missing data and no imputation methods are planned for this phase 2 study.  
 
8.1.9 
General Statistical Considerations 
 
Continuous variables will be summarized with means, standard deviations, medians and ranges. 
Categorical variables will be summarized with counts and percentages. P-values less than or equal to 0.05 
will be considered statistically significant. Because this is a phase 2 clinical trial and because it was not 
formally powered with statistical algorithms, no adjustments for multiple comparisons will be made to the 
results presented in this study. 
 
 
8.2 
Determination of Sample Size 
 
This is a Phase 2 clinical trial to evaluate safety and explore the potential efficacy of the study drug. 
Therefore, the number of subjects was not based on formal statistical power considerations. In this 
clinical trial, a total of 64 subjects was deemed sufficient and will be enrolled and randomly assigned to 
be administered with 1 of 3 dose levels of Cyclo-Z or placebo. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 34 of 53 
 
 
8.3 
Interim Analyses 
 
No interim analyses are planned for this Phase 2 study. 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 35 of 53 
9. 
ADVERSE EVENTS 
 
9.1 
Warnings / Precautions 
 
This study medication must be kept out of reach of children. See the Investigator’s Brochure for 
additional information. 
 
 
9.2 
Adverse Event Monitoring 
 
Subjects must be carefully monitored for AEs. AEs should be assessed in terms of their seriousness, 
severity, and relationship to the study drug.  
 
 
9.3 
Adverse Event Definitions 
 
9.3.1 
Adverse Event (AE) 
 
An AE is any untoward medical occurrence in a clinical trial subject administered with an investigational 
product under investigation. The AE does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product. 
 
AEs associated with the use of a drug in humans, whether or not considered drug related, include the 
following: 
• 
An AE occurring in the course of the use of a drug product in professional practice; 
• 
An AE occurring from an overdose whether accidental or intentional; 
• 
An AE occurring from drug abuse; 
• 
An AE occurring from drug withdrawal; 
• 
An AE where there is a reasonable possibility that the event occurred purely as a result of the 
subject participation in the study (e.g. AE or SAE due to discontinuation of ant-depressants 
during wash-out phase) must also be reported as an AE, even if it is not related to the 
investigational product. 
 
The clinical manifestation of any failure of expected pharmacological action is not recorded as an AE, if it 
is already reflected as a data point captured in the CRF. If, however, the event fulfills any of the criteria 
for a ‘serious’ AE, it must be recorded and reported as such. 
 
9.3.2 
Serious Adverse Event (SAE) 
 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death; 
• 
Is life-threatening; 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 36 of 53 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability or incapacity; 
• 
Is a congenital anomaly or birth defect; 
• 
Is an important medical event. 
 
Life-threatening: The term ‘life-threatening’ in the definition of ‘serious’ refers to an AE in which the 
subject was at risk of death at the time of the event. It does not refer to an AE that hypothetically might 
have caused death if it were more severe. 
 
Hospitalization: Any AE leading to hospitalization or prolongation of hospitalization will be considered 
as ‘serious’, UNLESS at least one of the following exceptions are met: 
• 
The admission results in a hospital stay of less than 12 hours OR, 
• 
The admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the 
study) OR, 
• 
The admission is not associated with an AE (e.g. social hospitalization for purposes of respite 
care). 
 
However, it should be noted that invasive treatment during any hospitalization may fulfill the criteria of 
‘medically important’ and as such may be reportable as a SAE dependent on clinical judgment. 
 
Disability means a substantial disruption of a person’s ability to conduct normal life’s functions. 
 
Important medical event: Any AE may be considered serious because it may jeopardize the subject and 
may require intervention to prevent another serious condition. As guidance for determination of important 
medical events refer to the ‘WHO Adverse Reaction Terminology – Critical Terms List’. These terms 
either refer to or might be indicative of a serious disease state. 
 
Such reported events warrant special attention because of their possible association with a serious disease 
state and may lead to more decisive action than reports on other terms. 
 
9.3.3 
Unexpected Adverse Event 
 
An unexpected AE is any adverse drug event, the specificity or severity of which is not consistent with 
the info presented in the current Investigator’s Brochure. Also, reports that add significant information on 
specificity or severity of known, already documented AE constitute unexpected AEs. For example, an AE 
more specific or more severe than described in the Investigator’s Brochure would be considered 
‘unexpected’. Specific examples would be: (a) acute renal failure as a labeled AE with a subsequent new 
report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis. 
 
9.3.4 
Relationship of Adverse Event to Investigational Product 
 
The assessment of the relationship of an AE to the administration of study drug is a clinical decision 
based on all available information at the time of the completion of the CRF. 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 37 of 53 
An assessment of ‘No’ would include: 
• 
The existence of a clear alternative explanation (e.g., mechanical bleeding at surgical site);  
• 
Non-Plausibility (e.g., the subject is struck by an automobile when there is no indication that the 
drug caused disorientation that may have caused the event); 
• 
Cancer developing a few days after the first drug administration. 
 
An assessment of ‘Yes’ indicates that there is a reasonable suspicion that the AE is associated with the 
use of the investigational drug. 
 
Factors to be considered in assessing the relationship of the AE to study drug include: 
• 
The temporal sequence from drug administration: The event should occur after the drug is given. 
The length of time from drug exposure to event should be evaluated in the clinical context of the 
event. 
• 
Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-challenge): 
Subject’s response after drug discontinuation (de-challenge) or subject’s response after drug 
reintroduction (re-challenge) should be considered in the view of the usual clinical course of the 
event in question. 
• 
Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the context of 
the natural history and course of the disease being treated and any other disease the subject may 
have. 
• 
Concomitant medication or treatment: The other drug the subject is taking or the treatment the 
subject receives should be examined to determine whether any of them may be suspected to cause 
the event in question. 
• 
The pharmacology and pharmacokinetics of the test drug: The pharmacokinetic properties 
(absorption, distribution, metabolism, and excretion) of the test drug, coupled with the individual 
subject’s pharmacodynamics should be considered. 
 
9.3.5 
Severity of Adverse Event 
 
The severity of AEs should be graded as follows: 
Mild – Usually transient in nature and generally not interfering with normal activities 
Moderate – Sufficiently discomforting to interfere with normal activities 
Severe – Prevents normal activities 
 
9.3.6 
Adverse Event Documentation 
 
All AEs occurring after the subject has signed the informed consent must be fully recorded in the 
subject’s CRF. 
 
Documentation must be supported by an entry in the subject’s file. A laboratory test abnormality 
considered clinically relevant, e.g., causing the subject to withdraw from the study, requiring treatment or 
causing apparent clinical manifestations, or judged relevant by the investigator, should be reported as an 
AE. Each event should be described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken, and outcome. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 38 of 53 
 
 
9.4 
Reporting of Serious Adverse Events/Pregnancy 
 
SAEs, including laboratory test abnormalities fulfilling the definition of serious, after signing the 
informed consent, and during follow-up period must immediately (within 24 hours of the investigator’s 
awareness) be reported to the person/parties as detailed in the study file. A SAE form must also be 
completed within 24 hours of the investigator’s awareness and forwarded to the designated person/parties 
as detailed in the study file. Each SAE must be followed up until resolution or stabilization by submission 
of updated reports to the designated person/parties. 
 
When required, and according to local law and regulations, SAEs must be reported to the IRB and 
Regulatory Authorities. 
 
Pregnancy occurring during a clinical investigation, although not considered a SAE, must be reported to 
the Sponsor within the same timelines as a SAE on Pregnancy Monitoring Form. The outcome of the 
mother or the child should be reported. This also applies to pregnancies following the administration of 
the investigational product to the father prior to sexual intercourse.  
 
 
9.5 
Procedures for Managing Hypoglycemia and Hyperglycemia 
 
Subjects will continue to be on their usual diabetes medications including insulin, sulfonylurea, 
metformin and/or glitathiazone derivatives. If a subject develops hypoglycemia during the study period 
per definitions stated in Appendix 4, the doses of antidiabetic agents will be adjusted to maintain 
glycemic control levels (fasting plasma glucose between 70-130 mg/dl). The standard of care mandated 
by the American Diabetes Association and optimal healthcare for all participants while meeting the study 
needs will be followed by the Investigator. Specifically, subjects will monitor and record their daily 
glucose levels twice daily (before breakfast and 2 hours after dinner) and be seen by the Investigator at 
each visit.  
 
If during this time a subject experiences hypoglycemia more than twice, he/she must consult with the 
Investigator. Reasons for hypoglycemia will be sought such as changes in dietary or exercise patterns. If 
there is no apparent reason for hypoglycemia, then a subject on insulin will be instructed to reduce his/her 
insulin dose by 4 units or 10% of  his/her usual insulin dose, observe the effects of the dose reduction for 
3 days, and then report to the Investigator. If the subject continues to develop hypoglycemia, the dose of 
insulin will be reduced by another 2-4 units.  Similarly, if the subject is on an oral hypoglycemic agent 
they will be instructed to reduce the dose of their oral hypoglycemic agent in a stepwise fashion. This life 
style modification is mandatory in the study protocol although the Investigator cannot monitor the 
individual’s compliance to the instruction. Subjects who experience symptomatic hypoglycemia will be 
instructed to ingest a rapidly absorbed sugar. The most convenient fast-acting sugar is found in glucose 
tablets or gels and will be provided to subjects. These interventions will be subject-specific and must be 
undertaken under the direction of the Investigator and/or their own health provider to prevent and solve 
unforeseen hypoglycemic problems.   


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 39 of 53 
 
If a subject experiences serious hypoglycemia on a frequent basis, the Investigator may direct the subject 
to discontinue the use of all anti-diabetic drug intake and insulin injections and may also discontinue the 
use of the study drug until the cause of the hypoglycemia is determined.  The subject will be instructed to 
continue to follow the protocol for record keeping, blood analysis and others. 
 
If a subject experiences an increase in FPG level of >270 mg/dl from baseline to Week 6 or >240 mg/dl 
from Week 6 to 12, the subject will be instructed to take his/her own hypoglycemic agent. It is expected 
that glucose levels can be controlled in most diabetic subjects by these treatments. If the subject's blood 
glucose levels do not decrease to an acceptable level (<240 mg/dl) after 2 weeks, the subject will be 
referred to a diabetologist and will be terminated from the study. The study physician will continue to 
evaluate and treat the subject as needed until healthcare is turned over to the diabetologist. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 40 of 53 
10. 
USE OF DATA AND PUBLICATION  
 
All data and results and all intellectual property rights in the data and results derived from the study will 
be the property of the Sponsor, who may utilize the data in various ways, such as for submission to 
government regulatory authorities or disclosure to other investigators. The investigator, while free to 
utilize data derived from the study for scientific purposes, must discuss any publication with the Sponsor 
prior to release and obtain written consent of the Sponsor on the intended publication. The Sponsor 
recognizes the right of the investigator to publish the results upon completion of the study. However, the 
investigator must send a draft manuscript of the publication or abstract to the Sponsor thirty days in 
advance of submission in order to obtain approval prior to submission of the final version for publication. 
This will be reviewed promptly and approval will not be withheld unreasonably. In case of a difference of 
opinion between the Sponsor and the investigator(s), the contents of the publication will be discussed in 
order to find a solution that satisfies both parties. 
 
