Conditions: Type 2 Diabetes Mellitus Insulin Resistance
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 14
Healthy volunteers: no

Brief summary:
The role of individual leukocyte populations in type 2 diabetes (T2D) and immunometabolism in general represent important gaps in knowledge to better understand the etiopathogenesis of T2D. Emerging evidence indicates that certain leukocyte populations serve as an important nexus of T2D-associated inflammation. This novel and innovative clinical trial will test the efficacy of a leukocyte-selective anti-inflammatory small drug as adjunctive therapy in improving insulin sensitivity in obese, insulin-resistant type 2 diabetic subjects. This trial also offers a first-in-kind opportunity to better understand the role of specific leukocyte populations in type 2 diabetes. The drug's clinical profile suggests that it will be well-tolerated with few, if any, side effects, and the existence of simple methods that can indirectly measure its activity in vivo

Detailed description:
Type 2 diabetes (T2D) is characterized by concomitant insulin resistance and pancreatic beta cell dysfunction. Disease prevalence continues to increase around the globe and is currently estimated to be at more than 385 million affected people. As many as 1 in 3 people in the United States could have diabetes by the year 2050 with significant economic consequences. In 2014, 1 in 5 health care dollars was spent to support the care of patients at a total estimated cost \> $245 billion. Overweight, insulin-resistant (IR) T2D individuals manifest a chronic systemic inflammation which impairs beta cells and peripheral insulin sensitivity. This systemic inflammation is associated with an atherogenic lipid profile and predisposes individuals to higher risk for micro- and macro-vascular disease, irrespective of well-controlled glycemia. Although a variety of pharmacologic approaches maintain daily glycemic control, it is becoming evident that there is an urgent need to identify adjunctive therapies to improve, insulin sensitivity, beta cell function, and HbA1c since they begin deteriorating quite substantially by 5 years following initial treatment. Ideally, such adjunctive therapies should be well-tolerated, easy to administer, should not promote hypoglycemia and should also attenuate the systemic inflammation. The role of neutrophils in T2D and metabolic inflammation represents an important gap in knowledge to better understand inflammation in T2D especially since neutrophils are the most abundant leukocyte population in humans and constitute the bulk of inflammatory leukocytes. Emerging evidence indicates that neutrophils along with neutrophil-derived elastase serve as an important nexus of T2D-associated inflammation. This trial offers a first-in-kind opportunity to better understand the role of neutrophils in T2D diabetics. We hypothesise that inhibition of neutrophil elastase (NE) will attenuate the chronic systemic background inflammation in overweight and obese, IR T2D subjects and that the potential improvement in insulin sensitivity and glucose control could concurrently facilitate functional maintenance and induce the rescue of pancreatic beta cell mass.

To test the hypothesis, we propose a clinical trial that is comprised of the following two aims:

Aim 1: To test whether orally-administered NEI adjunctive therapy in obese, IR T2D subjects improves insulin sensitivity, glucoregulation and glycemic control. The primary endpoint is the improvement of insulin sensitivity at 6 months compared to baseline, assessed by the hyperinsulinemic-euglycemic clamp method. Secondary endpoints will include: i) Safety (rate and severity of adverse events including hypoglycemia); ii) Glycemic and metabolic control variables; iii) Assessment of functional beta cell mass (improvement in baseline oral glucose tolerance test (OGTT) C-peptide levels and AUC, insulin secretion rate (ISR), body mass and body fat-corrected insulin sensitivity; and iv) Changes in inflammatory variables. Exploratory endpoints will include improvement of OGTT C-peptide (and C-peptide AUC) trajectory, ISR trajectory, and decreased dose and dose frequency of background drugs.

Aim 2: To inform the changes in innate and cellular immunity conferred by the trial study agents as a mechanistic approach to understanding the basis of potential efficacy. Evidence of suppression of systemic inflammation will be examined during the trial. Changes in gene expression of PBL and neutrophils may provide a signature of responder versus non-responder status and/or of effect of therapy.

Arms:
arm 1: 5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day) and 60 mg placebo tablet twice daily arm 2: 60 mg AZD9668 twice daily in addition to 5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day)

Interventions: intervention 1: Metformin intervention 2: saxagliptin intervention 3: AZD9668 intervention 4: placebo
Intervention descriptions: intervention 1: background drug intervention 2: background drug intervention 3: study drug intervention 4: placebo for AZD9668 to be added to background drugs

Protocol document:
Prot_SAP_ICF_000.pdf: 
COMPLETE CLINICAL PROTOCOL 
LONG TITLE: Neutrophil Elastase Inhibition 
as Adjunctive 
Therapy to Improve 
Glucometabolic Variables in Overweight and Obese, Insulin-Resistant Type 2 
Diabetic Patients (IMPALA) 
SHORT TITLE: AZD9668 adjunctive treatment  for T2D 
VERSION NUMBER: 15 
DATE OF LATEST VERSION: June 13, 2017 
IRB #: RC-6059 
IRB initial date of approval: August 11, 2015/Full Approval: September 8, 2015 
IND# and initial date assigned by FDA: 127407/Assigned  August  4th, 2015 
Clinicaltrials.gov ID: NCT02597101 
Study Sponsor/IND Sponsor & Holder: Nick Giannoukakis, Ph.D. 
NIH Funding Mechanism: UH3 
Protocol Chair/Study PI:  
Nick Giannoukakis, Ph.D. 
Associate Professor of Medicine 
Institute of Cellular Therapeutics 
Allegheny Health Network 
320 East North Avenue 
Pittsburgh, PA 15212 
Phone: 412-359-6394 
Cell: 412-304-6434 
E-mail: Nick.Giannoukakis@ahn.org 
NCATS Medical Monitor: 
Holli Hamilton, M.D., MPH, RAC 
NCATS/NIH 
6701 Democracy Boulevard 
Bethesda, MD 20892 
Tel 301-451-3852 
Cell 240 477 7713 
hamiltonho@mail.nih.gov 
Biostatistician: 
Jeffrey Krischer, Ph.D. 
Professor, Dept. of Pediatrics, 
Division of Bioinformatics and Biostatistics, 
Director, Univ. of South Florida Diabetes Ctr. 
And USF Pediatric Epidemiology Ctr. 
University of South Florida 
HLM 201, 3650 Spectrum Blvd. 
Tampa, FL, 33612 
Phone: 813-396-9501 
E-mail: 1andomi.krischer@epi.usf.edu 
and jkrische@health.usf.edu 
NCATS Program 
Officer: Christine 
Colvis, Ph.D. 
6701 Democracy Boulevard 
Bethesda, MD 20892 
Tel 301-451-3903 
Cell: 301-275-5864 
Email ccolvis@mail.nih.gov 
Central Laboratory: 
Allegheny Health Network 
West Penn Hospital Outpatient Lab, 
4800 Friendship Avenue, 
Pittsburgh, PA 15224. 
Tel: 412-578-5675 
Sponsor/PI  Signature:______________________________  Date: _____________________ 
Clinical protocol AZD9668 dated 06/13/2017 
Page 1 of 93 


Clinical protocol AZD9668 dated 06/13/2017 
Page 2 of 93 
Protocol Synopsis 
Title 
Neutrophil Elastase Inhibition as Adjunctive Therapy to 
Improve Glucometabolic Variables in Obese, Insulin- 
Resistant Type 2 Diabetic Patients (IMPALA) 
Short Title 
AZD9668 adjunctive treatment for T2D 
Clinical  Phase 
Phase II  AND Mechanistic or Observational 
Number of Sites 
One: Allegheny Health Network (AHN) with additional 
procedures being completed at University of 
Pittsburgh/UPMC. 
IND Sponsor/Number 
Nick Giannoukakis/ IND # 127407 
Investigational 
Product(s)/Intervention(s) 
INVESTIGATIONAL 
PRODUCTS: 
i) AZD9668 tablet (orally administered neutrophil elastase
inhibitor)
ii)Saxagliptin tablet (orally administered DPP-IV 
inhibitor)
iii)Metformin tablet (orally administered insulin sensitizing
drug)
iv)Placebo tablet for AZD9668
INTERVENTIONS: 
-oral ingestion of tablets 
i)venipuncture
ii)hyperinsulinemic-euglycemic clamp
-oral glucose tolerance test 
i)collection of peripheral whole blood following venipuncture
ii)collection of finger blood droplet after lancet puncture
iii)collection of urine
Study Objectives 
Primary Objective: 
To assess the efficacy of 60 mg bid 
AZD9668 PO bid versus 
placebo as adjunctive treatment to improve insulin sensitivity 
in obese, 
insulin-resistant T2D subjects as assessed by the 
hyperinsulinemic-euglycemic clamp method at baseline and 
6 months post randomization. 
Secondary  Objectives: 
i)To assess the safety of AZD9668 vs. placebo (rate and
severity of adverse events including hypoglycemia) in
obese, insulin-resistant T2D subjects;


Clinical protocol AZD9668 dated 06/13/2017 
Page 3 of 93 
ii)To measure the glycemic and metabolic control variables
(change in baseline HbA1c levels, fasting plasma glucose
levels, 2h-post-glucose challenge 
levels, body weight,
waist- and hip-circumference, HbA1c trajectory, metformin
and/or SAXA dose requirements) in 
AZD9668or placebo- 
treated obese, insulin-resistant T2D subjects;
iii)To measure changes in glucose, insulin and C-peptide
levels during a 3 hour oral glucose tolerance test (OGTT)
at 6 months from baseline. From the OGTT, parameters
of glucose metabolism will derived: 
insulinogenic index
using C-peptide and insulin [1-5]; glucose area under the
curve (AUC), and Matsuda Index of insulin resistance [6-
8], and the product of Matsuda index times the
insulinogenic index
iv) 
To identify changes in inflammatory variables
(concentrations of serum/plasma IL-6, high sensitivity-C- 
reactive protein, fibrinogen, TNF-alpha, soluble TNF-alpha
receptors) in 
AZD9668 or placebo-treated obese, insulin- 
resistant T2D subjects.
v)Biomarkers to Determine the Expression of Functional
Pharmacologic Activity of AZD9668: Desmosine levels in
serum and urine.
Exploratory/Pilot 
and Mechanistic Objectives: 
i) To investigate whether or not delayed
AZD9668administration (at 6 months) is inferior to the 
early AZD9668 treatment (at trial start) on IR 
improvements in insulin sensitivity, metabolic measures, 
and beta cell function; 
ii)To assess the effects of AZ9668 and placebo on the
frequency and absolute cell numbers of neutrophils, T- 
cells, B-cells, dendritic cells (DC) as well as other 
peripheral blood leukocytes (PBL) over the entire study 
period of both trial stages; 
iii)To determine the molecular signatures in PBL and
purified neutrophils in AZ9668 and placebo recipients 
over the entire study period of both trial stages including 
HLA and TCR levels; 
iv)To determine the changes in neutrophil cell surface
phenotype over the duration of the study in placebo and 
AZD9668-treated subjects; 
v) To identify cellular and molecular signatures of responder
versus non-responder status and/or of effect of therapy in 
AZD9668 
or placebo recipients over the entire study 
period of both trial stages; 
vi)To correlate changes in neutrophil absolute numbers with
activation of TCR and HLA-specific PBLs over time. 


