Clinical trial NCT04465877
Conditions: Diabetes Mellitus, Type 2
Keywords: JTT-662 Diabetes Safety Tolerability Pharmacokinetics Pharmacodynamics
Sponsor: Akros Pharma Inc.
Start date: 2020-06-15; Completion date: 2021-02-17
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JTT-662 administered once daily for 28 days in subjects with Type 2 diabetes mellitus (T2DM) who are receiving metformin monotherapy

Detailed description:

Arms: arm 1: JTT-662 5 mg orally once daily from Day 1 to Day 28, after a single dose of placebo on Day -1 arm 2: JTT-662 10 mg orally once daily from Day 1 to Day 28, after a single dose of placebo on Day -1 arm 3: JTT-662 20 mg orally once daily from Day 1 to Day 28, after a single dose of placebo on Day -1 arm 4: Placebo orally once daily from Day -1 to Day 28
Interventions: intervention 1: JTT-662 intervention 2: Placebo
Intervention descriptions: intervention 1: Active drug tablets containing JTT-662 intervention 2: Placebo tablets matching in appearance to the active drug tablets

Protocol documents:
Prot_000.pdf: 
 
ClinicalTrials.gov Posted Document Cover Page 
Clinical Study Protocol 
 
PROTOCOL TITLE:  
A Single-blind, Randomized, Placebo-controlled, Multiple Dose 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of JTT-662 Administered for 28 Days in 
Subjects with Type 2 Diabetes Mellitus on Metformin 
Monotherapy 
PROTOCOL NUMBER: AT662-U-20-003 
PROTOCOL DATE:  
29 January 2021 
NCT NUMBER: 
NCT04465877 
 
 
 


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Cover Page 
Akros Pharma Inc. 
Clinical Study Protocol 
 
PROTOCOL TITLE: 
A Single-blind, Randomized, Placebo-controlled, Multiple Dose 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of JTT-662 Administered for 28 Days in 
Subjects with Type 2 Diabetes Mellitus on Metformin 
Monotherapy 
PROTOCOL NUMBER: 
AT662-U-20-003 
DATE: 
29 January 2021 
IND NUMBER: 
 
SPONSOR: 
Akros Pharma Inc.  
302 Carnegie Center, Suite 300 
Princeton, NJ  08540 
SPONSOR CONTACT: 
 
Akros Pharma Inc
MEDICAL MONITOR: 
 
Confidentiality Statement 
The confidential information in this document is provided to you for review by you, your staff, and applicable Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others or use the information for any purpose other than the performance of your obligations 
pursuant to your and/or your employer’s agreement with us, our affiliate or our contractor, as the case may be, without prior written 
authorization from Akros Pharma Inc. (Akros). 


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Signature Page
Protocol Number: 
AT662-U-20-003
Protocol Title:
A Single-blind, Randomized, Placebo-controlled, Multiple Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of JTT-662 Administered for 28 Days in Subjects with Type 2 Diabetes 
Mellitus on Metformin Monotherapy
The signatures below indicate approval of the protocol.
Investigator’s Statement of Agreement:
I acknowledge possession of the JTT-662 Investigator’s Brochure (IB) and this protocol. Having 
fully reviewed all the information provided, I consider it ethically justifiable to give the study drug 
to subjects according to the agreed protocol. I will conduct the study in full accordance with this 
protocol and all applicable laws and regulations, including but not limited to current Good Clinical 
Practices.
Investigator
(Signature)
Date
(Printed Name)


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Table of Contents 
Cover Page...................................................................................................................................... 1 
Signature Page ............................................................................................................................... 2 
Table of Contents ........................................................................................................................... 3 
List of Figures ................................................................................................................................ 6 
List of Tables .................................................................................................................................. 6 
List of Abbreviations and Definition of Terms ............................................................................. 7 
Protocol Synopsis ......................................................................................................................... 10 
1 
Introduction .......................................................................................................................... 15 
1.1 
Background ................................................................................................................. 15 
1.1.1 Type 2 Diabetes Mellitus .......................................................................................... 15 
1.1.2 Treatment of Type 2 Diabetes Mellitus .................................................................... 15 
1.1.3 Sodium Glucose Co-Transporter 1 Inhibitor ............................................................ 16 
1.2 
JTT-662 ........................................................................................................................ 17 
1.2.1 Nonclinical Information ............................................................................................ 17 
1.2.2 Clinical Information .................................................................................................. 20 
1.3 
Justification of Dose Selection .................................................................................... 26 
2 
Study Objectives ................................................................................................................... 28 
3 
Investigational plan ............................................................................................................. 28 
3.1 
Number of Sites and Subjects .................................................................................... 28 
3.2 
Study Design ................................................................................................................ 28 
3.3 
Selection of Study Population .................................................................................... 29 
3.3.1 Inclusion Criteria ...................................................................................................... 29 
3.3.2 Exclusion Criteria ..................................................................................................... 30 
3.4 
Discontinuation of Subjects from the Study/Study Drug ........................................ 32 
3.5 
Study Suspension and Termination .......................................................................... 33 
3.6 
Study Procedures ........................................................................................................ 34 
3.6.1 Informed Consent...................................................................................................... 41 
3.6.2 Screening Period ....................................................................................................... 41 
3.6.3 Admission Period ...................................................................................................... 41 
3.6.4 Follow-up Period ...................................................................................................... 42 
3.6.5 Study Diet and Restrictions ...................................................................................... 43 
3.6.6 Previous and Concomitant Medication ..................................................................... 44 
3.6.7 Procedure Definitions ............................................................................................... 46 
3.6.8 Clinical Institutions and Laboratories ....................................................................... 52 
3.7 
Adverse Events ............................................................................................................ 53 
3.7.1 Safety Definitions ..................................................................................................... 53 


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3.7.2 Assessing Adverse Events ........................................................................................ 55 
3.7.3 Reporting Adverse Events ........................................................................................ 57 
3.8 
Identification of Treatments ...................................................................................... 59 
3.8.1 Method of Assigning Subjects to Treatment Groups ................................................ 59 
3.8.2 Identity of Investigational Products .......................................................................... 59 
3.8.3 Storage and Handling Procedures ............................................................................. 60 
3.8.4 Clinical Supplies Packaging ..................................................................................... 60 
3.8.5 Administration of Study Drug and Metformin ......................................................... 60 
3.8.6 Management of Clinical Supplies ............................................................................. 61 
3.8.7 Randomization .......................................................................................................... 61 
3.8.8 Blinding..................................................................................................................... 62 
3.8.9 Breaking the Blind .................................................................................................... 62 
3.9 
Statistical Methods ...................................................................................................... 62 
3.9.1 Subject Populations for Analysis .............................................................................. 62 
3.9.2 Sample Size ............................................................................................................... 63 
3.9.3 Interim Analysis ........................................................................................................ 63 
3.9.4 Safety Analysis ......................................................................................................... 63 
3.9.5 Pharmacokinetic Analysis ......................................................................................... 64 
3.9.6 Pharmacodynamic Analysis ...................................................................................... 64 
3.10 
Quality Control and Quality Assurance ................................................................... 66 
4 
Investigator Obligations ....................................................................................................... 66 
4.1 
Institutional Review .................................................................................................... 66 
4.2 
Subject Consent ........................................................................................................... 67 
4.3 
Data Collection ............................................................................................................ 67 
4.3.1 Case Report Forms .................................................................................................... 67 
4.3.2 Source Documents .................................................................................................... 68 
4.4 
Adherence to Protocol ................................................................................................ 68 
4.5 
Reporting Adverse Events .......................................................................................... 68 
4.6 
Investigator’s Final Report ........................................................................................ 68 
4.7 
Records Retention ....................................................................................................... 68 
4.8 
Confidentiality ............................................................................................................. 69 
4.9 
Publications ................................................................................................................. 69 
5 
Study Management .............................................................................................................. 70 
5.1 
Monitoring ................................................................................................................... 70 
5.2 
Management of Protocol Amendments and Deviations .......................................... 70 
5.3 
Study Termination ...................................................................................................... 70 
5.4 
Sponsor’s Final Report ............................................................................................... 71 


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6 
References ............................................................................................................................ 72 
7 
Appendices ............................................................................................................................ 75 


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List of Figures 
Figure 1. 
Planned Study Schema ...........................................................................................34 
 
List of Tables 
Table 1. 
Schedule of Study Procedures (Screening through Day -1) ...................................35 
Table 2. 
Schedule of Study Procedures (Day 1 and Day 2) .................................................37 
Table 3. 
Schedule of Study Procedures (Day 3 through Day 15) .........................................38 
Table 4. 
Schedule of Study Procedures (Day 16 through Day 29) .......................................39 
Table 5. 
Schedule of Study Procedures (Day 30 through Follow-Up Visit) ........................40 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
14C-JTT-662 
14C-labeled JTT-662 
ADR 
Adverse drug reaction 
AE 
Adverse event 
Aetotal 
Cumulative amount excreted into urine over entire collection interval 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ARAUCtau 
Accumulation ratio of area under the concentration-time curve during a 
dosing interval 
ARCmax 
Accumulation ratio of maximum concentration 
ARCtrough 
Accumulation ratio based on trough concentration  
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUCinf 
Area under the concentration-time curve from the time of dosing to 
infinity 
AUClast 
Area under the concentration-time curve from the time of dosing to the 
last quantifiable time point 
AUCtau 
Area under the concentration-time curve during a dosing interval 
AUC0-24 
Area under the concentration-time curve from the time of dosing until the 
24-hour time point 
AUEC 
Area under the observed effect-time curve 
AUEC0-4 
Area under the observed effect-time curve from the time of starting 
breakfast until the 4-hour time point 
AUEC0-24 
Area under the observed effect-time curve from the time of starting 
breakfast until the 24-hour time point 
BCRP 
Breast cancer resistance protein 
βhCG 
Human chorionic gonadotropin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CGGM 
Congenital glucose-galactose malabsorption 
C
  
CI 
Confidence interval 
CL_F 
Apparent oral clearance of drug following extravascular administration 
(total body clearance) 
CLr 
Renal clearance 
COVID-19 
Coronavirus Disease 
Cmax 
Maximum concentration 
Ctrough 
Trough concentration during multiple dosing prior to next dose 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
 


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Abbreviation 
Definition 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
ΔAUCs 
Area under the concentration-time curve of changes  
DPP-4 
Dipeptidyl peptidase-4 
ECG 
Electrocardiogram 
eGRF 
Estimated glomerular filtration rate 
fetotal 
Fraction of systemically available drug excreted into the urine over entire 
collection interval 
FPG 
Fasting plasma glucose 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP-1 
Glucagon-like peptide-1 
GLUT 
Glucose transporter 
GMR 
Geometric mean ratio 
GSIS 
Glucose-stimulated insulin secretion 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour(s) 
IB 
Investigator’s Brochure 
IC50 
Half maximal (50%) inhibitory concentration 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDF 
International Diabetes Federation 
IMP 
Investigation medicinal product  
IP 
Inorganic phosphorous 
IR 
Insulin resistance 
IRB 
Institutional Review Board 
λz 
Apparent elimination rate constant in the terminal phase by 
non-compartmental analysis 
MAD 
Multiple ascending dose  
 
NOAEL 
No observed adverse effect level 
OGTT 
Oral glucose tolerance test 
PCS  
Potentially clinically significant 
PD 
Pharmacodynamic(s) 
 
PK  
Pharmacokinetic(s) 
PPG 
Postprandial glucose 


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Abbreviation 
Definition 
PR 
Interval from beginning of the P wave to the beginning of the QRS 
complex in the frontal plane 
 
QD 
Once daily 
QRS 
Duration of QRS complex in the frontal plane 
QT 
Interval from beginning of the QRS complex to end of the T wave in the 
frontal plane  
QTcF 
Fridericia-corrected QT interval  
RBC 
Erythrocytes (red blood cells) 
RR 
Interval from beginning of the QRS complex in the frontal plane to the 
next QRS complex  
SAD 
Single ascending dose 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan  
SARS-CoV-2  
Severe acute respiratory syndrome coronavirus 2 
SGLT 
Sodium glucose co-transporter 
SGLT1 
Sodium glucose co-transporter 1 
SGLT2 
Sodium glucose co-transporter 2 
SOC 
System organ class 
SD 
Standard deviation 
t1/2 
Elimination half-life associated with the terminal slope (λz) of a 
semilogarithmic concentration-time curve  
t1/2(eff) 
Effective half-life 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to reach peak or maximum concentration following drug 
administration  
 
UGE0-24 
Urinary glucose excretion from the time of dosing until the 24-hour time 
point 
UCE0-24 
Urinary calcium excretion from the time of dosing until the 24-hour time 
point 
UNaE0-24 
Urinary sodium excretion from the time of dosing until the 24-hour time 
point 
Vz_F 
Volume of distribution during terminal phase (λz) following 
extravascular administration 
WBC 
Leukocytes (white blood cells) 


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Protocol Synopsis 
STUDY TITLE 
A Single-blind, Randomized, Placebo-controlled, Multiple Dose 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of JTT-662 Administered for 28 Days in 
Subjects with Type 2 Diabetes Mellitus on Metformin 
Monotherapy 
PROTOCOL NUMBER 
AT662-U-20-003 
CLINICAL PHASE 
Phase 1 
STUDY DURATION 
Study duration will be approximately 11 weeks per subject: 
• Up to a 28-day Screening Period 
• A 38-day Admission Period 
• An approximately 7-day Follow-up Period 
STUDY OBJECTIVES 
• To assess the safety and tolerability of multiple oral doses of 
JTT-662 in subjects with Type 2 Diabetes Mellitus (T2DM) on 
metformin monotherapy 
• To evaluate the pharmacokinetics (PK) of multiple oral doses of 
JTT-662 in subjects with T2DM on metformin monotherapy 
• To evaluate the pharmacodynamics (PD) of multiple oral doses 
of JTT-662 in subjects with T2DM on metformin monotherapy 


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STUDY DESIGN 
This is a single-blind, randomized, placebo-controlled, multiple 
dose study to assess the safety, tolerability, PK and PD of JTT-662 
administered for 28 Days in subjects with T2DM on metformin 
monotherapy. 
Approximately 36 subjects are planned to be randomized into three 
cohorts (JTT-662 5 mg [Cohort 1], 10 mg [Cohort 2] and 20 mg 
[Cohort 3]). Within each cohort, 9 subjects will be randomized to 
receive JTT-662 and 3 subjects will be randomized to receive 
placebo. Cohorts 1 and 2 may proceed simultaneously. Cohort 3 
will be initiated only after review of the safety, tolerability, PK (up 
to Day 29 for Cohort 2) and available PD data from Cohorts 1 and 2 
by the Sponsor, the Medical Monitor and the Investigator. The 
planned dose in Cohort 3 may be changed (not to exceed 40 mg) 
based on the data review. 
For all cohorts, eligible subjects will be admitted to the site on 
Day -3 and will be administered a single dose of placebo on Day -1 
following an overnight fast (for at least 10 hours) and 30 minutes 
before the start of a standard breakfast. JTT-662 or placebo will be 
administered once-daily (QD) for 28 consecutive days (Day 1 
through Day 28) following an overnight fast (for at least 10 hours) 
and 30 minutes before the start of a standard breakfast. 
Subjects will be discharged from the site on Day 35 and will return 
to the site on Day 42±3 for the Follow-up Visit. 
NUMBER OF SUBJECTS 
TO BE RANDOMIZED 
Approximately 36 subjects with T2DM are planned to be 
randomized in this study, as follows:  
Cohort 1: 
JTT-662 5 mg or placebo 
(9 active: 3 placebo) 
Cohort 2: 
JTT-662 10 mg or placebo 
(9 active: 3 placebo) 
Cohort 3:  
JTT-662 20 mg or placebo 
(9 active: 3 placebo) 
To ensure an adequate number of completers, replacement subjects 
may be enrolled in the study at the discretion of the Sponsor, as 
appropriate. Each replacement subject will be assigned the same 
treatment as the subject that is being replaced. 
 


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KEY ELIGIBILITY 
CRITERIA 
1. Male or female, 18 to 65 years (inclusive) of age at the 
Screening Visit; 
2. Subjects with a documented diagnosis of T2DM of at least 
12 weeks prior to the Screening Visit; 
3. Subjects on a stable oral dose (i.e., the dose and schedule of 
administration has not changed) of metformin monotherapy 
for at least 12 weeks prior to the Screening Visit and until 
Day -3; 
4. Subjects with a glycosylated hemoglobin (HbA1c) value of 
≥6.5% and ≤10.0% at the Screening Visit; 
5. Subjects with a fasting plasma glucose (FPG) value of 
≤280 mg/dL at the Screening Visit and on Day -3; 
6. Subjects with a body mass index (BMI) of 25 to 40 kg/m2 
(inclusive) at the Screening Visit. 
INVESTIGATIONAL 
PRODUCT  
FORMULATION, 
PLANNED DOSAGES,  
ROUTE AND TIME OF 
ADMINISTRATION  
JTT­662 
1 mg and 10 mg tablets (identical in appearance) 
5 mg, 10 mg and 20 mg  
Oral QD administration for 28 days from Day 1 through Day 28 
following an overnight fast (for at least 10 hours) and 30 minutes 
before the start of a standard breakfast 
REFERENCE 
PRODUCT, 
FORMULATION, 
PLANNED DOSAGES, 
ROUTE AND TIME OF 
ADMINISTRATION 
Placebo 
Tablets (identical in appearance to JTT-662 Tablets)  
Not applicable 
Single oral administration on Day -1 following an overnight fast 
(for at least 10 hours) and 30 minutes before the start of a 
standard breakfast. Oral QD administration for 28 days from 
Day 1 through Day 28 following an overnight fast (for at least 
10 hours) and 30 minutes before the start of a standard breakfast. 
EVALUATION 
CRITERIA 
Safety Assessments: 
• Adverse events (AEs), clinical laboratory safety tests 
(e.g., hematology, serum biochemistry, coagulation), vital 
signs, 12-lead electrocardiogram (ECG), Bristol Stool Chart 
findings, ketone bodies, 
 
 
 FPG and urinary calcium, sodium and 
glucose excretion 
 


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EVALUATION 
CRITERIA (CONT’D) 
Pharmacokinetic Assessments: 
• JTT-662 in plasma: maximum concentration (Cmax), trough 
concentration during multiple dosing prior to next dose 
(Ctrough), time to reach peak or maximum concentration 
following drug administration (tmax), area under the 
concentration-time curve during the dosing interval (AUCtau), 
volume of distribution during terminal phase (Vz_F), apparent 
oral clearance of drug following extravascular administration 
(total body clearance) (CL_F), elimination half-life associated 
with the terminal slope (λz) of a semilogarithmic 
concentration-time curve (t1/2), effective half-life (t1/2(eff)), 
accumulation ratio of maximum concentration (ARCmax) and 
accumulation ratio of area under the concentration-time curve 
during a dosing interval (ARAUCtau), and accumulation ratio 
based on trough concentration (ARCtrough) 
Pharmacodynamic Assessments: 
• Postprandial glucose (PPG): area under the observed 
effect-time curve from the start of breakfast until the 4-hour 
time point (AUEC0-4)  
SAFETY ANALYSIS 
The safety evaluation will summarize recorded AEs, Bristol 
Stool Chart findings, clinical safety laboratory test results, vital 
signs, 12-lead ECG parameters and any other parameters deemed 
necessary for safety assessment. 
 


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PHARMACOKINETIC 
ANALYSIS 
Appropriate PK parameters for JTT-662 (e.g., Cmax, tmax, 
apparent elimination rate constant in the terminal phase by 
non-compartmental analysis [λz], t1/2) will be derived by 
non­compartmental analysis using Phoenix® WinNonlin® 
(Version 6.4 or higher). Additional PK parameters may be 
calculated, as appropriate. 
Appropriate analyses to assess dose proportionality of JTT-662 
exposure will be performed using a power model. 
PHARMACODYNAMIC 
ANALYSIS 
Pharmacodynamic effects of JTT-662 on PPG will be assessed.  
STATISTICAL 
METHODS 
Appropriate statistical analysis will be performed using the 
computer program SAS for Windows® (SAS Institute Inc., Cary, 
NC 27512-8000, USA). 
 