The investigator is encouraged to participate in the evaluation of the data for scientific purposes but is 
expected to work with the Sponsor in the development of any scientific presentation or publication. Since 
the Sponsor authors will be included, it is expected that all co-authors of the manuscripts will have an 
opportunity for feedback in the content and conclusions. The technical and editorial resources of the 
Sponsor will be available to assist in the development of abstracts, presentations, and publications 
regarding this study, and it is expected that drafts will be sent to the Sponsor with adequate time for input 
and revisions prior to submission.  
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 41 of 53 
11. 
REFERENCES 
 
1. Harris MI, et al. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels 
in the US populations aged 24-70 years. Diabetes 36(4):523-534, 1987.  
2. Bergman RN. Lily Lecture 1989. Toward physiological understanding of glucose tolerance. 
Minimal model approach. Diabetes 38(12):1512-1527, 1989. 
3. Kahn CR. I Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. 
Diabetes 43(8):1066-1084, 1994. 
4. Nawaz S, et al. Clinical risk associated with contrast angiography in metformin treated patients: a 
clinical review. Clin Radiol 53(5):342-344, 1998. 
5. Papoushek C. The “GLITAZONES”: rosiglitazone and pioglitazone. J Obstet Gynaecol Can 
25(10):853-857, 2003.  
6. Kermani A and Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary 
edema. Mayo Clin Proc 78(9):1088-1091, 2003. 
7. Zinman B, et al. The effect of adding exanatide to thiozollidinedione in suboptimally controlled 
type 2 diabetes: a randomized trial. Ann Intern Med 146(7):477-485, 2007. 
8. Gallwitz B. New therapeutic strategies for the treatment of type 2 diabetes mellitus based on 
incretins. Rev Diabetes Stud 2(2):61-69, 2005. 
9. Hanefeld M, et al. Once daily, a dippetidyl peptidase-4 inhibitor, for the treatment of patients 
with type 2 diabetes. Curr Med Res Opin. 23(6):1329-1339, 2007. 
10. Goldstein BJ, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 
inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 
30(8):1979-1987, 2007. 
11. Flegal KM, et al. Prevalence and trends in obesity among US adults, 1999- 2008. J Am Mer 
Assoc 303(3):235-241, 2010. 
12. Boden G. Study of obese diabetics explains why low-carb diets produce fast results. Science 
Daily April 8, 2005 (http://www.sciencedaily.com/releases/2005/03/050326095632.htm). 
13. Colditz GA, et al. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Int 
Med 122(7):481-486, 1995. 
14. US Preventive Service Task Force. Screening for obesity in adults: recommendations and 
rationale. Ann Intern Med 139(11):930-932, 2003.  
15. Song MK, et al. Anti-hyperglycemic activities of cyclo (his-pro) in genetically diabetic Goto-
Kakizaki rats. Exp Biol Med 228(11):1338-1345, 2003. 
16. Hwang IK, et al. Effects of cyclo (his-pro) plus zinc on glucose metabolism in genetically 
diabetic obese (ob/ob) mice. Diabet Obe Metabol 5(5):317-324, 2003.  
17. Song MK, et al. Body weight reduction by oral treatment with zinc plus Cyclo (his-pro). Br J 
Pharmacol 158(2):442-450, 2009. 
18. Perlman RK & Rosner MR. Identification of zinc ligands of the insulin-degrading enzyme. J Biol. 
Chem. 269(52):33140-33145, 1994.  
19. Valera Mora ME, et al. Insulin clearance in obesity. J. Am. Coll. Nutr. 22(6):487-493, 2003.  


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 42 of 53 
20. Aguilar MV, et al. Effects of diabetes on the tissue Zn/Cu ratio. J Trace Elem Med Biol 12(3):155-
158, 1998.  
21. Terres-Martos C, et al. Serum zinc and copper concentrations and Cu/Zn ratios in patients with 
hepatopathies or diabetes. J Trace Elem Med Biol 12(1):44-49, 1998. 
22. Song MK and Mooradian AD. Intestinal zinc transport:Influence of streptozotocin-induced 
diabetes, insulin and arachidonic acid. Life Sci 42(6):687-694, 1988. 
23. Kinlaw WB, et al. Abnormal zinc metabolism in Type II diabetes mellitus. Am J Med 75(5):273-
277, 1983. 
24. Ghishan FK and Greene HL. Intestinal transport of zinc in the diabetic rat. Life Sci 32(15):1735-
1741, 1983.  
25. Johnson WT and Canfield WK. Intestinal absorption and excretion of zinc in streptozotocin-diabetic 
rats as  affected by dietary zinc and protein. J Nutr 115(9):1217-27, 1985. 
26. Kiilerich S, et al. 65 zinc absorption in patients with insulin-dependent diabetes mellitus assessed by 
whole-body counting technique. Clin. Chim. Acta 189(1):13-18, 1990. 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 43 of 53 
12. 
APPENDICES 
 
Appendix 1: Oral Glucose Tolerance Test (OGTT) 
 
Subjects will be advised to maintain similar exercise and eating habits 3 days prior to the OGTT. Each 
subject will be instructed not to take his or her usual oral medications or insulin injection and food at least 
12 hours before coming to the clinical site between 7:00 am and 8:30 am for an OGTT. Each subject will 
be allowed to drink only water during the 12-hour fasting period prior to the OGTT and advised not to 
consume any food. Initial blood will be drawn (15 min prior to OGTT) for serum chemical analysis. The 
subject will then consume a glucose solution (75 g), followed by one drop of blood drawn for glucose 
measurements with a glucometer at 0, 0.5, 1.0, 1.5, 2.0, 2.5 and 3 h in the clinical site. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 44 of 53 
Appendix 2: Daily Log 
 
Subject Diary 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study to Evaluate the 
Efficacy and Safety of Cyclo-Z in Patients with Obese Type 2 Diabetes 
 
 
Protocol No. 
NMP-CYZ-P2-001 
 
 
Subject Initial 
 
 
 
 
 
 
 
 
 
Screening No. 
 
- 
 
 
 
 
 
 
 
 
Code* 
 
Number 
 
                                                                                                       * Site Number 
< How to fill out this diary > 
Ø 
Please record this diary everyday starting the evening of the day it’s dispensed until the morning of your 
next visit to the hospital. 
Ø 
Return this diary to the person in charge of this study at your next visit. You will receive a new diary at 
each visit. 
Ø 
Study Site: This is the name of the hospital you will be visiting for the study. 
Ø 
Date Dispensed: This is the date you received this diary. Please record it in the format of 
DD/MMM/YYYY (Example: 03 Feb 2015). 
Ø 
Date: This is the date you checked your blood sugar levels and took the study medication. Please record 
it in the format of DD/MMM/YYYY (Example: 03 Feb 2015). 
Ø 
Blood Sugar: Please check the unit in which your blood sugar level is measured. 
Ø 
Fasting before breakfast: Write down your blood sugar level tested in a fasted state before breakfast. 
Ø 
2 hours after dinner: Write down your blood sugar level tested 2 hours after dinner. 
Ø 
Not done: If you did not check your blood sugar, please check the box and state the reason. 
Ø 
Study Medication: Please check whether you took the study medication or not.  On the evening before 
your visit to the hospital, indicate when you took study medication in a 24 hour format (Example: 6:00 
pm = 18:00, 8:00 pm = 20:00). 
Ø 
Not taken: If you did not take your study medication, please check the box and state the reason. 
Ø 
If you are unable to return to the study site 14 days after your previous visit, use the additional rows 
provided to continue recording your blood sugar levels and the study medication compliance until your 
next visit.  
Ø 
Comments: Please leave any comments, questions or concerns you may have.  Also inform the study 
staff of any changes to your diet or exercise regimen. 
Ø 
Diary return date and confirmation signature: Please record the date the diary is returned to the site and 
your signature to confirm. 
If you have any further questions or problems about filling out the diary or the study in general, 
please contact your clinical site. 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 45 of 53 
 
Date Dispensed 
(Example: 03 Feb 2015) 
Day 
Date (DD/MMM/YYYY) 
Blood Sugar ( □ mg/dl    □ mmol/L) 
1 
 
Fasting before breakfast 
2 hours after dinner 
N/A 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
2 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
3 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
4 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
5 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
6 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
7 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
8 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
9 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
10 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
11 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 46 of 53 
 
Please fill out the following when you return the diary at each visit. 
Diary Return Date (DD/MMM/YYYY) 
 
 
Subject Signature 
 
Reviewer Signature 
 
12 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
13 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
14 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
(  ) 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
(  ) 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
(  ) 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
(  ) 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
(  ) 
 
Fasting before breakfast 
2 hours after dinner 
 
 
□Not done (reason:                                                ) 
Study Medication: □Taken □Not taken (reason:                                                  ) 
Time you took your medication the evening before your visit to hospital: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments 
Please leave any comments, questions or concerns you may have.  Also inform the study staff of any 
changes to your diet or exercise regimen. 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 47 of 53 
Appendix 3: Audit of Diabetes-Dependent Quality of Life (ADDQoL) Questionnaire 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 48 of 53 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 49 of 53 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 50 of 53 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 51 of 53 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 52 of 53 
 
 
 
 
 


NovMetaPharma Co., Ltd.                                                                                              
Protocol No: NMP-CYZ-P2-001  
Cyclo-Z                                                                                                                                    
December 9, 2016 / Ver 2.4   
Confidential                                                                                                                                                                     Page 53 of 53 
Appendix 4: Determining Hypoglycemic and Hyperglycemic Episodes 
 
For this study, a subject will be described as having hypoglycemic or hyperglycemic episodes when the 
following definitions are met: 
• 
Documented Symptomatic Hypoglycemia is defined as an event during which typical symptoms 
of hypoglycemia are accompanied by a measured plasma glucose concentration ≤70 mg/dl. 
• 
Asymptomatic Hypoglycemia is defined as an event not accompanies by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤70 mg/dl. 
• 
Probable symptomatic hypoglycemia is defined as an event during which symptoms of 
hypoglycemia are not accompanied by a plasma glucose determination, but that was presumably 
caused by a plasma glucose concentration ≤70 mg/dl. 
• 
Relative Hypoglycemia is defined as an even during which the person with diabetes reports of the 
typical symptoms of hypoglycemia, and interprets those as indicative of hypoglycemia, but with a 
measured plasma glucose concentration >70 mg/dl. 
• 
Severe Hypoglycemia is defined as an event requiring assistance of another person to actively 
administer carbohydrate, glucagons, or other resuscitative actions, or when a measured plasma 
glucose concentration is <40 mg/dl. 
• 
Hyperglycemia is defined as plasma glucose level >140 mg/dl. 
• 
Severe hyperglycemia is defined as plasma glucose level >300 mg/dl. 
 