Clinical protocol AZD9668 dated 06/13/2017 
Page 4 of 93 
Study Design 
This is a phase II trial to be conducted in the USA. The trial 
consists of a 2-arm, randomized, double-blinded, placebo- 
controlled, crossover study in 42 T2D subjects between 21-75 
years of age, inclusive, with a monitoring period of 12 months 
following a 1:1 randomisation into AZD9668:placebo arms. 
Subjects will be randomised following a 3 month run-in period 
to achieve/maintain an HbA1c level <=8.5 using metformin 
(MET) with saxagliptin (SAXA). 
Subjects will then receive 60 mg  AZD9668 PO bid (two 
tablets of 30 mg each, twice a day) or placebo as adjunctive 
treatment for a 6 month period. Then, the treatment arms will 
be crossed over to AZD9668 or placebo. 
Insulin sensitivity, assessed by the hyperinsulinemic- 
euglycemic clamp method and AE monitoring of all arms will 
continue to 12 months. 
Primary Endpoint(s) 
The primary efficacy endpoint is the improvement of insulin 
sensitivity by 40% or greater at 6 months compared to 
baseline, assessed by the hyperinsulinemic-euglycemic 
clamp method. 
Secondary  Endpoint(s) 
SAFETY 
Identification of AEs: 
i)
rate and severity of all adverse events including
hypoglycemia
ii)
rate and severity of known Aes of AZD9668
iii)
rate and severity of known Aes of SAXA
iv)
rate and severity of known Aes of Metformin
EFFICACY: 
i)
Improvement in glycated HbA1c levels
(range=0.2 – 1.5 or better) at 6 months compared
to baseline;
ii)
Improvement in OGTT-derived measurements,
namely: glucose  
tolerance, Matsuda  
Index of
insulin resistance [6-8], insulinogenic index


Clinical protocol AZD9668 dated 06/13/2017 
Page 5 of 93 
using C-peptide [1-5]; and the product of the 
Matsuda Index times the Insulinogenic Index. 
iii)
Improvement in fasting plasma glucose by 6%
or better at 6 months compared to baseline; and
iv)
Decreased concentrations of serum/plasma IL-6,
high sensitivity-C-reactive 
protein, fibrinogen,
TNF-alpha, soluble TNF-alpha receptors at 6
months compared to baseline
Mechanistic Endpoint(s) 
i)
To assess the effects of AZD9668 
and placebo on
the frequency and absolute cell numbers of
neutrophils, T-cells, B-cells, dendritic cells (DC) as
well as other peripheral blood leukocytes (PBL)
over the entire study period of both trial stages;
ii)
To determine the molecular signatures in PBL and
purified neutrophils in AZD9668 
and placebo
recipients over the entire study period of both trial
stages 
including HLA and TCR levels;
iii)
To determine the changes in neutrophil cell
surface phenotype over the duration of the study
in placebo and AZD9668-treated subjects;
iv)
To identify cellular and molecular signatures of
responder versus non-responder status and/or of
effect of therapy in AZD9668 or placebo
recipients over the entire study period of both trial
stages;
v)
To correlate changes in neutrophil absolute
numbers with activation of TCR and HLA-specific
PBLs over time.
Exploratory/Pilot 
Endpoint(s) 
To investigate whether or not delayed AZD9668 
administration (at 6 months) is inferior to the early AZ9668 
treatment (at trial start) on IR improvements in insulin 
sensitivity, metabolic measures, and beta cell function 
Accrual  Objective 
42 
Study Duration 
The subject’s complete participation in this trial will last 
approximately 15 months (up to 66 weeks). 
Treatment Description 
Screening: Will include reviewing medical histories from the 
volunteers (most will have had a diagnosis of insulin-resistant 
T2D based on clinical criteria), focusing on age, timing of the 
diagnosis of diabetes, and on medication use. At the initial 
screening visits, HbA1c, liver function tests (ALT/AST), 
hematocrit, and blood serum creatinine levels will be 
measured  and pregnancy testing in women with reproductive 
potential performed in addition to immune competence and 


Clinical protocol AZD9668 dated 06/13/2017 
Page 6 of 93 
the other measurements used to determine 
inclusion/exclusion (see further below). Once eligibility has 
been confirmed, subjects will proceed to the run-in period. 
Run-in Period: The run-in period will be used to determine the 
subject’s ability to adhere to the study protocol and to 
optimise, as much as possible, the background drug dosage 
and the HbA1c levels. Subjects will adjust MET doses up to 
2000 mg daily, as tolerated. Subjects who cannot tolerate at 
least 1000 mg daily of immediate or extended-release 
MET by 
the time of final run-in will be excluded from further 
participation. Subjects who have been treated with >2000 mg 
per day will have their dose adjusted to 2000 mg. If a subject 
is also on a DPPIV inhibitor, a GLP-1 analog, or a 
sulfonylurea, it will be replaced by 5 mg SAXA qd and the 
metformin dosage will be adjusted to achieve a glycated 
HbA1c target of <=8.5 by the time of the final run-in visit. 
Study subjects who exhibit FPG <=140 and HbA1c <=8.5% 
following any titrated metformin dose <2000 mg/day will 
remain on that dose (between 500-2000 mg/day) until such 
time as further titration is required (not to exceed 2000 
mg/day) to maintain this FPG/HbA1c level. Any subject who, 
despite achieving FPG <=140 and HbA1c <=8.5%, cannot 
tolerate at minimum 1000 mg/day of metformin during any 
stage of titration (i.e. exhibits SAEs confirmed to be attributed 
to metformin) will be discontinued from the study. 
The run-in period will be no less than 6 weeks and not more 
than 3 months [usually 8 to 12 weeks will allow equilibration 
of the HbA1c on the background treatment (MET+SAXA)]. 
The run-in period will also be used to familiarize the study 
subjects with the study and the study staff with the study 
subjects. 
Randomisation: Eligible study participants will be randomised 
within one week following the end of the run-in period and will 
be assigned a study randomisation number to which a 
treatment group assignment has been made. 
Treatment Period A: 
i)The AZD9668 arm will remain on the optimized
MET+SAXA as established during the run-in period and 
will be treated with 60 mg AZ9668 bid (two tablets of 30 
mg, twice daily) as adjunctive treatment for a 6 month 
period; 
ii)The placebo arm will remain on the optimized MET+SAXA
as established during the run-in period and will be treated 
with a color and flavor matched placebo tablet bid as 
adjunctive treatment for a 6 month period. 
Washout Period: The crossover design obviates the 


Clinical protocol AZD9668 dated 06/13/2017 
Page 7 of 93 
requirement of a washout period, since the AZD9668 arm will 
go on placebo (i.e. the background drugs) and vice versa. 
CROSSOVER INTO: 
Treatment Period B: 
i)At the start of month 7, subjects originally in the placebo
arm will be crossed over into the AZD9668 arm. These
subjects will remain on the optimized MET+SAXA as
established during the run-in period and will be treated
with 60 mg AZD9668 bid (two tablets of 30 mg, twice
daily) as adjunctive treatment for a 6 month period;
ii)At the start of month 7, subjects originally in the AZD9668
arm will be crossed over into the placebo arm. These
subjects will remain on the optimized MET+SAXA as
established during the run-in period and will be treated
with oral placebo bid that is flavor and color matched to
the 30 mg AZD9668 tablets as adjunctive treatment for a
6 month period.
Enrollment Inclusion 
Criteria 
1.Patients 21-75 years of age inclusive who meet the
American Diabetes Association standard criteria for type 2
diabetes mellitus (T2D).
2. Subjects are currently on metformin (at least 1000 mg per
day) for a minimum of 4 weeks prior to screening visit,
alone or in combination with any of the following diabetes
medications:
a. DPPIV inhibitor (any dose level/frequency)
b. Sulfonylurea (any dose level/frequency)
c. GLP1 agonist (any dose level/frequency)
d. Sulfonylurea (any dose level/frequency) + GLP1
agonist (any dose level/frequency)
e. Meglitinide (any dose level/frequency)
f. SGLT2 inhibitor (any dose level/frequency)
3.Patients must have a body-to-mass index (BMI) of greater
than or equal to 27 kg/m
2.
4.Patients exhibit glycated HbA1c between 7.3-11 during
eligibility screening and then <=8.5 at final run-in visit.
5.Willingness to replace current diabetes therapies (listed in
inclusion 2) with metformin and saxagliptin and to adjust
metformin dose during run-in period.
6.Subjects present adequate immune competence as
assessed by immunoreactivity to viral antigens (CEF Pool
Assay) in vitro at the time of screening.
7.Participants of childbearing potential must agree to practice
an effective form of birth control which may include any
one of the following: barrier method, oral contraception, or


Clinical protocol AZD9668 dated 06/13/2017 
Page 8 of 93 
surgery. These measures must be maintained throughout 
the study. 
8.Subjects must have good peripheral venous access for the
hyperinsulinemic-euglycemic clamp  and  the  3-hr. OGTT 
procedures. 
9.Patients understand the study procedures, alternative
treatments available, risks involved in the study, and 
voluntarily agree to participate by giving informed and 
signed written consent for screening and enrollment. 
10.Participants can be on anti-inflammatory therapies that
are not diabetes-focused (e.g. non-salicylate anti- 
inflammatory therapies, non-salicylate NSAIDs) and/or 
anti-hypertensive medicaments or statins. 
Enrollment Exclusion Criteria  
1. Patients with type 1 diabetes mellitus as defined by the
American Diabetes Association criteria or a history of 
ketoacidosis, or the patients are assessed by the study 
team as possibly having type 1 diabetes mellitus confirmed 
with the presence of at least one of the typical 
autoantibodies (insulin, GAD65, IA-2, ZnT8) AND a serum 
C-peptide level of <0.7 ng/mL. 
2.Patients have been treated with any therapies specific for
their diabetes other than those listed in the inclusion 
criteria within 4 weeks of the screening visit. 
3.Patients have been treated with insulin within 2 months of
the screening visit. 
4.Patients are currently participating in or have participated
in another study with an investigational compound or 
device within the prior 12 weeks of signing the informed 
consent or do not agree to refrain from participating in any 
other study while participating in this study. 
5.Patients have a history of hypersensitivity or any
contraindication to DPPIV inhibitors, including saxagliptin 
(Onglyza), or metformin based upon the labels of the USA. 
6.Patients are on a weight loss medication (such as orlistat,
phentermine, Qsymia, or Belviq) within the prior 6 weeks. 
7.Patients are required by treating physicians to remain on
any one of these agents during the trial: macrolide 
antibiotics, cisapride, anti-arrhythmics, steroids, rifampicin, 
phenobarbital, phenytoin, secobarbital, carbamazepine, 
norethindrone, isoniazid. AZD9668 is metabolized by 
CYP3A4, 3A5, and 2B6. SAXA is metabolized by CYP3A4 
and 3A5, potentially leading to drug-drug interactions with 
hypothetical adverse events in patients on the above 
agents. Also, AZD9668 causes weak inhibition of CYP2C9 
and therefore patients on fluconazole, amiodarone, 
fenofibrate, fluvoxamine, phenylbutazone, probenecid, 