 
 


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1 INTRODUCTION 
1.1 Background 
1.1.1 Type 2 Diabetes Mellitus 
As published by the International Diabetes Federation (IDF) in 2019, it is estimated that 
463 million people around the world have diabetes, and unless effective measures are taken, the 
number of patients with diabetes is expected to increase continuously in the future and to reach 
700 million by 2045.1 Since around 90% of diabetic patients are classified to have 
non-insulin-dependent (type 2) diabetes mellitus (T2DM), measures to treat T2DM are urgently 
needed around the world, and there is a continuing strong demand for the development of new 
treatment drugs. 
Type 2 diabetes mellitus (T2DM) develops due to insufficient insulin action resulting from 
impaired insulin secretion and insulin resistance (IR) induced by interactions of various genetic 
factors and additional environmental factors such as overeating, lack of exercise, obesity and 
stress. Postprandial hyperglycemia is one of the earliest abnormalities of glucose homeostasis 
associated with T2DM and is exaggerated in diabetic patients with fasting hyperglycemia.2-5 The 
chronic hyperglycemic state promotes the occurrence and development of diabetic complications 
including microvascular complications (retinopathy, nephropathy and neuropathy) and 
macrovascular 
complications 
(ischemic 
heart 
disease, 
cerebrovascular 
disorder 
and 
arteriosclerosis obliterans).6 
1.1.2 Treatment of Type 2 Diabetes Mellitus 
There are several epidemiologic studies indicating that postprandial hyperglycemia can be a 
critical risk factor of macroangiopathy in patients with diabetes and abnormal glucose tolerance.7-12 
An intervention study of acarbose, an α-glucosidase inhibitor (α-GI), and a meta-analysis including 
multiple clinical studies have shown that amelioration of postprandial hyperglycemia can suppress 
development of diabetes mellitus and further decrease the risk of macroangiopathy.13,14 These 
results have revealed the importance of ameliorating postprandial hyperglycemia. There is a 
growing recognition that postprandial hyperglycemia should be controlled from an early stage of 
diabetes in parallel with glycosylated hemoglobin (HbA1c). 
For glycemic control in patients with T2DM, various drugs such as metformin, sulfonylureas, 
thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium glucose co-transporter 2 
(SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulin are 
currently used, and appropriate combination drug therapies using drugs with different mechanisms 
of action are then implemented.15 Currently available oral hypoglycemic drugs that ameliorate 
postprandial hyperglycemia are α-GIs (delay carbohydrate absorption), meglitinides (enhance 
acute insulin secretion), DPP-4 inhibitors (enhance glucose-stimulating insulin secretion by 
increasing the GLP-1 levels) and SGLT2 inhibitors (block glucose reabsorption in the proximal 
renal tubule). The α-GIs have a weaker effect on lowering HbA1c compared with other oral 
hypoglycemic drugs, and cause gastrointestinal (GI) symptoms such as diarrhea, abdominal 
distention and flatus. Meglitinides have a risk of causing hypoglycemia, because they enhance 


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insulin secretion. In addition, after the pathological condition progresses to an insulin-dependent 
state, they become less effective. Furthermore, these drugs have to be taken three times daily before 
each meal, leading to low drug compliance rates. The DPP-4 inhibitors and SGLT2 inhibitors do 
not have a very strong ameliorating effect on postprandial hyperglycemia. Based on these, there is 
a strong demand for new oral hypoglycemic drugs that ameliorate postprandial hyperglycemia, 
decrease HbA1c levels more effectively, have a superior safety profile, allow once daily (QD) 
dosing regimens and are widely effective regardless of the stage of T2DM. 
1.1.3 Sodium Glucose Co-Transporter 1 Inhibitor 
Glucose is transported intracellularly or extracellularly by cell membrane proteins called sodium 
glucose co-transporters (SGLTs) and glucose transporters (GLUTs). Sodium glucose 
co-transporters are involved in the active transport of glucose against the concentration gradient 
coupling with sodium transport, and GLUTs facilitate diffusion transport along the concentration 
gradient. It has been reported that these transporter families have multiple isoforms that differ in 
their 
tissue 
expressions 
and 
affinities 
for 
monosaccharides.16 
Sodium 
glucose 
co-transporter 1 (SGLT1), which was cloned in 1987, is a 73-kDa membrane protein consisting of 
664 amino acid residues and is mainly expressed in the brush border membrane of the small 
intestine. It plays a critical role in transporting glucose and galactose from the luminal surface to 
the epithelial cells in the small intestine. It is also expressed in the renal tubule and is partially 
involved in reabsorption of glucose filtered in the glomeruli.16 Meanwhile, glucose filtered in the 
glomerulus is reabsorbed in the renal tubule mainly by SGLT2.16 It has been reported that the 
expression of messenger ribonucleic acid and protein of SGLT1 in the small intestine is increased 
in patients with T2DM, Otsuka Long-Evans Tokushima Fatty rats (a type 2 diabetic model) and 
streptozotocin-induced diabetic rats with chronic hyperglycemia. This suggests that glucose 
absorption from the GI tract is enhanced in diabetes mellitus.17-19 Congenital glucose-galactose 
malabsorption (CGGM) is caused by a defect in glucose and galactose transport in the brush border 
membrane of the small intestine due to an SGLT1 dysfunctional mutation. Congenital 
glucose-galactose malabsorption is characterized by watery diarrhea similar to the diarrhea that 
can develop in infants following ingestion of breast milk or regular infant formulas, both of which 
contain glucose and galactose. It is known that such severe diarrhea can be controlled with 
fructose-based formulas that do not contain glucose or galactose.20 Elevation of plasma glucose 
levels after glucose loading was completely prevented in patients with CGGM, indicating that 
SGLT1 plays a critical role in absorption of dietary glucose in the intestine.21,22 It is assumed that 
SGLT1 inhibition in the small intestine will reduce the absorption of dietary glucose effectively. 
Therefore, SGLT1 inhibitors are expected to prevent postprandial glucose (PPG) elevations 
independent of endogenous insulin effect by modulating the glucose absorption in the small 
intestine. This characteristic suggests that SGLT1 inhibitors have a low potential of causing 
hypoglycemia, body weight gain and burden on β-cell function, and thus provides an opportunity 
of combination therapies with currently available drugs for the treatment of T2DM. 


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Clinical Study Protocol AT662-U-20-003 
 
 
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1.2 JTT-662 
A brief summary of the nonclinical findings to date is included below. Additional details are 
described in the JTT-662 Investigator’s Brochure (IB).  
1.2.1 Nonclinical Information 


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1.2.2 Clinical Information 
 
 


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Clinical Study Protocol AT662-U-20-003 
 
 
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Clinical Study Protocol AT662-U-20-003 
 
 
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Clinical Study Protocol AT662-U-20-003 
 
 
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Clinical Study Protocol AT662-U-20-003 
 
 
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Clinical Study Protocol AT662-U-20-003 
 
 
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1.3 Justification of Dose Selection 
The objective of this single-blind, randomized, placebo-controlled, multiple dose study is to 
evaluate the safety, tolerability, PK and pharmacodynamics (PD) of JTT-662 following QD 
administration for 28 days in subjects with T2DM on metformin monotherapy. 
The planned JTT-662 doses for this study are 5 mg QD, 10 mg QD and 20 mg QD,
s
 
 
 


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Clinical Study Protocol AT662-U-20-003 
 
 
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The secondary objective of this study is to evaluate the effect of multiple doses of JTT-662 on 
PPG. O
 
 


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In this study, to assure safety, the subjects will remain in-house at the site for the duration of dosing 
and for approximately 7 days after the last dose, under the direct oversight by the Investigator and 
the continuous supervision of the site research staff. During this period, extensive safety 
assessments, including AE collection and evaluation, laboratory, 12-lead ECG and vital sign 
assessments will be carried out to identify and address any emerging safety signals. After 
completion of the two lower dose cohorts, dose escalation to the highest planned dose level will 
be implemented following careful review of the appropriate safety parameters (i.e., AEs, 
laboratory safety tests, 12-lead ECG and vital sign parameters), PK data (up to Day 29 for 
Cohort 2) and PD data including exposure comparison with nonclinical data, dose proportionality 
and PD assessments from the previous cohorts. 
2 STUDY OBJECTIVES  
• To assess the safety and tolerability of multiple oral doses of JTT-662 in subjects with T2DM 
on metformin monotherapy 
• To evaluate the PK of multiple oral doses of JTT-662 in subjects with T2DM on metformin 
monotherapy 
• To evaluate the PD of multiple oral doses of JTT-662 in subjects with T2DM on metformin 
monotherapy 
3 INVESTIGATIONAL PLAN 
3.1 Number of Sites and Subjects 
Approximately 36 male and female subjects with T2DM are planned to be randomized in the study 
at a single site. To ensure an adequate number of completers, replacement subjects may be enrolled 
in the study at the discretion of the Sponsor, as appropriate. 
3.2 Study Design 
This is a single-blind, randomized, placebo-controlled, multiple dose study to assess the safety, 
tolerability, PK and PD of JTT-662 administered for 28 Days in subjects with T2DM on metformin 
monotherapy. 
Approximately 36 subjects are planned to be randomized into three cohorts (JTT-662 5 mg 
[Cohort 1], 10 mg [Cohort 2] and 20 mg [Cohort 3]). Within each cohort, 9 subjects will be 
randomized to receive JTT-662 and 3 subjects will be randomized to receive placebo. Cohorts 1 
and 2 may proceed simultaneously. Cohort 3 will be initiated only after review of the safety, 
tolerability, PK (up to Day 29 for Cohort 2) and available PD data from Cohorts 1 and 2 by the 
Sponsor, the Medical Monitor and the Investigator. The planned dose in Cohort 3 may be changed 
(not to exceed 40 mg) based on the data review. 
For all cohorts, eligible subjects will be admitted to the site on Day -3 and will be administered a 
single dose of placebo on Day -1 following an overnight fast (for at least 10 hours) and 30 minutes 
before the start of a standard breakfast. JTT-662 or placebo will be administered QD for 
28 consecutive days (Day 1 through Day 28) following an overnight fast (for at least 10 hours) and 
30 minutes before the start of a standard breakfast. 


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Subjects will be discharged from the site on Day 35 and will return to the site on Day 42±3 for the 
Follow-up Visit. 
3.3 Selection of Study Population 
In response to the ongoing coronavirus disease (COVID-19) pandemic, the site will make every 
effort to proactively avoid enrolling subjects suspected of or positive for COVID-19. Special 
policies to protect the study participants and staff at the site against COVID-19 will be developed 
and agreed upon with the Sponsor prior to the start of the study. The specific procedures regarding 
this will be described in appropriate separate documents. 
Written informed consent must be obtained prior to performing any study-related procedures. A 
copy of the informed consent will be provided to each subject. 
3.3.1 Inclusion Criteria 
To qualify for the study, the subject must satisfy the following criteria: 
1. Male or female, 18 to 65 years (inclusive) of age at the Screening Visit; 
2. Subjects with a documented diagnosis of T2DM of at least 12 weeks prior to the Screening 
Visit; 
3. Subjects on a stable oral dose (i.e., the dose and schedule of administration has not changed) 
of metformin monotherapy for at least 12 weeks prior to the Screening Visit and until Day -3; 
4. Subjects with a HbA1c value of ≥6.5% and ≤10.0% at the Screening Visit; 
5. Subjects with a FPG value of ≤280 mg/dL at the Screening Visit and on Day -3; 
6. Subjects with a body mass index (BMI) of 25 to 40 kg/m2 (inclusive) at the Screening Visit; 
7. Subjects who have clinical laboratory test results (excluding glucose-related parameters) 
clinically acceptable to the Investigator at the Screening Visit and on Day -3; 
8. Females may participate if they meet one of the following criteria: 
• surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or 
• post-menopausal, as defined by permanent cessation of menstruation for ≥12 months 
without an alternative medical cause at the Screening Visit. 
All other females will be considered of childbearing potential and must agree to be compliant 
with either:  
a) practice sexual abstinence*, or 
b) have same-sex partner and not planning a pregnancy, or 
c) use one highly effective contraceptive method of birth control, which includes intrauterine 
devices, male partner sterilization (at least six months prior to screening with the 
appropriate post-vasectomy documentation of the absence of sperm in the ejaculate and the 
vasectomized male partner should be the sole partner for that subject), tubal ligation, 
intrauterine hormone-releasing systems, or 
d) use a double-barrier method of birth control, which includes a combination of male condom 
with either diaphragm, cervical cap or vaginal sponge, all with spermicide; 


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Clinical Study Protocol AT662-U-20-003 
 
 
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Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and concomitant use of a female and male condom 
are not acceptable methods of contraception. 
The above-described contraception methods must be maintained during treatment and until 
30 days after the last dose of study drug. 
9. Males may participate if they agree to one of the following criteria:  
• practice sexual abstinence, have same-sex partner, use a barrier contraceptive method with 
spermicide (for the duration of the treatment period and until 30 days after the last dose of 
study drug), or 
• be sterilized at least six months prior to screening (with appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate). 
Notes: Males who are sterile or who have sterile or post-menopausal female partners are not 
required to use contraception with that partner. Males must not donate sperm for the duration 
of the study and for 30 days after the last dose of study drug. 
If the female partner is of childbearing potential, she must agree to use at least one of the 
acceptable forms of birth control listed above (in addition to the method utilized by the male 
subject) for the duration of the study and for at least 30 days after the subject takes the last 
dose of study drug. 
 
11. Able and willing to give written informed consent. 
3.3.2 Exclusion Criteria 
The following criteria will exclude a subject from participating in the study: 
1. Subjects who have a known history or presence of type 1 diabetes mellitus, Maturity Onset 
Diabetes of the Young (MODY) or secondary forms of diabetes (i.e., diabetes that results as a 
consequence of another medical condition); 
2. Subjects who have had a dose change or change in schedule of administration of metformin 
monotherapy from the Screening Visit through Day -3; 
3. Subjects who test positive for COVID-19 at the Screening Visit or on Day -3; 
4. Subjects who have a known history or presence of diabetic complications including: 
retinopathy, 
nephropathy, 
neuropathy, 
gastroparesis, 
ketoacidosis, 
lactic 
acidosis, 
hyperosmolar coma or clinically significant foot ulcers or blisters;  
5. Subjects with acute coronary syndrome (e.g., myocardial infarction or unstable angina), 
clinically significant cardiac arrhythmia, New York Heart Association class II through IV heart 
failure, history of percutaneous coronary intervention (or similar procedures), history of 
coronary artery bypass graft surgery, cerebrovascular accident or transient ischemic attack 
within 24 weeks prior to Screening Visit or a history of severe peripheral vascular disease 
(e.g., manifested by claudication); 
6. Subjects with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.0 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN at the Screening Visit; 


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Clinical Study Protocol AT662-U-20-003 
 
 
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7. Subjects who have taken anti-diabetic medications (other than metformin) or medications that 
act mainly in the GI tract (e.g., orlistat, acarbose) within 12 weeks prior to the Screening Visit 
or from the Screening Visit to Day -3; 
8. Subjects who have taken non-diabetic medications (e.g., diuretics and sympathomimetics), 
which may affect glucose homeostasis, within 12 weeks prior to the Screening Visit or from 
the Screening Visit to Day -3, except if the subject has been on a stable dose from 12 weeks 
prior to the Screening Visit and from the Screening Visit to Day -3; 
9. Subjects who have participated in a clinical study involving an investigational drug or device 
within 30 days, five half-lives, or twice the duration of the biological effect of the 
investigational product, if known (whichever is longer) prior to the Screening Visit; 
10. Subjects with uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic 
blood pressure ≥95 mmHg) at the Screening Visit; 
Notes: Up to three repeat measurements are allowed at the discretion of the Investigator. 
Subjects who are taking anti-hypertensive medication(s), must be on a stable dose for at least 
12 weeks prior to the Screening Visit and from the Screening Visit through Day -3. 
11. Subjects who have taken systemic steroids within 2 weeks prior to Day -3; 
Note: Inhaled, intranasal and topical corticosteroids are permitted as needed. 
12. Subjects who have used medications, which could affect gastric motility or result in diarrhea, 
within 2 weeks prior to Day -3; 
13. Smokers or subjects who have used tobacco or nicotine-containing products within 12 weeks 
prior to the Screening Visit or from the Screening Visit to Day -3; 
14. Subjects who report a general pattern of two or more episodes of Type 6 or 7 bowel movements 
per day, based on Bristol Stool Chart definitions provided at the Screening Visit; 
15. Subjects who report a general pattern of two or more episodes of Type 6 or 7 bowel movements 
per day within 3 days prior to Day -3, based on Bristol Stool Chart definitions provided at the 
Screening Visit; 
16. Subjects who cannot comply with the planned study menu due to clinically significant food 
allergies or intolerances; 
17. Subjects who have diets incompatible with the planned study menu; 
18. Subjects who have recent significant changes in weight (i.e., ≥7%) within 12 weeks prior to 
Day -3; 
19. Subjects with a known pre-existing condition or GI surgery interfering with normal GI 
anatomy or motility, and/or hepatic function (with the exception of Gilbert’s syndrome), biliary 
function (e.g., cholecystectomy) that could interfere with the absorption, metabolism, and/or 
excretion of the study drug; 
20. Subjects with a history or presence of malignancies with the exception of adequately treated 
or excised non-metastatic basal cell or squamous cell carcinoma of the skin or cervical 
carcinoma in situ within 6 months prior to Screening Visit; 


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21. Subjects with a history or presence of any lymphoproliferative disorders (e.g., Epstein Barr 
Virus related lymphoproliferative disorder, lymphoma, leukemia, multiple myeloma) or signs 
and symptoms suggestive of current lymphatic disease, such as Hodgkin's or Non-Hodgkin's 
lymphoma; 
22. Subjects with impaired renal function defined as estimated glomerular filtration rate 
(eGFR) <60 mL/min/1.73 m2 using the 4-variable Modification of Diet in Renal Disease 
equation) at the Screening Visit: 
eGFR (mL/min/1.73 m2) = 175 × Serum Creatinine -1.154 × age -0.203 × 1.212 (if subject is black) 
× 0.742 (if female). 
23. Subjects who test positive for hepatitis B virus surface antigen (HBsAg), hepatitis C virus 
(HCV) antibodies or human immunodeficiency virus (HIV) antibodies at the Screening Visit; 
24. Subjects with a history of drug or alcohol abuse within 24 weeks prior to the Screening Visit; 
Notes: Alcohol abuse is defined as an average weekly intake of >21 drinks for males or 
>14 drinks for females. One drink is equivalent to 12 ounces (360 mL) of beer, 
5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of hard liquor.  
25. Subjects who have a positive test result for drugs of abuse or alcohol at the Screening Visit or 
on Day -3, unless results are due to a medically relevant reason; 
26. Females who are pregnant as determined by a positive serum beta human chorionic 
gonadotropin (βhCG) test result at the Screening Visit or on Day -3; 
27. Females who are lactating at the Screening Visit or on Day -3; 
28. Subjects who have donated more than 500 mL of blood or received any blood or blood products 
within 8 weeks prior to Day -3; 
29. Subjec  who have previously participated in a JTT-662 study 
 
); 
30. Subjects with any other condition that, in the opinion of the Investigator, would compromise 
the safety of the subjects or confound the study objectives; 
31. Subjects who are unwilling or unable to comply with the requirements of the study. 
3.4 Discontinuation of Subjects from the Study/Study Drug 
A subject may prematurely discontinue from the study/study drug administration under the 
following conditions: 
• Withdrawal by Subject: subjects have the right to withdraw from the study at any time. 
However, if a subject withdrew because of an AE, the reason for discontinuation should be 
documented as an AE. 
• Investigator Decision: the Investigator decides a subject should be discontinued. The 
reason for the decision should be documented. 
• Adverse Event: a medical condition(s), requiring study drug discontinuation, whether or 
not related to the study drug (e.g., COVID-19). 
• Non-compliance with Study Drug 


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• Protocol Deviation: the subject is non-compliant with protocol requirements, as determined 
by Akros or the Investigator. These are limited to important protocol deviations (e.g., Good 
Clinical Practice [GCP] deviations, important deviations related to the inclusion or 
exclusion criteria). 
• Lost to Follow-up 
• Death 
• Study Terminated by Sponsor: the sponsor may suspend or terminate the study or part of 
the study at any time for any reason (see Section 3.5). 
• Pregnancy 
• Other: (e.g., subjects who have taken placebo on Day -1 but are not randomized on Day 1 
into Cohort 3 will be discontinued from the study). 
Subjects who test positive for COVID-19 after study drug administration on Day 1 will be 
discontinued from study drug and appropriate follow-up actions will be taken as per the site’s 
standard operating procedures and COVID-19 management guidelines.  
Subjects who discontinue the study/study drug after placebo adminstration on Day -1 but before 
randomization on Day 1 will be discharged from the site at the discretion of the Investigator. These 
subjects will be requested to complete a follow-up telephone call from the site within 7 days after 
being discontinued from the study. The follow-up call will be conducted to assess the general 
health of the subject. In addition, the subject will be asked to report if any AEs occurred, if any 
medication was taken and if there were any changes to medications during the 7 day period after 
the subject was discontinued from the study. 
Subjects who discontinue the study/study drug after study drug administration on Day 1 will be 
requested to undergo all procedures described for Day 35 as soon as possible after the last dose of 
study drug. Additionally, these subjects will be requested to return to the site and complete all 
procedures described for the Follow-up Visit approximately 14 days after the last dose of study 
drug. 
For all early discontinued subjects (after study drug administration on Day 1), every effort will be 
made to collect at least three blood samples for JTT-662 PK assessments at approximately 3-hour 
intervals, starting as close as possible to the time when the study drug was discontinued. 
Any subject withdrawn from study drug due to an AE, SAE or clinically significant abnormal 
laboratory test result will be evaluated by the Investigator. The subject will be treated and/or 
followed-up until the symptoms or laboratory values have either resolved or are assessed as stable 
by the Investigator. 
3.5 Study Suspension and Termination 
The sponsor may suspend or terminate the study at any time for any reason, including decisions 
made by the Investigator, Medical Monitor and Sponsor based on the review of the safety and/or 
PK data. 


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Clinical Study Protocol AT662-U-20-003 
 
 
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Dosing will be suspended, or escalation to Cohort 3 will be postponed depending on the review of 
the information by the Investigator, Medical Monitor and the Sponsor, if any of the following 
criteria are met: 
1. 
A serious adverse drug reaction (i.e., SAE considered related to JTT-662) develops in one 
subject;  
2. 
Severe non-serious AEs considered related to JTT-662 develop in two subjects in the same 
cohort, either within or not within the same system-organ-class. 
 