* Definitions of hypoglycemic episodes were defined per “Defining and Reporting Hypoglycemia: A report from 
the American Diabetes Association Workgroup on Hypoglycemia” from May, 2005 issue of Diabetes Care. 
 

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NovMetaPharma Co., Ltd. 
NMP-CYZ-P2-001 
 
Statistical Analysis Plan                                                                                                                     Version 1.2 
 
 
 
CONFIDENTIAL 
Page 3 
16 October 2017 
Document Version History 
 
Version 
Date 
Author 
Description of Changes 
1.0 
21 June 2017 
Hyun Ji Kim 
Initial version 
1.1 
29 August 2017 
Hyun Ji Kim 
Modified the following by sponsor request. 
1. Added exploratory efficacy analysis for TAFGC. 
2. Added paired t-test (or Wilcoxon signed-rank test) to 
    analysis the change of efficacy endpoints within each group. 
3. Deleted Analysis for unexpected adverse events. 
1.2 
16 October 2017 
Hyun Ji Kim 
Modified the following by sponsor request. 
1. Added 1 exploratory efficacy endpoint – BMI. 
2. Added exploratory efficacy analyses for BMI. 
3. Updated calculation for TAFGC. 
4. Added sponsor defined definitions for Hypoglycemia and  
    Hyperglycemia 
5. Added section for Subgroup Analysis. 
6. Added section for Post-hoc Analysis. 
 
 
 


NovMetaPharma Co., Ltd. 
NMP-CYZ-P2-001 
 
Statistical Analysis Plan                                                                                                                     Version 1.2 
 
 
 
CONFIDENTIAL 
Page 4 
16 October 2017 
Table of Abbreviations 
 
Abbreviation 
Description 
AE 
Adverse Event 
ADDQoL 
Audit of Diabetes-Dependent Quality of Life 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BSA 
Bio-Statistics Associate 
BSM 
Bio-statistics Manager 
BW 
Body Weight 
cGMP 
Current Good Manufacturing Practice 
CHP 
Cyclo (His-pro) 
CRO 
 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cyclo 
Cyclic dipeptide 
DBMS 
Database Management System 
DM 
Diabetes Mellitus 
DPP 
Dipeptidyl Peptidase 
DW 
Distilled Water 
eCRF 
Electronic Case Report Form 
EAS 
Efficacy Analysis Set  
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
G-K 
Goto-Kakizaki 
GLP 
Good Laboratory Practice 
GLP-1 
Glucagon-like protein-1 
GLUT-4 
Glucose transporter-4 
GMP 
Good Manufacturing Practice 
HbA1c 
Hemoglobin A1c 
hCG 
human chorionic gonadotropin 
IB 
Investigator‟s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Insulin Degrading Enzyme 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MsSQL 
Microsoft Structured Query Language 
NIDDM 
Non-insulin-dependent Diabetes Mellitus 
ODBC 
Open Database Connectivity 
OGTT 
Oral Glucose Tolerance Test 
PT 
Preferred Term 


NovMetaPharma Co., Ltd. 
NMP-CYZ-P2-001 
 
Statistical Analysis Plan                                                                                                                     Version 1.2 
 
 
 
CONFIDENTIAL 
Page 5 
16 October 2017 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
S-D 
Sprague-Dawley 
SEM 
Standard Error of the Mean 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TAFGC 
Three-hour-area-average Above Fasting Glucose Concentration 
TSH 
Thyroid Stimulating Hormone 
T3 
Triiodothyronine 
T4 
Thyroxine 
WHODRUG 
World Health Organization Drug  
 
 


NovMetaPharma Co., Ltd. 
NMP-CYZ-P2-001 
 
Statistical Analysis Plan                                                                                                                     Version 1.2 
 
 
 
CONFIDENTIAL 
Page 6 
16 October 2017 
Table of Contents 
DOCUMENT VERSION HISTORY ...............................................................................................................3 
TABLE OF ABBREVIATIONS .......................................................................................................................4 
TABLE OF CONTENTS ..................................................................................................................................6 
1. 
INTRODUCTION ......................................................................................................................................8 
2. 
STUDY OBJECTIVE(S) ...........................................................................................................................8 
2.1  Primary Objective ..............................................................................................................................8 
2.2  Secondary Objective ..........................................................................................................................8 
3. 
STUDY OVERVIEW.................................................................................................................................8 
3.1  Study Design ......................................................................................................................................8 
3.1.1 Overall Study Design ................................................................................................................................ 8 
3.1.2 Schedule of Assessment ............................................................................................................................ 9 
3.2 
Study Population ..............................................................................................................................10 
3.2.1 Inclusion Criteria .................................................................................................................................... 10 
3.2.2 Exclusion Criteria ................................................................................................................................... 10 
3.3 
Sample Size Considerations .............................................................................................................11 
3.4 
Randomization and Blinding ...........................................................................................................11 
3.4.1 Randomization ........................................................................................................................................ 11 
3.4.2 Blinding .................................................................................................................................................. 12 
4. 
STUDY ENDPOINTS AND COVARIATES .........................................................................................12 
4.1 
Primary Endpoints ...........................................................................................................................12 
4.2 
Secondary Endpoints .......................................................................................................................12 
4.3 
Exploratory Endpoints .....................................................................................................................12 
4.4 
Safety Endpoints ..............................................................................................................................13 
4.5 
Cyclo (His-pro) (CHP) Concentration Evaluation ...........................................................................13 
5. 
HYPOTHESES .........................................................................................................................................13 
6. 
DEFINITIONS .........................................................................................................................................13 
7. 
ANALYSIS SUBSETS .............................................................................................................................14 
7.1 
Full Analysis Set ..............................................................................................................................14 
7.2 
Efficacy Analysis Set .......................................................................................................................15 
7.3 
Per Protocol Set ................................................................................................................................15 
7.4 
Safety Analysis Set ..........................................................................................................................15 
8. 
INTERIM ANALYSIS.............................................................................................................................16 
9. 
DATA SCREENING AND ACCPETANCE .........................................................................................16 
9.1 
General Principles ............................................................................................................................16 
9.2 
Data Handling and Electronic Transfer of Data ...............................................................................16 
9.3 
Handling of Missing and Incomplete Data ......................................................................................16 
9.3.1 Missing and Incomplete Dates ................................................................................................................ 16 
9.3.2 Missing Baseline Evaluation ................................................................................................................... 17 
9.3.3 Missing Post-Baseline Evaluation .......................................................................................................... 17 
9.3.4 Handling of Repeated Laboratory Test Results ...................................................................................... 17 
9.4 
Handling of Early Termination ........................................................................................................17 


NovMetaPharma Co., Ltd. 
NMP-CYZ-P2-001 
 
Statistical Analysis Plan                                                                                                                     Version 1.2 
 
 
 
CONFIDENTIAL 
Page 7 
16 October 2017 
9.5 
Outliers Detection ............................................................................................................................18 
9.6 
Bias Detection ..................................................................................................................................19 
9.7 
Distributional Characteristics ...........................................................................................................19 
9.8 
Validation of Statistical Analyses ....................................................................................................19 
10. STATISTICAL ANALYSES ...................................................................................................................19 
10.1 General Principles ............................................................................................................................19 
10.2 Subject Disposition ..........................................................................................................................20 
10.3 Protocol Deviations ..........................................................................................................................20 
10.4 Demographic and Baseline Characteristics ......................................................................................20 
10.4.1 Demographic Characteristics .................................................................................................................. 20 
10.4.2 Medical History ...................................................................................................................................... 21 
10.4.3 Concomitant Medications ....................................................................................................................... 21 
10.4.4 Efficacy Variables at Baseline ................................................................................................................ 21 
10.5 Efficacy Analyses ............................................................................................................................21 
10.5.1 Primary Efficacy Analyses ..................................................................................................................... 23 
10.5.2 Secondary Efficacy Analyses ................................................................................................................. 24 
10.5.3 Exploratory Efficacy Analyses ............................................................................................................... 25 
10.6 Safety Analyses ................................................................................................................................26 
10.6.1 Adverse Events ....................................................................................................................................... 26 
10.6.2 Laboratory Test Results .......................................................................................................................... 28 
10.6.3 Vital Signs .............................................................................................................................................. 28 
10.6.4 Physical Examination and 12-lead ECG ................................................................................................. 28 
10.6.5 Exposure to IP ......................................................................................................................................... 28 
10.6.6 Concomitant Medication Use ................................................................................................................. 29 
10.7 CHP Concentration Analysis ...........................................................................................................29 
10.8 Subgroup Analysis ...........................................................................................................................29 
10.9 Post-hoc Analysis .............................................................................................................................29 
11. REPORTING CONVENTIONS .............................................................................................................29 
12. ADJUSTED STATISTICAL ANALYSIS METHOD ..........................................................................30 
13. CHANGES IN THE STATISTICAL ANALYSIS FROM THE PROTOCOL ..................................30 
14. REFERENCES .........................................................................................................................................33 
 
 
 


NovMetaPharma Co., Ltd. 
NMP-CYZ-P2-001 
 
Statistical Analysis Plan                                                                                                                     Version 1.2 
 
 
 
CONFIDENTIAL 
Page 8 
16 October 2017 
1. INTRODUCTION 
 
This Statistical Analysis Plan (SAP) is developed to guide the details of the statistical analysis method of the 
phase 2 study to evaluate the efficacy and safety of Cyclo-Z in patients with obese type 2 diabetes. The SAP 
includes detailed definitions of the populations to be analyzed, the subject characteristics and the efficacy and 
safety endpoints, as well as the specific statistical analysis methods to be performed. 
 
2. STUDY OBJECTIVE(S) 
 
2.1  
Primary Objective 
 
The primary objective is to assess the dose-dependent efficacy of Cyclo-Z for the treatment of subjects with 
obese type 2 diabetes. 
 
2.2  
Secondary Objective 
 
The secondary objective is to assess the safety of Cyclo-Z in the treatment of subjects with obese type 2 
diabetes. 
 
3. STUDY OVERVIEW  
 
3.1  
Study Design 
3.1.1 
Overall Study Design 
 
This is a double-blind, randomized, placebo-controlled, parallel-group comparison study to evaluate the 
efficacy and safety of Cyclo-Z vs. placebo in adult subjects with obese type 2 diabetes. Up to four sites may 
be utilized in the United States so that a total of 80 subjects (a potential 20% screening failure rate) may be 
screened for total 16-week study period (2 weeks for screening, 12 weeks for treatment, and 2 weeks for 
safety follow-up). 
 