Clinical protocol AZD9668 dated 06/13/2017 
Page 9 of 93 
sertraline, will also be excluded to avoid the hypothetical 
adverse events due to this effect. 
8.Patients have undergone surgery within the prior 6 weeks
or have any type or form of major surgery planned during 
the study (at the discretion of the physician). 
9. Patients are on or are likely to require treatment with 14
consecutive days or repeated courses of pharmacologic 
doses of corticosteroids or any other immunomodulatory 
agent. For example, patients requiring chronic systemic 
corticosteroids (does not include topical or inhaled 
corticosteroids). Exceptions are over the counter non- 
salicylate NSAIDs. 
10.
Enrollment or history of enrollment in a drug, or
biologic therapy clinical trial that affects the immune 
system within the past 12 months (e.g., systemic 
immunosuppressive pharmacologics, immunosuppressive 
cytokines, therapeutic immunomodulating 
antibodies, 
therapeutic immunomodulating 
fusion proteins and/or 
cytokine receptor decoys as well as any intervention 
and/or non-intervention induced immunodeficiencies). 
11. 
Prior history of coronary artery disease (defined as
myocardial infarction, angina, bypass surgery, or 
angioplasty) 
12. 
Prior history of arrhythmia 
(excludes premature beats)
13. 
Prior history of heart failure defined as i) symptomatic OR
ii)pulmonary edema, 
leg edema or low ejection fraction
(<40%)
14.Evidence of refractory chronic migraine (defined in ICHD-
3 and Martelletti et al. [9,10] ).
15.History of persistent bradycardia within the last year prior
to screening visit (more than three episodes in a calendar
year of a heart rate <60 beats per minute that required
hospitalization on each of these occasions).
16. Leukopenia (<3000 leukocytes/microliter), 
neutropenia
(<1500 neutrophils/microliter), 
lymphopenia (<800
lymphocytes/microliter), 
or thrombocytopenia (<125000
platelets/microliter), 
any other clinically relevant abnormal
hematology value.
17.Positivity for HIV, active CMV, chlamydia, any evidence of
serious fungal infection, active HSV1, HSV2, hepatitis B
or C, or history of HSV1 or HSV2 at screening. Minor skin
fungus, or minor candidiasis is not an enrollment or
treatment exclusion criterion. Also, with the exception of
HIV history, hepatitis B and C, successfully-treated,
disease-free individuals (> 6 months between time of
successful treatment confirmation and time at screening)
would be eligible for enrollment in this trial.
18.Patients are required by treating physician to remain on
any medications listed in inclusion #2 (that directly affect
glucose metabolism such as, but not limited to


Clinical protocol AZD9668 dated 06/13/2017 
Page 10 of 93 
thiazolidinediones, pramlintide, or amylin. 
19.Vaccination with any form of live vaccine product within
the last 3 months prior to initiation of study agent 
administration. 
20.Any chronic disease that in the opinion of the
investigators would affect the patient’s safety and/or the 
integrity of the study outcome. This does not include 
dyslipidemia, patients on statin or anti-hypertension 
treatment, or patients with well-controlled hypo- or 
hyperthyroidism. Evidence of liver dysfunction, with ALT 
or AST> 1.5 times the upper limit of normal. 
21.Evidence of renal insufficiency as indicated by blood
creatinine of > 2 times the upper limit of normal at 
baseline screening OR an eGFR < 45 mL/min OR A past 
history or current clinical evidence of renal failure or low 
creatinine clearance at screening. 
22.Females who are pregnant at the time of screening or
unwilling to defer pregnancy during the study period. 
23. Lactating women.
24.Poor accessibility to veins for the 3-hour OGTT and
hyperinsulinemic-euglycemic clamp procedures.
25.The following therapies cannot be administered while
patients are undergoing treatment on this protocol: i)
radiation therapy; ii) chemotherapy; 
iii) corticosteroids
(except for very short courses of topical or inhaled); iv)
agents used to treat attention deficit and hyperactivity
disorder (ADHD); v) rifampicin or phenytoin; vi) other
protein, particle or cell vaccine immunomodulation
therapies. If these therapies are essential for treatment of
other conditions, participation in this study will be
terminated.
26.A condition which interferes with the ability to accurately
determine glycated HbA1c. Examples include: blood
transfusion, Genetic variants (e.g. HbS trait, HbC trait),
elevated fetal hemoglobin (HbF) and chemically modified
derivatives of hemoglobin (e.g. carbamylated Hb in
patients with renal failure); Any condition that shortens
erythrocyte survival or decreases mean erythrocyte age
(e.g., recovery from acute blood loss, hemolytic anemia);
iron deficiency anemia, iron replacement therapy
27.Subjects who cannot tolerate at least 1000 mg daily of
immediate or extended release metformin by the time of
final run-in will be excluded from further participation.
28.Subjects who do not exhibit a glycated HbA1c level <=8.5
by the end of the run-in period.


Clinical protocol AZD9668 dated 06/13/2017 
Page 11 of 93 
Study Stopping 
Rules 
 
1.The NCATS, FDA, the IRB or the DSMB requires
termination of the study upon review of the safety data. 
2.Any death possibly or definitely related to AZD9668.
3.If within the first three months of their first dose, three or
more of the first (initial) 6 participants treated with AZD9668 
experience a study-related serious adverse event resulting in 
the permanent discontinuation of the treatment (as defined in 
Section 4.7.2). 
4.Infection that persists for > 2 weeks from expected time of
mean clearance (except for skin fungus) 
5.Any expected adverse event considered possibly or
definitely related to AZD9668 that occurs at a greater severity 
than previously observed or listed in the study documents 
and is therefore considered unexpected and classified as an 
AE of special interest (AESI). 
The FDA, IRB and DSMB will be immediately notified of any 
such event. Resumption of enrollment is contingent upon a 
favorable IRB and DSMB review. 


Clinical protocol AZD9668 dated 06/13/2017 
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Table of Contents 
Page(s) 
Glossary  of Abbreviations 
….....................................................................................  16-17 
1.0 PROJECT SUMMARY…………………………………………………………………… 18-33 
1.1 TITLE 
1.2 INDICATION 
1.3 RATIONALE 
1.4 HYPOTHESIS 
1.5.BACKGROUND 
AND SIGNIFICANCE23 
1.5.1 Obesity, inflammation, IR and neutrophils in T2D 
1.6 STUDY MEDICATION INFORMATION AND PRIOR RESEARCH EXPERIENCE 
1.6.1 Saxagliptin 
1.6.2 Metformin 
1.6.3 AZD9668 
1.6.4 AZD9668 placebo 
1.7 STUDY MEDICATION RISK INFORMATION FROM PREVIOUS TRIALS 
1.7.1 Metformin 
1.7.2 Saxagliptin 
1.7.3 AZD9668 
1.8 STUDY OBJECTIVES 
1.8.1 Study endpoints 
2.0 RESEARCH DESIGN.................................................................................................... 34-37 
2.1 STUDY AGENTS 
2.2 STUDY AGENT DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN 
2.2.1 Labeling, packaging, storage, dispensing, and return of clinical supplies 
2.2.2 Product descriptions 
2.2.3 Packaging information 
2.2.4 Clinical supplies disclosure 
2.2.5 Storage and handling requirements 
2.3 STANDARD POLICIES/RETURN 
OF CLINICAL SUPPLIES 
2.4 DISTRIBUTING TO SITE AND DISPENSING TO PATIENTS 
2.5 KNOWN AND POTENTIAL RISKS OF STUDY MEDICATIONS 
2.6 POTENTIAL RISKS OF STUDY PROCEDURES 
2.6.1 Oral glucose tolerance test (OGTT) 
2.6.2 Hyperinsulinemic-euglycemic clamp (Clamp) 
2.6.3 Venipuncture 
2.6.4 DEXA total body scan 
3.0 STUDY POPULATION……………………………………………………………………  38-41 
3.1 INCLUSION CRITERIA 
3.2 EXCLUSION CRITERIA 
3.3 STOPPING RULES 
3.4 STUDY TIMELINE AND MILESTONE PLAN 
3.4.1 Go/No Go points 


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3.4.2 Procedure and pace of enrollment and study duration 
3.4.3 Milestone grid (Figure 1) 
4.0 COMPLETE PROTOCOL…………………………………………………………………  42-62 
4.1 OVERVIEW 
4.2 STUDY PROTOCOL DIAGRAM/FLOW CHART (Figure 2 and Figure 3) 
4.3 RECRUITMENT 
4.4 INFORMED CONSENT 
4.5 STUDY APPROACH (Figure 4) 
4.5.1 Screening 
4.5.2 Run-in 
4.5.3 Randomization 
4.5.4 Treatment Period A 
4.5.5 Washout 
4.5.6 Treatment Period B 
4.5.7 Unscheduled visits 
4.5.8 End of Study Procedures 
4.6 STUDY PROCEDURES 
4.6.1 Laboratory Monitoring 
4.6.2 Metformin titration and dosing (Figure 6) 
4.6.3 Saxagliptin dosing 
4.6.4 AZD9668/placebo 
dosing 
4.6.5 Standard diabetes education 
4.6.6 Glucose monitoring 
4.6.6.1 Management of hypoglycemia 
4.6.6.2 Management of procedure associated hypoglycemia 
4.6.6.3 Treatment of hypoglycemia 
4.6.7 Complete physical exam 
4.6.8 Medical history 
4.6.9 DEXA 
4.6.10 80 mU/m2 min-1 hyperinsulinemic-euglycemic clamp test 
4.6.11 3-hour multi-point oral glucose tolerance test 
4.6.12 Safety assessments 
4.6.13 Concomitant medications 
4.6.13.1 Prohibited medications 
4.7 INTERRUPTION OF STUDY MEDICATION/DISCONTINUATION 
4.7.1 Metformin/saxagliptin 
interruption 
4.7.2 Reasons for discontinuation 
4.8 MEDICATION COMPLIANCE 
4.9 UNBLINDING 
4.10 EFFICACY MEASURES 
4.11 SAFETY MEASURES 
4.12 PREGNANCY TESTING AND CONTRACEPTION 
4.12.1 Reporting of pregnancy 
4.13 IMMUNE/IMMUNOMODULATION ASSAYS 
5.0 ADVERSE EVENTS REPORTING………………………………………………………  63-70 
5.1 SAFETY MONITORING 
5.1.1 Data and Safety Monitoring Board 
5.1.2 Definitions 
5.1.2.1 Adverse Event (AE 