3.6 Study Procedures 
 
 
 
 
Figure 1. 
Planned Study Schema  
 


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AKROS PHARMA INC. 
Clinical Study Protocol AT662-U-20-003 
 
 
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Amendment 1, Version 2.0 – 29 Jan 2021 
 
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Table 1. 
Schedule of Study Procedures (Screening through Day -1) 
 
 
Screening 
Period
(Day)
-31 to -4a
Time from JTT-662/Placebo Administration (hr)
-72±3
-68
-62
-48±3
-44
-38
-24.5
-24
-23.5
-23
-22.5
-22
-21.5
-20
-19.5
-16
-13.5
-12
COVID-19 Test
X
X
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Demographic Information
X
Medical History 
X
X
X
Previous/Concomitant Medications
X
X
Review Study Restrictions
X
X
Weight (kg)
X
X
X
Height (cm) and BMI
X
Drugs of Abuse and Alcohol Screen
X
X
Viral Serology 
X
Serum Pregnancy test (all females)
X
X
eGFR
X
Physical Examination
X
X
Vital Signs
X
X
X
12-Lead ECG 
X
X
X
Serum Biochemistry
X
X
Hematology
X
X
Coagulation
X
X
Urinalysis
X
X
HbA1c
X
Plasma Glucoseb
X
X
X
X
X
X
X
X
X
Bristol Stool Chart Fecal Assessment
X
X
Meals 
X
X
X
X
X
X
X
X
X
Placebo Administration
X
Calcium, Sodium and Glucose Urine Collectiond
Adverse Events
X
X
X
X
X
X
Admission Period 
-1a
-2a
-3a


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Clinical Study Protocol AT662-U-20-003 
 
 
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a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. Administration of study drug, plasma glucose 
 
 sample collection (
) should have priority with respect to the scheduled (nominal) time; however, if scheduled at the same 
time point, study drug administration should occur last. Vital signs and 12-lead ECGs should occur prior to blood sample collection. 
b. 
When blood samples for plasma glucose
 are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
Subjects’ general stool patterns will be assessed by the site staff using the BSC assessment at the Screening Visit. Subjects will be trained by a member of the site staff to 
perform the BSC assessment unassisted during the 3-day period prior to Day -3; the subjects will record the assessments in the BSC source document. The date and time of each 
subject bowel movement should be recorded anytime a subject has a bowel movement during the admission period (from Day -3, Hour -68 to Day 35, Hour 168) and each stool 
should be characterized using the BSC. All BSC assessments should be recorded in the CRF. 
d. 
Shaded urine collection intervals represent continuous calcium, sodium and glucose urine collection. The intervals depicted by the bidirectional arrows represent the duration 
of each individual collection interval. An aliquot for urine calcium, sodium and glucose analysis should be obtained from the pooled sample at the end of each collection interval. 
 
  


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Clinical Study Protocol AT662-U-20-003 
 
 
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Table 2. 
Schedule of Study Procedures (Day 1 and Day 2) 
 
a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. Administration of study drug, PK, plasma glucose 
 
s sample collection should have priority with respect to the scheduled (nominal) time; however, if scheduled at the same time point, study drug 
administration should occur last. However, if scheduled at the same time point, study drug administration should occur last. Vital signs and 12-lead ECGs should occur prior to 
blood sample collection.  
b. 
When blood samples for 
 are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
Anytime a subject has a bowel movement, the date and time should be recorded and the stool should be characterized using the Bristol Stool Chart. 
d. 
When a PK sample is scheduled at the same time point as study drug administration, the PK sample should be collected first. 
e. 
Shaded urine collection intervals represent continuous calcium, sodium and glucose urine collection. The intervals depicted by the bidirectional arrows represent the duration 
of each individual collection interval. Aliquots for urine calcium, sodium, and glucose analysis should be obtained from the pooled sample at the end of each collection interval. 
(Day)
Time from JTT-662/Placebo Administration (hr)
-0.5
0
0.5
1
1.5
2
2.5
3
4
4.5
6
8
10
10.5
12
0
0.5
4.5
10.5
12
Physical Examination
X
X
Weight (kg)
X
X
Vital Signs
X
X
X
X
X
X
12-Lead ECG 
X
X
X
X
X
X
Serum Biochemistry
X
X
Hematology
X
X
Coagulation
X
Urinalysis 
X
X
Plasma Glucoseb
X
X
X
X
X
X
X
X
Ketone Bodies (β-hydroxybutyrate and acetoacetate)
X
X
Bristol Stool Chart Fecal Assessmentc
Meals 
X
X
X
X
X
X
Randomization
X
JTT-662/Placebo Administration 
X
X
JTT-662 PK Blood Samplesd
X
X
X
X
X
X
X
X
X
X
X
X
Calcium,  Sodium and Glucose Urine Collectione
Adverse Events 
X
X
X
X
X
X
2a
1a


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Table 3. 
Schedule of Study Procedures (Day 3 through Day 15) 
 
a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. Administration of study drug, PK, plasma glucose 
 
 sample collection should have priority with respect to the scheduled (nominal) time; however, if scheduled at the same time point, study drug 
administration should occur last. Vital signs and 12-lead ECGs should occur prior to blood sample collection. 
b. 
When blood samples for 
 are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
Anytime a subject has a bowel movement, the date and time should be recorded and the stool should be characterized using the Bristol Stool Chart. 
d. 
Shaded urine collection intervals represent continuous calcium, sodium and glucose urine collection. The intervals depicted by the bidirectional arrows represent the duration 
of each individual collection interval. An aliquot for urine calcium, sodium and glucose analysis should be obtained from the pooled sample at the end of each collection interval. 
e. 
Performed on Days 7 and 10 only. 
(Day)
Time from JTT-662/Placebo Administration (hr)
0
0.5
4.5
10.5
12
-0.5
0
0.5
1
1.5
2
2.5
4
4.5
6
8
10.5
12
0
0.5
4.5
10.5
12
Physical Examination
Xe
X
Vital Signs
Xe
Xe
X
X
X
X
12-Lead ECG 
Xe
Xe
X
X
X
X
Weight (kg)
Xe
X
Serum Biochemistry
Xe
X
Hematology
Xe
X
Coagulation
Xe
X
Urinalysis 
e
X
Plasma Glucoseb
X
X
X
X
X
X
X
Ketone Bodies (β-hydroxybutyrate and acetoacetate)
X
Bristol Stool Chart Fecal Assessmentc
Meals 
X
X
X
X
X
X
X
X
X
JTT-662/Placebo Administration 
X
X
X
JTT-662 PK Blood Samples
Xe
X
X
X
X
X
Calcium, Sodium and Glucose Urine Collectiond
Adverse Events 
X
X
X
X
X
X
X
X
X
14a
3 to 13a
Admission Period 
15a


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Table 4. 
Schedule of Study Procedures (Day 16 through Day 29) 
 
 
a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. Administration of study drug, PK, plasma glucose 
 
 sample collection should have priority with respect to the scheduled (nominal) time; however, if scheduled at the same time point, study drug 
administration should occur last. Vital signs and 12-lead ECGs should occur prior to blood sample collection. 
b. 
When blood samples for 
n are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
Anytime a subject has a bowel movement, the date and time should be recorded and the stool should be characterized using the Bristol Stool Chart. 
d. 
Shaded urine collection intervals represent continuous calcium, sodium and glucose urine collection. The intervals depicted by the bidirectional arrows represent the duration 
of each individual collection interval. An aliquot for urine calcium, sodium and glucose analysis should be obtained from the pooled sample at the end of each collection interval. 
e. 
Performed on Days 19 and 24 only. 
f. 
Performed on Day 21 only.
(Day)
Time from JTT-662/Placebo Administration (hr)
0
0.5
4.5
10.5
12
-0.5
0
0.5
1
1.5
2
2.5
3
4
4.5
6
8
10
10.5
12
24
24.5
28.5
34.5
Physical Examination
Xe
X
Weight (kg)
Xe
X
Vital Signs
Xe
Xe
X
X
X
X
12-Lead ECG 
Xe
Xe
X
X
X
X
Serum Biochemistry
Xe
X
Hematology
Xe
X
Coagulation
Xe
X
Urinalysis 
Xe
X
Plasma Glucoseb
Xe
X
X
X
X
X
X
X
Ketone Bodies (β-hydroxybutyrate and acetoacetate)
X
Bristol Stool Chart Fecal Assessmentc
Meals 
X
X
X
X
X
X
X
X
X
JTT-662/Placebo Administration 
X
X
JTT-662 PK Blood Samples
Xf
X
X
X
X
X
X
X
X
X
X
X
X
Calcium, Sodium and Glucose Urine Collectiond
Adverse Events 
X
X
X
X
X
X
X
X
28a
16 to 27a
29a
Admission Period


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Table 5. 
Schedule of Study Procedures (Day 30 through Follow-Up Visit) 
 
 
a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. PK blood sample collection should have priority with respect to 
the scheduled (nominal) time. Vital signs and 12-lead ECGs should occur prior to blood sample collection. 
b. 
When ketone bodies (β-hydroxybutyrate and acetoacetate) samples are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
The date and time of each subject bowel movement should be recorded up to Day 35, Hour 168. During the Follow-up Period, the subject will perform the assessment unassisted. Each 
stool should be characterized using the Bristol Stool Chart.
Follow-Up 
Period
(Day)
35a
42 ±3a
Time from JTT-662/Placebo Administration (hr)
48.5 52.5 58.5 72.5 76.5 82.5 96.5 100.5
106.5
120.5
124.5
131
144.5
148.5 154.5
168
Previous/Concomitant Medications
X
Review Study Restrictions
X
Weight (kg)
X
X
X
Serum Pregnancy test (all females)
X
Physical Examination
X
X
X
Vital Signs
X
X
X
12-Lead ECG 
X
X
X
Serum Biochemistry
X
X
X
Hematology
X
X
X
Coagulation
X
X
X
Urinalysis 
X
X
X
Ketone Bodies (β-hydroxybutyrate and acetoacetate)
X
X
JTT-662 PK Blood Samples
X
X
X
X
Bristol Stool Chart Fecal Assessmentc
X
Meals 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
Admission Period 
34a
30a
31a
32a
33a


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3.6.1 Informed Consent  
Written informed consent must be obtained prior to performing any study-related procedures. 
A copy of the informed consent will be provided to the subject.  
3.6.2 Screening Period 
Day -31 to Day -4 
At the Screening Visit, subjects should arrive to the site under the fasted condition (overnight fast, 
at least 10 hours prior to blood and urine sample collection). If a subject arrives for the visit not 
having fasted (for at least 10 hours prior to blood and urine sample collection), all study procedures 
except the blood/urine collection assessments may be performed; the blood/urine collection will 
be rescheduled on a subsequent day within the Screening Period and the subject will be reminded 
to fast for at least 10 hours. In light of the current COVID-19 pandemic, the site will test all subjects 
for COVID-19 during the Screening Visit. If the subject tests positive, the subject will not be 
allowed to participate in the study. 
Subjects who do not fulfill the eligibility criteria for this study are considered screen failures and 
these subjects must not be randomized. The reason for screen failure will be recorded in the CRF. 
Subjects who were previously randomized and received study drug on Day 1 cannot be re-screened 
in this study. Subjects who previously screen failed or discontinued the study prior to study drug 
administration on Day 1, could be re-screened in this study at the Investigator’s discretion. 
Please refer to Table 1 for the list of screening procedures to be performed in the study. Repeat 
testing of vital signs (refer to exclusion #10) and safety laboratory tests are permitted, at the 
discretion of the Investigator. If the repeat test results are not clinically acceptable to the 
Investigator, the subject should be excluded from the study.  
Subjects’ general stool patterns will be self-reported, based on Bristol Stool Chart definitions, at 
the Screening Visit. Subjects will be trained by a member of the site staff to perform the BSC 
assessment unassisted during the 3-day period prior to Day -3; the subjects will record the date, 
time and stool type of each stool on a site-provided document. 
3.6.3 Admission Period 
Day -3 to Day 35 
Prior to Day -3 visit, the site should remind the subject to bring the BSC assessment document to 
the site and to fast at least 10 hours before arriving at the site. 
On the morning of Day -3, the site will test all subjects for COVID-19. If a subject tests positive, 
the subject will not be allowed to participate in the study. 


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During the Admission Period, subjects are required to fast overnight for at least 10 hours prior to 
blood and urine sample collection (except for non-fasting PK, PD and urine calcium, sodium and 
glucose measurements). Study restrictions must be followed (Section 3.6.5). Please refer to Table 1 
through Table 5 for the list of procedures to be performed during the Admission Period. 
Subjects will be discharged from the site on Day 35. A subject may be required to remain at the 
site for a longer period (e.g., subject has ongoing AEs or has abnormal lab test results), at the 
discretion of the Investigator. Prior to discharge on Day 35, subjects must be re-trained by a 
member of the site staff to perform the BSC assessment unassisted. The subjects will record the 
date, time and stool type of each stool during the Follow-up period on a site-provided source 
document. 
If a subject discontinues the study/study drug prematurely, refer to Section 3.4 for follow-up 
actions. 
3.6.4 Follow-up Period 
Day 42±3 
The Follow-up Visit will occur approximately 14 days after the last dose of study drug. Subjects 
should arrive under the fasted condition (i.e., overnight fast, at least 10 hours prior to blood and 
urine sample collection). Please refer to Table 5 for the list of follow-up procedures to be 
performed.  
Subjects who discontinue the study/study drug after study drug adminstration on Day -1 but before 
randomization on Day 1 will be discharged from the site at the discretion of the Investigator. These 
subjects will be requested to complete a Follow-up telephone call from the site within 7 days after 
being discontinued from the study.  
Subjects who discontinue the study/study drug after study drug administration on Day 1 will be 
requested to undergo all procedures described for Day 35 as soon as possible after the last dose of 
study drug. Additionally, these subjects will be requested to return to the site and complete all 
procedures described for the Follow-up Visit approximately 14 days after the last dose of study 
drug. 
For all early discontinued subjects (after study drug administration on Day 1), every effort will be 
made to collect at least three blood samples for JTT-662 PK assessments at approximately 
3-hour intervals, starting as close as possible to the time when the study drug was discontinued.  


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Any subject withdrawn from treatment due to an AE, SAE or clinically significant abnormal 
laboratory test result will be evaluated by the Investigator. The subject will be treated and/or 
followed-up until the symptoms or laboratory results have either resolved or are assessed as stable 
by the Investigator. 
3.6.5 Study Diet and Restrictions 
3.6.5.1 
Study Diet 
The standard meals used for this study will be in accordance with the recommendations of the 
American Diabetes Association (50-60% of calorie intake from carbohydrates, 15-20% from 
protein and 25-35% from fat31). Total daily caloric intake will be approximately 2300 kcal.  
On Days -1, 1, 14 and 28, identical meals for breakfast, identical meals for lunch and identical 
meals for dinner will be served for all subjects. Subjects should consume each meal completely 
and within 30 minutes. The percent consumed for each meal on Days -1, 1, 14 and 28 as well as 
all fluid intake (i.e., volume), including that taken during meal times, will be recorded in the case 
report form (CRF). 
The menu of the standard meals will be prepared by a certified/registered dietician at the study site 
according to the meal components as defined above and finalized after agreements from the 
Investigator and the Sponsor. This diet should not include citrus drinks (especially grapefruit 
juice), grapefruit, sour oranges, caffeinated products or alcohol. 
 
3.6.5.2 
Study Restrictions 
Alcohol, Diet and Exercise Restrictions: 
• Subjects must fast for at least 10 hours prior to study drug administration (Day -1 until Day 28) 
and prior to blood sample collections on Days 31 and 35. 
• Alcohol is not permitted from 48 hours prior to the Admission Period through the Follow-up 
Visit. 
• Caffeinated products are not permitted for at least 72 hours prior to the Admission Period 
through the Follow-up Visit. 
• Citrus containing foods, specifically grapefruit juice, grapefruit and sour oranges, are not 
permitted for at least 7 days prior to the Admission Period through the Follow-up Visit. 
• Strenuous exercise should be avoided for at least 7 days prior to the Admission Period through 
the Follow-up Visit. 


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3.6.6 Previous and Concomitant Medication 
3.6.6.1 
Permitted Medications 
• Tylenol at doses < 2 g/day is permitted at any time during the study 
• Inhaled, intranasal and topical corticosteroids are permitted at any time during the study 
• Stable* oral metformin dose 
• Stable* anti-hypertension medications 
• Stable* dyslipidemia medications 
 
 
 
 
*Medication regimens are considered stable if the dose and schedule of administration has not 
changed within 12 weeks prior to the Screening Visit and up to the Follow-up Visit. 
Notes: Subjects will remain on their pre-study stable permitted concomitant medication doses 
(e.g., oral doses of metformin, anti-hypertension medications) during the Admission Period 
and through the Follow-up Period of the study. All concomitant medications should be 
administered and stored according to product labelling and will not be provided by the Sponsor. 
Other concomitant medications may be considered on a case by case basis after review by the 
Medical Monitor, the Investigator and the Sponsor.  
3.6.6.2 
Prohibited Medications 
Use of the following prescription and non-prescription medications could confound the efficacy 
or pose a safety risk to subjects and are not permitted for the periods indicated below: 
• 12 weeks prior to the Screening Visit until the Follow-up Visit: diabetic medications (other 
than metformin), medications that act mainly in the GI tract (e.g., orlistat, acarbose), 
P-gp substrates (digoxin, apixaban, edoxaban, rivaroxaban and dabigatran) and tobacco or 
nicotine-containing products. 
• 12 weeks prior to the Screening Visit until the Follow-up Visit: non-diabetic medications that 
may affect glucose homeostasis (e.g., diuretics and sympathomimetics). Exception: if the 
subject has been on a stable dose for at least 12 weeks prior to the Screening Visit and from 
the Screening Visit to Day -3. These medications need to be agreed upon by the Investigator 
and the Sponsor. 


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• 30 days or 5 half-lives, which is longer, prior to the Screening Visit until the Follow-up Visit: 
investigational drug or device 
 
 
Other medications (including vitamins, herbal and dietary supplements) may be considered on a 
case by case basis and will be allowed (if agreed between the Investigator and the Sponsor) if the 
medication is not expected to interfere with study procedures or compromise subject safety.  
The site should contact the Medical Monitor if a subject requires concomitant therapy. All 
medications taken by the subject (whether permitted or excluded by the protocol) must be 
documented in the CRF. 


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3.6.7 Procedure Definitions 
Multiple assessments scheduled for the same time point should be performed within 60 minutes 
of the scheduled time. Administration of study drug, PK, plasma glucose 
 
 sample collection should have priority with respect to the scheduled (nominal) time; 
however, if scheduled at the same time point, study drug administration should occur last. Vital 
signs and 12-lead ECGs should occur prior to blood sample collection. Additional safety 
assessments (e.g., vital signs, 12-lead ECG, serum biochemistry, hematology, coagulation, 
urinalysis) may be performed if deemed necessary by the Investigator. Refer to the laboratory 
manual for specific instructions for the collection and processing of COVID-19 tests, blood and 
urine samples. 
3.6.7.1 
Coronavirus Disease Test  
Respiratory specimens (e.g., nasopharyngeal, oropharyngeal, nasal) will be collected at the 
Screening Visit and on Day -3 to assess for the presence of severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) ribonucleic acid that causes COVID-19 using reverse transcription 
polymerase chain reaction. 
3.6.7.2 
Previous and Concomitant Medications/Procedures 
The information related to the medication (name of drug, dose, route of administration, duration 
of administration, reason for initiation of each medication) and/or the procedures (e.g., name[s] of 
therapy, duration of therapy, reason for initiation) should be investigated. If the medications and/or 
procedures are measures taken to treat an AE, the AE should be recorded as the reason for initiation 
of the medication/procedure in the CRF. 
3.6.7.3 
Physical Examination 
Physical examinations will be performed by a physician or qualified designee according to the 
schedules summarized in Table 1 through Table 5, and will include examination of the following 
body systems: general appearance, skin (including hair and nails), head, ears, eyes, nose, throat, 
neck/thyroid, chest/lungs, cardiovascular, GI, neurological, psychiatric/emotional, lymphatic and 
musculoskeletal. 
3.6.7.4 
Height and Weight Measurements, and Body Mass Index Calculation 
Height and weight measurements will be performed according to the schedules summarized in 
Table 1 through Table 5. Subjects will remove their shoes and wear light clothing in order to be 
consistent between measurements of height and/or weight. The BMI will be calculated at the 
Screening Visit using the following equation: (weight (kg)/[height (m)]2), where the weight in 
kilograms will be documented to one decimal place and the height in centimeters will be rounded 
to the nearest whole number. 


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3.6.7.5 
Medical History 
A complete medical history will be obtained at the Screening Visit. The medical history will 
include past and present conditions prior to the ICF signature date. Between the ICF signature date 
and Day -1, prior to placebo dosing, the Investigator should exercise medical and scientific 
judgement in deciding whether a medical condition, clinically significant laboratory or assessment 
finding (e.g., clinically significant abnormalities in 12-lead ECG, physical examination, vital signs 
and laboratory test results that are evidently chronic in nature) could be considered medical history 
or an AE. 
3.6.7.6 
Vital Signs 
Vital sign assessments including systolic and diastolic blood pressure, HR, respiratory rate and 
body temperature (°C) will be performed according to the schedules summarized in Table 1 
through Table 5. Subjects must lay in the supine position for at least 5 minutes in preparation for 
blood pressure and HR assessments. Repeat testing of vital signs is permitted (refer to 
exclusion #10), if considered appropriate by the Investigator. 
3.6.7.7 
12-Lead Electrocardiogram 
12-lead ECG recordings and conduction intervals including interval from beginning of the QRS 
complex in the frontal plane to the next QRS complex (RR), interval from beginning of the P wave 
to the beginning of the QRS complex in the frontal plane (PR), duration of QRS complex in the 
frontal plane (QRS), interval from beginning of the QRS complex to end of the T wave in the 
frontal plane (QT) and Fridericia-corrected QT interval (QTcF) will be obtained according to the 
schedules summarized in Table 1 through Table 5. Subjects must lay supine for at least five 
minutes prior to 12-lead ECG assessments.  
3.6.7.8 
Adverse Events 
Adverse events information will be collected at the specified time points in Table 1 through 
Table 5, as well as at any time when a site staff becomes aware of an AE after signing the ICF. 
3.6.7.9 
Serum Pregnancy Test 
Blood samples to assess pregnancy status by βhCG will be collected from all female subjects 
according to the schedules summarized in Table 1 and Table 5.  
3.6.7.10 Estimated glomerular filtration rate  
Estimated glomerular filtration rate (eGFR) will be calculated at the Screening Visit using the 
4-variable MDRD equation: 
eGFR (mL/min/1.73 m2) = 175 × Serum Creatinine -1.154 × age -0.203 × 1.212 (if participant is black) 
× 0.742 (if female). 