Subjects who meet preliminary inclusion and exclusion criteria at Screening will undergo a 2-week 
assessment period of record-keeping compliance. Subjects will be asked to record daily blood glucose values 
(fasting before breakfast and two hours after dinner) and study medication adherence throughout study 
participation. 
 
Sixty-four (64) qualified subjects will be assigned randomly to either the placebo arm or to one of the three 
treatment groups requiring the oral intake of a single gel capsule of Cyclo-Z or placebo once daily before 
bedtime for 12 consecutive weeks. 
 
Refer to the schedule of assessment of Section 3.1.2 for a display of all assessments to be conducted. All 
visits are to be scheduled according to their time from the randomization visit (Visit 2).  


NovMetaPharma Co., Ltd. 
NMP-CYZ-P2-001 
 
Statistical Analysis Plan                                                                                                                     Version 1.2 
 
 
 
CONFIDENTIAL 
Page 9 
16 October 2017 
3.1.2 
Schedule of Assessment 
Screening 
Treatment Period 
Follow-
up 
Study Visits 1) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Screen 
(Week -2) 
Baseline 
(Week 0) Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Demographic (including 
height) 
X 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
 
 
 
 
Physical Examination  
X 
X 
 
X 
 
X 
 
X 
 
Vital Signs and Body 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
Blood Sampling for serum 
chemistry, hematology, 
FPG, HbA1c, hCG, TSH, 
T3, and T4 2) 
X 
X 
 
X 
 
X 
 
X 
 
Blood Sampling for zinc, 
insulin, adiponectin, C-
peptide, leptin, glucagon, 
[CHP in a subset of  
subjects 3)] 
 
X 
 
X 
 
X 
 
X 
 
Urine Sampling for glucose, 
microalbumin, copper, and 
zinc  
 
X 
 
X 
 
X 
 
X 
 
Dispense and Review  
Daily Log 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense and Review 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
 
Waist Circumference 
 
X 
 
X 
 
X 
 
X 
 
OGTT 4)  
 
X 
 
 
 
 
 
X 
 
ADDQoL Questionnaire 
 
X 
 
 
 
 
 
X 
 
Review of Adverse Event 
and Concomitant 
Medication 5) 
 
X 
X 
X 
X 
X 
X 
X 
X 
1)  Visits 3 to 8 have ±3 day visit window and Visit 9 has +7 day visit window. 
2) 
Serum chemistry, hematology: Weeks -2, 0, 4, 8, and 12 
         HbA1c: Weeks -2, 0, 4, 8, and 12 
         FPG: Weeks 0, 4, 8, and 12 
         TSH, T3, T4: Weeks 0 and 12  
         Serum hCG (pregnancy): Weeks -2 and 12 
3) 
CHP levels may be analyzed in a subset of subjects if residual serum and/or plasma samples are available after  
         completion of protocol-required tests. 
4)  Subjects will be advised to maintain similar exercise and eating habits 3 days prior to the OGTT. Each subject will be 
instructed not to take his or her usual oral medications or insulin injection and food at least 12 hours before coming to the 
clinical site between 7:00 am and 8:30 am for an OGTT. Each subject will be allowed to drink only water during the 12-
hour fasting period prior to the OGTT and advised not to consume any food. Initial blood will be drawn (15 min prior to 
OGTT) for serum chemical analysis. The subject will then consume a glucose solution (75 g), followed by one drop of 
blood drawn for glucose measurements with a glucometer at 0, 0.5, 1.0, 1.5, 2.0, 2.5 and 3 h in the clinical site. 
5)  Assess hypoglycemic & hyperglycemic episodes at Visits 2 to 8 only. 
 
 


NovMetaPharma Co., Ltd. 
NMP-CYZ-P2-001 
 
Statistical Analysis Plan                                                                                                                     Version 1.2 
 
 
 
CONFIDENTIAL 
Page 10 
16 October 2017 
3.2 
Study Population 
3.2.1 
Inclusion Criteria 
 
To be enrolled in the study, a subject must meet all of the following criteria: 
 
1) Males or females aged 18 or older. 
2) Subjects diagnosed with type 2 diabetes mellitus according to the American Diabetes Association (ADA) 
criteria. 
3) Subjects treated with stable doses of insulin and/or other hypoglycemic agent(s) for type 2 diabetes 
mellitus for at least 2 months prior to randomization. 
4) Subjects whose fasting blood glucose levels are reasonably stable for at least 2 months prior to 
randomization and during the 2-week screening period. Stable glucose levels are defined based on the fact 
that the study subjects did not change the dose and/or type of insulin injection and/or other hypoglycemic 
agent(s) during the last 2 months and during the 2-week screening period to adjust blood glucose. 
5) Subjects who have Hemoglobin A1c levels of 7.5 to 10.0 % at Screening. 
6) Subjects whose BMI is 30 or above. 
7) Subjects who can give written informed consent. 
 
3.2.2 
Exclusion Criteria 
 
A subject must not be enrolled in the study if any of the following criteria are met: 
 
1) Subjects who have any DM-related end-organ damages.  
2) Subjects who have a history of diabetic ketoacidosis or hyperosmolar non-ketotic coma. 
3) Subjects who have any disease likely to limit life span and/or increase risks of interventions such as: 
• 
Carotid B-mode ultrasound test results indicating clinically significant stenosis in the common carotid 
arteries requiring intervention by angioplasty or resection. 
• 
Cancer treatment in the past 5 years, with the exception of cancers which have been cured, and carry 
a good prognosis. 
• 
Infectious disease: HIV positivity, active tuberculosis, or pneumonia. 
4) Subjects who have any of the following conditions related to cardiovascular disease: 
• 
Hospitalization for the treatment of heart disease in the past 12 months. 
• 
New York Heart Association Functional Class > 2. 
• 
Left Bundle branch block on ECG at Screening. 
• 
Third degree atrioventricular block on ECG at Screening. 
• 
Uncontrolled hypertension with average systolic blood pressure of > 160 mmHg or diastolic blood 
pressure > 95 mmHg at Screening and Baseline. 
• 
Pulse rate > 95 beats per minute at Screening and Baseline. 
• 
Stroke or transient ischemic attack in the past 12 months. 
5) Subjects who have any of the following conditions related to gastrointestinal disease: 
• 
Chronic hepatitis or cirrhosis. 
• 
Episode of alcoholic hepatitis or alcoholic pancreatitis in the past 2 months. 
• 
Inflammatory bowel disease requiring treatment in the past 12 months. 


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• 
Significant abdominal surgery (e.g., gastrectomy, gastric bypass) in the past 2 months. 
6) Subjects who have serum creatinine > 1.5 mg/dL for male or > 1.4 mg/dL for female. 
7) Subjects who have chronic obstructive airway disease or asthma requiring daily therapy or home use 
oxygen. 
8) Subjects who have hematocrit < 36.0% for male or < 33.0% for female. 
9) Subjects who have any of the following conditions or behaviors likely to affect the conduct of the study: 
• 
Weight loss of > 10% in the past 6 months. 
• 
Unable to walk without assisted device. 
• 
Major psychiatric disorder which would impede conduct of the research. 
• 
Excessive alcohol intake (i.e., more than 2 drinks/day). 
10) Subjects who take any of the following medications: 
• 
Psychoactive agents such as monoamine oxidase inhibitors and antidepressants (e.g., lithium, Prozac, 
Zoloft, Serzone, Paxil, Effexor). 
• 
Any other medications that may pose harm to the subject. 
11) Female subjects who have a positive serum pregnancy test at Screening, plan a pregnancy during study 
period, or are breast feeding.  
12) Female subjects who don‟t meet any of the following criteria: 
• 
Surgically sterile (i.e., have had bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at 
least 6 months before randomization.  
• 
Post-menopausal for at least 12 months prior to Screening. 
• 
If sexually active, they should use oral contraceptives, double barrier contraception (e.g., condom 
with spermicide), intrauterine device, or other methods approved by the Sponsor. 
 
3.3 
Sample Size Considerations 
 
This is a Phase 2 clinical trial to evaluate safety and explore the potential efficacy of the study drug. Therefore, 
the number of subjects was not based on formal statistical power considerations. In this clinical trial, a total of 
64 subjects was deemed sufficient and will be enrolled and randomly assigned to be administered with 1 of 3 
dose levels of Cyclo-Z or placebo. 
 
3.4 
Randomization and Blinding 
3.4.1 
Randomization 
 
At Visit 2 (Week 0), subjects who meet the inclusion/exclusion criteria will be randomly assigned to receive 
placebo or 1 of 3 doses of Cyclo-Z in accordance with the randomization code, which will be generated by 
other Bio-statistics associate (BSA) at Medihelpline rather than the BSA in charge. Specifically, the subjects 
will be randomly assigned in a 1:1:1:1 ratio to the following: 
 
• 
Dose A: Cyclo-Z containing 23 mg zinc plus 3 mg CHP – 16 subjects 
• 
Dose B: Cyclo-Z containing 23 mg zinc plus 9 mg CHP – 16 subjects 
• 
Dose C: Cyclo-Z containing 23 mg zinc plus 15 mg CHP – 16 subjects 
• 
Dose D: Placebo – 16 subjects 


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3.4.2 
Blinding 
 
As this is a double-blind study, blinding of the drug contents from the subjects, Investigator, and other study 
personnel at each site is necessary. The subject will be assigned with an identification number at Visit 2 
which will remain with the subject throughout the study. 
 
A code-break document including the randomization code information will be retained by each site and can 
be opened, revealing the randomization information, for emergency purposes only. The Investigator should 
note that the occurrence of a SAE should not routinely precipitate immediate unblinding. An attempt to 
contact the Sponsor must be made prior to unblinding. If unblinding occurs, the study medication for the 
subject must be discontinued; a written explanation on the relevant form must be prepared immediately. 
 