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5.1.2.2 Serious Adverse Event (SAE) 
5.1.2.3 Unexpected Adverse Event 
5.1.2.4 Adverse reaction and suspected adverse reaction 
5.1.2.4.1 Unanticipated problems 
5.1.2.5 Collecting and reporting procedures 
5.1.2.6 Recording procedure 
5.1.2.7 Grading and attribution of all adverse events 
5.1.2.7.1 Grading criteria 
5.1.2.8 Definition of attribution (Table 2) 
5.1.3 Event reporting procedures 
5.2 DEFINITION OF AN OVERDOSE FOR THIS PROTOCOL 
5.2.1 Reporting of overdosage 
5.3 GUIDANCE ON ADVERSE EVENTS RELATED TO GLYCEMIA 
5.3.1 Guidance of adverse events related to hyperglycemia 
5.3.2 Guidance on adverse events related to hypoglycemia 
5.4 GUIDANCE ON ADVERSE EVENTS RELATED TO ARTHRALGIA 
5.5 ASSESSMENT OF COMPLIANCE WITH STUDY DRUGS 
5.6 PROTOCOL NON-COMPLIANCE 
5.6.1 Protocol Violations 
5.6.1.1 Drug compliance < 75% 
5.6.1.2 Use of prohibited medications 
5.6.1.3 Incorrect study medications 
5.7 UPDATING SOURCE DOCUMENTATION 
6.0 STATISTICAL ANALYSIS PLANS……………………………………………………  71-74 
6.1 GENERAL ANALYSIS STRATEGIES 
6.1.1 General statistical analysis 
6.2 PRIMARY OUTCOMES 
6.2.1 Primary study endpoint 
6.3 OTHER OUTCOMES 
6.3.1 Secondary study endpoints 
6.3.2 Exploratory endpoints 
6.4 INTERIM ANALYSES 
6.5 SAMPLE SIZE AND POWER (Table 3) 
6.6 SECONDARY OUTCOMES 
6.7 INTERIM ANALYSES 
6.7.1 Interim analysis of efficacy data 
6.7.2 Interim analysis of safety data 
6.7.3 Futility analysis 
6.8 MISSING DATA 
6.9 LABORATORY VALUES BELOW LIMITS OF QUANTIFICATION 
AND REPEAT TESTING 
7.0 ETHICAL CONSIDERATIONS AND COMPLIANCE 
WITH GOOD CLINICAL  PRACTICE……………………………………………………  75 
7.1 STATEMENT OF COMPLIANCE 
7.2 PRIVACY AND CONFIDENTIALITY 
8.0 IDENTIFICATION AND ACCESS TO SOURCE DATA………………………………  76-77 
8.1 IDENTIFYING SOURCE DATA 


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8.2 PERMITTING ACCESS TO SOURCE DATA 
8.3 STUDY SUBJET CONFIDENTIALITY 
8.4 SAMPLE AND DATA STORAGE 
8.5 PRESERVATION OF THE INTEGRITY OF THE STUDY 
8.6 QUALITY CONTROL AND QUALITY ASSURANCE 
8.7 DATA HANDLING 
9.0 STUDY ADMINISTRATION……………………………………………………………… 78-79 
9.1 STUDY LEADERSHIP AND GOVERNANCE 
9.2 STEERING COMMITTEE 
9.3 EXECUTIVE COMMITTEE 
9.4 RESEARCH CENTER AND CHAIRMAN’SOFFICE 
9.5 DATA AND SAFETY MONITORING BOARD AND PLAN 
10.0 CONFLICT OF INTEREST/DUALITY OF INTEREST…………………………………  80 
11.0 PUBLICATION POLICY………………………………………………………………….  80 
12.0 LITERATURE CITED/BIBLIOGRAPHY………………………………………………..  81-90 
13.0 APPENDICES……………………………………………………………………………..  91-93 
Appendix A: Clinical Laboratory Measures – Core Lab 
Appendix B: Exploratory Laboratory Measures – Investigator Study Lab 


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Glossary  of Abbreviations 
AE 
Adverse Event(s) 
AZD9668 
Astra-Zeneca Drug 9668 
Breg(s) 
B-regulatory cells 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DC 
Dendritic Cell(s) 
DSMB 
Data Safety Monitoring Board 
EXPT 
Experimental 
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HbA1c 
Hemoglobin A1c 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IL 
Interleukin 
IR 
Insulin Resistant 
IMM 
Independent Medical Monitor 
IMPALA 
IMProving insulin resistance with ALvelestat Adjunctive therapy 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MET 
Metformin 
MOP 
Manual of Procedures 
NCATS 
National Center for Advancing Translational Sciences (NIH) 
NIH 
National Institutes of Health 
NE 
Neutrophil Elastase 
NEI 
Neutrophil Elastase Inhibitor 
OGTT 
Oral Glucose Tolerance Test 
PC 
Protocol Chair 
PI 
[Site] Principal Investigator 


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SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event(s) 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SAXA 
Saxagliptin 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
T2D 
Type 2 Diabetes Mellitus 
TCC 
Trial Coordinating Center 
Treg(s) 
T-regulatory cell(s) 
UP 
Unanticipated Problem(s) 


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1.0 PROJECT SUMMARY 
1.1 TITLE 
Neutrophil Elastase Inhibition as Adjunctive Therapy to Improve Glucometabolic Variables in 
Overweight and Obese, Insulin-Resistant Type 2 Diabetic Patients 
1.2 INDICATION 
AZD9668 will be an adjunctive therapy in combination with saxagliptin and metformin 
to improve insulin 
sensitivity in overweight and obese, type 2 diabetic (T2D) individuals. Although AZD9668 has been used 
in previous trials approved by the FDA (e.g. clinicaltrials.gov - NCT01054170, NCT01023516, 
NCT00769119, NCT00757848), it is considered an investigational new drug (IND) for the purposes of 
this trial. Saxagliptin is marketed as a treatment option for T2D along with other antidiabetic agents 
including metformin (an established treatment option on its own for T2D). 
1.3 RATIONALE 
Overweight, insulin-resistant (IR) T2D individuals manifest a chronic systemic inflammation which 
impairs beta cells and peripheral insulin sensitivity. This systemic inflammation is associated with an 
atherogenic lipid profile and predisposes individuals to higher risk for micro- and macro-vasular 
disease, irrespective of well-controlled glycemia. Although a variety of pharmacologic approaches 
maintain daily glycemic control, it is becoming evident that there is an urgent need to identify adjunctive 
therapies to improve, insulin sensitivity, beta cell function, and HbA1c since they begin deteriorating 
quite substantially by 5 years following initial treatment. Ideally, such adjunctive therapies should be 
well-tolerated, easy to administer, should not promote hypoglycemia and should also attenuate the 
systemic inflammation. 
The role of neutrophils in T2D and metabolic 
inflammation represents an important gap in knowledge to 
better understand inflammation in T2D especially since neutrophils are the most abundant leukocyte 
population in humans and constitute the bulk of inflammatory leukocytes. Emerging evidence 
indicates 
that neutrophils along with neutrophil-derived elastase serve as an important nexus of T2D-associated 
inflammation. This trial offers a first-in-kind opportunity to better understand the role of neutrophils in 
T2D diabetics. 
1.4 HYPOTHESIS 
We hypothesize that inhibition of neutrophil elastase (NE) will attenuate the chronic systemic background 
inflammation in overweight and obese, IR T2D subjects and that the potential 
improvement in insulin 
sensitivity and glucose control could concurrently facilitate functional maintenance and induce the 
rescue of pancreatic beta cell mass. 


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1.5 BACKGROUND AND SIGNIFICANCE 
AZD9668 is a potent orally-administered 
competitive inhibitor of neutrophil elastase (NE) with 
considerable selectivity for human NE over other serine proteases, 
including human cathepsin G (680- 
fold), and >1900-fold selectivity over chymotrypsin, pancreatic elastase, trypsin and proteinase-3 
(proprietary data from Astra-Zeneca). Obese, insulin-resistant (IR) type 2 diabetic (T2D) patients are 
characterized by a chronic systemic inflammation which affects insulin sensitivity and pancreatic beta 
cell function [11,12]. Emerging evidence points to an important role of neutrophils as responders of the 
obese state, as well as participants in the maintenance and persistence of the systemic inflammation 
(reviewed in [13-20], and see further below). NE deficiency and NE inhibition has been shown to 
substantially and significantly improve obesity-induced IR and to suppress adipose and liver 
inflammation in animal models [21,22]. These, along with other facets of neutrophil biology in systemic 
and metabolic inflammation, compel a novel use for AZD9668 as an adjunctive therapy in T2D which 
can short-circuit the systemic inflammation that exacerbates obesity-associated IR. The hypothesis 
underlying this clinical trial is  
that inhibition of NE will attenuate the chronic 
systemic background 
inflammation in overweight and/or obese, IR T2D subjects and that the potential 
improvement in insulin 
sensitivity and glucose control could concurrently facilitate functional maintenance and induce the 
rescue of pancreatic beta cell mass (Figure 1). 
Both IR and beta cell dysfunction are involved in the pathogenesis of T2D [11,12,23] whose prevalence 
continues to increase around the globe [24,25] and is currently estimated to be at more than 385 
million[26]. As many as 1 in 3 people in the United States could have diabetes by the year 2050[27] 
with significant economic consequences. In 2014, 1 in 5 health care dollars was spent to support the 
care of patients at a total estimated cost > $245 billion [28] [29,30]. Many of these costs are associated 
with the long-term complications of the disease (cardiovascular, microvascular, renal, nervous, 
ophthalmic, wound healing, and infections). Without concerted efforts to address the pathogenesis and 
treatment of this syndrome, the harmful macrovascular and microvascular outcomes of T2D will remain a 
major burden for decades to come. Of particular concern and alarm is the growing trend of T2D onset in 
youth and children[24,31-38], and even higher in Asia and China [24,31-35,39]. 
1.5.1 Obesity, inflammation, IR and neutrophils 
in T2D 
Obesity, an outcome of the overweight state, is often characterized by systemic inflammation, and 
preclinical evidence links systemic inflammation to beta cell dysfunction[40,41]. Systemic inflammation is 
also associated with insulin sensitivity and beta cell function[42,43]
,[44,45]. 
The expansion of adipose 
tissue is associated with accumulation of activated macrophages secreting several proinflammatory 
molecules which locally impair insulin 
signaling [46,47]. An explosion of studies in the past decade have 
begun to reveal the contributions of inflammation to the development of IR and subsequent metabolic 
abnormalities in other tissues, such as liver [48-53] and most recently brain [54]. Adipose tissue 
macrophages are the main component of adipose tissue immune cells (40–60 % of all adipose tissue 
immune cells), and their number increases progressively after only 1 week of high-fat diet feeding [55]. 
In addition to macrophages, additional leukocyte subpopulations have recently been demonstrated to 
be involved in obesity and IR, such as T cells, B cells, eosinophils, mast cells, natural killer cells,  
but 
most importantly 
as concerns 
humans  - neutrophils. In contrast to rodents, in humans, 
lymphocytes account for the minority of implicated immune cells; granulocytes appear to be the more 
relevant immune cell population. In fact, granulocytes comprise 60-79% of human blood leukocytes and 
more than 90% of the granulocytes are neutrophils thus making up the largest fraction of white blood 
cells. Neutrophils directly interact with macrophages, dendritic cells, and lymphocyte subsets and 
modulate their effector functions, and accumulating evidence implicates them in T2D and T1D (Reviewed 
in [16,56-59]). For example, activated neutrophils induce Th1 and Th17 cell chemotaxis [60]. In acute 
inflammation, neutrophils are the leukocyte subpopulation arriving first in the inflamed tissue 