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3.6.7.11 Serum Biochemistry 
Blood samples to assess ALT, albumin, alkaline phosphatase, AST, bilirubin (direct and total), 
BUN, calcium, carbon dioxide, chloride, creatine kinase, creatinine, gamma­glutamyl transferase, 
globulin, glucose, high-density lipoprotein cholesterol, high sensitivity C-reactive protein, lactate 
dehydrogenase, low-density lipoprotein cholesterol (calculated), phosphate, potassium, total 
protein, sodium, total cholesterol, triglycerides and urate will be obtained under the fasted 
condition according to the schedules summarized in Table 1 through Table 5.  
3.6.7.12 Hematology 
Blood samples to assess complete blood count including erythrocytes (RBC), hematocrit, 
hemoglobin, platelet count, leukocytes (WBC) and differential (percent and absolute [neutrophils, 
eosinophils, basophils, lymphocytes, monocytes]) will be obtained under the fasted condition 
according to the schedules summarized in Table 1 through Table 5. 
3.6.7.13 Coagulation 
Blood samples to assess prothrombin time and activated partial thromboplastin time (aPTT) will 
be obtained as measures of blood coagulation according to the schedules summarized in Table 1 
through Table 5. International normalized ratio will also be calculated. 
3.6.7.14 Viral Serology 
Blood samples to assess HBsAg, HCV antibodies and HIV antibodies will be obtained at the 
Screening Visit.  
3.6.7.15 Drugs of Abuse and Alcohol Screen 
Urine samples to assess amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, 
ethanol, opiates, oxycodone, methadone and methylenedioxymethamphetamines will be obtained 
according to the schedule summarized in Table 1. 
3.6.7.16 Urinalysis 
Urine samples to assess bilirubin, occult blood, color, glucose, ketones, leukocyte esterase, nitrite, 
logarithmic measure of hydrogen ion concentration, protein, specific gravity, turbidity and 
urobilinogen, as well as for a microscopic exam including bacteria, casts, crystals, epithelial cells, 
mucous threads, RBC, trichomonas, WBC and yeast budding, will be obtained under the fasted 
condition according to the schedules summarized in Table 1 through Table 5. Samples for 
urinalysis may be obtained from the first void of the morning when in-house, if applicable.  
3.6.7.17 Glycosylated Hemoglobin  
Blood samples to assess HbA1c will be collected a
 
 


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3.6.7.19 Plasma Glucose 
Blood samples to assess plasma glucose will be collected according to the schedules summarized 
in Table 1 through Table 4. 
3.6.7.20 Ketone Bodies 
Blood samples to assess ketone bodies (β-hydroxybutyrate and acetoacetate) will be collected 
according to the schedules summarized in Table 2 through Table 5. 
 


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3.6.7.28 Bristol Stool Chart 
Subjects will report their stool pattern to the site staff at three visits (Screening Visit, Day -3 and 
the Follow-up Visit). 
At the Screening Visit, the subjects’ stool pattern will be recorded based on the subjects’ 
recollection and review of the BSC definitions. Subjects will be trained by a member of the site 
staff on how to perform the assessment and document the stool type, date and time on the BSC 
source document, which will be provided to each subject for completion during the 3 days prior to 
Day -3. On Day -3, the completed BSC source document will be returned to the site. 
During the Admission Period (Day -3 through Day 35), every time a subject has a bowel 
movement, a member of the site staff will assist the subject in characterizing the stool using the 
BSC including documentation of the date and time (see Appendix 1). 
A BSC source document will be provided to the subject for completion during the Follow-up 
Period. At the Follow-up Visit, completed site-provided BSC source documents will be returned 
to the site by the subjects. 
3.6.7.29 Urine Calcium, Sodium and Glucose 
Urine samples to assess calcium, sodium and glucose will be collected according to the schedules 
summarized in Table 1 through Table 4.  


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3.6.7.30 Pharmacokinetic Procedures 
3.6.7.30.1 BLOOD SAMPLES FOR PHARMACOKINETIC ASSESSMENTS 
Blood samples will be obtained according to the schedules summarized in Table 1 through Table 5 
for the quantification of JTT-662 in plasma. 
If needed, PK plasma samples may be used for JTT-662 metabolite profiling. The laboratory 
performing JTT-662 metabolite profiling will be unblinded to facilitate analysis of the plasma 
samples from the JTT-662-treated subjects and the placebo-treated subjects. The residual PK 
plasma samples from this study may also be used for additional exploratory biomarkers and/or 
metabolomic evaluations, if needed. 
If needed, PK plasma samples obtained for JTT-662 analysis from this study may be used for 
metformin concentration determination. The laboratory performing the metformin concentration 
determination will be unblinded to facilitate analysis of the plasma samples from the 
JTT-622-treated subjects. 
The actual dosing time and sample collection time will be collected for PK data analysis. In 
addition, the site must accurately record the dose and time(s) of dosing of metformin during the 
PK collection period.  
Refer to the laboratory manual for specific instructions for the collection and processing of blood 
samples for PK assessments. 
3.6.7.30.2  ANALYSIS OF JTT-662/PLACEBO IN PLASMA  
JTT-662 will be analyzed in plasma using a validated high-performance liquid 
chromatography/tandem mass spectrometry method. All samples from JTT-662-treated subjects 
will be analyzed. Plasma samples obtained on Day 28 at hours 2 and 4 from placebo-treated 
subjects will be analyzed. For placebo-treated subjects that discontinue the study prior to Day 28, 
the samples obtained on Day 1 at hours 2 and 4 will be analyzed. Additional plasma samples from 
placebo-treated subjects may be analyzed as needed.  


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3.6.8 Clinical Institutions and Laboratories 


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3.7 Adverse Events 
3.7.1 Safety Definitions 
Akros complies with the following International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) AE definitions: 
Adverse Event: An AE is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which 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 a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
For the purpose of this study, AEs are defined as any medical conditions occurring or worsening 
after the ICF signature. 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to signing the ICF 
should be recorded as medical history. Any medical occurrences which are new or worsened from 
the time of informed consent and up to and including the Follow-up Visit must be reported as AEs 
or SAEs. All AEs and SAEs must be recorded irrespective of whether they are considered study 
drug related. For additional details regarding medical history and AEs, please refer to 
Section 3.6.7.  
Subjects will be monitored throughout the study for adverse reactions to the study drug and/or 
procedures. Questions will be posed in a non-leading manner so as not to bias the response. In 
addition to questioning at specific time points, subjects will be encouraged to spontaneously report 
any AEs. Any subject with an AE, SAE or clinically significant abnormal laboratory test result 
will be evaluated by the Investigator and will be treated and/or followed-up until the symptoms or 
laboratory values have resolved or are assessed as stable by the Investigator. A physician or 
appropriate personnel, either at the Investigative site or at a nearby hospital emergency room, will 
administer treatment of any SAEs. When appropriate, medical tests and examinations may be 
performed to ensure that an AE has fully resolved. 


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Serious Adverse Event: An SAE is defined as any AE that meets any of the following criteria: 
• results in death 
• is life-threatening 
• requires inpatient 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 
Note: Important medical events are events that may not result in death, be life-threatening, or 
require hospitalization but, may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject or may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition above. Examples of such 
important medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.  
Adverse Drug Reaction: All noxious and unintended responses to an investigational medicinal 
product (IMP), related to any dose administered. 
Note: The phrase "responses to a medicinal product" means that a causal relationship between 
the medicinal product and an AE is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. 
Unexpected Adverse Drug Reaction: An adverse drug reaction (ADR) of which nature 
(specificity) or severity is not consistent with the applicable product information (e.g., IB). 
Death: Death represents an outcome and an SAE criterion, not an event term. The medical 
condition with the fatal outcome should be reported unless the cause of death is unknown, in which 
case the term “Death” is acceptable. 
Inpatient Hospitalization/Prolongation of Hospitalization: Any admission (even if less than 
24 hours) to a healthcare facility. Admission also includes transfer within the hospital to an 
acute/intensive care unit (e.g., medical floor to the coronary care unit). Initial and prolonged 
hospitalizations that do not meet this SAE criterion include those due to social and/or convenience 
reasons (e.g., lack of personal care at home, unable to transfer to non-acute facility), admission to 
rehabilitation/hospice/skilled 
nursing 
facilities, 
emergency 
room 
visits, 
same-day/outpatient/ambulatory procedures, and those for pre-planned, elective procedures for a 
pre-existing condition that did not worsen after the ICF has been signed (no AE recorded). 
However, if the hospitalization was prolonged due to a complication of a pre-existing condition, 
the complication (same diagnosis) would qualify as an SAE. 
Disability: A substantial disruption of a person’s ability to conduct normal life functions. 
Life-threatening: Any AE that places the patient or subject, in the view of the Investigator, at 
immediate risk of death, i.e., it does not include an event that had it occurred in a more severe 
form, might have caused death. 


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Physical Examination, Vital Signs, Laboratory Test and ECG Abnormalities: Any 
abnormalities fulfilling the criteria for an SAE should be reported as such, in addition to being 
recorded as an AE in the CRF. Any abnormal vital sign, physical finding or laboratory/ECG result 
which is clinically significant (i.e., meets one or more of the following conditions) should be 
recorded as a single entry on the AE page of the CRF: 
• Accompanied by clinical signs/symptoms, 
• Leads to permanent discontinuation of study drug, 
• Requires a change in concomitant therapy (e.g., addition of, interruption of, discontinuation 
of, or any other change in a concomitant medication, therapy or treatment).  
This does not apply to abnormal vital signs, physical finding or laboratory/ECG results that do not 
meet the clinical-significance criteria, are part of an AE which has already been reported, are 
associated with the disease being studied (unless judged by the Investigator as more severe than 
expected for the subject’s condition), or conditions present or detected at the start of the study and 
do not worsen. 
The Investigator will exercise medical and scientific judgement in deciding whether an abnormal 
clinical laboratory finding or other abnormal assessment is clinically significant. 
3.7.2 Assessing Adverse Events 
When completing appropriate forms for reporting an AE, the Investigator should assess the AEs 
as follows: 
Reported Term for Adverse Event: 
Individual signs or symptoms, will be recorded AEs, in the absence of a diagnosis. If a diagnosis 
is available based on the signs or symptoms, the diagnosis, should be recorded as the AE term. 
Seriousness of Adverse Event: 
• Serious: The AE meets a criterion of the SAE definition. 
• Not Serious: The AE does not meet a criterion of the SAE definition. 
Severity of Adverse Event:  
The severity of an AE should be graded as one of the following three grades: mild, moderate or 
severe. To determine the severity of AEs, refer to “Common Terminology Criteria for Adverse 
Events (CTCAE)” and categorize Grade 1, Grade 2 and Grade 3 or higher grades of CTCAE32 into 
mild, moderate and severe, respectively. The investigator should determine the severity, taking 
into account the general status of the subject, baseline values, outcomes, as well as the severity 
grade. An AE of Grade 4 or Grade 5 should be assessed whether or not it meets the criteria listed 
under the SAE definition (see Section 3.7.1). 
• Mild: The AE is usually transient and may require only minimal treatment or therapeutic 
intervention. The AE does not generally interfere with usual activities of daily living. 
• Moderate: The AE is usually alleviated with additional specific therapeutic intervention. The 
AE interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the subject. 


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• Severe: The AE interrupts usual activities of daily living, or significantly affects clinical status 
of the subject, or may require intensive therapeutic intervention. 
Relationship to the Study Drug (Causality) of Adverse Event: 
The Investigator’s causality assessment is the determination whether there is a reasonable 
possibility that the IMP caused or contributed to the AE. Generally, the facts (evidence) or 
arguments to suggest causal relationship should be documented. Factors to be taken into 
consideration when assessing causality include: subject’s underlying and pre-existing conditions, 
prior/concomitant medications, timing of onset relative to study drug (i.e., JTT-662 or placebo) 
administration, the known PK characteristics of study drug, the currently-known safety profile of 
study 
drug, 
known 
class 
effects 
of 
similar 
mechanism 
of 
action 
drugs, 
the 
de-challenge/re-challenge response (if available) and any other information that is considered 
relevant by the Investigator. Causality will be judged in two categories: “not related” or “related”.  
• Not Related: Sufficient information exists to indicate that the etiology is clearly related to a 
cause other than the study drug. 
• Related: The AE follows a reasonable temporal sequence from the administration of the study 
drug; follows a known or expected response pattern to the study drug; is confirmed by 
improvement on stopping the dosage of the study drug (de-challenge); and cannot be 
reasonably explained by the participant’s clinical state. 
Action Taken with Regard to Study Drug: 
• Dose Not Changed: The subject was on treatment with the study drug when the AE occurred, 
and the study drug dosing was maintained at the same dose level. 
• Drug Interrupted: The subject was on treatment with the study drug when the AE occurred, 
and the study drug dosing was temporarily discontinued and then re-started. 
• Drug Withdrawn: The subject was on treatment with the study drug when the AE occurred, 
and the study drug dosing was permanently discontinued. 
• Not Applicable: The subject was not receiving treatment with the study drug when the AE 
occurred (i.e., AE occurred before placebo dosing on Day -1 or after the last study drug 
administration), or if the subject died. 
Outcome of Adverse Event: 
One outcome should be recorded for each AE and the outcome of each AE should be classified as 
follows: 
• Not Recovered/Not Resolved: The subject has not yet recovered from the AE; the event has 
not improved (follow-up of all SAEs and all related AEs will be continued until the overall 
clinical outcome is ascertained). 
• Recovering/Resolving: The subject has not yet recovered from the AE, however, the event is 
improving (follow-up of all SAEs and all related AEs will be continued until the overall clinical 
outcome is ascertained).  
• Recovered/Resolved: The subject recovered from the AE with no sequelae. 
• Recovered/Resolved with Sequelae: The subject recovered from the AE with sequelae. 
• Fatal: The subject’s death was a result of the AE.  


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Start Date and Time, and End Date and Time of Adverse Event: 
The start date and time of each AE with an onset time during the period for AE assessment should 
be recorded. The end date and time of each AE should be recorded in the following manner:  
• If the outcome of AE is “Recovered/Resolved” or “Recovered/Resolved with Sequelae”, 
record the date and time of the AE outcome. 
• If the outcome of AE is “Fatal,” record the date of the death. 
• If the outcome of AE is “Recovering/Resolving” or “Not recovered/Not resolved”, the end date 
and time of the AE outcome should NOT be recorded. 
For AEs related to abnormalities in parameters such as vital signs, ECGs, record the date/time 
when the test was performed as the start date/time and end date/time. For AEs related to 
abnormalities in laboratory values, record the date/time when the sample was collected for the test 
as the start date/time and end date/time. 
If an identical AE occurs repeatedly in a subject, the Investigator (or designee) should judge 
whether it is a single event or a composite of more than one event considering the features, 
frequency and severity of the AE from a medical perspective. 
3.7.3 Reporting Adverse Events 
Adverse Events Reporting: 
Adverse events occurring (initial occurrence or a worsening of a pre-existing condition) after the 
ICF has been signed and up to the day when the decision to screen fail the subject is made (for 
screen failure subjects), up to 7 days (for subjects discontinuing the study after dosing on Day -1, 
but before dosing on Day 1) or 14 days (for subjects discontinuing the study after dosing on Day 1) 
after the last dose of study drug will be reported and entered in the CRFs. Conditions detected 
prior to the ICF signature should be documented as medical history. Other conditions identified 
between the ICF signature and Day 1 (prior to dosing) could be included in the medical history, 
based on the Investigator’s medical and scientific judgement. For guidance, refer to Section 3.6.7.5 
of the protocol.  
Adverse events will be reported on the AE CRF page. 
When a subject withdraws from the study due to a non-serious AE, whether or not related to study 
drug, the Investigator must notify Akros within 24 hours of the study center being informed of the 
withdrawal. 
Serious Adverse Event Reporting: 
Reporting by Investigator 
Detailed instructions regarding SAE reporting will be provided in the appropriate documents 
outside of this protocol. A brief, non-all-inclusive summary is provided below. 
Any SAE experienced by a study subject after signing the informed consent up to the day when 
the decision to screen fail the subject is made (for screen failure subjects), 7 days (for subjects 
discontinuing the study after dosing on Day -1, but before dosing on Day 1) or 14 days (for subjects 


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discontinuing the study after dosing on Day 1) after the last dose of study drug will be reported to 
the Sponsor or designee. Additionally, SAEs that occur after this period will also be reported to 
The Sponsor or designee, if the Investigator considers the SAE related to the study drug. 
Serious AEs (both initial reports and follow-up information) must be reported to the Sponsor or 
designee within 24 hours of the Investigator’s (site’s) awareness or notification of the event. 
The Investigators should make every effort to provide complete information when reporting the 
SAE (both for initial reports, as well as for follow-ups). 
Notes: The Investigator should make every effort to assess the causality of the SAE prior to 
transmission of the initial SAE report, even if the Investigator has minimal information. The SAE 
report should be amended, if the Investigator changes his/her opinion of causality based on the 
follow‑up information. 
Personal information that could potentially identify the subject MUST NOT be included in any 
document that is sent to Sponsor or designee as per ICH GCP Principles 2.11 and other applicable 
laws and legislations. 
The Investigator must continue to follow the subject until the SAE has subsided, the condition 
becomes chronic in nature, the condition stabilizes (in case of persistent impairment), or the subject 
dies. Within 24 hours of receipt of follow-up information, the Investigator must submit it to the 
Sponsor or designee. 
The Investigator is also required to submit SAE reports to the IRB, in accordance with local 
requirements. The Investigator will receive all Suspected Unexpected Serious Adverse Reaction 
(SUSAR) reports for onward submission to their local IRB, as required. 
Reporting by the Sponsor 
Competent authorities will be informed by the Sponsor or designee of SUSARs.  
Exposure in Utero Reporting: 
If a female subject or a female partner of a male subject participating in the study becomes pregnant 
after the subject receives study drug on Day 1 and up to 30 days after the last dose of study drug, 
the Investigator should report the pregnancy to the Sponsor or designee within 24 hours of being 
notified. To report the pregnancy, the site must complete the Exposure in Utero Form which is 
provided separately to the Investigator. 
The female subject or the female partner of a male subject should be followed by the Investigator 
until completion of the pregnancy if the subject received active (i.e., JTT-662) treatment. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify the 
Sponsor or designee. At the completion of the pregnancy, the Investigator should document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., spontaneous abortion, stillbirth, neonatal death or congenital 
anomaly), the Investigator should follow the procedures for reporting an SAE as described above. 


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Overdose Reporting: 
An overdose is a significant variation from the recommended/scheduled dosage for a product. For 
the purposes of this study, overdose is defined as any confirmed use of study drug more than 
indicated by the protocol. Information on overdose in subjects is collected by the Sponsor or 
designee, via a separate form provided to the Investigator. If a subject experiences an overdose 
during the course of the study, the Investigator or qualified designee must report it to the Sponsor 
or the designee as soon as possible after he/she first becomes aware of it. If any overdose leads to 
an AE or SAE, the AE should be documented and the SAE should be reported to the Sponsor or 
designee, as described under the SAE reporting section. 
3.8 Identification of Treatments 
3.8.1 Method of Assigning Subjects to Treatment Groups 
After signing the ICF, potential study subjects will be assigned a screening number (XXX) 
consecutively. The screening number will be used throughout the study. Following confirmation 
of eligibility on Day 1, the pharmacist at the site will assign a four digit randomization number 
XXYY, where XX represents the cohort number (beginning with 01) and YY represents a 
consecutively assigned number beginning with 01 ending with 12 in each cohort. Subjects that 
took placebo on Day -1 but are not randomized into Cohort 1 on Day 1, Hour 0 can be randomized 
into Cohort 2 on the same day, if still eligible, and will be assigned a randomization number XXYY 
where XX represents the cohort number (beginning with 02) and YY represents a consecutively 
assigned number. 
To ensure an adequate number of evaluable subjects, replacement subjects may be enrolled in the 
study at the discretion of the Sponsor, as appropriate. Each replacement subject will be assigned 
the same treatment as the subject that is being replaced. The first digit in the randomization number 
of the replacement subject will be five (i.e., the replacement subject for the first subject [0101], 
becomes 5101). 
3.8.2 Identity of Investigational Products  
 
 
 
 
 


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3.8.3 Storage and Handling Procedures 
JTT-662 Tablets, 1 mg or 10 mg and Placebo Tablets should be stored between 20 – 25°C in a 
secure location with restricted access. 
3.8.4 Clinical Supplies Packaging 
A sufficient quantity of JTT-662 Tablets, 1 mg or 10 mg and Placebo Tablets will be supplied by 
Akros or designee, to the site. 
Bulk JTT-662 and Placebo Tablets are packaged in glass bottles with a low-density polyethylene 
cushioning material, two alumina/silica desiccant packs (1 g) and capped with a polypropylene 
screw cap fitted with a polypropylene/polyethylene liner. Each bottle contains 30 tablets of either 
JTT-662 (1 mg or 10 mg) or Placebo Tablets, and will be labeled appropriately. Each label will 
bear appropriate text as specified by regulatory requirements. 
Glass bottles and closures will be provided by Akros or designee, to the pharmacy for 
subject-specific packaging of JTT-662 or Placebo Tablets. Each label will bear the appropriate text 
as specified by regulatory requirements.  
Study drug should be packaged for subject administration on the day of dosing, however, if this is 
not feasible, the weekday dose may be packaged up to 24 hours prior to dosing. Weekend dosing 
may be packaged up to 72 hours in advance of dosing. 
3.8.5 Administration of Study Drug and Metformin 
On the morning of Day -1, all subjects will receive a single oral administration of placebo 
following an overnight fast (for at least 10 hours) and 30 minutes before the start of a standard 
breakfast. On the morning of Day 1, randomized subjects will receive oral QD administration of 
JTT-662 or placebo, for 28 days from Day 1 through Day 28 following an overnight fast (for at 
least 10 hours) and 30 minutes before the start of a standard breakfast. Standardized lunch and 
dinner will be provided at 4.5 and 10.5 hours, respectively, post-dose. Metformin should be 
administered with food as per the label.  
Water will be restricted for 1 hour before and after study drug administration for all cohorts. The 
planned dose levels and the number of tablets to be administered are provided below: 
 
 


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* Cohort 3 will be initiated only after a review of the safety, tolerability, PK (up to Day 29 for 
Cohort 2) and available PD data from Cohorts 1 and 2 by the Sponsor, the Medical Monitor and 
the Investigator. 
 