4. STUDY ENDPOINTS AND COVARIATES 
 
4.1 
Primary Endpoints 
 
The primary clinical efficacy variables used to evaluate the efficacy of Cyclo-Z are: 
 
• 
Change of HbA1c level from baseline at Week 12  
• 
Change of body weight (BW) from baseline at Week 12 
 
4.2 
Secondary Endpoints 
 
The secondary clinical efficacy variables used to evaluate the efficacy of Cyclo-Z are: 
 
• 
Change of fasting plasma glucose (FPG) level from baseline at Week 12 
• 
Proportion of subjects achieving HbA1c goal of < 7.0% at Week 12 
• 
Proportion of subjects achieving HbA1c goal of < 6.5% at Week 12 
• 
Change in waist circumference from baseline at Week 12 
• 
Change of postprandial (2 hours after dinner) blood glucose level from baseline at Week 12 
• 
Change of OGTT from baseline at Week 12 
• 
Change of score in Audit of Diabetes-Dependent Quality of Life (ADDQoL) Questionnaire from baseline 
at Week 12 
 
4.3 
Exploratory Endpoints 
 
In addition to the primary and secondary endpoints, the following exploratory efficacy variables will be 
separately evaluated for the change from baseline at Week 12: 
 
• 
Thyroid Function Test: Thyroid Stimulating Hormone (TSH), Triiodothyronine (T3) and Thyroxine (T4) 
• 
Serum Parameters: zinc, insulin, adiponectin, C-peptide, leptin and glucagon 
• 
Urine Parameters: zinc, glucose, microalbumin and copper 
• 
Three-hour-area-average Above Fasting Glucose Concentration (TAFGC) 
• 
Body Mass Index (BMI) 


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4.4 
Safety Endpoints 
 
The following safety parameters will be evaluated for the change from baseline assessment: 
 
• 
Blood samples for complete laboratory evaluation 
• 
ECG evaluation 
• 
Physical examination 
• 
Vital signs 
• 
Adverse events 
• 
Episodes of hypoglycemia and hyperglycemia 
 
4.5 
Cyclo (His-pro) (CHP) Concentration Evaluation 
 
In a subset of subjects where residual serum and/or plasma are available after completion of study-required 
tests, CHP levels in blood may be measured for the change from baseline. 
 
5. HYPOTHESES 
 
The primary objective is to assess the dose-dependent efficacy of Cyclo-Z for the treatment of subjects with 
obese type 2 diabetes. The hypothesis of this study is set as follows. 
 
The dose-dependent efficacy of Cyclo-Z will be demonstrated by identifying statistically significant 
difference in the change of HbA1c level and BW from baseline at Week 12 in Dose A, B, C, and D using one-
way analysis of variance (ANOVA) methods. Specifically, all three experimental groups will be compared to 
the control group on the change: Dose A vs. D, B vs. D, and C vs. D. 
 
                
          
 
   the mean of the primary clinical efficacy variables by each of the four dose groups 
 
6. DEFINITIONS  
 
• 
Baseline is defined as the last non-missing measurement taken on Week 0.  
 
• 
Study day 1 is defined as the first IP dose date. For subjects who are randomized but not dosed after 
randomization, the study day 1 is defined as the date of randomization. 
 
• 
Study day is defined as the number of days from study day 1. 
 
Before study day 1:  
study day = (date of interest – date of study day 1) 
On or after study day 1:  
study day = (date of interest – date of study day 1) + 1 
 
Therefore, the day prior to study day 1 is -1. 


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• 
Study drug exposure day is defined as the number of days that subjects were on the study drug. 
 
• 
Age (years) is calculated as follows, and is rounded down to an integer. 
 
                                          
      
 
 
• 
Diabetes disease period (years) is calculated as follows, and is rounded down to an integer. 
 
                                                            
      
 
 
*If the month and day of date of diagnosis are unknown, it will be converted into January, first day. 
 
• 
OGTT of secondary endpoint is used glucose value at 2 hour after glucose intake. 
 
• 
TAFGC is calculated as follows: 
 
      ∑[                 ( )                                            ]
 
 
 
  
                                   
 
• 
BMI (kg/m2) is calculated as follows: 
 
    
            (  )
       ( )         ( ) 
 
• 
Compliance (%) is calculated as follows: 
 
           
                        
                                                     
 
*By visit:              ( )               (   ), where n=3, 4, 5, 6, 7, and 8 
  Overall: ∑(             ( )               (   ))
 
, where n=3, 4, 5, 6, 7, and 8 
 
7. ANALYSIS SUBSETS 
 
This study is planned to analyze in analysis subsets of four groups: Full Analysis Set, Efficacy Analysis Set, 
Per Protocol Set, and Safety Analysis Set. For efficacy analysis, the Efficacy Analysis Set will be considered 
primarily and the Per Protocol Set will be considered as supportive. The Safety Analysis Set will be used in 
the safety analysis. 
 
7.1 
Full Analysis Set  
 
The Full Analysis Set (FAS) includes all subjects who were randomized in the study. Subjects will be 
analyzed according to their randomized treatment, regardless of the treatment received. Tabulations of subject 


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enrollment by site, subject disposition, analysis subsets, demographic and baseline characteristics including 
diabetes disease, past and present medical history, concomitant medication, and protocol deviations including 
major protocol deviations will utilize this analysis set. 
 
7.2 
Efficacy Analysis Set  
 
The Efficacy Analysis Set (EAS) will be used to carry out the efficacy analyses of efficacy endpoints, which 
is a subset of the FAS consisting of subjects who received at least one dose of study medication and who had 
baseline and any post-baseline efficacy data. Subjects will be analyzed according to their randomized 
treatment, regardless of the treatment received. Analyses for efficacy endpoints will utilize this analysis set. 
  
7.3 
Per Protocol Set  
 
All subjects valid for EAS who meet ALL the following criteria will be „valid per protocol‟ (also called „valid 
for efficacy‟): 
 
• 
Complete at least 2 weeks of treatment after randomization. 
• 
Have both baseline and at least 2 weeks of efficacy data. 
• 
Subject did not have any significant violation after randomization. 
 
Major protocol deviations that will potentially impact the primary analysis of efficacy endpoints at Week12 or 
violate GCP at site will be discussed and decided prior to the database lock and will be applied in per protocol 
analysis: 
 
The following cases are excluded from the Per Protocol Set: 
 
• 
Informed consent was not provided 
• 
Subjects who were withdrawn/early terminated 
• 
Subjects who have not met inclusion/exclusion criteria 
• 
Subjects who received excluded concomitant medications 
• 
Subjects who have major protocol deviations - all protocol deviations will be classified as major or minor 
under the discussion with Sponsor before database is locked. 
 
Additional criteria maybe added prior to unblinding of the study database. 
 
The Per Protocol Set will be used to perform the sensitivity analysis on the primary, the secondary, and 
the exploratory efficacy endpoints. 
 
7.4 
Safety Analysis Set 
 
The Safety Analysis Set will consist of all randomized subjects who received at least one dose of study 
medication and had any post-randomization safety data collected will be included in the evaluation of safety. 
Analyses of demographic and baseline characteristics, safety endpoints and summary of study medication 
administration will utilize this analysis set. 


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8. INTERIM ANALYSIS 
 
No interim analyses are planned for this Phase 2 study. 
 
9. DATA SCREENING AND ACCPETANCE 
 
9.1 
General Principles 
 
The objective of data screening is to assess the quantity, quality, and statistical characteristics of the data 
relative to the requirements of the planned analyses. The Bio-statistics associate (BSA) who is in charge of 
this study will check errors of raw data prior to the beginning of data analysis.  
 
9.2 
Data Handling and Electronic Transfer of Data 
 
After database is locked, a raw data validated by using Microsoft Structured Query Language (MsSQL) will 
be directly accessed using SAS Open Database Connectivity (ODBC) Driver. The raw data needed for 
analysis will be transferred from Database Management System (DBMS) to standard folder to store the raw 
data on the server via SAS ODBC, and the analysis dataset will be created in „DATASET‟ folder. The 
analysis dataset will be generated using SAS software version 9.4 according to analysis dataset specification 
created in accordance with this SAP. 
 
9.3 
Handling of Missing and Incomplete Data 
 
If subjects either discontinues from the clinical trial or the outcome measurement at any point is missing post-
baseline, then the missing data will be imputed from the last measured outcome value using the Last 
Observation Carried Forward (LOCF) method. 
 
9.3.1 
Missing and Incomplete Dates 
 
Missing or incomplete dates will be listed as it is in any listings. 
 
Incomplete start date of an adverse event or concomitant medication taken will be handled by following rule: 
 
Start Date 
Missing 
Imputation 
Exception 
Adverse Event 
Concomitant Medication 
Day 
01 
Default to Study Day 1 if an AE starts at the same 
year and month as Study Day 1 and the flag 
indicates that the AE started on or after the first 
dose on the AE CRF 
Day/Month 
01JAN 
Default to Study Day 1 if an AE started at the 
same year as Study Day 1 and the flag indicates 
that the AE started on or after the first dose on the 
AE CRF 
Day/Month/Year No Imputation 
 


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9.3.2 
Missing Baseline Evaluation 
 
Missing baseline will not be imputed. 
 
9.3.3 
Missing Post-Baseline Evaluation 
 
Primary analysis of continuous efficacy endpoints will be analyzed based on observed data without 
imputation. 
 
In the sensitivity analysis of primary and the secondary efficacy endpoints, missing continuous efficacy 
endpoints will be handled using the LOCF method. 
 
In the LOCF method, post-baseline missing continuous endpoints will be imputed using the last observed 
value including baseline value. For example, if subject has all of the post-baseline values as missing, then all 
of the post-baseline values will be imputed using the observed baseline value. 
 
9.3.4 
Handling of Repeated Laboratory Test Results 
 
Repeated laboratory test data will be handled after identifying the reason. If it is due to a test error, then the 
last value of the visit will be used, and if a clinical opinion is required, then the team will request the 
clinician‟s opinion and will decide what value to use. 
 
9.4 
Handling of Early Termination  
 
In order to analyze and summarize the data consistently, the last visit performed for Early Termination will be 
mapped to their closest to scheduled visit within the analysis dataset. 
 
For example, if a subject completed efficacy measurement at Week 0, then the subject got early terminated 
from the study 4 weeks later and completed efficacy measurement, then the efficacy measurement for ET will 
be mapped to Week 4 visit.  
 
Example #1: 
 
Before: 
Week 0 (02FEB2017)  
ET (02MAR2017) 
Efficacy Measurement – Done  
Efficacy Measurement – Done  
 
After:  
Week 0 (02FEB2017)  
Week 4 (02MAR2017) 
Efficacy Measurement – Done  
Efficacy Measurement – Done  
Note: Week 2 to Week 12 have ± 3 day visit window 
 
 
 


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Example #2: 
 
Before: 
Week 0 (02FEB2017)  
ET (05MAR2017) 
Efficacy Measurement – Done  
Efficacy Measurement – Done  
 
After:  
Week 0 (02FEB2017)  
Week 4 (05MAR2017) 
Efficacy Measurement – Done  
Efficacy Measurement – Done  
Note: Week 2 to Week 12 have ± 3 day visit window 
 
For example, if a subject completed efficacy measurement at Weeks 0, 4, 8 then the subject got early 
terminated from the study 4 weeks later after Week 8 and completed efficacy measurement, and then the 
efficacy measurement for ET will be mapped to Week 12 visit.  
  
Example #3: 
 
Before: 
Week 0 (29MAR2017)  
Week 4 (26APR2017) 
Week 8 (24MAY2017) 
ET (21JUN2017) 
Efficacy Measurement – 
Done  
Efficacy Measurement – 
Done  
Efficacy Measurement – 
Done 
Efficacy Measurement – 
Done 
 
After:  
Week 0 (29MAR2017)  
Week 4 (26APR2017) 
Week 8 (24MAY2017) 
Week 12 (21JUN2017) 
Efficacy Measurement – 
Done  
Efficacy Measurement – 
Done  
Efficacy Measurement – 
Done 
Efficacy Measurement – 
Done 
Note: Week 2 to Week 12 have ± 3 day visit window 
 
Each case will be discussed and decided with the study team and will be documented in the analysis dataset 
specification. 
 