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and promote the subsequent recruitment of inflammatory monocytes by producing MCP-1 and other 
chemokines [61]. Neutrophil-derived proteases regulate the biological activity of cytokines in the 
inflammatory microenvironment. For instance, human and murine NE and cathepsin G cleave full- length 
IL-33 into mature forms [62]. Neutrophils also participate in inflammation through the process of 
neutrophil extracellular trap-associated apoptosis (“NET”osis), a form of suicide that consists of a 
stepwise progression of chromatin decondensation, nuclear swelling, spilling of the nucleoplasm into the 
cytoplasm, and finally membrane perforation [63,64]. In men, elevated neutrophil markers, especially 
myeloperoxidase, are present in the plasma of obese subjects [65]. Abnormal expansion of visceral 
adipose tissue is accompanied by influx of immune cells, including neutrophils. Activated neutrophils 
infiltrate adipose tissue early during diet-induced obesity in mice in an attempt to limit the local 
inflammatory process [66]. Moreover, in vitro studies have shown that neutrophils physically bind 
adipocytes in a CD11b/ICAM-1 interaction and in a manner dependent on their activation state [66]. 
Neutrophils are rare in adipose in a lean state; however, a high-fat diet causes neutrophils to infiltrate 
white AT early after nutrient excess, and increased neutrophil recruitment to the obese AT is seemingly 
sustained over a longer period [67]. Most interestingly, obesity-induced, AT-invading neutrophils 
(CD11b+ Ly6g+ F4/80  CD11c ), established local IR by secreting elastase [68]. 
The deletion of NE in high-fat diet-induced obese mice led to reduced macrophage content, improved 
glucose tolerance, and improved AT and liver insulin sensitivity, accompanied by a marked reduction in 
neutrophil recruitment to the white AT [18]. Intriguingly, NE can degrade IRS-1 protein and reduce 
insulin-induced Akt phosphorylation in adipocytes [18]. This mechanism may be involved in the 
neutrophil- and NE-dependent effect on IR in diet-induced obesity, as the levels of IRS-1 were higher in 
the AT and liver of elastase-deficient mice, as compared to elastase-sufficient mice [18]. Similar results 
were obtained in a very recent study by another group [21,69]. In humans, an increased blood level of 
myeloperoxidase, a marker of neutrophils, in obese women [65], and increased activity of neutrophils in 
obese subjects have also been noted [69]. Very recently, myeloperoxidase-deficient mice were shown to 
exhibit resistance to diet-induced obesity, glucose intolerance and diabetes [70]; the enzyme deficiency 
was further shown to be neutrophil-relevant. NE can increase the expression of 
proinflammatory genes in peritoneal macrophages in a TLR4-dependent manner [18]. Consistently, NE- 
deficient white AT displayed a decrease in expression of proinflammatory markers concomitantly with 
an increase of anti-inflammatory markers, while reduced numbers of M1-polarised macrophages were 
observed in the NE-deficient obese AT [18]. Thus, a dual mechanism of action of NE, involving 
interference with insulin signaling, as well as activation of the TLR4-dependent AT inflammation, could 
account for its role in promoting development of IR. The profound phenotype of NE deficiency on AT 
inflammation and IR is intriguing. NE can activate immune cells via protease-activated receptors and by 
interacting with beta2 integrins, thereby activating leukocyte adhesion [71-73]. Moreover, NE can 
modify the chemokine and cytokine network by proteolytic activation or inactivation [74]. 
Non-insulin, anti-inflammatory T2D therapeutics and the potential for neutrophil-targeting 
drugs: The 
increasing prevalence of T2D has stimulated development of many approaches to safely treat 
hyperglycemia. Metformin is generally recommended as the initial drug for patients with T2D, but most 
patients eventually require a second, third, or even fourth drug to achieve target glycemic control [75- 
80]. Concerning inflammation, high-dose sodium salicylate or acetylsalicylic acid can diminish glycosuria 
and IR, improve glycemic control and HbA1c in diabetic patients[81-84]. Randomized clinical trials have 
shown that the blockade of IL-1b by anakinra or IL-1b antibodies reduced systemic inflammation and 
improved glycemia of T2D[85-95]. Etanercept, a TNFa antagonist, can block inflammation[96]. Several 
studies have been conducted to test whether etanercept improves glucose 
tolerance in T2D patients; however, despite a suppressive effect on systemic inflammation, the 
attenuation of glucose tolerance or IR has not yet been achieved[96-98]. The major classes of anti- 
inflammatory agents that target neutrophils and neutrophil function include corticosteroids, macrolides, 


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cAMP-elevating agents (including cyclooxygenases), 5-lipoxygenase inhibitors and leukotriene receptor 
antagonists, chemokine receptor antagonists, kinase inhibitors, non-steroidal activators of histone 
deacetylase-2 (HDAC2), and anti-oxidants[99-119]. 
Corticosteroids are not specific to neutrophils and as 
general immunosuppressives 
they possess the additional adverse effect of inducing glycogenolysis and 
raising blood glucose levels[120,121]. Large clinical trials with high doses of antioxidants have 
been disappointing[122]. 
The use of the other classes of agents is associated with varying adverse 
events and grades of adverse events >2. Our novel approach,  targeting 
NE in order to 
decouple the inflammatory 
cycle,  we believe, represents a first-in-kind adjunctive 
therapy, realizing  the objective 
of modulating 
the three pressure  points  in T2D: IR, 
insulin sensitivity 
and beta cell insulin production. 
Two NE inhibitors have been developed 
and tested in human patients; infusion sivelestat sodium hydrate [123-126] considered for acute lung 
injury associated with sepsis and systemic inflammation and AZD9668, a fully reversible orally-
administered 
inhibitor considered for chronic inflammatory lung disease [127-131]. Given the better 
known safety data for AZD9668 [127- 
129,131-133], we believe that it is a candidate better positioned as an adjunctive therapy to attenuate 
the systemic inflammation in T2D thereby improving metabolic and glucose control. Especially 
important is the oral route of administration (tablets) which usually facilitates patient compliance to the 
treatment. 
1.6. Study Medication 
Information & Prior Clinical  Research Experience 
This section summarises the indications, known mechanisms of action, and Standard-of-Care or 
investigational use. Detailed information (preclinical/clinical studies prior to marketing [where a study 
agent is on the market] can be found in the respective product inserts of the marketed agents 
(saxagliptin and metformin) and in the Investigator’s Brochure (AZD9668). 
1.6.1 SAXAGLIPTIN 
Saxagliptin (Astra-Zeneca) is a white to light yellow or light brown powder. It is soluble in polyethylene 
glycol 400, acetone, acetonitrile, ethanol, isopropyl alcohol, methanol; sparingly soluble in water and 
slightly soluble in ethyl acetate. Each film-coated tablet of saxagliptin contains either 2.5 mg or 5 mg of 
saxagliptin free base (as saxagliptin hydrochloride) and the following inactive ingredients: lactose, 
microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyvinyl alcohol, macrogol 
3350, titanium dioxide, talc-purified, iron oxide yellow CI77492 (2.5 mg tablet only), iron oxide red 
CI77491 (5 mg tablet only) and Opacode Blue (printing ink). 
Mechanism of action: 
Saxagliptin is an orally-active inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of 
type 2 diabetes mellitus. It is a member of a class of oral anti-hyperglycaemic 
agents called DPP-4 
inhibitors. Saxagliptin is a reversible, competitive, DPP-4 inhibitor with nanomolar potency. Saxagliptin 
demonstrates selectivity for DPP-4 versus other DPP enzymes, with greater than 75 fold selectivity 
over DPP-8 and DPP-9. Saxagliptin has extended binding to the DPP-4 active site, prolonging 
its 
inhibition of DPP-4. Saxagliptin differs in chemical structure and pharmacological action from GLP-1 
analogues, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferators-activated 
receptor gamma agonists, alpha-glucosidase 
inhibitors, and amylin analogues. It is increasingly being 
used as the main adjunctive drug to metformin that with diet and exercise together results in better 
management of type 2 diabetes to maintain normal glycated HbA1c levels as well as to keep blood 
glucose within a normal range on a daily average basis. Saxagliptin, like other orally-available and 
active DPP-IV inhibitors does not elicit hypoglycemia. Saxagliptin exerts its actions in patients with type 
2 diabetes by slowing the inactivation of incretin hormones, including glucagon-like peptide-1 (GLP-1) 
and glucose-dependent insulinotropic polypeptide (GIP). Concentrations of these active intact incretin 
hormones are increased by saxagliptin, thereby increasing and prolonging the actions of these 