. 
Tablets will be administered with 240 mL of potable water, followed by a hand check, if 
applicable, and a mouth check. Subjects having difficulty swallowing the required number of 
tablets with 240 mL of water may receive additional, documented amount of water sufficient to 
complete drug administration. Only authorized members of the site will administer the study drug. 
Dosing times will be staggered between subjects for practical reasons. The time of dosing will be 
recorded for each subject. 
All subjects should remain semi-recumbent for 2 hours after study drug administration except for 
non-supine assessments, breakfast and restroom visits. 
3.8.6 Management of Clinical Supplies 
The Investigator will have responsibility for the control and proper administration of all 
study-related drugs (which includes any investigational product or interacting product) in 
accordance with this protocol. The Investigator at the site is responsible for ensuring that all 
study-related drugs will be stored at recommended storage temperatures, in a secured area, free of 
environmental extremes, with restricted access. The Investigator at the site also agrees that all 
study-related drugs will be dispensed only to study subjects who have provided written informed 
consent and have met all inclusion criteria and none of the exclusion criteria. 
3.8.7 Randomization 
Approximately 36 healthy subjects will be randomized in this study in 3 planned cohorts. In each 
cohort, 12 subjects will be randomized to receive JTT-662 or placebo (9 active: 3 placebo) on 
Day 1. 
Cohort 
Study Treatment  
Number of Tablets (Per Dose) 
1 
Day -1: Placebo single dose 
Day 1 through Day 28: JTT-662 
5 mg (or placebo) QD 
Five tablets of placebo 
Five tablets of JTT-662 1 mg or five tablets of 
placebo 
2 
Day -1: Placebo single dose 
Day 1 through Day 28: JTT-662  
10 mg (or placebo) QD 
One tablet of placebo 
One tablet of JTT-662 10 mg or one tablet of placebo 
3* 
Day -1: Placebo single dose 
Day 1 through Day 28: JTT-662  
20 mg (or placebo) QD 
Two tablets of placebo 
Two tablets of JTT-662 10 mg or two tablets of 
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The randomization code will be prepared by an unblinded statistician or designee using an in-house 
program written in SAS®, a computer software package. Akros or designee will provide the 
randomization code to the pharmacy at the site, as well as to select laboratories, as appropriate 
(see Section 3.8.8). 
3.8.8 Blinding  
On the morning of Day -1, all subjects will receive a single oral dose of placebo in an unblinded 
manner. From the morning of Day 1 to the morning of Day 28, all randomized subjects will receive 
JTT-662 or placebo QD in a single-blind manner. JTT-662 and Placebo Tablets will be supplied 
as unbranded tablets which are identical in appearance.  
The pharmacist at the site will be responsible for packaging and dispensing the study drug in order 
to maintain the blind. The treatment assigned to each subject will not be disclosed to the subject; 
however, the Investigator and site staff will be unblinded. The treatment codes will be controlled 
by the site’s pharmacy or designee. 
The laboratory performing the JTT-662, metabolite and metformin (if analyzed) plasma 
concentration assessments (
7
) 
will be unblinded to facilitate analysis of all samples from the JTT-662-treated subjects and 
appropriate samples from the placebo-treated subjects (see Section 3.6.7.30). 
3.8.9 Breaking the Blind 
Not applicable. 
3.9 Statistical Methods 
This section provides an abbreviated statistical analysis plan (SAP) for safety, PK, PD 
 
 parameters. A formal SAP will be developed at a later time. Statistical issues not 
addressed in the present section may be developed in the formal SAP. Any deviations to the SAP 
will be discussed in the study report. 
3.9.1 Subject Populations for Analysis 
Randomized Population: All subjects randomized to receive JTT-662 or placebo on Day 1. 
Safety Population: All subjects who received at least one dose of JTT-662 or placebo, including 
those who do not complete the study. 
Pharmacokinetic Population: All randomized subjects who received at least one dose of JTT-662 
or placebo, and have evaluable JTT-662 plasma concentration data. Subjects will be excluded or 
partially excluded from the statistical analysis of PK parameters if they significantly violated the 
inclusion or exclusion criteria or deviated significantly from the protocol. 


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Pharmacodynamic Population: All randomized subjects who received at least one dose of 
JTT-662 or placebo, and have evaluable PD data to facilitate the calculation of PD parameters. 
Subjects will be excluded or partially excluded from the statistical analysis if they significantly 
violate the inclusion or exclusion criteria or deviated significantly from the protocol.  
3.9.2 Sample Size 
Approximately 36 subjects (3 cohorts, 12 subjects per cohort [9 active: 3 placebo]) will be 
randomized into this study. The sample size is not statistically determined. 
3.9.3 Interim Analysis 
Interim analysis is not planned for this study. 
3.9.4 Safety Analysis 
All subjects in the safety population will be included in the safety data analysis. 
The safety evaluation will include AEs, clinical safety laboratory tests (e.g., hematology, serum 
biochemistry, coagulation, urinalysis), vital signs, 12-lead ECGs, Bristol Stool Chart findings, 
ketone bodies, 
, FPG, urinary calcium excretion from 
the time of dosing until the 24-hour time point (UCE0-24), urinary sodium excretion from the time 
of dosing until the 24-hour time point (UNaE0-24) and UGE0-24. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities and will be 
summarized by SOC and preferred term. 
Observed values and change from baseline of vital signs, ECG parameters and clinical laboratory 
data will be presented in tabular form with arithmetic mean, standard deviation (SD), median, 
minimum and maximum, or in frequency tabulation form as appropriate. For the laboratory safety 
data, out of range values and clinically significantly abnormal values will be flagged in the data 
listings. 
Observed values and change from baseline of ketone bodies, 
 
 FPG will be summarized by treatment and time point. 
Urine Calcium, Sodium and Glucose 
Urinary calcium excretion from the time of dosing until the 24-hour time point (UCE0-24), UGE0-24 
and UNaE0-24 will be computed for Days -1, 1, 14 and 28. Observed and change from baseline of 
total excreted amount within 24 hours will be summarized by treatment and day. 
Statistical analysis for change from baseline in UGE0-24 will be performed using a mixed effect 
model with repeated measures (MMRM). The model will include fixed effects for treatment, day, 
treatment by day interaction and baseline value. The treatment difference of each JTT-662 dose 
group relative to placebo at the same day will be estimated, along with two-sided 90% and 95% CIs 
and p-values. 


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Bristol Stool Chart 
Total number of stools and percent of stools at each stool type will be summarized by treatment. 
Post-treatment highest stool type score will be also derived for each subject, and number and 
percent of subjects by the highest stool type will be summarized by treatment. 
Other safety parameters may be summarized as appropriate.  
3.9.5 Pharmacokinetic Analysis 
Pharmacokinetic analysis will be performed on the PK population unless otherwise stated.  
3.9.5.1 
Pharmacokinetic Parameters 
The following PK parameters will be derived by non-compartmental analysis using Phoenix® 
WinNonlin® (Version 6.4 or higher) and/or SAS® (Version 9.4 or higher) as appropriate. 
Additional PK parameters may be calculated, as appropriate. 
• JTT-662 in plasma: Cmax, trough concentration during multiple dosing prior to next dose 
(Ctrough), tmax, AUCtau, Vz_F, CL_F, t1/2, t1/2(eff), accumulation ratio of maximum concentration 
(ARCmax) and accumulation ratio of area under the concentration-time curve during a dosing 
interval (ARAUCtau), and accumulation ratio based on trough concentration (ARCtrough). 
3.9.5.2 
Pharmacokinetic Data Analysis 
Descriptive statistics will be performed for all subjects in the PK population. The plasma 
concentration data and the PK parameters will be summarized in terms of the number of 
subjects (n), arithmetic mean, SD, CV%, median, minimum and maximum by treatment and day. 
In addition, geometric mean will be reported for all PK parameters except tmax. 
Dose proportionality of Cmax and appropriate AUC values on Day 1 and Day 28 will be assessed 
for JTT-662. The relationship between each parameter and dose is written as a power function:  
  
 
 
Parameter = A*dose
b  (Equation 1) 
Where “A” is a constant, “b” is the proportionality constant and “parameter” is the PK parameter 
of interest (e.g., Cmax and AUCtau). Each PK parameter will be plotted against dose. The exponent, 
b, will be estimated by performing linear regression of the (natural) log-transformed parameter on 
the log-dose, since taking logarithm on both sides of (Equation 1) gives the linear relationship, log 
parameter = a + b*log dose, where a = log(A). Therefore the exponent, b, is estimated by the slope 
of the resulting regression line. A value of b close to 1 indicates dose proportionality. Dose 
proportionality will be assessed descriptively by presenting the estimate of b, its standard error and 
the 90% CI. 
3.9.6 Pharmacodynamic Analysis 
Area under the observed effect-time curve from the time of starting breakfast until the 4-hour time 
point (AUEC0-4) will be calculated for PPG on Days -1, 1, 14 and 28.  


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Postprandial glucose (PPG) concentrations will be summarized by treatment group and time point 
in terms of the number of subjects, arithmetic and geometric means, standard deviation, CV%, 
median, minimum and maximum.  
A linear mixed effect model including day as the fixed effect and subject as the random effect will 
be fitted on the natural logarithm of the PD parameter for each treatment group separately. The 
ratio of the geometric means (Day 1/Day -1, Day 14/Day -1 and Day 28/Day -1) of AUEC0-4 and 
the 90% and 95% CIs of the GMR will be calculated. 
Additionally, the change from baseline of AUEC0-4 will be analyzed using the MMRM model. The 
model will include fixed effects for treatment, day, treatment by day interaction, subject as 
repeated measures and baseline value. The treatment differences between each JTT-662 dose 
group relative to placebo at the same day will be estimated, along with two-sided 90% and 
95% confidence intervals (CIs) and p-values. 


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3.10 Quality Control and Quality Assurance 
This study will be conducted in compliance with the protocol, GCP as defined by the United States 
21 Code of Federal Regulations (CFR) Parts 50, 56 and 312, Sponsor policies and procedures and 
all applicable state regulations. 
The following steps will be taken to ensure the accuracy, consistency, completeness and reliability 
of the data: 
a) Routine site monitoring; 
b) CRF review against source documents; 
c) Data management quality control checks; 
d) Statistical quality control checks; 
e) Continuous data acquisition and cleaning; and 
f) Quality control of final report. 
A representative from Akros and/or authorized representatives may conduct periodic audits of the 
site and study processes, including, but not limited to, the clinical database and the final report. 
The study may also be subject to inspection by regulatory authorities. The Investigator hereby 
agrees to allow access to required subject records and other documentation and facilities related to 
the review and conduct of the study. 
4 INVESTIGATOR OBLIGATIONS 
4.1 Institutional Review 
The Investigator shall assure that an IRB that complies with the requirements set forth in the US 
21 CFR Part 56 will be responsible for the initial and continuing review and approval of the 
proposed clinical study. The Investigator shall also assure that he or she will promptly report to 
the IRB all changes in the research activity and all unanticipated problems involving risk to human 
subjects or others and that he or she will not make any changes in the research without IRB 
approval, except where necessary to eliminate apparent immediate hazards to human subjects. 
All advertisements used in conjunction with this study must be reviewed and approved by Akros 
prior to use and the IRB, if applicable. The IRB’s approval will be documented in writing and sent 
to the Investigator. The Investigator will forward a copy of the IRB approval document to Akros. 
The Investigator will not begin the study until Akros has authorized release of investigational drug 
product. 
Any amendments to the protocol must be approved in writing by the IRB prior to implementation 
by the Investigator. However, any change to the protocol to eliminate an apparent immediate 
hazard to the subjects may be implemented immediately, provided that the IRB is subsequently 
notified in accordance with US 21 CFR Part 56.104(c). 


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The Investigator will also provide the IRB with a current copy of the IB at the start of the study, 
as well as an updated version of the IB if revised during the study or supplement(s) to the IB if 
prepared during the study. 
A progress report will be submitted by the Investigator to the IRB at intervals established by the 
IRB and not less than annually. The Investigator will retain a copy of this report in the 
Investigator’s Documentation File. After completion or termination of the study, the Investigator 
will submit a final report to the IRB. Copies of all reports will be provided to Akros. 
4.2 Subject Consent 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirement(s), i.e., US 21 CFR Part 50 and should adhere to GCP. Prior to 
the beginning of the study, the Investigator should have the IRB written approval of the written 
informed consent form and any other written information to be provided to subjects. 
The written informed consent form and any other written information to be provided to subjects 
must be revised whenever important new information becomes available that may be relevant to 
the subject’s consent. Any revised written informed consent form and written information must 
receive the IRB approval in advance of use. The subject must be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the study. The communication of this information should be documented. 
The Investigator or a person designated by the Investigator, should fully inform the subject of all 
pertinent aspects of the study including the written information and the approval by the IRB. A 
copy shall be given to the person signing the form. 
4.3 Data Collection 
It is the Investigator’s responsibility to ensure that data are collected and reported according to the 
study protocol. The Investigator will ensure the accuracy, completeness and timeliness of the data 
reported on the CRF and in all required reports. Efforts should be made to complete the CRFs as 
soon as possible after the scheduled visit and to have all CRFs completed within 3 days after 
Day 42. 
Additionally, laboratory data 
 may be received by Clinical Data Management from 
the appropriate clinical laboratory(ies) a
 in electronic format. These data files may 
be merged with the clinical database. 
4.3.1 Case Report Forms 
Electronic CRFs will be produced according to protocol requirements and access/training will be 
provided to the site in order for the Research Staff to record the data obtained on each subject 
during the study. 
Case Report Forms must be completed for each subject who signed the ICF to participate in the 
study. 


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Case Report Forms will be reviewed by the Clinical Monitor. At a minimum, important safety, 
eligibility and endpoint data as defined in the data management plan will be verified against source 
documents. The CRFs must be kept up-to-date so that they always reflect the latest observations 
on the subjects randomized in the study. All records should be kept in conformance to applicable 
national laws and regulations. 
4.3.2 Source Documents 
It is the responsibility of the Investigator to collect and record all study data on source documents. 
The Investigator must provide access to source data/documents for study-related monitoring, 
audits, IRB review and regulatory inspection. 
4.4 Adherence to Protocol 
By signing the Investigator Signature Page of this protocol, the Investigator confirms in writing 
that he/she has read, understands and will strictly adhere to the study protocol. This study will be 
conducted in accordance with GCP regulations. Additional information regarding management of 
protocol amendments can be found in Section 5.2. 
4.5 Reporting Adverse Events 
For details regarding AE and SAE reporting, see Section 3.7.3.  
4.6 Investigator’s Final Report 
Upon completion of the study, the Investigator will provide Akros with a copy of the summary of 
the study’s outcome provided to the IRB. 
4.7 Records Retention 
The Investigator is required to maintain adequate records of the disposition of the drug, including 
dates, quantity and use by subjects. If the investigation is terminated, suspended, discontinued or 
completed, the Investigator shall return the unused supplies of the drug to the sponsor or otherwise 
provide for disposition of the unused supplies of the drug under the US 21 CFR Part 312.59. 
The Investigator shall retain records required to be maintained under this part for a period of two 
years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not approved 
for such indication, until two years after the investigation is discontinued and the Food and Drug 
Administration is notified. 
Akros should inform the Investigator(s)/institution(s) in writing of the need for record retention 
and should notify the Investigator(s)/institution(s) in writing when the study related records are no 
longer needed. 


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Custody of the records may be transferred to another responsible party, acceptable to Akros, who 
agrees to abide by the retention policies. Written notice of transfer must be submitted to Akros. 
The Investigator must contact Akros and obtain prior written permission prior to disposing of or 
transferring any study records. 
4.8 Confidentiality 
The Investigator, Akros and its representatives, agree to protect the privacy and confidentiality of 
the protected health information in accordance with applicable laws and regulations. 
Subject’s medical information obtained by the study is confidential and disclosure to third parties 
is prohibited unless required by law. The Investigator shall retain all such information and any 
other information designated by Akros as confidential or is otherwise of reasonably confidential 
nature, in confidence and shall not use such information for any purpose other than the 
performance of obligations pursuant to the agreement with Akros and designated affiliates or 
contractors, as the case may be, without prior written authorization from Akros. 
At the subject’s request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection on request by representatives of 
regulatory authorities, Akros and the IRB(s) if appropriate. 
4.9 Publications 
The Investigator agrees that all data, calculations, interpretations, opinions and recommendations 
regarding the study shall be the sole and exclusive property of Akros and that Akros may make 
any use thereof at its discretion without obligation to Investigator. The Investigator agrees to 
consider the results as information subject to confidential and use restrictions. 
In the event that the study results are published in the scientific literature by Akros, 
acknowledgment will be made to the Investigator(s) in the accepted style, as appropriate. The 
names of the Investigators or their representatives shall not be used by Akros in publications, for 
advertising, for other commercial purposes or otherwise, without appropriate written permission, 
unless required by law or government regulation. 
Individual study center manuscript(s) for publication, text for talks, abstracts of papers, poster 
presentations and similar material will be submitted to Akros for review and comment prior to 
publication or disclosure. In order to ensure that Akros will be able to make comments and 
suggestions where pertinent, material for public dissemination will be submitted to Akros for 
review at least sixty (60) days prior to submission for publication, public dissemination or review 
by a third party committee. Akros will have sixty (60) days from receipt of such information to 
review and comment on and discuss the contents thereof with the Investigator. 


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If Akros requests, the Investigator will remove any and all confidential information (other than 
study results) prior to submitting or presenting the materials. Upon Akros request, the Investigator 
will delay submitting or presenting the materials for a further sixty (60) days to permit Akros to 
take necessary actions to protect its confidential information, including filing of patent applications 
thereon. 
5 STUDY MANAGEMENT  
5.1 Monitoring 
Monitoring visits will be conducted by Akros or designee according to applicable regulations and 
guidelines for GCP. The Investigator will permit Akros and/or designee to make regular site visits 
during the study. The frequency of monitoring visits will be agreed upon by Akros and/or designee. 
At each visit, the Investigator and staff will be expected to cooperate with Akros or designee for 
the review and verification of protocol compliance, AE reporting, CRFs, source documents, 
clinical supplies and inventory records and any additional records as may have been previously 
arranged between the Investigator and Akros or designee. 
The Investigator and/or other designated study personnel are expected to contact the Akros monitor 
or designee as needed regarding study concerns and/or questions. 
5.2 Management of Protocol Amendments and Deviations 
With the exception of emergency situations, implementation of any change in the protocol that 
affects safety of the subjects, scope of the investigation or scientific quality of the study will not 
be permitted until Akros and the Investigator have approved the protocol amendment and the IRB 
responsible for review and approval of the study has reviewed and approved the protocol change. 
Implementation of changes that do not affect the safety of subjects, scope of the investigation or 
scientific quality of the study cannot be made until the protocol changes are reviewed and approved 
by Akros and the Investigator. The IRB must be notified of these protocol changes. The 
Investigator will not deviate from the protocol without prior written approval from Akros. 
5.3 Study Termination 
The study may be terminated at any time at the request of Akros with proper and timely notification 
of all parties concerned. The IRB will be informed promptly and reasons for the termination or 
suspension will be provided by Akros, as specified in the applicable regulatory requirements. The 
study can be considered complete and/or terminated after Akros has received the following data 
and materials: 
• Laboratory findings, clinical data and all special test results from screening through the end of 
the Follow-up Period 
• CRFs properly completed by appropriate study personnel (including correctly answered and 
closed system or manually-generated edit checks) and signed by the Investigator 
• Completed Drug Accountability Records 
• Statement of outcome for each SAE reported 


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• Approval/notification of protocols and protocol amendments from IRB as well as relevant 
health authorities (if applicable) 
5.4 Sponsor’s Final Report 
A final report will be prepared by Akros or a designee at the conclusion of this clinical study. 


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6 REFERENCES 
1. International Diabetes Federation. IDF DIABETES ATLAS. Ninth edition 2019. 
2. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory 
dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 
1999;104(6):787-94. 
3. Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of 
Type II diabetes mellitus. Diabetologia. 2001;44(8):929-45. 
4. Gerich JE. Pathogenesis and treatment of type 2 (noninsulin-dependent) diabetes mellitus 
(NIDDM). Horm Metab Res. 1996;28(9):404-12. 
5. Monnier L, Colette C, Dunseath GJ, Owens DR. The loss of postprandial glycemic control 
precedes 
stepwise 
deterioration 
of 
fasting 
with 
worsening 
diabetes. 
Diabetes Care. 2007;30(2):263-9. 
6. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of 
glycaemia with macrovascular and microvascular complications of type 2 diabetes 
(UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-12. 
7. DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and 
cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern 
Med. 2001;161(3):397-405. 
8. Nakagami T, Qiao Q, Tuomilehto J, Balkau B, Tajima N, Hu G, et al. Screen-detected diabetes, 
hypertension and hypercholesterolemia as predictors of cardiovascular mortality in five 
populations of Asian origin: the DECODA study. Eur J Cardiovasc Prev Rehabil. 
2006;13(4):555-61. 
9. Levitan EB, Song Y, Ford ES, Liu S. Is nondiabetic hyperglycemia a risk factor for 
cardiovascular 
disease? 
A 
meta-analysis 
of 
prospective 
studies. 
Arch Intern Med. 2004;164(19):2147-55. 
10. Sorkin JD, Muller DC, Fleg JL, Andres R. The relation of fasting and 2-h postchallenge plasma 
glucose concentrations to mortality: data from the Baltimore Longitudinal Study of Aging with 
a critical review of the literature. Diabetes Care. 2005;28(11):2626-32. 
11. Cavalot F, Petrelli A, Traversa M, Bonomo K, Fiora E, Conti M, et al. Postprandial blood 
glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 
diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study. 
J Clin Endocrinol Metab. 2006;91(3):813-9.  
12. Cavalot F, Pagliarino A, Valle M, Di Martino L, Bonomo K, Massucco P, et al. Postprandial 
blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 
14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study. Diabetes Care. 
2011;34(10):2237-43. 
13. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial 
Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM 
randomised trial. Lancet. 2002;359(9323):2072-7. 