9.5 
Outliers Detection 
 
Histograms or raw data review will be examined to identify outliers in any of the continuous variables used in 
the analyses. Unexpected and/or unexplained values in categorical data will be identified by utilizing 
frequency tables. 
 
Outliers due to data entry errors will be corrected by the study team before the database lock. The validity of 
any questionable values or outliers will be confirmed. Outliers or any questionable values with confirmed 
validity will be included in the analyses. However, ad-hoc sensitivity analyses may be conducted to evaluate 
the influence of extreme values in the data.  If it is deemed necessary after the team reviews the output from 
the planned analyses after the database lock, post-hoc analyses excluding subjects with outliers may be 
performed. 


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9.6 
Bias Detection 
 
Randomization and blinding are performed for avoiding bias in this phase 2 study. Major protocol deviations 
will be listed and or/tabulated in the clinical study report (CSR). Any breaking of the blind for individual 
subjects prior to unblinding of the study will be documented in the CSR. The timing of and reasons for 
premature withdrawal from treatment and from study will be tabulated and /or listed. 
 
9.7 
Distributional Characteristics 
 
Continuous endpoints of change from baseline value will be analyzed under normality assumption. If they 
deviate appreciably from normality, then appropriate non-parametric alternatives will be considered. 
 
9.8 
Validation of Statistical Analyses 
 
The procedure for the validation of the analysis result is as follows: 
 
1) Self-check: The BSA in charge will check for oneself that the SAS program code, output, execution log, 
etc. are written correctly. 
2) Double programming and the review: The BSA in charge and other BSA will write SAS program code 
independently, and the Bio-statistics manager (BSM; Reviewer) will compare the outputs such as table, 
graph, listing that are printed by the SAS program code. 
3) Source code check: The BSM will check the written source code visually, and will check whether it is 
properly processed according to its purpose. 
4) Table/Graph: The BSM will check the values displayed in tables and graphs. 
5) Listing/Raw data: The BSM will check whether the raw data and listing are the same or not. 
 
10. STATISTICAL ANALYSES 
 
10.1 
General Principles 
 
Statistical analysis will be conducted after database is locked and performed using SAS software version 9.4 
according to this SAP. If statistical analysis methods are changed, it will be described in the final clinical 
study report. 
 
Continuous variables will be summarized with means, standard deviations, medians, 25th & 75th percentiles, 
minimums, and maximums. Categorical variables will be summarized with counts and percentages. P-values 
less than 0.05 will be considered statistically significant. No adjustments for multiple comparison will be 
made to the result presented in this study because this is a phase 2 clinical trial and it is not formally powered 
with statistical algorithms. 
 
 
 


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10.2 
Subject Disposition 
 
The disposition of all randomized patients will be tabulated by randomized treatment group. The numbers of 
all patients classified as follows will be summarized with count, percentage and flow chart by site and 
treatment group. 
 
• 
All patients who enrolled into the study 
• 
Patients who were randomized 
• 
Patients who were treated  
• 
Patients who were completed 
• 
Prematurely withdrawn  
• 
The reasons for premature withdrawal 
 
10.3 
Protocol Deviations  
 
• 
All protocol deviations occurred during this study will be summarized by treatment group. Subjects who 
have protocol deviations will be categorized as follows; 
 
1) Subjects who have visits outside window 
2) Subjects who have not met inclusion criteria or met exclusion criteria but were entered into the study 
3) Subjects who received an excluded concomitant medications/treatment 
4) Subjects who have other protocol deviations 
 
• 
Individual patients with these protocol deviations will be listed by site. 
 
10.4 
Demographic and Baseline Characteristics 
 
Demographic characteristics, medical history, medication history, extent of exposure, and efficacy variables 
at baseline will be summarized using descriptive statistics by randomized treatment group and overall study 
population using FAS and Safety Analysis Set. Continuous variables will be summarized with mean, standard 
deviation, median, 25th & 75th percentiles, minimum and maximum. Categorical variables will be summarized 
with count (number of subjects and/or number of events) and percentage. Because, in theory, the goal of 
randomization is to balance out the subject characteristics, statistical tests are not planned for these variables. 
 
10.4.1 Demographic Characteristics 
 
• 
Sex (Male, Female) 
• 
Age 
• 
Ethnicity (Hispanic, Non-Hispanic) 
• 
Race (Black or African American, Native Hawaiian or other Pacific Islander, Native American Indian or 
Native Alaskan, Asian, White, Other) 
• 
Height 
 


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10.4.2 Medical History 
 
• 
Type of Diabetes (Type I Diabetes, Type II Diabetes, Gestational Diabetes) 
• 
Diabetes disease period 
• 
Past medical history status (Yes, No) and past medical history classified by System Organ Class (SOC) 
and Preferred Term (PT) according to MedDRA (Medical Dictionary for Regulatory Activities) version 
20.0. 
• 
Present medical history status (Yes, No) and present medical history classified by SOC and PT according 
to MedDRA version 20.0 
 
10.4.3 Concomitant Medications 
 
• 
Status (Yes, No) of concomitant medications and concomitant medications classified by Level1 and 
Level2 according to Anatomical Therapeutic Chemical (ATC) code WHODRUG version 2017 at V1 
(screening) 
 
10.4.4 Efficacy Variables at Baseline 
 
• 
HbA1c 
• 
Body Weight (BW) 
• 
FPG level 
• 
Waist Circumference 
• 
Mean value of postprandial (2 hours after dinner) blood glucose level 
• 
OGTT 
• 
ADDQoL questionnaire scores 
• 
Thyroid Function Test: TSH, T3, and T4 
• 
Serum parameters: zinc, insulin, adiponectin, C-peptide, leptin, and glucagon 
• 
Urine parameters: zinc, glucose, microalbumin, and copper 
• 
TAFGC 
• 
BMI  
 
10.5 
Efficacy Analyses 
 
The analyses of efficacy endpoints will utilize EAS. Subjects will be analyzed according to their randomized 
treatment group regardless of the actual treatment received during the study. Per protocol analyses of the 
primary, secondary, and exploratory endpoints will utilize the Per Protocol Set. 
 
 
 


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Detailed primary analysis methods, sensitivity analyses are summarized in the table below. 
 
 
Endpoints 
Primary Analysis and 
Analysis Method 
 
Sensitivity Analysis at Week 12 
Primary Endpoints 
Change of HbA1c level from 
baseline at Week 12 
Change of BW from baseline at 
Week 12 
1. EAS: Summary statistics by 
visit using observed data 
2. EAS: ANOVA model and 
Dunnett's test, and paired t-test 
1. LOCF, EAS: Summary statistics 
and analyze using an ANOVA model 
and Dunnett's test, and paired t-test 
2. Per Protocol Set: Same as primary 
summary and analysis method at 
Week 12 
Secondary Endpoints 
Change of FPG level from baseline  
at Week 12 
1. EAS: Summary statistics by 
visit using observed data 
2. EAS: ANOVA model and 
Dunnett's test, and paired t-test 
1. LOCF, EAS: Summary statistics 
and analyze using an ANOVA model 
and Dunnett's test, and paired t-test 
2. Per Protocol Set: Same as primary 
summary and analysis method at 
Week 12 
Proportion of subjects achieving 
HbA1c goal of < 7.0% at Week 12 
1. EAS: Summary statistics by 
visit using observed data 
2. EAS: Chi-square test 
 
1. LOCF, EAS: Summary statistics 
and analyze using chi-square test 
2. Per Protocol Set: Same as primary 
summary and analysis method at 
Week 12 
Proportion of subjects achieving 
HbA1c goal of < 6.5% at Week 12 
Same as above 
Same as above 
Change in waist circumference from 
baseline at Week 12 
1. EAS: Summary statistics by 
visit using observed data 
2. EAS: ANOVA model and 
Dunnett's test, and paired t-test 
1. LOCF, EAS: Summary statistics 
and analyze using an ANOVA model 
and Dunnett's test, and paired t-test 
2. Per Protocol Set: Same as primary 
summary and analysis method at 
Week 12 
Change of postprandial (2 hours 
after dinner) blood glucose level 
from baseline at Week 12 
Same as above 
Same as above 
Change of OGTT from baseline at 
Week 12 
Same as above 
Same as above 
Change of score in ADDQoL 
questionnaire from baseline at  
Week 12 
 
 
 
 
Same as above 
Same as above 


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Endpoints 
Primary Analysis and 
Analysis Method 
 
Sensitivity Analysis at Week 12 
Exploratory Endpoints  
Change of following variables from 
baseline at Week 12: 
Thyroid Function Test: TSH, T3, 
and T4 
Serum Parameters: zinc, insulin, 
adiponectin, C-peptide, leptin, and    
glucagon 
Urine Parameters: zinc, glucose, 
microalbumin, and copper 
TAFGC 
BMI 
1. EAS: Summary statistics by 
visit using observed data 
2. EAS: ANOVA model and 
Dunnett's test, and paired t-test 
 
1. Per Protocol Set: Same as primary 
summary and analysis method at 
Week 12 
 
10.5.1 Primary Efficacy Analyses 
 
• 
The change of HbA1c level from baseline at Week 12 will be summarized with mean, standard deviation, 
median, 25th & 75th percentiles, minimum, and maximum, overall and by each of the four groups, 
separately. To identify statistically significant difference in the change of HbA1c level from baseline at 
Week 12 between the four groups, one-way ANOVA will be performed. The tests between the 
experimental groups and the control group will be performed using Dunnett's test. If the change variables 
are markedly non-normally distributed then Kruskal-Wallis test and Wilcoxon rank-sum test will be used 
respectively. Specifically, all three experimental groups will be compared to the control group on the 
change: Dose A vs. D, B vs. D, and C vs. D. Also, to identify statistical significant difference between 
baseline and Week 12, one-sample t-test (paired t-test) or Wilcoxon signed-rank test will be performed 
within each of the four groups. 
 
• 
The change of BW from baseline at Week 12 will be summarized with mean, standard deviation, median, 
25th & 75th percentiles, minimum, and maximum, overall and by each of the four groups, separately. To 
identify statistically significant difference in the change of BW from baseline at Week 12 between the 
four groups, one-way ANOVA will be performed. The tests between the experimental groups and the 
control group will be performed using Dunnett's test. If the change variables are markedly non-normally 
distributed then Kruskal-Wallis test and Wilcoxon rank-sum test will be used respectively. Specifically, 
all three experimental groups will be compared to the control group on the change: Dose A vs. D, B vs. D, 
and C vs. D. Also, to identify statistical significant difference between baseline and Week 12, one-sample 
t-test (paired t-test) or Wilcoxon signed-rank test will be performed within each of the four groups. 
 