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hormones. Saxagliptin also inhibits the cleavage of other substrates in vitro, but the relevance or 
consequences of DPP-4 inhibition for these substrates in patients is unknown. 
Incretin hormones are released by the intestine throughout the day and concentrations are increased in 
response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are 
part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When 
blood glucose concentrations are elevated GLP-1 and GIP increase 
insulin synthesis and release from 
pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to 
reduced hepatic glucose production. 
Concentrations of GLP-1 are reduced in patients with type 2 diabetes, but saxagliptin increases active 
GLP-1 and GIP, potentiating these mechanisms. By increasing and prolonging active incretin 
concentrations, saxagliptin increases insulin release and decreases glucagon concentrations in the 
circulation in a glucose-dependent 
manner. 
Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in 
patients with type 2 diabetes through improvements in alpha and beta cell function as reflected by the 
actions described below. 
Fasting glucose-dependent 
insulin secretion: Saxagliptin increases pancreatic beta-cell responsiveness 
to glucose in the fasting state and leads to enhanced insulin secretion and glucose disposal in the 
presence of elevated glucose concentrations. 
Postprandial glucose-dependent 
insulin secretion: Saxagliptin increases pancreatic beta-cell 
responsiveness to glucose in the postprandial state and leads to enhanced postprandial insulin 
secretion and glucose disposal. 
Postprandial glucagon secretion: In type 2 diabetes, paradoxical increases in glucagon secretion from 
alpha cells following meals stimulate hepatic glucose production and contribute to glycaemic 
dysregulation. Saxagliptin moderates glucagon secretion and lowers postprandial glucagon 
concentrations. 
Standard-of-Care Use 
Add-on combination 
Dual Oral Combination Therapy 
Saxagliptin is indicated 
in patients with type 2 diabetes mellitus, to improve glycemic control, in 
combination with metformin, a sulfonylurea, or a thiazolidinedione, as an adjunct to diet and exercise, 
when the single agent alone does not provide adequate glycaemic control. 
Triple Oral Combination Therapy 
Saxagliptin is indicated 
in patients with type 2 diabetes mellitus to improve glycaemic control in triple 
combination with metformin plus a sulfonylurea (SU), when the two agents, with diet and exercise, do 
not provide adequate glycaemic control. 
Combination Therapy with Insulin 
Saxagliptin is indicated in patients with type 2 diabetes mellitus to improve glycaemic control as add-on 
therapy to premixed or basal insulin (with or without metformin) when premixed or basal insulin (with or 
without metformin) used with diet and exercise, do not provide adequate glycaemic control. Saxagliptin 


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has not been studied in a regimen combining intermediate or long-acting insulin with mealtime bolus 
doses of short-acting 
insulin (basal:bolus regimens) and its efficacy in this context has not been 
established. 
Initial combination 
Saxagliptin is indicated for use as initial combination therapy with metformin, in patients with type 2 
diabetes mellitus, to improve glycaemic control as an adjunct to diet and exercise, when dual 
saxagliptin and metformin 
therapy is appropriate. (i.e. high initial HbA1c levels and poor prospects for 
response to monotherapy). 
1.6.2 METFORMIN 
Metformin HCl will be the generic brand supplied by the clinical trial pharmacy at AHN. 
Mechanism of action: 
Metformin is an orally-active biguanide anti-diabetic agent in common use as an adjunct to diet and 
exercise for the management of type 2 diabetes to maintain normal glycated HbA1c levels as well as to 
keep blood glucose within a normal range on a daily average basis. Metformin, generally, is the 
preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus. 
Metformin 
lowers blood glucose concentrations 
in patients with type 2 diabetes mellitus without 
increasing insulin secretion from pancreatic beta cells. Ineffective in the absence of some endogenous 
or exogenous insulin. Usually does not lower glucose concentrations below euglycemia, but 
hypoglycemia 
occasionally may occur with overdosage. Lowers both basal (fasting) and postprandial 
glucose concentrations 
in patients with type 2 diabetes mellitus. Improves insulin sensitivity by 
decreasing hepatic glucose production and enhancing insulin-stimulated uptake and utilization of 
glucose by peripheral tissues (e.g., skeletal muscle, adipocytes). Insulin secretion usually remains 
unchanged. 
Standard-of-Care Use 
Metformin HCl generally is the preferred initial oral antidiabetic agent for patients with type 2 diabetes 
mellitus. Potential advantages of metformin compared with sulfonylureas or insulin include minimal risk 
of hypoglycemia, more favorable effects on serum lipids, reduction of hyperinsulinemia, and weight loss 
or lack of weight gain. 
Used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus. 
May be used in combination with a sulfonylurea, repaglinide, DPPIV inhibitor or thiazolidinedione 
antidiabetic 
agent for the management of type 2 diabetes mellitus in patients who do not achieve 
adequate glycemic control on monotherapy with metformin or any of these drugs. Also used 
concomitantly with nateglinide. May be used with insulin to improve glycemic control and/or decrease 
the required dosage of insulin. 
Monotherapy 
Oral 
Conventional tablets or oral solution: Initially, 500 mg twice daily or 850 mg once daily with meals. 
Increase daily dosage by 500 mg at weekly intervals or by 850 mg at biweekly (every 2 week) intervals 
up to a maximum of 2 g daily given in divided doses. May increase dosage from 500 mg twice daily to 


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850 mg twice daily after 2 weeks. Clinically important responses generally not observed at dosages 
<1.5 g daily. 
Initial dosage of 500 mg once daily suggested by some experts. For additional glycemic control, 
increase dosage (as conventional tablets or oral solution) up to a maximum daily dosage of 2.55 g 
given in divided doses. 
Extended-release tablets (Glucophage XR) in patients ≥17 years of age: Initially, 500 mg once daily with 
the evening meal. Increase daily dosage by 500 mg at weekly intervals to a maximum of 2 g daily. If 
glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily. If >2 g daily 
is required, switch to conventional tablet formulation and increase dosage up to 2.55 g daily in divided 
doses (preferably 3 doses per day for daily dosages >2 g). 
Extended-release tablets (Fortamet) in patients ≥17 years of age: Initially, 1 g once daily with the 
evening meal; 500 mg once daily may be used when clinically appropriate. Increase daily dosage by 
500 mg at weekly intervals to a maximum of 2.5 g daily with the evening meal. 
Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet) 
Oral 
Individualize dosage based on the patients current regimen, effectiveness, and tolerability while not 
exceeding the maximum recommended daily dosage of 2 g of metformin hydrochloride and 100 mg of 
sitagliptin. 
Patients currently receiving metformin: Initially, 500 mg of metformin hydrochloride and 50 mg of 
sitagliptin twice daily; gradually increase dosage as needed. 
Patients currently receiving metformin: Initial dosage should provide 50 mg of sitagliptin twice daily and 
the dosage of metformin hydrochloride currently being taken. Patients currently taking metformin 
hydrochloride 850 mg twice daily should receive an initial fixed-combination dosage of 50 mg of 
sitagliptin and 1 g of metformin hydrochloride twice daily. 
Safety and efficacy of transferring to Janumet from therapy with other oral antidiabetic agents not 
established; undertake any such change with caution and appropriate monitoring. 
1.6.3 AZD9668 
AZD9668 is a potent and selective inhibitor of human neutrophil elastase (NE); a serine protease 
implicated in cigarette smoke induced inflammation, lung injury and emphysema. AZD9668 has been 
evaluated in clinical studies of up to 12 week duration by Astra Zeneca as a potential novel oral 
treatment to control the symptoms and exacerbations of chronic obstructive pulmonary disease (COPD), 
and reduce the progression and severity of the disease. 
Mechanism of action 
In vitro potency determinations for purified human NE and a number of other serine proteases were 
performed by measuring the cleavage of fluorogenic or chromogenic peptide substrates to fluorescent 
or coloured products. Potency (pIC50) was defined as the negative logarithm of the molar concentration 
of AZD9668 required to inhibit the formation of product by 50%. 


Clinical protocol AZD9668 dated 06/13/2017 
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AZD9668 was a potent inhibitor of human NE with IC50 and pIC50 values of 0.012 microM (12 nM)
and 7.9 respectively. Lineweaver-Burk analysis of the effect of substrate concentration on the 
Michaelis-Menten constant (Km) and maximum rate of metabolism (Vmax) values in the presence of 
AZD9668 indicated competitive inhibition and simultaneous non-linear curve fitting of data generated a 
pKi of 7.7 (19 nM). 
AZD9668 showed considerable selectivity for human NE over other serine proteases, including human 
cathepsin G (680-fold), and >1900-fold selectivity over chymotrypsin, pancreatic elastase, trypsin and 
proteinase-3. 
The binding of AZD9668 to human NE was reversible, with a fast rate of formation of enzyme inhibitor 
complex (Kon) of 2.5 x 10 6 M-1s-1 and rate of dissociation of enzyme inhibitor complex (Koff) of 1.2 
x10-2 s-1. The off rate t1
⁄2 was 1.1 minutes and the calculated dissociation constant (KD) was 0.005 
microM (5 nM). 
Compared to its potent inhibitory activity on human NE (IC50/pIC50 0.012 microM/7.9), AZD9668 
inhibited NE from other species with only moderate potency; values for mouse, rat and dog were 0.29 
microM/6.5, 0.22 microM/6.7 and 0.39 microM/6.4 respectively) 
Instillation of NE (2 mg/kg) into the trachea of mice induces vascular 
injury, haemorrhage, and 
degradation of the lung structural proteins, elastin and collagen. AZD9668, given orally, dose 
dependently inhibited haemorrhage induced by instillation of human NE; interpolated ED50 and ED80 
values were 0.85 mg/kg and 2.25 mg/kg (1.6 micromol/kg and 4.1 micromol/kg), respectively. The 
interpolated total blood concentration of AZD9668 at ED80 was 0.046 microM (46 nM). 
Clinical studies/Investigational 
Data 
AZD9668 was being developed by AstraZeneca as a novel oral treatment to control the symptoms and 
exacerbations of chronic obstructive pulmonary disease (COPD), and reduce the progression and 
severity of the disease. However, the development in COPD was stopped following the completion of 2 
Phase IIb/II studies (BREEZE/MISTRAL). 
In these two large studies evaluating the efficacy of AZD9668 on background therapies of tiotropium and 
budesonide/formoterol, 
respectively, there was no evidence of a beneficial effect across a range of lung 
function and symptom variables measured at clinic and at home during 12 weeks of treatment with 
AZD9668 compared to placebo. 
An additional exploratory Phase IIb study, MASCOT, evaluated MSCT in COPD patients treated with 
AZD9668 compared to placebo on tiotropium background therapy. All patients in MASCOT have 
completed and the study is under analysis. Initial results 
indicate no differences between treatment 
groups for the primary variable of airway wall thickness or for clinic based spirometry measures. 
Improvements in some secondary measures were observed in this small exploratory study but were not 
confirmed by the larger BREEZE study. 
No treatment-emergent 
deaths were reported in patients receiving AZD9668 in the 12 completed 
studies. There were no treatment-emergent 
SAEs reported during the Phase I study programme. In the 
Phase II/IIb studies in COPD, the most common SAE in the BREEZE and MISTRAL was exacerbation 