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14. Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M. Acarbose reduces the 
risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term 
studies. Eur Heart J. 2004;25(1):10-6. 
15. American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatment: 
Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S73-S85. 
16. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. 
Physiol Rev. 2011;91(2):733-94. 
17. Dyer J, Wood IS, Palejwala A, Ellis A, Shirazi-Beechey SP. Expression of monosaccharide 
transporters in intestine of diabetic humans. Am J Physiol Gastrointest Liver Physiol. 
2002;282(2):G241-8. 
18. Fujita Y, Kojima H, Hidaka H, Fujimiya M, Kashiwagi A, Kikkawa R. Increased intestinal 
glucose absorption and postprandial hyperglycaemia at the early step of glucose intolerance in 
Otsuka Long-Evans Tokushima Fatty rats. Diabetologia. 1998;41(12):1459-66. 
19. Miyamoto K, Hase K, Taketani Y, Minami H, Oka T, Nakabou Y, et al. Diabetes and glucose 
transporter gene expression in rat small intestine. Biochem Biophys Res Commun. 
1991;181(3):1110-7. 
20. Wright EM. I. Glucose galactose malabsorption. Am J Physiol. 1998;275(5 Pt 1):G879-82. 
21. Booth IW, Patel PB, Sule D, Brown GA, Buick R, Beyreiss K. Glucose-galactose 
malabsorption: demonstration of specific jejunal brush border membrane defect. Gut. 
1988;29(12):1661-5. 
22. Wright EM, Turk E, Zabel B, Mundlos S, Dyer J. Molecular genetics of intestinal glucose 
transport. J Clin Invest. 1991;88(5):1435-40. 
23. Sanwa Kagaku Kenkyusho Co., Ltd., PMDA. Investigator’s Brochure for Seibule Tablets. 
2.4.4 Overall summary of preclinical studies. Toxicity studies. 2005:21-31. 
24. Til HP. Subchronic (90-Day) Oral Toxicity Study with AO-128 in Beagle Dogs. Japanese 
Pharmacology & Therapeutics. 1991;19(10):209-31. 
25. Lina BRR. Subchronic (90-Day) Oral Toxicity Study with AO-128 in Rats. Japanese 
Pharmacology & Therapeutics. 1991;19(10):181-208 
26. Lord GH, Newberne PM. Renal mineralization--a ubiquitous lesion in chronic rat studies. Food 
Chem Toxicol. 1990;28(6):449-55. 
27. Grice HC, Goldsmith LA. Levrat MA, Rémésy C, Demigné C. Sucralose--an overview of the 
toxicity data. Food Chem Toxicol. 2000;8 Suppl 2:S1-6. 
28. Roe FJ. Relevance for man of the effects of lactose, polyols and other carbohydrates on calcium 
metabolism seen in rats: a review. Hum Toxicol. 1989 Mar;8(2):87-98. 
29. El-Harith EA, Dickerson JW, Walker R. Potato starch and cecal hypertrophy in the rat. Food 
Cosmet Toxicol. 1976;14:115-21. 
30. Courtney CL. Cecal torsion in rodents associated with chronic administration of clinafloxacin. 
Toxicol Pathol. 2000;28(5):643-8. 
31. American Diabetes Association. Evidence-Based Nutrition Principles and Recommendations 
for 
the 
Treatment 
and 
Prevention 
of 
Diabetes 
and 
Related 
Complications. 
Diabetes Care. 2002 Jan:25(1):202-12. 


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32. U.S. Department of Health and Human Services. National Institutes of Health. National Cancer 
Institute. Common terminology criteria for adverse events (CTCAE). Version 5.0 2017 
Nov 27. 


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7 APPENDICES 
Appendix 1. 
Bristol Stool Chart 
 
Appendix 3.  Strategies for the Treatment of Hypoglycemia in Subjects with T2DM 
 


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Appendix 1.  Bristol Stool Chart 
 
 
 
 
 


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Appendix 3.  Strategies for Treatment of Hypoglycemia in Subjects with T2DM  
JTT-662 is expected to have a glucose-lowering effect by reducing intestinal glucose absorption 
via selective inhibition of SGLT1. JTT-662 did not cause hypoglycemia in animals or in healthy 
subjects receiving JTT­662 
 
 
 
 Therefore, the risk of hypoglycemia in T2DM subjects may be low (even in combination 
with metformin). However, appropriate precautionary measures should be taken to ensure early 
recognition and appropriate management of hypoglycemic events throughout the study duration. 
 
 
In reporting an AE of hypoglycemia, the following definitions should be used: 
• Asymptomatic hypoglycemia: plasma glucose measurements <70 mg/dL (<3.9 mmol/L) 
without associated symptoms. 
• Symptomatic hypoglycemia: plasma glucose measurements <70 mg/dL (<3.9 mmol/L) and 
associated with characteristic symptoms of hypoglycemia (e.g., chills, sweats, shakes, 
tachycardia, altered mental status, dizziness/lightheadedness, withdrawn attitude). 
• Severe hypoglycemia: plasma glucose measurements <50 mg/dL (<2.7 mmol/L) regardless of 
symptoms. 
Symptoms associated with plasma blood glucose levels of 70 mg/dL (3.9 mM) or greater should 
be reported as such, and not reported as hypoglycemia.  
Managing Hypoglycemic AEs: 
• The Investigator (or designee) will educate the subjects to recognize signs and symptoms 
associated with hypoglycemia and to notify the site staff immediately if they occur. 
•
 
• If the subjects experience severe hypoglycemia, parenteral glucose may be considered. 
• In case of emergency (e.g., stupor, coma, abnormal breathing, general or focal seizures) the 
local emergency services should be immediately contacted by the site staff. 
• If repeated hypoglycemic episodes are encountered by a subject without an underlying 
explanatory condition, the Investigator may decide to discontinue JTT-662 administration in 
that subject. 
 
The above are suggested measures, and the Investigator should exercise medical and scientific 
judgement in treating subjects, as other standard of care strategies could apply. 
 
 

SAP_001.pdf: 
 
ClinicalTrials.gov Posted Document Cover Page 
Clinical Study Statistical Analysis Plan (SAP) 
 
PROTOCOL TITLE:  
A Single-blind, Randomized, Placebo-controlled, Multiple Dose 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of JTT-662 Administered for 28 Days in 
Subjects with Type 2 Diabetes Mellitus on Metformin 
Monotherapy 
PROTOCOL NUMBER: AT662-U-20-003 
SAP DATE:  
10 March 2021 
NCT NUMBER: 
NCT04465877 
 


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Akros Pharma Inc. 
 
Protocol AT662-U-20-003 
 
A Single-blind, Randomized, Placebo-controlled, Multiple Dose Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of JTT-662 Administered for 28 Days in Subjects 
with Type 2 Diabetes Mellitus on Metformin Monotherapy 
 
Statistical Analysis Plan 
 
 
Version 1.0 
10 MARCH 2021 
 
 


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SIGNATURE PAGE 
Protocol Number: 
AT662-U-20-003  
Protocol Title: 
A Single-blind, Randomized, Placebo-controlled, Multiple Dose Study 
to 
Evaluate 
the 
Safety, 
Tolerability, 
Pharmacokinetics 
and 
Pharmacodynamics of JTT-662 Administered for 28 Days in Subjects 
with Type 2 Diabetes Mellitus on Metformin Monotherapy 
 
The signatures below indicate approval of the Statistical Analysis Plan 
 
 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................ 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 7 
 
INTRODUCTION ......................................................................................... 10 
 
STUDY OBJECTIVES .................................................................................. 11 
 
STUDY DESIGN ........................................................................................... 12 
3.1 
Study Procedures .................................................................................... 12 
3.2 
Number of Subjects to be Enrolled ......................................................... 20 
3.3 
Randomization and Treatment Assignments .......................................... 20 
3.4 
Blinding of Treatment Assignment ......................................................... 20 
3.5 
Breaking the Blind .................................................................................. 20 
 
ANALYSIS PARAMETERS......................................................................... 21 
4.1 
Baseline Parameters ................................................................................ 21 
4.1.1 
Demographic Parameters and baseline characteristics ........................... 21 
4.1.2 
Medical History ...................................................................................... 21 
4.1.3 
Prior and Concomitant Medications ....................................................... 21 
4.2 
Pharmacokinetic Parameters ................................................................... 21 
4.3 
Pharmacodynamic Assessments ............................................................. 22 
 
4.5 
Safety Parameters.................................................................................... 23 
4.5.1 
Adverse Events ....................................................................................... 23 
4.5.2 
Clinical Laboratory Assessments ............................................................ 24 
4.5.3 
Vital Signs ............................................................................................... 25 
4.5.4 
12-Lead Electrocardiogram .................................................................... 25 
4.5.5 
Physical Examinations ............................................................................ 25 
4.5.6 
Other Safety Assessments ....................................................................... 25 
 
ANALYSIS POPULATIONS ........................................................................ 27 
 
STATISTICAL METHODS .......................................................................... 28 
6.1 
Sample Size ............................................................................................. 28 
6.2 
Subject Disposition ................................................................................. 29 
6.3 
Protocol Deviation Reporting ................................................................. 29 
6.4 
Subject Demographics and Baseline Characteristics .............................. 29 
6.5 
Medical and Surgical History ................................................................. 29 
6.6 
Extent of Exposure .................................................................................. 29 
6.7 
Pharmacokinetic Analysis ....................................................................... 29 
6.7.1 
Method of Pharmacokinetic data representation ..................................... 29 
6.7.2 
Descriptive Statistics of Plasma Concentrations ..................................... 30 
6.7.3 
Descriptive Statistics of Pharmacokinetic Parameters ............................ 30 


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6.7.4 
Statistical Analysis of Pharmacokinetic Parameters ............................... 30 
6.8 
Pharmacodynamic Analysis .................................................................... 31 
 
 
 
6.10 
Analysis of Safety Data .......................................................................... 34 
6.10.1 
Adverse Events ....................................................................................... 34 
6.10.2 
Safety Laboratory Assessments .............................................................. 35 
6.10.3 
Vital Signs and Body Weight ................................................................. 40 
6.10.4 
Electrocardiogram ................................................................................... 40 
6.10.5 
Prior and Concomitant Medications and Procedures .............................. 41 
6.10.6 
Other Safety Data .................................................................................... 41 
6.11 
Interim Analysis ...................................................................................... 42 
6.12 
Handling of Dropouts or Missing Data ................................................... 42 
6.13 
Multicenter Studies ................................................................................. 42 
6.14 
Examination of Subgroups ...................................................................... 42 
 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS .................................................................................................... 43 
 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR 
DATA ANALYSIS ........................................................................................ 44 
 
LIST OF FIGURES 
Figure 1. 
Study Schema.......................................................................................... 12 
 
LIST OF TABLES 
Table 1. 
Schedule of Study Procedures (Screening through Day -1) ................... 13 
Table 2. 
Schedule of Study Procedures (Day 1 and Day 2) .................................. 15 
Table 3. 
Schedule of Study Procedures (Day 3 through Day 15) ......................... 16 
Table 4. 
Schedule of Study Procedures (Day 16 and Day 29) .............................. 18 
Table 5. 
Schedule of Study Procedures (Day 30 through Follow-Up Visit) ........ 19 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ARAUCtau 
Accumulation ratio of area under the concentration-time curve during a 
dosing interval 
ARCmax 
Accumulation ratio of maximum concentration 
ARCtrough 
Accumulation ratio based on trough concentration  
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the concentration-time curve 
AUCtau 
Area under the concentration-time curve during a dosing interval 
AUEC0-4 
Area under the observed effect-time curve from the time of starting breakfast 
until the 4-hour time point 
AUEC0-24 
Area under the observed effect-time curve from the time of starting breakfast 
until the 24-hour time point 
β-hCG 
β human chorionic gonadotropin 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
CI 
Confidence interval 
CL_F 
Apparent oral clearance of drug following extravascular administration (total 
body clearance) 
Cmax  
Maximum concentration 
COVID-19 
Coronavirus Disease 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough concentration during multiple dosing prior to next dose 
 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
electronic case report form  
eGFR 
Estimated glomerular filtration rate 
FPG 
Fasting plasma glucose 
HbA1c 
Hemoglobin A1c/ Glycosylated Hemoglobin 
HBsAg 
Hepatitis B surface antigen 


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HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
 
ICF 
Informed consent form 
IR 
Insulin resistance 
z 
Apparent elimination rate constant in the terminal phase by 
non-compartmental analysis 
LLN 
Lower limit of normal 
 
MDRD 
Modification of Diet in Renal Disease Study 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not applicable 
PCS 
Potentially clinically significant 
PD 
Pharmacodynamic(s) 
 
PK 
Pharmacokinetic(s) 
PPG 
Postprandial glucose 
PT 
Preferred Term  
  
QD 
Once daily 
RBC 
Erythrocytes (red blood cells) 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2  
SD 
Standard deviation 
SOC 
System organ class 
t1/2 
Elimination half-life associated with the terminal slope (λz) of a 
semi-logarithmic concentration-time curve 
t1/2(eff) 
Effective half-life  
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment-emergent adverse event 
TEPCS 
Treatment-emergent potentially clinically significant  
tmax  
Time to reach peak or maximum concentration following drug 
administration 
 


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UCE0-24 
Urinary calcium excretion from the time of dosing until the 24-hour time 
point 
UGE0-24 
Urinary glucose excretion from the time of dosing until the 24-hour time 
point 
ULN 
Upper limit of normal 
UNaE0-24 
Urinary sodium excretion from the time of dosing until the 24-hour time 
point 
Vz_F 
Volume of distribution during terminal phase (λz) following extravascular 
administration 
WBC 
Leukocytes (white blood cells) 


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 INTRODUCTION 
This statistical analysis plan describes the statistical methods and data presentations to be used in 
the listings, summary tables and figures of the Phase 1 study AT662-U-20-003.  
This document is consistent with the statistical methods section of the final study protocol 
(Amendment 1, Version 2.0, dated 29 January 2021) and includes additional detail of the 
pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability summaries to be 
included in the clinical study report (CSR). 


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 STUDY OBJECTIVES  
 To assess the safety and tolerability of multiple oral doses of JTT-662 in subjects with 
Type 2 Diabetes Mellitus (T2DM) on metformin monotherapy 
 To evaluate the PK of multiple oral doses of JTT-662 in subjects with T2DM on 
metformin monotherapy 
 To evaluate the PD of multiple oral doses of JTT-662 in subjects with T2DM on 
metformin monotherapy 


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 STUDY DESIGN 
This is a single-blind, randomized, placebo-controlled, multiple dose study to assess the safety, 
tolerability, PK and PD of JTT-662 administered for 28 Days in subjects with T2DM on metformin 
monotherapy. 
Approximately 36 subjects are planned to be randomized into three cohorts (JTT-662 5 mg 
[Cohort 1], 10 mg [Cohort 2] and 20 mg [Cohort 3]). Within each cohort, 9 subjects will be 
randomized to receive JTT-662 and 3 subjects will be randomized to receive placebo. Cohorts 1 
and 2 may proceed simultaneously. Cohort 3 will be initiated only after review of the safety, 
tolerability, PK (up to Day 29 for Cohort 2) and available PD data from Cohorts 1 and 2 by the 
Sponsor, the Medical Monitor and the Investigator. The planned dose in Cohort 3 may be changed 
(not to exceed 40 mg) based on the data review. 
For all cohorts, eligible subjects will be admitted to the site on Day -3 and will be administered a 
single dose of placebo on Day -1 following an overnight fast (for at least 10 hours) and 30 minutes 
before the start of a standard breakfast. JTT-662 or placebo will be administered once-daily (QD) 
for 28 consecutive days (Day 1 through Day 28) following an overnight fast (for at least 10 hours) 
and 30 minutes before the start of a standard breakfast. 
Subjects will be discharged from the site on Day 35 and will return to the site on Day 42±3 for the 
Follow up Visit. 
3.1 Study Procedures 
Figure 1. 
Study Schema 
 
 
 
 


JTT-662 
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Clinical Study Protocol AT662-U-20-003 
 
 
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CONFIDENTIAL 
Table 1. 
Schedule of Study Procedures (Screening through Day -1) 
 
 
Screening 
Period
(Day)
-31 to -4a
Time from JTT-662/Placebo Administration (hr)
-72±3
-68
-62
-48±3
-44
-38
-24.5
-24
-23.5
-23
-22.5
-22
-21.5
-20
-19.5
-16
-13.5
-12
COVID-19 Test
X
X
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Demographic Information
X
Medical History 
X
X
X
Previous/Concomitant Medications
X
X
Review Study Restrictions
X
X
Weight (kg)
X
X
X
Height (cm) and BMI
X
Drugs of Abuse and Alcohol Screen
X
X
Viral Serology 
X
Serum Pregnancy test (all females)
X
X
eGFR
X
Physical Examination
X
X
Vital Signs
X
X
X
12-Lead ECG 
X
X
X
Serum Biochemistry
X
X
Hematology
X
X
Coagulation
X
X
Urinalysis
X
X
HbA1c
X
Plasma Glucoseb
X
X
X
X
X
X
X
X
X
Bristol Stool Chart Fecal Assessmentc
X
X
Meals 
X
X
X
X
X
X
X
X
X
Placebo Administration
X
Calcium, Sodium and Glucose Urine Collectiond
Adverse Events
X
X
X
X
X
X
Admission Period 
-1a
-2a
-3a


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a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. Administration of study drug, plasma glucose and 
 
 sample collection 
) should have priority with respect to the scheduled (nominal) time; however, if scheduled at the same time point, study drug 
administration should occur last. Vital signs and 12-lead ECGs should occur prior to blood sample collection. 
b. 
When blood samples for plasma glucose, 
are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
Subjects’ general stool patterns will be assessed by the site staff using the BSC assessment at the Screening Visit. Subjects will be trained by a member of the site staff to perform the 
BSC assessment unassisted during the 3-day period prior to Day -3; the subjects will record the assessments in the BSC source document. The date and time of each subject bowel 
movement should be recorded anytime a subject has a bowel movement during the admission period (from Day -3, Hour -68 to Day 35, Hour 168) and each stool should be characterized 
using the BSC. All BSC assessments should be recorded in the CRF. 
d. 
Shaded urine collection intervals represent continuous calcium, sodium and glucose urine collection. The intervals depicted by the bidirectional arrows represent the duration of each 
individual collection interval. An aliquot for urine calcium, sodium and glucose analysis should be obtained from the pooled sample at the end of each collection interval. 
 
  
 
 


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Clinical Study Protocol AT662-U-20-003 
 
 
Version 1.0 – 10 MAR 2021 
 
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Table 2. 
Schedule of Study Procedures (Day 1 and Day 2) 
 
a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. Administration of study drug, PK, plasma glucose and 
 
 sample collection should have priority with respect to the scheduled (nominal) time; however, if scheduled at the same time point, study drug administration should occur 
last. However, if scheduled at the same time point, study drug administration should occur last. Vital signs and 12-lead ECGs should occur prior to blood sample collection.  
b. 
When blood samples 
 are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
Anytime a subject has a bowel movement, the date and time should be recorded and the stool should be characterized using the Bristol Stool Chart. 
d. 
When a PK sample is scheduled at the same time point as study drug administration, the PK sample should be collected first. 
e. 
Shaded urine collection intervals represent continuous calcium, sodium and glucose urine collection. The intervals depicted by the bidirectional arrows represent the duration of each 
individual collection interval. Aliquots for urine calcium, sodium, and glucose analysis should be obtained from the pooled sample at the end of each collection interval. 
 
(Day)
Time from JTT-662/Placebo Administration (hr)
-0.5
0
0.5
1
1.5
2
2.5
3
4
4.5
6
8
10
10.5
12
0
0.5
4.5
10.5
12
Physical Examination
X
X
Weight (kg)
X
X
Vital Signs
X
X
X
X
X
X
12-Lead ECG 
X
X
X
X
X
X
Serum Biochemistry
X
X
Hematology
X
X
Coagulation
X
Urinalysis 
X
X
Plasma Glucoseb
X
X
X
X
X
X
X
X
Ketone Bodies (β-hydroxybutyrate and acetoacetate)
X
X
Bristol Stool Chart Fecal Assessmentc
Meals 
X
X
X
X
X
X
Randomization
X
JTT-662/Placebo Administration 
X
X
JTT-662 PK Blood Samplesd
X
X
X
X
X
X
X
X
X
X
X
X
Calcium,  Sodium and Glucose Urine Collectione
Adverse Events 
X
X
X
X
X
X
2a
1a


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Clinical Study Protocol AT662-U-20-003 
 
 
Version 1.0 – 10 MAR 2021 
 
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Table 3. 
Schedule of Study Procedures (Day 3 through Day 15) 
 
a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. Administration of study drug, PK, plasma glucose and 
 sample collection should have priority with respect to the scheduled (nominal) time; however, if scheduled at the same time point, study drug administration should occur 
last. Vital signs and 12-lead ECGs should occur prior to blood sample collection. 
b. 
When blood samples 
 are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
Anytime a subject has a bowel movement, the date and time should be recorded and the stool should be characterized using the Bristol Stool Chart. 
(Day)
Time from JTT-662/Placebo Administration (hr)
0
0.5
4.5
10.5
12
-0.5
0
0.5
1
1.5
2
2.5
4
4.5
6
8
10.5
12
0
0.5
4.5
10.5
12
Physical Examination
Xe
X
Vital Signs
Xe
Xe
X
X
X
X
12-Lead ECG 
Xe
Xe
X
X
X
X
Weight (kg)
Xe
X
Serum Biochemistry
Xe
X
Hematology
Xe
X
Coagulation
Xe
X
Urinalysis 
e
X
Plasma Glucoseb
e
X
X
X
X
X
X
X
Ketone Bodies (β-hydroxybutyrate and acetoacetate)
X
Bristol Stool Chart Fecal Assessmentc
Meals 
X
X
X
X
X
X
X
X
X
JTT-662/Placebo Administration 
X
X
X
JTT-662 PK Blood Samples
Xe
X
X
X
X
X
Calcium, Sodium and Glucose Urine Collectiond
Adverse Events 
X
X
X
X
X
X
X
X
X
14a
3 to 13a
Admission Period 
15a


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d. 
Shaded urine collection intervals represent continuous calcium, sodium and glucose urine collection. The intervals depicted by the bidirectional arrows represent the duration of each 
individual collection interval. An aliquot for urine calcium, sodium and glucose analysis should be obtained from the pooled sample at the end of each collection interval. 
Performed on Days 7 and 10 only. 