• 
Sensitivity analysis described below will be performed for the primary endpoints at Week 12: 
 
1. Summary statistics and ANOVA model for continuous endpoints using imputed data by LOCF, EAS. 
2. Primary summary and analysis method based on Per Protocol Set. 
 
 


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10.5.2 Secondary Efficacy Analyses 
 
• 
The change of FPG level from baseline at Week 12 will be summarized with mean, standard deviation, 
median, 25th & 75th percentiles, minimum, and maximum, overall and by each of the four groups, 
separately. To identify statistically significant difference in the change of FPG level from baseline at 
Week 12 between the four groups, one-way ANOVA will be performed. The tests between the 
experimental groups and the control group will be performed using Dunnett's test. If the change variables 
are markedly non-normally distributed then Kruskal-Wallis test and Wilcoxon rank-sum test will be used 
respectively. Specifically, all three experimental groups will be compared to the control group on the 
change: Dose A vs. D, B vs. D, and C vs. D. Also, to identify statistical significant difference between 
baseline and Week 12, one-sample t-test (paired t-test) or Wilcoxon signed-rank test will be performed 
within each of the four groups. 
 
• 
The proportion of subjects achieving HbA1c goal of < 7.0% at Week 12 will be summarized with count 
and percentage, overall and by each of the four groups, separately. The proportion of subjects achieving 
HbA1c goal of < 7.0% at Week 12 will be compared for the experimental groups versus the control group 
using chi-square test method. In a case when the expected cell frequencies are less than 5 in >20%, 
Fisher‟s exact test will be used. 
 
• 
The proportion of subjects achieving HbA1c goal of < 6.5% at Week 12 will be summarized with count 
and percentage, overall and by each of the four groups, separately. The proportion of subjects achieving 
HbA1c goal of < 6.5% at Week 12 will be compared for the experimental groups versus the control group 
using chi-square test method. In a case when the expected cell frequencies are less than 5 in >20%, 
Fisher‟s exact test will be used. 
 
• 
The change in waist circumference from baseline at Week 12 will be summarized with mean, standard 
deviation, median, 25th & 75th percentiles, minimum, and maximum, overall and by each of the four 
groups, separately. To identify statistically significant difference in the change in waist circumference 
from baseline at Week 12 between the four groups, one-way ANOVA will be performed. The tests 
between the experimental groups and the control group will be performed using Dunnett's test. If the 
change variables are markedly non-normally distributed then Kruskal-Wallis test and Wilcoxon rank-sum 
test will be used respectively. Specifically, all three experimental groups will be compared to the control 
group on the change: Dose A vs. D, B vs. D, and C vs. D. Also, to identify statistical significant 
difference between baseline and Week 12, one-sample t-test (paired t-test) or Wilcoxon signed-rank test 
will be performed within each of the four groups. 
 
• 
The change of postprandial (2 hours after dinner) blood glucose level from baseline at Week 12 will be 
summarized with mean, standard deviation, median, 25th & 75th percentiles, minimum, and maximum, 
overall and by each of the four groups, separately. To identify statistically significant difference in the 
change of postprandial (2 hours after dinner) blood glucose level from baseline at Week 12 between the 
four groups, one-way ANOVA will be performed. The tests between the experimental groups and the 
control group will be performed using Dunnett's test. If the change variables are markedly non-normally 
distributed then Kruskal-Wallis test and Wilcoxon rank-sum test will be used respectively. Specifically, 


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all three experimental groups will be compared to the control group on the change: Dose A vs. D, B vs. D, 
and C vs. D. Also, to identify statistical significant difference between baseline and Week 12, one-sample 
t-test (paired t-test) or Wilcoxon signed-rank test will be performed within each of the four groups. 
 
• 
The change of OGTT from baseline at Week 12 will be summarized with mean, standard deviation, 
median, 25th & 75th percentiles, minimum, and maximum, overall and by each of the four groups, 
separately. To identify statistically significant difference in the change of OGTT from baseline at Week 
12 between the four groups, one-way ANOVA will be performed. The tests between the experimental 
groups and the control group will be performed using Dunnett's test. If the change variables are markedly 
non-normally distributed then Kruskal-Wallis test and Wilcoxon rank-sum test will be used respectively. 
Specifically, all three experimental groups will be compared to the control group on the change: Dose A 
vs. D, B vs. D, and C vs. D. Also, to identify statistical significant difference between baseline and Week 
12, one-sample t-test (paired t-test) or Wilcoxon signed-rank test will be performed within each of the 
four groups. 
 
• 
The change of score in ADDQoL questionnaire from baseline at Week 12 will be summarized with mean, 
standard deviation, median, 25th & 75th percentiles, minimum, and maximum, overall and by each of the 
four groups, separately. To identify statistically significant difference in the change of score in ADDQoL 
questionnaire from baseline at Week 12 between the four groups, one-way ANOVA will be performed. 
The tests between the experimental groups and the control group will be performed using Dunnett's test. 
If the change variables are markedly non-normally distributed then Kruskal-Wallis test and Wilcoxon 
rank-sum test will be used respectively. Specifically, all three experimental groups will be compared to 
the control group on the change: Dose A vs. D, B vs. D, and C vs. D. Also, to identify statistical 
significant difference between baseline and Week 12, one-sample t-test (paired t-test) or Wilcoxon 
signed-rank test will be performed within each of the four groups. 
 
• 
Sensitivity analysis described below will be performed for the secondary endpoints at Week 12: 
 
1. Summary statistics and ANOVA model for continuous endpoints using imputed data by LOCF, EAS. 
2. Primary summary and analysis method based on Per Protocol Set. 
 
10.5.3 Exploratory Efficacy Analyses 
 
The exploratory efficacy variables will be summarized with mean, standard deviation, median, 25th & 75th 
percentiles, minimum, and maximum, overall and by each of the four groups, separately. To identify 
statistically significant difference in the exploratory efficacy variables between the four groups, one-way 
ANOVA will be performed. The tests between the experimental groups and the control group will be 
performed using Dunnett's test. If the change variables are markedly non-normally distributed then Kruskal-
Wallis test and Wilcoxon rank-sum test will be used respectively. Specifically, all three experimental groups 
will be compared to the control group on the change: Dose A vs. D, B vs. D, and C vs. D. Also, to identify 
statistical significant difference between baseline and Week 12, one-sample t-test (paired t-test) or Wilcoxon 
signed-rank test will be performed within each of the four groups. 
 


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• 
Thyroid Function Test: TSH, T3, and T4 
• 
Serum Parameters: zinc, insulin, adiponectin, C-peptide, leptin, and glucagon 
• 
Urine Parameters: zinc, glucose, microalbumin, and copper 
• 
TAFGC 
• 
BMI 
 
• 
Sensitivity analysis described below will be performed for the exploratory endpoints at Week 12: 
 
1. Primary summary and analysis method based on Per Protocol Set. 
 
10.6 
Safety Analyses 
 
Safety analysis will be performed based on data of safety analysis set. Safety variables will be summarized 
with descriptive statistics, overall and by each of the four groups, separately. Continuous safety variables will 
be summarized with mean, standard deviation, median, 25th & 75th percentiles, minimum, and maximum. 
Categorical safety variables will be summarized with count and percentage.  
 
No statistical testing comparing treatment groups will be performed in the safety analyses. 
 
10.6.1 Adverse Events 
 
• 
All adverse events (AEs) in CRF will be classified by SOC and PT according to MedDRA version 20.0.  
 
• 
A treatment-emergent AE (TEAE) will be defined as an AE that began or worsened on or after the first 
treatment dose. AEs recorded prior to the first application of study treatment will be considered non-
treatment-emergent. AEs with insufficient date or time information to determine whether or not they were 
treatment-emergent will be considered treatment-emergent. 
 
• 
All reported AEs (treatment-emergent or not) will be listed. Only TEAEs will be summarized. 
 
(1) TEAEs will be summarized with the number of subjects who have AEs, incidence rate of AEs, and 
the number of AEs by categorizing as follows; 
① AE/ADR* (Adverse event/Adverse drug reaction) 
*TEAEs which have the relationship to investigational product as 'Definite', 'Probable', and 
'Possible' are regarded as Drug-Related Adverse Events (ADR). 
② SAE/SADR (Serious adverse event/Serious adverse drug reaction) 
 
(2) TEAEs will also be summarized with the number of subjects who have AEs, incidence rate of AEs, 
the number of AEs, and its percentage by categorizing as follows. 
① Outcome 
- 
Recovered or Resolved 
- 
Recovering or Resolving 
- 
Recovered or Resolved with Sequelae 
- 
Not Recovered or Not Resolved 


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- 
Death Related to Adverse Event 
- 
Unknown 
② Severity 
- 
Mild 
- 
Moderate 
- 
Severe 
③ Relationship to Investigational Product (IP) 
- 
Definite 
- 
Probable 
- 
Possible 
- 
Not Likely 
- 
Not Related 
④ Action Taken Regarding IP 
- 
None 
- 
Reduced 
- 
Increased 
- 
Interrupted 
- 
Discontinued 
⑤ Treatment Required 
- 
Yes 
- 
No 
⑥ Seriousness 
- 
Is life-threatening 
- 
Requires in-patient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant disability or incapacity 
- 
Is a congenital anomaly or birth defect 
- 
Is an important medical event 
- 
Results in death 
 
• 
Episodes of hypoglycemia and hyperglycemia (V2-V8) 
 
(1) Hypoglycemia occurred after previous visit will be summarized with the number of subjects who are 
occurred episode and the count of episode by each visit separately. 
 
(2) Hyperglycemia occurred after previous visit will be summarized with the number of subjects who are 
occurred episode and the count of episode by each visit separately. 
 
(3) Sponsor defined Hypoglycemia (blood glucose ≤ 70 mg/dL) occurred after previous visit will be 
summarized with the number of subjects who are occurred episode and the count of episode by each 
visit separately. 
 


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(4) Sponsor defined Hyperglycemia (blood glucose ≥ 180 mg/dL) occurred after previous visit will be 
summarized with the number of subjects who are occurred episode and the count of episode by each 
visit separately. 
 
10.6.2 Laboratory Test Results 
 
• 
Laboratory tests are: 
 
- 
Hematology: RBC, WBC, Neutrophil count, Lymphocyte count, Monocyte count, Eosinophil count, 
Basophil count, Hematocrit, Hemoglobin, Platelets, MCH, MCHC, MCV, and RDW 
 
- 
Chemistry: ALT, Albumin, Alkaline phosphatase, AST, Total Bilirubin, BUN, Calcium, Bicarbonate, 
Chloride, Creatinine, Potassium, Total Protein, Sodium, and Glucose 
 
• 
Laboratory test results will be collected at V1, V2, V4, V6, and V8. These variables will be summarized 
with mean, standard deviation, median, 25th & 75th percentiles, minimum, and maximum by each 
treatment group and by each visit separately.  
 