Clinical protocol AZD9668 dated 06/13/2017 
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of COPD; other SAEs were typically reported at single incidences. In the MASCOT study (all patients 
have completed and the study is under analysis), there were no SAEs reported in patients receiving 
AZD9968. 
In Phase I studies, in both Caucasian and Japanese healthy subjects, single oral doses of AZD9668 up 
to 120 mg once daily and multiple oral doses of AZD9668 up to 70 mg orally bid were found to be safe 
and generally well-tolerated. In Phase II studies AZD9668 (60 mg bid) was well tolerated in patients 
with COPD, cystic fibrosis and bronchiectasis. 
The AE most frequently reported in the Phase I studies and the studies in patients with cystic fibrosis or 
bronchiectasis was headache, reported by more subjects on AZD9668 than on placebo. In patients with 
COPD (Study D0520C00002), the AE reported by the greatest number of patients was also headache, 
reported by fewer patients on AZD9668 than on placebo. 
In the Phase II/IIb studies in COPD, the most commonly 
reported AE was nasopharyngitis (BREEZE 
and MASCOT), headache (MISTRAL). 
In one cystic fibrosis patient treated with AZD9668, creatinine phosphokinase, ALT, AST and LDH 
increased during treatment. An initial peak was temporally associated with unaccustomed heavy 
exercise; however there was insufficient information for a second peak in values to attribute the 
changes to exercise and therefore a relationship to study drug could not be excluded. In one 
bronchiectasis patient with raised ALT and AST, transaminases increased during treatment with 
AZD9668, started to decline while the patient continued treatment and returned to baseline levels after 
the end of the study. There were no associated symptoms; bilirubin and other liver function tests 
remained normal. A relationship to study drug of the raised transaminases in this patient cannot be 
excluded. 
Elevations in liver transaminases were observed during the Phase II/IIb programme in COPD: 
-BREEZE - the proportion of patients with elevation of ALT to 3 x upper limit of normal (ULN) was 
highest in the AZD9668 5 mg and 60 mg groups, both with 4 (2%) patients vs. 1 (<1%) in both the 
placebo and AZD9668 20 mg groups. No patients reported elevation of total bilirubin to 2 x ULN in the 
placebo group with 1 (<1%) in each of the AZD9668 groups. One patient (E2201001), in the AZD9668 
5 mg group reported an elevation of ALT to >3 x ULN and total bilirubin to >2 x ULN on Day 97, 27 
days after stopping study treatment. This patient was later diagnosed to have a cholangiocarcinoma 
of 
the bile duct. 
-Although definite evidence of dose relationship was lacking, there was a suggestion of an increased 
incidence of liver transaminase elevations in patients on AZD9668 for which there were no definite 
alternative explanations. The highest transaminase elevations occurred in the highest AZD9668 dose 
(60 mg). 
-MISTRAL - there were a few isolated cases of elevated hepatic biochemistry measurements but 
overall the number of patients with hepatic biochemistry above 1.5 x ULN was small. A higher 
proportion of patients in the AZD9668 60 mg group had raised transaminases (ALT and AST) above 
the AstraZeneca ULN (between 1 x ULN and 3 x ULN) compared with the placebo group. 
MASCOT - no patients developed high transaminase values (ALT or AST to ␣3 x ULN) in the AZD9668
60 mg dose group during this study. 


Clinical protocol AZD9668 dated 06/13/2017 
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There were no other clinically relevant changes in clinical chemistry data in the completed studies with 
AZD9668. No clinically relevant changes in urinalysis were observed in the 12 completed studies with 
AZD9668. In the completed studies there were no changes in ECG or vital signs data that indicated a 
clear treatment effect of AZD9668. 
1.6.4 AZD9668 Placebo: 
Tablet identical in color and shape but without the API. 
1.7 STUDY MEDICATION RISK INFORMATION FROM PREVIOUS TRIALS 
1.7.1 Metformin: 
Hypoglycemia: Although uncommon 
in patients receiving metformin as monotherapy, debilitated, 
malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or pituitary 
insufficiency may be particularly susceptible. Strenuous exercise, alcohol ingestion, 
insufficient caloric 
intake, or use in combination with other antidiabetic agents may increase risk. Hypoglycemia may be 
difficult to recognize in geriatric patients or in those receiving beta-adrenergic blocking agents. 
Hematologic Effects: Decreased serum vitamin B12 concentrations, with or without clinical 
manifestations (e.g., anemia). Symptoms rapidly reversible following discontinuation of metformin or 
supplementation with vitamin B12. 
Common Adverse Effects: Diarrhea, nausea, vomiting, abdominal bloating, abdominal cramping or pain, 
flatulence, and anorexia have all been reported as common AEs. 
Drugs That May Antagonize Hypoglycemic Effects: Calcium-channel blocking agents, corticosteroids, 
thiazide diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, 
sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline). 
1.7.2 Saxagliptin: 
Hypersensitivity Reactions: During postmarketing experience the following adverse reactions have 
been reported with use of saxagliptin: serious hypersensitivity reactions, including anaphylaxis and 
angioedema. Because these reactions are reported voluntarily from a population of uncertain size, it is 
not possible to reliably estimate their frequency 
Pancreatitis: During postmarketing experience, there have been spontaneously reported adverse 
reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute 
pancreatitis: persistent, severe abdominal pain. 
Use in Patients with Renal Impairment: Assessment of renal function is recommended prior to initiation 
of saxagliptin and periodically thereafter. No dosage adjustment is required in patients with mild renal 
impairment (CrCL >50 to ≤80 mL/min). A single dosage adjustment is recommended 
in patients with 
moderate (CrCL 30 to ≤50 mL/min) or severe (CrCL <30mL/min) renal impairment. The experience in 
patients with severe renal impairment is very limited. 
Skin disorders: Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in 
non-clinical toxicology studies. Although skin lesions were not observed at an increased incidence in 


Clinical protocol AZD9668 dated 06/13/2017 
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clinical trials, there is limited experience in patients with diabetic skin complications. Postmarketing 
reports of rash have been described in the DPP-IV 
inhibitor class. Rash is also noted as an adverse 
event for saxagliptin. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin 
disorders, such as blistering, ulceration or rash, is recommended. 
Immunocompromised 
patients: Pathology-related, 
immunocompromised 
patients, as well as patients 
with non-intervention-induced 
immunodeficiency have not been studied in the saxagliptin clinical 
program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been 
established. 
In a 24-week, active-controlled study of initial therapy of ONGLYZA in combination with metformin, the 
adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are: 
headache (7.5% combination 5 mg saxagliptin + metformin vs. 6.3% saxagliptin 10 mg alone vs. 5.2% 
metformin alone), and nasopharyngitis (6.9% combination 5 mg saxagliptin + metformin vs. 4.2. 
saxagliptin 10 mg alone vs. 4.0% metformin alone). In this trial, the less common adverse events when 
saxagliptin was offered in combination with metformin as initial therapy, reported in => 2% of patients, 
included:: bronchitis, dyspepsia, back pain, nasopharyngitis and headache. 
Hypoglycemia: When saxagliptin is added to metformin as initial therapy, the incidence of 
hypoglycaemia was 3.4% in patients given saxagliptin 5 mg plus metformin, 1.5% in patients given 
saxagliptin 10 mg alone, and 4.0% in patients given metformin 
alone. Under longer term use, the 
incidence of hypoglycaemia was 4.4% in patients given saxagliptin 5 mg plus metformin, 1.8% in 
patients given saxagliptin 10 mg alone, and 5.2% in patients given metformin alone. 
Laboratory Tests: Across clinical studies, the incidence of laboratory adverse events was similar in 
patients treated with saxagliptin 5 mg alone or in combination compared to patients treated with 
placebo. A small decrease in absolute lymphocyte count was observed. From a baseline mean absolute 
lymphocyte count of approximately 2.2 x 10
9 c/L, a mean decrease of approximately 0.1 x 10
9 c/L 
relative to placebo was observed in a pooled analysis of five placebo-controlled 
clinical studies. Mean 
absolute lymphocyte counts remained stable and within the normal limits with daily dosing up to 
102 weeks in duration. In the short term period, the proportion of patients who were reported to have a 
lymphocyte count ≤750 cells/microL was 1.5% and 0.4% in the saxagliptin 5 mg and placebo groups, 
respectively. In the short-term combined with long-term extension period of the pooled studies, the 
proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 1.6% and 
1.0% in the saxagliptin 5 mg and placebo groups, respectively. The decreases in lymphocyte count 
were not associated with clinically relevant adverse reactions. The clinical significance of this decrease 
in lymphocyte count relative to placebo is not known. 
Postmarketing experience: During postmarketing experience the following adverse reactions have been 
reported with use of saxagliptin: acute pancreatitis and hypersensitivity reactions, including anaphylaxis, 
angioedema, rash, and urticaria. Because these reactions are reported voluntarily from a population of 
uncertain size, it is not possible to reliably estimate their frequency. 
Postmarketing reports of severe and disabling arthralgia: The FDA, by searching the FDA Adverse Event 
Reporting System (FAERS) Database as well as the medical literature [134-137], identified cases of 
severe joint pain associated with the use of DPP-IV inhibitors as a class of drugs. 33 cases of severe 
arthralgia reported with the use of DPP-IV inhibitors from October 16, 2006, approval date of the first 
DPP-IV inhibitor, through December 31, 2013. Each case involved the use of one or more DPP-IV 
inhibitor. Sitagliptin (n=28) was the most frequently reported, followed by saxagliptin (n=5), linagliptin 
(n=2), alogliptin (n=1), and vildagliptin (n=2; although it is not marketed in the United States). In five 
cases, the patient experienced severe arthralgia with two different DPP-IV inhibitors. All 33 patients 