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Clinical Study Protocol AT662-U-20-003 
 
 
Version 1.0 – 10 MAR 2021 
 
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Table 4. 
Schedule of Study Procedures (Day 16 and Day 29) 
 
a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. Administration of study drug, PK, plasma glucose and 
 
 sample collection should have priority with respect to the scheduled (nominal) time; however, if scheduled at the same time point, study drug administration should occur 
last. Vital signs and 12-lead ECGs should occur prior to blood sample collection. 
b. 
When blood samples 
 are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
Anytime a subject has a bowel movement, the date and time should be recorded and the stool should be characterized using the Bristol Stool Chart. 
d. 
Shaded urine collection intervals represent continuous calcium, sodium and glucose urine collection. The intervals depicted by the bidirectional arrows represent the duration of each 
individual collection interval. An aliquot for urine calcium, sodium and glucose analysis should be obtained from the pooled sample at the end of each collection interval. 
e. 
Performed on Days 19 and 24 only. 
f. 
Performed on Day 21 only. 
(Day)
Time from JTT-662/Placebo Administration (hr)
0
0.5
4.5
10.5
12
-0.5
0
0.5
1
1.5
2
2.5
3
4
4.5
6
8
10
10.5
12
24
24.5
28.5
34.5
Physical Examination
Xe
X
Weight (kg)
Xe
X
Vital Signs
Xe
Xe
X
X
X
X
12-Lead ECG 
Xe
Xe
X
X
X
X
Serum Biochemistry
Xe
X
Hematology
Xe
X
Coagulation
Xe
X
Urinalysis 
Xe
X
Plasma Glucoseb
Xe
X
X
X
X
X
X
X
Ketone Bodies (β-hydroxybutyrate and acetoacetate)
X
Bristol Stool Chart Fecal Assessmentc
Meals 
X
X
X
X
X
X
X
X
X
JTT-662/Placebo Administration 
X
X
JTT-662 PK Blood Samples
Xf
X
X
X
X
X
X
X
X
X
X
X
X
Calcium, Sodium and Glucose Urine Collectiond
Adverse Events 
X
X
X
X
X
X
X
X
28a
16 to 27a
29a
Admission Period


JTT-662 
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Clinical Study Protocol AT662-U-20-003 
 
 
Version 1.0 – 10 MAR 2021 
 
CONFIDENTIAL 
Table 5. 
Schedule of Study Procedures (Day 30 through Follow-Up Visit) 
 
 
a. 
Multiple assessments scheduled for the same time point should be performed within 60 minutes of the scheduled time. PK blood sample collection should have priority with respect 
to the scheduled (nominal) time. Vital signs and 12-lead ECGs should occur prior to blood sample collection. 
b. 
When ketone bodies (β-hydroxybutyrate and acetoacetate) samples are scheduled at the same time point as a meal, the blood samples will be collected prior to the meal. 
c. 
The date and time of each subject bowel movement should be recorded up to Day 35, Hour 168. During the Follow-up Period, the subject will perform the assessment unassisted. 
Each stool should be characterized using the Bristol Stool Chart. 
Follow-Up 
Period
(Day)
35a
42 ±3a
Time from JTT-662/Placebo Administration (hr)
48.5 52.5 58.5 72.5 76.5 82.5 96.5 100.5
106.5
120.5
124.5
131
144.5
148.5 154.5
168
Previous/Concomitant Medications
X
Review Study Restrictions
X
Weight (kg)
X
X
X
Serum Pregnancy test (all females)
X
Physical Examination
X
X
X
Vital Signs
X
X
X
12-Lead ECG 
X
X
X
Serum Biochemistry
X
X
X
Hematology
X
X
X
Coagulation
X
X
X
Urinalysis 
X
X
X
Ketone Bodies (β-hydroxybutyrate and acetoacetate)b
X
X
JTT-662 PK Blood Samples
X
X
X
X
Bristol Stool Chart Fecal Assessmentc
X
Meals 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
Admission Period 
34a
30a
31a
32a
33a


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3.2 Number of Subjects to be Enrolled 
Approximately 36 subjects with T2DM are planned to be enrolled in this study, as follows:  
Cohort 1: 
JTT-662 5 mg or placebo 
 
 
(9 active: 3 placebo) 
Cohort 2: 
JTT-662 10 mg or placebo 
 
 
(9 active: 3 placebo) 
Cohort 3:  
JTT-662 20 mg or placebo 
 
 
(9 active: 3 placebo) 
To ensure an adequate number of completers, replacement subjects may be enrolled in the study 
at the discretion of the Sponsor, as appropriate. Each replacement subject will be assigned the same 
treatment as the subject that is being replaced. 
3.3 Randomization and Treatment Assignments 
In each cohort, 12 subjects will be randomized to receive JTT-662 or placebo (9 active: 3 placebo) 
on Day 1. The randomization code will be prepared by an unblinded statistician or designee using 
an in house program written in SAS®, a computer software package. 
Eligible subjects will be assigned to a treatment according to the list of subject randomization 
assignments. 
3.4 Blinding of Treatment Assignment 
On the morning of Day -1, all subjects will receive a single oral dose of placebo in an unblinded 
manner, following an overnight fast (for at least 10 hours) and 30 minutes before the start of a 
standard breakfast. From the morning of Day 1 to the morning of Day 28, all randomized subjects 
will receive either JTT-662 or placebo QD in a single-blind manner, following an overnight fast 
(for at least 10 hours) and 30 minutes before the start of a standard breakfast. JTT-662 and placebo 
tablets will be supplied as unbranded tablets which are identical in appearance.  
The pharmacist at the site will be responsible for packaging and dispensing the study drug in order 
to maintain the blind. The treatment assigned to each subject will not be disclosed to the subject; 
however, the Investigator and site staff will be unblinded. The treatment codes will be controlled 
by the site’s pharmacy or designee. 
The laboratory performing the JTT-662, metabolite and metformin (if analyzed) plasma 
concentration assessments 
 
will be unblinded to facilitate analysis of all samples from the JTT-662-treated subjects and 
appropriate samples from the placebo-treated subjects. 
3.5 Breaking the Blind 
Not applicable. 


JTT-662 
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Statistical Analysis Plan - Protocol No. AT662-U-20-003 
 
 
 
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 ANALYSIS PARAMETERS 
4.1 Baseline Parameters 
4.1.1 
Demographic Parameters and baseline characteristics 
Demographic variables include age, gender, ethnicity, race, weight, height and body mass index 
(BMI) measured at the Screening Visit. Hemoglobin A1c (HbA1c) and fasting plasma glucose 
(FPG) will be measured at the Screening Visit as part of the inclusion criteria assessments.  
4.1.2 
Medical History 
A complete medical history will be obtained at the Screening Visit. The medical history will 
include past and present conditions prior to the informed consent form (ICF) signature date. 
Between the ICF signature date and Day 1, prior to dosing, the Investigator should exercise 
medical and scientific judgement in deciding whether a medical condition, clinically significant 
laboratory 
or 
assessment 
finding 
(e.g., clinically 
significant 
abnormalities 
in 
12-lead electrocardiogram [ECG], physical examination, vital signs and laboratory test results that 
are evidently chronic in nature) could be considered medical history or an adverse event (AE).  
4.1.3 
Prior and Concomitant Medications 
Prior/concomitant medications will be assessed throughout the study for all subjects by the 
investigator.  
The information related to the medication (name of drug, dose, route of administration, duration 
of administration, reason for initiation of each medication) and/or the procedures (e.g., name[s] of 
therapy, duration of therapy, reason for initiation) will be recorded. 
4.2 Pharmacokinetic Parameters 
Blood samples will be obtained according to the schedules summarized in Table 1 through Table 5 
for the quantification of JTT-662 in plasma.  
If needed, PK plasma samples obtained for JTT-662 analysis from this study may be used for 
metformin concentration determination. The laboratory performing the metformin concentration 
determination will be unblinded to facilitate analysis of the plasma samples from the 
JTT-662-treated subjects. 
The actual dosing time and sample collection time will be collected for PK data analysis. In 
addition, the dose and time(s) of dosing of metformin during the PK collection period will also be 
recorded. 
The PK parameters of JTT-662 will be determined from the plasma concentration-time profiles 
for all subjects in the PK population. Actual sampling times will be used in all computations 
involving sampling times. Additional PK parameters may also be estimated from the plasma PK 
data. The PK parameters will be derived by non-compartmental analysis using Phoenix® 
WinNonlin® (Version 6.4 or higher) and/or SAS® (Version 9.4 or higher). 


JTT-662 
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Statistical Analysis Plan - Protocol No. AT662-U-20-003 
 
 
 
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For the purpose of PK analysis, concentrations that are below the lower limit of quantification 
(BLQ) will be treated as zero with the exception that a BLQ value between two positive 
concentrations will be set as missing. Missing concentrations will be treated as missing from the 
PK parameter calculations. If consecutive BLQ concentrations are followed by quantifiable 
concentrations in the terminal phase, those concentrations after BLQ concentrations will be treated 
as missing. A minimum of 4 consecutive measurable concentration-time data points will be 
required to perform the PK analysis on an individual subject profile. 
The following PK parameters will be calculated from PK profiles. 
JTT-662 in plasma:  
Parameter 
Definition 
AUCtau  
Area under the concentration-time curve during the dosing interval 
CL_F 
Apparent oral clearance of drug following extravascular administration (total 
body clearance) 
Cmax  
Maximum concentration 
t1/2(eff) 
Effective half-life 
t1/2 
Elimination half-life associated with the terminal slope (λz) of a semi-
logarithmic concentration time curve 
tmax  
Time to reach peak or maximum concentration following drug administration 
Ctrough 
Trough concentration during multiple dosing prior to next dose 
λz 
Apparent elimination rate constant in the terminal phase by non-compartmental 
analysis 
Vz_F 
Volume of distribution during terminal phase (λz) following extravascular 
administration 
ARCmax 
Accumulation ratio of maximum concentration 
ARAUCtau 
Accumulation ratio of area under the concentration-time curve during a dosing 
interval 
ARCtrough 
Accumulation ratio based on trough concentration  
 
In the linear up/log down method of AUC calculation, the linear trapezoidal rule is used any time 
when the concentration data are not decreasing, and the logarithmic trapezoidal rule is used any 
time when the concentration data are decreasing. The AUCs, terminal phase half-life (t1/2) and 
effective half-life (t1/2(eff)) will be calculated 
 
 
4.3 Pharmacodynamic Assessments 
Postprandial glucose (PPG): Blood samples to assess plasma glucose will be collected according 
to the schedules summarized in Table 1 through Table 4 and area under the observed effect-time 
curve from the start of breakfast until the 4-hour time point (AUEC0-4) will be calculated. The PD 
parameters will be estimated using 
. Below Limit of 


JTT-662 
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Statistical Analysis Plan - Protocol No. AT662-U-20-003 
 
 
 
Version 1.0 – 10 MAR 2021 
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CONFIDENTIAL 
Quantification values will be treated as zero for PD parameter estimation. Area under the 
observed effect-time curve will be calculated using the linear trapezoidal rule.  
4.5 Safety Parameters 
4.5.1 
Adverse Events 
Adverse events occurring (initial occurrence or a worsening of a pre-existing condition) after the 
ICF has been signed and up to the day when the decision to screen fail the subject is made (for 
screen failure subjects), up to 7 days (for subjects discontinuing the study after dosing on Day -1, 
but before dosing on Day 1) or 14 days (for subjects discontinuing the study after dosing on Day 1) 
after the last dose of study drug will be reported and entered in the case report forms (CRFs).  
The Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0 will be used to map 
verbatim AEs to preferred term (PT) and their respective primary system organ class (SOC). 
However, a different (non-primary) system organ class may be selected where appropriate after a 
medical review of the mapping.  


JTT-662 
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4.5.2 
Clinical Laboratory Assessments 
Hematology, coagulation, serum biochemistry, and urinalysis are collected as scheduled in Table 1 
through Table 5. The following information will be derived for each of the hematology, 
coagulation, serum biochemistry, urinalysis, and other parameters: 
 
Change from baseline at all post-baseline time points 
 
Classification relative to the normal range (‘Low’, ‘Normal’, or ‘High’) 
 
Potentially clinically significant (PCS) abnormalities, if applicable 
In addition, the following tests will be performed: 
 Serum Pregnancy Test: Blood samples to assess pregnancy status by beta-human chronic 
gonadotropin (β-hCG) will be collected from all female subjects according to the schedules 
summarized in Table 1 and Table 5. 
 Estimated glomerular filtration rate: Estimated glomerular filtration rate (eGFR) will be 
calculated at the Screening Visit using the 4-variable Modification of Diet in Renal Disease 
Study (MDRD) equation: 
eGFR (mL/min/1.73 m2) = 175  Serum Creatinine -1.154  age -0.203  1.212 (if participant is 
black)  0.742 (if female). 
 Viral Serology: Blood samples to assess Hepatitis B surface antigen (HBsAg), Hepatitis C 
virus (HCV) antibodies and human immunodeficiency virus (HIV) antibodies will be 
obtained at the Screening Visit. 
 Drugs of Abuse and Alcohol Screen: Urine samples to assess amphetamine, barbiturates, 
benzodiazepine, cannabinoids, cocaine, ethanol, opiate, oxycodone, methadone and 
methylenedioxymethamphetamines will be obtained according to the schedule summarized in 
Table 1. 
 Ketone Bodies: Blood samples to assess ketone bodies (β-hydroxybutyrate and 
acetoacetate) will be collected according to the schedules summarized in Table 2 through 
Table 5. 
 Urine Calcium, Sodium and Glucose: Urine samples to assess calcium, sodium and glucose 
will be collected according to the schedules summarized in Table 1 through Table 4. 


JTT-662 
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Statistical Analysis Plan - Protocol No. AT662-U-20-003 
 
 
 
Version 1.0 – 10 MAR 2021 
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4.5.3 
Vital Signs 
Vital sign assessments including systolic and diastolic blood pressure, heart rate, respiratory rate 
and body temperature (°C) will be performed according to schedules summarized in Table 1 
through Table 5. The following information will be derived for all vital signs and body weight: 
 
Change from baseline at all post-baseline time points 
 
PCS abnormalities  
4.5.4 
12-Lead Electrocardiogram 
12-lead ECG recordings and conduction intervals including interval from beginning of the QRS 
complex in the frontal plane to the next QRS complex (RR), interval from beginning of the P wave 
to the beginning of the QRS complex in the frontal plane (PR), duration of QRS complex in the 
frontal plane (QRS), interval from beginning of the QRS complex to end of the T wave in the 
frontal plane (QT) and Fridericia-corrected QT interval (QTcF) will be obtained according to the 
schedules summaried in Table 1 through Table 5. The following information will be derived for 
each of the 12-lead ECG measurements: 
 
Change from baseline at all post-baseline time points 
 
PCS abnormalities  
The overall clinical interpretation of an ECG will be assessed as follows: normal, abnormal not 
clinically-significant or abnormal clinically-significant. 
4.5.5 
Physical Examinations 
Physical examinations will be performed by a physician or qualified designee according to the 
schedules summarized in Table 1 through Table 5, and will include examination of the following 
body systems: general appearance, skin (including hair and nails), HEENT (head, ears, eyes, nose, 
throat), 
neck/thyroid, 
chest/lungs, 
cardiovascular, 
gastrointestinal, 
neurological, 
psychiatric/emotional, lymphatic and musculoskeletal.  
Clinically-significant abnormal physical examination findings will be recorded as medical history 
or AE where appropriate.  
4.5.6 
Other Safety Assessments 
Height and weight measurements will be performed according to the schedules summarized in 
Table 1 through Table 5. The BMI will be calculated at the Screening Visit using the following 
equation: (weight (kg)/[height (m)]2), where the weight in kilograms will be documented to one 
decimal place and the height in centimeters will be rounded to the nearest whole number. 
In addition, the following assessments will be performed according to the schedules summarized 
in Table 1 through Table 5: 


JTT-662 
AKROS PHARMA INC. 
Statistical Analysis Plan - Protocol No. AT662-U-20-003 
 
 
 
Version 1.0 – 10 MAR 2021 
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CONFIDENTIAL 
 Bristol Stool Chart: Subjects will report their stool pattern to the site staff at three visits 
(Screening Visit, Day -3 and the Follow-up Visit). During the Admission Period (Day -3 
through Day 35), every time a subject has a bowel movement, a member of the site staff will 
assist the subject in characterizing the stool using the Bristol stool chart (BSC) including 
documentation of the date and time. 
 Coronavirus Disease Test: Respiratory specimens (e.g., nasopharyngeal, oropharyngeal, 
nasal) will be collected at the Screening Visit and on Day -3 to assess for the presence of severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid that causes 
COVID-19 using reverse transcription polymerase chain reaction. 


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 ANALYSIS POPULATIONS 
Randomized Population: All subjects randomized to receive JTT-662 or placebo on Day 1. 
Safety Population: All subjects who receive at least one dose of JTT-662 or placebo, including 
those who do not complete the study. Subjects who were dosed on Day -1 only (placebo 
run-in) will also be included in the safety population. 
Pharmacokinetic Population: All randomized subjects who received at least one dose of JTT-662 
starting on Day 1, and have evaluable JTT-662 plasma concentration data. Subjects will be 
excluded or partially excluded from the statistical analysis of PK parameters if they significantly 
violated the inclusion or exclusion criteria or deviated significantly from the protocol. 
Pharmacodynamic Population: All randomized subjects who received at least one dose of 
JTT-662 or placebo starting on Day 1, and have evaluable PD data to facilitate the calculation of 
PD parameters. Subjects will be excluded or partially excluded from the statistical analysis if they 
significantly violated the inclusion or exclusion criteria or deviated significantly from the 
protocol. 


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 STATISTICAL METHODS 
The statistical analysis will be conducted following the principles specified in the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Topic E9 Statistical Principles for Clinical Trials (CPMP/ICH/363/96).  
No formal inferential test will be performed in this Phase 1 study. 
All statistical tabulations and analyses will be performed using 
. 
Any changes to the analyses described in this plan will be detailed in the CSR. 
All results collected in the database will be presented in listings. All continuous data will be listed 
with the same precision as will be presented in the database. Data listings will be sorted by 
treatment group, subject ID, and time point. 
Unless otherwise noted, continuous variables will be summarized using number of non-missing 
observations (n), arithmetic mean (mean), standard deviation (SD), median, minimum, and 
maximum. For PK parameters, summary statistics will also include the coefficient of variation 
(CV%) and geometric mean (geometric mean will not be presented for tmax). For plasma 
concentrations and PD parameters, summary statistics will also include the CV%. Categorical 
variables will be summarized using the frequency count and the percentage of subjects in each 
category.  
All subjects randomized to placebo on Day 1 will be included in the placebo treatment group unless 
otherwise specified. 
In the data listings, study day relative to first dose of study drug on Day 1 may be presented. Study 
day relative to first dose of study drug on Day 1 will be calculated as: event date – first dose date 
on Day 1 (+ 1 if event date ≥ first dose date on Day 1). 
Baseline will be the latest non-missing measurement prior to the first dose of study drug on Day 1, 
unless otherwise specified
 
For safety summaries, the unscheduled and repeat assessments will not be summarized; however, 
all results will be included in the data listings. 
Disposition, demographics, and baseline characteristics and all categorical safety parameters will 
be summarized by each treatment group and overall. 
6.1 Sample Size 
Approximately 36 subjects (3 cohorts, 12 subjects per cohort [9 active: 3 placebo]) will be 
randomized into this study. The sample size is not statistically determined. 


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6.2 Subject Disposition 
Summaries of analysis populations and subject disposition will be presented by treatment group 
and overall for the safety population and will contain the following information: 
 
Number and percent of subjects in each population (safety, randomized, PK, PD) 
 
Number and percent of subjects who were dosed (safety population) 
 
Number and percent of subjects who completed the dosing period 
 
Number and percent of subjects who completed the study including follow-up visit 
 
Number and percent of subjects who discontinued early and reason for early discontinuation 
Subject disposition and analysis populations will be tabulated and presented in listings. Percentage 
will be calculated based on number of subjects in the safety population. Screen failure reasons will 
also be summarized and listed. 
6.3 Protocol Deviation Reporting 
Protocol deviations will be listed. 
6.4 Subject Demographics and Baseline Characteristics 
Subject demographic data and baseline characteristics will be summarized using descriptive 
statistics and include the following parameters collected at screening: sex, age, race, ethnicity, 
height, body weight, BMI, HbA1c and FPG. Demographic data and baseline characteristics will 
be presented by treatment group and overall for the safety population and also be listed. 
6.5 Medical and Surgical History 
Medical and surgical history will be coded using the MedDRA (Version 23.0). Medical history 
data along with the corresponding SOC and PT coded from the MedDRA dictionary will be 
presented in the data listing. 
6.6 Extent of Exposure  
Exposure data will be presented in the data listing.  
6.7 Pharmacokinetic Analysis 
Pharmacokinetic analysis will be performed for JTT-662 for the PK population. 
6.7.1 
Method of Pharmacokinetic data representation 
The PK data including individual data and descriptive statistics for plasma concentrations, PK 
parameters and the result of PK data analysis will be represented with three significant values 
except for CV% which will be represented to one decimal place. 