• 
Normality of laboratory test results [Normal, Abnormal (CS, NCS)] will be summarized with count 
(number of subjects) and percentage by each treatment group and by each visit separately.  
 
10.6.3 Vital Signs 
 
• 
Vital signs [Sitting blood pressure (systolic, diastolic), Heart rate, Breathing, and Temperature] will be 
collected at V1, V2, V3, V4, V5, V6, V7, V8, and V9. These variables will be summarized with mean, 
standard deviation, median, 25th & 75th percentiles, minimum and maximum by each treatment group and 
by each visit separately.  
 
10.6.4 Physical Examination and 12-lead ECG 
 
• 
Result of physical examination (General Appearance, Head-Ears-Eyes-Nose-Throat, Neck, Heart, Lungs, 
Abdomen, Lymph Nodes, Genitourinary, Extremities, Neurological, Skin, Musculoskeletal, and Others) 
will be collected at V1, V2, V4, V6, and V8. These results (Normal, Abnormal) will be summarized with 
count (number of subjects) and percentage by each treatment group and by each visit separately.  
 
• 
Result of 12-lead ECG will be collected at V1 and V8. This result [Normal, Abnormal (CS, NCS)] will be 
summarized with count and percentage by each treatment group and by each visit separately. 
 
10.6.5 Exposure to IP 
 
• 
Study drug exposure day will be summarized with mean, standard deviation, median, 25th & 75th 
percentiles, minimum, and maximum by each treatment group and by each visit separately.  
 


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• 
Number of Capsules taken will be summarized with mean, standard deviation, median, 25th & 75th 
percentiles, minimum, and maximum by each treatment group and by each visit separately.  
 
• 
Compliance will be summarized with mean, standard deviation, median, 25th & 75th percentiles, minimum, 
and maximum by each treatment group and by each visit separately.  
 
10.6.6 Concomitant Medication Use 
 
• 
Concomitant medications status (Yes, No) collected at V2-V9 will be summarized with count and 
percentage by each treatment group separately. Concomitant medications classified by Level1 and Level2 
according to ATC code WHODRUG version 2017 will be also summarized. 
 
10.7 
CHP Concentration Analysis 
 
Levels of CHP assessed in blood for a subset of subjects if there are residual serum and/or plasma after 
completion of protocol-required tests will be summarized with mean, standard deviation, median, 25th & 75th 
percentiles, minimum, and maximum.  
 
No statistical tests are planned for these data. 
 
10.8 
Subgroup Analysis  
 
To explore the robustness of efficacy signal, primary, secondary, and exploratory efficacy endpoints may also 
be analyzed separately by excluding potential outliers.  
 
10.9 
Post-hoc Analysis  
 
To understand the data better for future study design, post-hoc analyses may also be performed separately. 
 
11. REPORTING CONVENTIONS 
 
All results of analysis will be reported in table or figure format to assist the understanding for the study results. 
The descriptive summary statistics for continuous variables will be presented in the number of subjects (n), 
mean, standard deviation, median, 25th & 75th percentiles, minimum, and maximum and the descriptive 
summary statistics for categorical variables will be given as frequencies, percentages.  
 
The number of decimal places presented for each statistic will be as follows: 
 
• 
Mean, median, 25th percentile, 75th percentile: one more than the number of decimal places recorded x  
• 
Standard deviation: two more than the number of decimal places recorded x  
• 
Minimum and maximum: equal to the number of decimal places recorded  
• 
Percentage: reported to one decimal place using rounding off 
• 
P-value: reported to four decimal places and if p-values smaller than 0.0001 will be written as „<0.0001‟. 
 
All dates will be displayed in DDMMMYYYY format (for example, 11JAN2015). 


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Data for individual subjects will be presented in data listings.  
 
12. ADJUSTED STATISTICAL ANALYSIS METHOD 
 
Not applicable. 
 
13. CHANGES IN THE STATISTICAL ANALYSIS FROM THE PROTOCOL 
 
Section 4.3 Two exploratory endpoints have been added. The endpoints are as follows: 
 
• 
Change in TAFGC from baseline at Week 12 
• 
Change in BMI from baseline at Week 12 
 
Section 6 New definitions have been added for Baseline, Study Day. The definitions are as follows: 
 
Baseline is defined as the last non-missing measurement taken on Week 0.  
 
Study day 1 is defined as the first IP dose date. For subjects who are randomized but not dosed after 
randomization, the study day 1 is defined as the date of randomization. 
 
Study day is defined as the number of days from study day 1. 
 
Before study day 1:  
study day = (date of interest – date of study day 1) 
On or after study day 1:  study day = (date of interest – date of study day 1) + 1 
 
Therefore, the day prior to study day 1 is -1. 
 
Section 7.1 Full Analysis Set has been added. The definition of FAS is as follows:  
 
The Full Analysis Set (FAS) includes all subjects who were randomized in the study. Subjects will be 
analyzed according to their randomized treatment, regardless of the treatment received. Tabulations of subject 
enrollment by site, analysis subsets, demographic and baseline characteristics including diabetes disease, past 
and present medical history, concomitant medication, subject disposition, and major protocol deviations will 
utilize this analysis set. 
 
Section 7.2 Efficacy Analysis Set has been replaced with Intent-to-Treat Set. The updated definition of EAS 
is as follows:  
 
The Efficacy Analysis Set (EAS) will be used to carry out the efficacy analyses of efficacy endpoints, which 
is a subset of the FAS consisting of subjects who received at least one dose of study medication and who had 
baseline and any post-baseline efficacy data. Subjects will be analyzed according to their randomized 
treatment, regardless of the treatment received. Analyses for efficacy endpoints will utilize this analysis set.  
 


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Section 9.3 Handling of missing, incomplete data, and repeated laboratory test data has been added in detail. 
The details are as follows: 
 
Only participants whose efficacy variable were measured least once after baseline. If participants either 
discontinues from the clinical trial or the outcome measurement at any point is missing, then the missing data 
will be imputed from the last measured outcome value using the Last Observation Carried Forward (LOCF) 
method. 
 
If repeated laboratory test data collected is due to a test error, then the last value of the visit will be used, and 
if a clinical opinion is required, then it will be used one value determined under discussion. 
 
No imputation methods are planned for safety analysis. 
 
Section 9.4 Handling of Early Termination has been added in detail. The details are as follows:  
 
In order to analyze and summarize the data consistently, the last visit performed for Early Termination will be 
mapped to their closest to scheduled visit within the analysis dataset. See Section 9.4 of this SAP to see more 
examples in detail. 
 
Section 10.5 Efficacy Analyses. The detailed primary analysis methods, sensitivity analyses are added and 
summarized in the table below. 
 
Endpoint 
Primary Analysis and Analysis 
Method 
Sensitivity Analysis at Week 12 
Primary Endpoints 
Change of HbA1c level from 
baseline at Week 12 
Change of BW from baseline at 
Week 12 
1. EAS: Summary statistics by visit 
using observed data 
2. EAS: ANOVA model and 
Dunnett's test, and paired t-test 
1. LOCF, EAS: Summary statistics 
and analyze using an ANOVA 
model and Dunnett's test, and 
paired t-test 
2. Per Protocol Set: Same as 
primary summary and analysis 
method at Week 12 
Secondary Endpoints 
Change of FPG level from baseline 
at Week 12 
1. EAS: Summary statistics by visit 
using observed data 
2. EAS: ANOVA model and 
Dunnett's test, and paired t-test 
1. LOCF, EAS: Summary statistics 
and analyze using an ANOVA 
model and Dunnett's test, and 
paired t-test 
2. Per Protocol Set: Same as 
primary summary and analysis 
method at Week 12 
Proportion of subjects achieving 
HbA1c goal of < 7.0% at Week 12 
1. EAS: Summary statistics by visit 
using observed data 
2. EAS: Chi-square test 
1. LOCF, EAS: Summary statistics 
and analyze using chi-square test 
2. Per Protocol Set: Same as 


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Endpoint 
Primary Analysis and Analysis 
Method 
Sensitivity Analysis at Week 12 
 
primary summary and analysis 
method at Week 12 
Proportion of subjects achieving 
HbA1c goal of < 6.5% at Week 12 
Same as above 
Same as above 
Change in waist circumference 
from baseline at Week 12 
1. EAS: Summary statistics by visit 
using observed data 
2. EAS: ANOVA model and 
Dunnett's test, and paired t-test 
1. LOCF, EAS: Summary statistics 
and analyze using an ANOVA 
model and Dunnett's test, and 
paired t-test 
2. Per Protocol Set: Same as 
primary summary and analysis 
method at Week 12 
Change of postprandial (2 hours 
after dinner) blood glucose level 
from baseline at Week 12 
Same as above 
Same as above 
Change of OGTT from baseline at 
Week 12 
Same as above 
Same as above 
Change of score in ADDQoL 
questionnaire from baseline at 
Week 12 
Same as above 
Same as above 
Exploratory Endpoints  
Change of following variables 
from baseline at Week 12: 
Thyroid Function Test: TSH, T3, 
and T4 
Serum Parameters: zinc, insulin, 
adiponectin, C-peptide, leptin, and 
glucagon 
Urine Parameters: zinc, glucose, 
microalbumin, and copper 
TAFGC 
BMI 
1. EAS: Summary statistics by visit 
using observed data 
2. EAS: ANOVA model and 
Dunnett's test, and paired t-test 
 
1. Per Protocol Set: Same as 
primary summary and analysis 
method at Week 12 
 
Section 10.6.1 New definition of Hypoglycemia and Hypoglycemia have been added in detail. The details are 
as follows:  
 
(1) 
Sponsor defined Hypoglycemia (blood glucose ≤ 70 mg/dL) occurred after previous visit will be 
summarized with the number of subjects who are occurred episode and the count of episode by each 
visit separately. 
 


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(2) 
Sponsor defined Hyperglycemia (blood glucose ≥ 180 mg/dL) occurred after previous visit will be 
summarized with the number of subjects who are occurred episode and the count of episode by each 
visit separately. 
 
Section 10.8 Subgroup Analysis has been added. The details are as follows: 
 
To explore the robustness of efficacy signal, primary, secondary, and exploratory efficacy endpoints may also 
be analyzed separately by excluding potential outliers.  
 
Section 10.9 Post-hoc Analysis has been added. The details are as follows: 
 
To understand the data better for future study design, post-hoc analyses may also be performed separately. 
 
14. REFERENCES 
 
Clinical Study Protocol “A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study to 
Evaluate the Efficacy and Safety of Cyclo-Z in Patients with Obese Type 2 Diabetes”, Version 2.4, December 
9, 2016