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All concentration values reported as no results (not collected or not determined) values will be 
treated as missing. Plasma concentration values that are BLQ will be set to zero for calculation of 
summary statistics and plotting mean concentration profiles.  
6.7.2 
Descriptive Statistics of Plasma Concentrations 
The plasma concentration data will be summarized by JTT-662 dose levels and nominal time point. 
Mean and individual plasma concentration-time profiles will be plotted by dose levels on linear 
and semi-logarithmic scales. Scheduled (nominal) sampling times will be used for all summary 
tables and plots of plasma concentration data.  
6.7.3 
Descriptive Statistics of Pharmacokinetic Parameters 
The PK parameters will be summarized by JTT-662 dose levels and day for the PK population.  
6.7.4 
Statistical Analysis of Pharmacokinetic Parameters 
Dose proportionality of Cmax and appropriate AUC values on Day 1 and Day 28 will be assessed 
for JTT-662. The relationship between each parameter and dose is written as a power function:  
 
 
 
Parameter = A*dose
b  (Equation 1) 
Where “A” is a constant, “b” is the proportionality constant and “parameter” is the PK parameter 
of interest (e.g., Cmax and AUCtau). Each PK parameter will be plotted against dose. The exponent, 
b, will be estimated by performing linear regression of the (natural) log-transformed parameter on 
the log-dose, since taking logarithm on both sides of (Equation 1) gives the linear relationship, log 
parameter = a + b*log dose, where a = log(A). Therefore the exponent, b, is estimated by the slope 
of the resulting regression line. A value of b close to 1 indicates dose proportionality. Dose 
proportionality will be assessed descriptively by presenting the estimate of b, its standard error and 
the 90% confidence interval (CI). 
The estimated geometric means at each dose level, the estimate of the slope (b), its 90% and 95% 
CIs, and model residual error will be obtained from the model. Furthermore, the geometric means 
based on the raw data and the dose normalized ratio for each pair of doses will be presented. Cmax 
and AUCtau will be plotted against dose on the log-scale. 
The sample SAS code (with appropriate changes) for calculating the slope of dose proportionality 
will be: 
PROC MIXED DATA= DATASET; 
 
MODEL LNPKPARM=LNDOSE /SOLUTION CL ALPHA=0.1*; 
 
ODS OUTPUT SOLUTIONF=SOLUTION1(RENAME= (ESTIMATE=EST STDERR=SE)); 
RUN; 
*alpha = 0.05 and 0.1 
 


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In addition, a model fit test will be performed by testing the quadratic term in a quadratic 
regression, and the p-value for the quadratic term will be presented. 
The sample SAS code (with appropriate changes) will be used for quadratic regression: 
PROC GLM DATA= DATASET; 
 
MODEL LNPKPARM=LNDOSE LNDOSE*LNDOSE/SOLUTION CL ALPHA=0.1; 
RUN; 
6.8 Pharmacodynamic Analysis 
Observed values and change from baseline of PPG concentrations will be summarized by treatment 
group and time point in terms of the number of subjects, arithmetic mean, SD, CV%, median, 
minimum and maximum. Baseline for PPG concentrations will be the pre-dose (Hour 0) value of 
the PPG profile on each PPG collection day. Concentrations will be listed, mean and individual 
plots will also be presented.  
The plasma glucose excursion defined as the maximum glucose value observed after breakfast 
(0-4 hours after breakfast) minus the pre-dose (Hour 0) value will also be summarized for observed 
values and change from baseline on Days -1, 1, 14 and 28. Day -1 will be baseline. 
Area under the observed effect-time curve from the time of starting breakfast until the 4-hour time 
point (AUEC0-4) will be calculated for PPG on Days -1, 1, 14 and 28 for the PD population. 
Observed values and change from baseline of AUEC0-4 will be summarized descriptively. Baseline 
will be the corresponding parameter value on Day -1. 
A linear mixed effect model including day as the fixed effect and subject as the random effect will 
be fitted on the the PD parameter for each treatment group separately. The difference of the least 
square means of AUEC0-4 between the compared days (Day 1 vs. Day -1, Day 14 vs. Day -1, Day 
28 vs. Day -1 and Day 28 vs. Day 14) and the 90% and 95% CIs of the least square mean difference 
will be calculated. 
The following sample SAS code may be used, with appropriate changes, for the analysis: 
PROC MIXED DATA=DATASET; 
BY TREATMENT; 
 
    CLASS SUBJID DAY; 
    MODEL PDPARVAL = DAY / DDFM=KR; 
    RANDOM SUBJID; 
    LSMEANS DAY / CL; 
    ESTIMATE ‘Day 1 Vs. Day -1' Day 1 0 0 -1/ALPHA = 0.05 CL;   
    ESTIMATE ‘Day 14 Vs. Day -1' Day 0 1 0 -1/ALPHA = 0.05 CL; 
    ESTIMATE ‘Day 28 Vs. Day -1 ' Day 0 0 1 -1/ALPHA = 0.05 CL;  
    ESTIMATE ‘Day 28 Vs. Day 14 ' Day 0 -1 1 0/ALPHA = 0.05 CL;    
    ESTIMATE ‘Day 1 Vs. Day -1' Day 1 0 0 -1/ALPHA = 0.1 CL;   
    ESTIMATE ‘Day 14 Vs. Day -1' Day 0 1 0 -1/ALPHA = 0.1 CL; 
    ESTIMATE ‘Day 28 Vs. Day -1 ' Day 0 0 1 -1/ALPHA = 0.1 CL;  
    ESTIMATE ‘Day 28 Vs. Day 14 ' Day 0 -1 1 0/ALPHA = 0.1 CL; 
  RUN; 


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Additionally, the change from baseline (Day -1) of AUEC0-4 will be analyzed using the mixed 
effect model with repeated measures (MMRM). The model will include fixed effects for treatment, 
day, and treatment by day interaction, subject as repeated measures and baseline value as a 
covariate. The difference of the least squares means between each JTT-662 dose group relative to 
placebo at the same day will be estimated, along with two-sided 90% and 95% CIs and p-values. 
Least squares means will also be presented. 
The following sample SAS code may be used, with appropriate changes, for the analysis: 
PROC MIXED DATA=DATASET; 
 
    CLASS DAY TREATMENT; 
    MODEL CHG = DAY TREATMENT DAY*TREATMENT BASELINE / DDFM=KR; 
    REPEATED /SUBJECT=SUBJECT(TREATMENT) TYPE=UN*; 
    LSMEANS DAY*TREATMENT /PDIFF CL ALPHA=0.1**; 
  RUN; 
* Other covariance structure will be used if UN leads to non-convergence of the model. 
** alpha = 0.05 and 0.1. 
 
 


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6.10 
Analysis of Safety Data 
Safety analyses will be conducted on the Safety Population and will be performed for all safety 
variables specified below.  
The safety evaluation will include AEs, clinical safety laboratory tests (e.g., hematology, serum 
biochemistry, coagulation, urinalysis), vital signs, 12-lead ECGs, BSC findings, ketone bodies, 
 urinary calcium excretion from the time of dosing 
until the 24-hour time point (UCE0-24) and urinary sodium excretion from the time of dosing until 
the 24-hour time point (UNaE0-24) and UGE0-24.  
Observed and change from baseline of vital signs, ECG parameters and clinical laboratory data 
will be presented in tabular form with arithmetic mean, SD, median, minimum and maximum, or 
in frequency tabulation form as appropriate. For the laboratory safety data, out of range values and 
PCS abnormalities will be flagged in the data listings. 
Potentially clinically significant abnormalities will be defined according to the Akros Safety 
Reporting Standards 
. Potentially clinically 
significant values for vital signs, ECG, and laboratory data will be flagged in data listings. 
Treatment-emergent PCS values will be summarized, presenting the number and percentage of 
subjects who had at least one PCS value after study drug administration on Day 1. The denominator 
is always the number of subjects in the safety population, regardless of whether the subject had 
any post-baseline measurements. The numerator is any PCS value in the treatment-emergent 
period if the baseline is normal or missing; and is any worsening PCS value in the 
treatment-emergent period if the baseline is also a PCS value.  
A worsening PCS is defined as a > (<) 0 change from baseline if a high (low) value indicating 
undesirable outcome; or the PCS value is in the opposite direction of the baseline PCS value. 
6.10.1 
Adverse Events 
Adverse events will be coded using the MedDRA (Version 23.0) and will be summarized by SOC 
and PT. 
A treatment-emergent adverse event (TEAE) is defined as any AE with an onset date/time at or 
after the placebo dosing on Day -1. A pre-treatment AE is defined as any AE with an onset date 
before the placebo dosing on Day -1. 
The summary of TEAEs will be presented for the following groups: 
 Placebo run-in: including AEs with onset between the placebo dosing on Day -1 and before 
dosing on Day 1 for all subjects in the safety population. 
 Placebo treatment group: including AEs with onset at or after the placebo dosing on Day 1 
for the subjects who are randomized to placebo on Day 1. 
 JTT-662 5 mg: including AEs with onset at or after the JTT-662 5 mg dosing on Day 1 for 
the subjects who are randomized to JTT-662 5 mg on Day 1. 


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 JTT-662 10 mg: including AEs with onset at or after the JTT-662 10 mg dosing on Day 1 
for the subjects who are randomized to JTT-662 10 mg on Day 1. 
 JTT-662 XX mg (XX represents JTT-662 dose level for Cohort 3): including AEs with 
onset at or after the JTT-662 XX mg dosing on Day 1 for the subjects who are randomized 
to JTT-662 XX mg on Day 1. 
The overall incidence of TEAEs (number and percentage of subjects) as well as the number of 
events will be summarized for each treatment group.  
Summaries of TEAEs will include the following: Incidence of TEAEs (overview including number 
and percentage of participants with any TEAEs, serious TEAEs, discontinuations due to TEAEs, 
drug-related TEAEs, severe TEAEs, all deaths (AEs leading to death regardless of treatment 
emergence) and TEAEs leading to death; event counts will also be included). 
The TEAEs will be summarized by SOC, PT, and treatment group using frequency counts and 
percentages (number and percentage of subjects with an event). Each subject may only contribute 
once to each of the incidence rates, regardless of the number of occurrences. In addition, the 
following summaries will be performed for the summary groups as described above: 
 TEAEs by SOC, PT  
 TEAEs by SOC, PT and maximum reported severity 
 TEAEs by SOC, PT and causality 
 TEAEs by PT (in order of descending frequency in the total JTT-662 group). 
 Serious Adverse Events (SAE) by SOC, and PT 
Listings of AEs, SAEs, AEs leading to study discontinuation will also be presented. The AEs with 
onset in the placebo run-in period will be flagged in the listings. 
6.10.2 
Safety Laboratory Assessments 
Observed and change from baseline for each parameter of continuous safety laboratory values 
(hematology, serum chemistry, coagulation, and urinalysis) will be summarized by treatment 
group at each time point using descriptive statistics.   
Any post-baseline abnormal laboratory finding will be assessed to calculate overall 
treatment-emergent potentially clinically significant (TEPCS) status as described in tables PCS 
Criteria for Laboratory Parameters. Values assessed as TEPCS will be summarized categorically 
per treatment group and overall. 
A listing of all safety laboratory data for each subject at each time point will be presented. Out of 
range values and PCS values will be flagged in the data listing. Safety laboratory values that are 
outside the normal ranges will be presented in a separate listing together with normal ranges values. 
For the listing presenting all abnormal values, if a subject has any abnormal value for a test, all 
values of that test of the subject will be presented. 


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Qualitative urine parameters are generally reported by a descriptive score, which may differ 
between laboratories. For pooling the data, a four-point scale is used. A clinical review will be 
performed on the mapping of the descriptive scores to the four-point scale; and the descriptive 
scores will be remapped where appropriate. The four-point scale will be used in the summary of 
the PCS abnormality analysis. 
 
 
 
Five-point scale  
 
Four-point scale 
 
 
 
Negative 
 
 
Negative 
 
 
 
Trace  
 
 
Rare/Mild 
 
 
 
1+ 
 
 
 
Rare/Mild 
 
 
 
2+ 
 
 
 
Moderate 
 
 
 
3+ 
 
 
 
Severe 
The mean profile by treatment group will be presented for selected laboratory parameters. 
If the non-numeric result is reported for quantitative laboratory parameter then for summary and 
analysis it will be changed as follows into numerical value:  
a) If less than ‘<’ sign is used then the value will be reduced by 1 point from the last 
precision digit  
b) If greater than ‘>’ sign is used then 1 point will be added to the last precision digit. 
 
Eg: if the laboratory parameter is reported to 2 decimal precision, <40.01 then for summary and 
analysis it will be treated as 40.00, if laboratory parameter is reported as whole number >40 then 
it will be considered as 41 and if the parameter is reported with 1 decimal precision <40.1 then it 
will be considered as 40.0. 
 


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Potentially Clinically Significant Criteria for Laboratory Parameters 
Hematology 
Parameter 
CDISC 
Code 
SDTM 
Definition 
C51948 Leukocytes 
White blood cell 
count 
C51946 Erythrocytes 
Red blood cell 
count 
C64848 Hemoglobin 
Hemoglobin 
C64796 Hematocrit 
Hematocrit 
C64799 Ery. Mean 
Corpuscular Volume 
Mean corpuscular 
volume 
C64798 
Ery. Mean 
Corpuscular HGB 
Concentration 
Mean corpuscular 
hemoglobin 
concentration 
C51951 Platelets 
Platelets 
Differential WBC 
 
C64827 Neutrophils/ 
Leukocytes 
Neutrophils (%) 
C63321 Neutrophils 
Neutrophils 
C64820 Lymphocyte/ 
Leukocytes 
Lymphocytes (%) 
C51949 Lymphocytes 
Lymphocytes 
C64824 Monocytes/ 
Leukocytes 
Monocytes (%) 
C64823 Monocytes 
Monocytes 
C64604 Eosinophils/ 
Leukocytes 
Eosinophils (%) 
C64550 Eosinophils 
Eosinophils 
C64471 Basophils/ 
Leukocytes 
Basophils (%) 
C64470 Basophils  
Basophils 
 
 


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Biochemistry 
Parameter 
CDISC 
Code 
SDTM 
Definition 
C64858 
Protein 
Total protein 
C64431 
Albumin 
Albumin 
C64467 
Aspartate 
Aminotransferase 
Aspartate 
aminotransferase 
C64433 
Alanine 
Aminotransferase 
Alanine 
aminotransferase 
C38037 
Bilirubin 
Total bilirubin 
C64481 
Direct Bilirubin 
Direct bilirubin 
C64432 
Alkaline 
Phosphatase 
Alkaline 
phosphatase 
C64855 
Lactate 
Dehydrogenase 
Lactate 
dehydrogenase 
C64847 
Gamma Glutamyl 
Transferase 
Gamma glutamyl 
transferase 
C64489 
Creatine Kinase 
Creatine kinase, 
Creatinine 
phosphokinase 
C125949 Urea Nitrogen 
Blood urea nitrogen
C64547 
Creatinine 
Creatinine 
C64814 
Urate 
Uric acid 
C64809 
Sodium 
Sodium 
C64495 
Chloride 
Chloride 
C64853 
Potassium 
Potassium 
C64488 
Calcium 
Calcium 
C64857 
Phosphate 
Inorganic 
phosphorus, 
Inorganic 
phosphate 
C105586 Cholesterol 
Total cholesterol 
C105587 HDL Cholesterol 
High density 
lipoprotein 
cholesterol 
C105588 LDL Cholesterol 
Low density 
lipoprotein 
cholesterol 
C64812 
Triglycerides 
Triglycerides 
C105585 Glucose 
Glucose 


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Parameter 
CDISC 
Code 
SDTM 
Definition 
C64548 
C Reactive Protein C-reactive protein 
 
 
Coagulation 
Parameter 
CDISC 
Code 
SDTM 
Definition 
C64805 Prothrombin Intl. 
Normalized Ratio 
Prothrombin 
C38462 Activated Partial 
Thromboplastin 
Time 
Activated partial 
thromboplastin 
time 
 
Urinalysis 
Parameter 
CDISC 
Code 
SDTM 
Definition 
C64832 
Specific 
Gravity 
Urine specific 
gravity 
C45997 
pH 
Urinary pH 
C105585 
Glucose 
Qualitative urine 
glucose 
C64858 
Protein 
Qualitative urine 
protein 
C74686 
Occult Blood Urine occult blood
C64854 
Ketones 
Qualitative urine 
ketone bodies 
C38037 
Bilirubin 
Qualitative urine 
bilirubin 
C64816 
Urobilinogen Qualitative urine 
urobilinogen 
 
 


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6.10.3 
Vital Signs and Body Weight 
Observed values and change from baseline for continuous vital signs parameters (blood pressure, 
heart rate, respiratory rate, and temperature) and weight will be summarized by treatment group at 
each time point using descriptive statistics. Percent change from baseline in weight will also be 
summarized descriptively by treatment group. 
Any post-baseline abnormal vital sign finding assessed as TEPCS values will also be summarized. 
Vital sign data will be listed by subject and time point collected. In addition, values meeting PCS 
criteria will be flagged in the listing.  
Potentially Clinically Significant Criteria for Vital Sign Values  
Parameter 
CDISC 
Code 
SDTM 
Definition 
C49676 
Pulse Rate 
Pulse rate 
C25298 
Systolic Blood 
Pressure 
Systolic blood 
pressure 
C25299 
Diastolic Blood 
Pressure 
Diastolic blood 
pressure 
C49678 
Respiratory Rate Respiratory rate 
C25206 
Temperature 
Body temperature 
C25208 
Weight 
Body weight 
 
6.10.4 
Electrocardiogram 
Observed values and change from baseline for each parameter of continuous ECG parameters (RR 
interval, PR interval, QRS duration, QT interval, and QTcF interval) will be summarized by 
treatment group at each time point using descriptive statistics. 
The overall ECG interpretation will be summarized by treatment group at each time point using 
descriptive statistics.  
Any post-baseline abnormal ECG findings assessed as TEPCS values will also be summarized. 
ECG data will be listed by subject at each visit and time point collected with indicated clinically 
significant results. In addition, values meeting PCS criteria will be flagged in listing. 


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Potentially Clinically Significant Criteria for ECG Parameters 
Parameter 
CDISC 
Code 
SDTM 
Definition 
C117773 
PR Interval, 
Aggregate 
PR 
C117791 
RR Interval, 
Aggregate 
RR 
C117779 
QRS Duration, 
Aggregate 
QRS 
C117783 
QT Interval, 
Aggregate 
QT interval 
C117784 
QTcB Interval, 
Aggregate 
Bazett-corrected QT 
interval 
C117786 
QTcF Interval, 
Aggregate 
Fridericia-corrected 
QT interval 
 
6.10.5 
Prior and Concomitant Medications and Procedures 
Prior medications are defined as those medications that started and stopped prior to the placebo 
dosing on Day -1. Concomitant medications are defined as those medications with a start date on 
or after placebo dosing on Day -1 or started prior to the placebo dosing on Day -1 and continued 
after the placebo dosing on Day -1.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (Version March 2020) and classified according to Anatomical Therapeutic Chemical 
(ATC) code levels 2 (therapeutic sub-level) and 3 (pharmacological sub-level). Prior medications 
and concomitant medications will be presented in the data listings. Concomitant medications will 
be summarized by treatment, ATC Level 3 term and PT. The concomitant procedures will also be 
listed. 
6.10.6 
Other Safety Data  
Observed values and change from baseline of ketone bodies,
 
 will be summarized by treatment group and time point.  
Listing with subjects impacted by COVID-19 will be presented. Also, eGFR values will be listed. 
Urine Calcium, Glucose and Sodium  
The UCE0-24, UGE0-24 and UNaE0-24 will be computed for Days -1, 1, 14 and 28. Observed values 
and change from baseline (Day -1) of total excreted amount within 24 hours will be summarized 
by treatment group and day. Descriptive statistics for 24-hour urine volume and fluid intake on 
Days -1, 1, 14 and 28 will be also presented for observed values and change from baseline. 
Statistical analysis for change from baseline in UGE0-24 in the original scale will be performed 
using MMRM similar to that for PPG AUEC0-24. 


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Bristol Stool Chart 
Total number of stools and percent of stools at each stool type will be summarized by treatment 
group. Post-treatment highest stool type score will be also derived for each subject, and number 
and percent of subjects by the highest stool type will be summarized by treatment group and 
overall. A plot will be created for individual assessments over time. 
Other safety parameters may be summarized as appropriate. 
6.11 Interim Analysis 
An interim analysis is not planned for this study. 
6.12 Handling of Dropouts or Missing Data 
Missing data will not be imputed. Any PK concentrations reported missing data will be handled 
according to the specifications in Section 4.2. 
6.13 Multicenter Studies 
This is a single-center study. 
6.14 Examination of Subgroups 
None 


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 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS 
There are no changes in the study conduct relative to the study protocol. The protocol specifies 
that the natural logarithm of the PD parameter values will be analyzed. This SAP has changed to 
analyze the PD parameters in the original scale, as it is considered more appropriate to assume 
normal distribution for the PD parameters and analyze change from baseline, which could be 
negative values, in the original scale.  


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 QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR DATA 
ANALYSIS 
The following steps will be taken to ensure the accuracy, consistency, completeness and reliability 
of the statistical reports:  
 Production of statistical analysis plan and statistical analysis reports in accordance with 
 Standard Operating Procedures (SOP) and guidelines. 
After database lock, the data will be retrieved from the database using SAS® version 9.4 or higher.