Clinical protocol AZD9668 dated 06/13/2017 
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experienced arthralgia that resulted in a substantial reduction in their prior level of activity, including 10 
patients who were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 
month of initiation of treatment with a DPP-IV inhibitor. In 20 of the 33 cases, the DPP-IV inhibitor was 
suspected as a possible cause of arthralgia and was discontinued within a month following the onset of 
symptoms. However, 8 of the remaining 13 cases reported a period of 44 days to 1 year between the 
onset of symptoms and discontinuation of the DPP-IV inhibitor. In 23 of the 33 cases, symptoms 
resolved less than 1 month after discontinuation of the drug. Reports of eight of the 33 cases 
documented a positive rechallenge. In these eight cases, 
individuals discontinued treatment, 
experienced a resolution of symptoms, restarted therapy with a DPP-IV 
inhibitor (a different member of 
the class in six of the eight cases), experienced the reappearance of the arthralgia, and subsequently, 
experienced resolution of the symptoms when DPP-IV inhibitor therapy was again discontinued. 
Twenty-one of the 33 patients were treated for arthritis with drug therapies that included corticosteroids, 
nonsteroidal anti-inflammatory drugs, methotrexate, and immune-modulating 
drugs. The FDA reviewed 
the clinical details in the FAERS cases to determine whether the severe joint pain could have been 
caused by an autoimmune condition rather than the DPP-IV 
inhibitors. Ten of the 33 cases reported 
fever and chills, rash, and swelling, which are suggestive of an immunological reaction. Of the 13 cases 
with available results of laboratory assays for systemic autoimmune disorders, 8 reported a negative or 
normal test result. Five cases reported positive test results: antinuclear antibody (n=2), erythrocyte 
sedimentation rate (n=1), C-reactive protein (n=1), and antinuclear cytoplasmic antibody (n=1). However, 
none of these tests are specific for a particular autoimmune condition that can cause severe joint pain. 
The FDA also searched the medical literature and identified seven case reports [134-137] two of which 
were also identified in the FAERS database [134,137]. All seven reports described patients who 
developed arthralgia after starting therapy with either sitagliptin (n=6) or vildagliptin (n=1). In six cases, 
patients had partial or complete resolution of symptoms within 6 weeks of discontinuing the drug. Only 
one case reported the pain to be disabling, and none reported the need for hospitalization. 
1.7.3 AZD9668: 
Emerging safety profile 
The following events have been identified as adverse drug reactions associated with AZD9668: 
Headache. Alanine aminotransferase increased, and Aspartate aminotransferase 
increased 
Headache was the most frequently reported AE among 8/12 studies completed to date. In Study 
D0520C00001, it was reported by 13/36 (36%) subjects who received single doses of AZD9668, and 
7/18 (39%) of those who received multiple doses, and was seen on both active and placebo. There 
seemed to be a dose effect in the SAD part, which was not apparent in the MAD part of the study. Most 
of the headaches were mild in intensity, although 1 subject had severe headache. In Study 
D0520C00004 the headaches generally occurred in a higher proportion of subjects on AZD9668 than on 
placebo. There was no evidence of a dose-related increase in the incidence of headache in either 
Japanese or Caucasian subjects. In the first study in patients with COPD (D0520C00002) headache was 
reported by fewer patients on AZD9668 (1/12 patients) than on placebo (4/6 patients). In the study 
in patients with cystic fibrosis (D0520C00009) it was reported by 5/29 (17%) patients on placebo and by 
7/26 (27%) patients on AZD9668, and in the bronchiectasis study (D0520C00010) it was reported by 
2/16 (13%) patients on placebo and by 7/22 (32%) patients on AZD9668. In the BREEZE 
(D0520C00012) and MISTRAL (D0520C00020) COPD studies, headache remained one of the most 
common AEs reported and was the most commonly reported treatment-related AEs (3 patients in the 
AZD9668 60 mg group) in the MISTRAL study. 


Clinical protocol AZD9668 dated 06/13/2017 
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Liver function In the Phase IIb COPD program there were 14 instances where patients experienced 
raised ALT or AST to =>3 x ULN across the studied doses (AZD9668 5, 20 and 60 mg bid); there were 
no cases of Hy’s law during the treatment period. Although definite evidence of dose relationship was 
lacking, there was a suggestion of an increased incidence of liver transaminase elevations in patients on 
AZD9668 for which there were no definite alternative explanations. The highest transaminase 
elevations occurred in the highest AZD9668 dose (60 mg). Elevations in hepatic biochemistry 
assessments (transaminases) observed in patients in the AZD9668 studies were not always consistent 
with alcohol use and suggest alcohol use was unlikely to be a potential confounding factor in most 
cases. 
A total of 57 treatment-emergent 
non-serious adverse events (AEs) were reported by 27 subjects. Most 
of the AEs were mild; 2 AEs (in the same subject) were reported as severe: syncope associated with a 
bradycardia, 4 h 36 minutes after AZD9668 2 mg. Both these events resolved with supportive care 
within 3 minutes. Six AEs were reported as moderate in intensity, including headache (1 subject on 
AZD9668 30 mg and 1 subject on 150 mg), migraine (1 subject on placebo and 1 subject on AZD9668 
120 mg), influenza (1 subject on AZD9668 30 mg) and dizziness (1 subject on AZD9668 120 mg). 
The most frequently reported AE in the SAD part of the study was headache, mostly mild in intensity. 
Treatment-emergent 
headache was reported by 11/36 subjects on AZD9668, including 5 of the 6 
subjects on AZD9668 150 mg, compared with 3/12 on placebo; a further 2 subjects on AZD9668 had 
headaches that started before treatment and continued after dosing. In the subject who developed 
moderate headache on the 150 mg dose, the investigator considered this to be causally related to the 
study drug. The 2 events of blurred vision (subjects on AZD9668 60 mg) were mild and were 
considered unlikely to be related to study treatment. Two subjects on AZD9668 2 mg had vasovagal 
syncope (in 1 case associated with a bradycardia). 
One subject on AZD9668 120 mg developed a non-sustained broad complex monomorphic tachycardia 
(5 beats, 2 seconds) 37 minutes after dosing. This subject was noted to have frequent supra-ventricular 
extrasystoles prior to dosing. The investigator considered this event not related to the study drug. 
Adverse events following multiple doses of AZD9668: Multiple doses of AZD9668 in healthy subjects 
(Study D0520C00001): There were no deaths, other SAE, or Other Significant Adverse Events. Two 
subjects discontinued study drug and were prematurely withdrawn from the study because of AEs. One 
subject on AZD9668 70 mg was withdrawn from the study after 2 doses, because of an AE of a run of 
premature atrial contractions on Day 1 of the study, 1 h 25 min post-dose; 
AE was not considered to be drug-related. A subject on AZD9668 120 mg was withdrawn after a single 
dose because of AEs of severe headache, followed by nausea and vomiting (onset 1 to 2 h post-dose), 
which were considered to be drug-related. 
Most AEs were mild (2 were moderate in intensity and 1 was severe). The AEs recorded as moderate 
in intensity were headache (on AZD9668 30 mg) and dyspepsia (on placebo). The severe AE was 
headache (on AZD9668 120 mg), which led to withdrawal from the study. 
As in the SAD part of the study, the most frequently reported AE in the MAD part was headache (2/9 
subjects on placebo, 3/6 subjects on AZD9668 30 mg, 1/6 subjects on AZD9668 70 mg and 3/6 
subjects on AZD9668 120 mg 
Hematology and clinical chemistry (Single and multiple doses of AZD9668 in healthy subjects): 
Study D0520C00001: There were no clinically relevant AZD9668 dose-related changes or trends in any 


Clinical protocol AZD9668 dated 06/13/2017 
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clinical laboratory parameters in Study D0520C00001. 
Study D0520C00004: In Study D0520C00004, raised blood creatine phosphokinase was reported in 3 
subjects; in 2 cases (both Caucasians) the finding was reported as a severe AE (1 subject who 
received a single dose of 30 mg AZD9668, and 1 subject who received placebo). A third subject, on 
placebo, also had raised creatine phosphokinase. There were no other clinically relevant AZD9668 
dose-related changes or trends in any clinical laboratory parameters. 
Studies D0520C00007, D0520C00016, D0520C00017 and D0520C00021 There were no clinically 
relevant changes in safety laboratory variables. 
Vital signs and ECG (Single and multiple doses of AZD9668 in healthy subjects): 
Study D0520C00001: there were no changes in vital signs judged to be of clinical significance in any of 
the studies. Evaluation of the digital ECG measurements in the SAD part of Study D0520C00001 
indicated that there were no observations of QTcF interval (QT interval corrected using Fridericia’s 
method) >450 ms; 3 subjects had a change from baseline QTcF >30 ms (all <36 ms). In the MAD part 
of the study, 1 subject had a QTcF measurement >450 ms (467 ms), and 4 subjects had a change from 
baseline greater than 30 ms, but less than 60 ms. None of the changes was considered to be of clinical 
significance. 
No clinically relevant changes in vital signs or ECG were observed in Studies D0520C00004, 
D0520C00007, D0520C00016, D0520C00017 and D0520C00021. 
Cystic fibrosis (Study D0520C00009): No clinically relevant changes in vital signs or ECG were 
observed in Study D0520C00009. 
Bronchiectasis (Study D0520C00010): In Study D0520C00010, abnormal ECGs were observed in 15 
patients (7/16 on placebo and 8/22 on AZD9668), but none was considered to be of clinical significance. 
COPD Study D0520C00002: In Study D0520C00002, no patient had a QTcF >450 ms, or prolongation 
from baseline of QTcF >60 ms. One out of the 12 patients on AZD9668 had an increase in QTcF >30 
ms (37 ms), but overall the ECG data indicated no evidence of clinically relevant changes related to 
study treatment. 
Study D0520C00012 BREEZE: Across the AZD9668 treatment groups, there was no evidence of any 
dose-dependent changes in vital signs and ECG and no apparent difference in each AZD9668 
treatment group compared to placebo. 
Study D0520C00020 MISTRAL: There were no clinically relevant findings in vital signs or 
electrocardiograms 
during the study. 
Study D0520C00014 MASCOT (draft data): The results for vital signs and ECG were unremarkable. 
1.8 STUDY OBJECTIVES AND ENDPOINTS 
The primary objective of this trial is to assess the efficacy of 60 mg bid AZD9668 PO bid versus 
placebo as adjunctive treatment to improve insulin sensitivity in obese, insulin-resistant T2D subjects as 
assessed by the hyperinsulinemic-euglycemic clamp method at baseline and 6 months post 
randomization.. 
Secondary objectives 
include: 


Clinical protocol AZD9668 dated 06/13/2017  
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i) To assess the safety of AZD9668 vs. placebo (rate and severity of adverse events including
hypoglycemia) in obese, insulin-resistant T2D subjects;
ii)To measure the glycemic and metabolic control variables (change in baseline HbA1c levels,
fasting plasma glucose levels, 2h-post-glucose challenge 
levels, body weight, waist- and hip- 
circumference, HbA1c trajectory, metformin and/or SAXA dose requirements) in AZD9668or
placebo-treated obese, insulin-resistant T2D subjects;
iii)To measure changes in glucose, insulin and C-peptide levels during a 3 hour oral glucose
tolerance test (OGTT) at 6 months from baseline. From the OGTT, parameters of glucose
metabolism will derived: insulinogenic index using C-peptide and insulin [1-5]; glucose area
under the curve (AUC), and Matsuda Index of insulin resistance [6-8], and the product of
Matsuda index times the insulinogenic index
iv)To identify changes in inflammatory variables (concentrations of serum/plasma IL-6, high
sensitivity-C-reactive 
protein, fibrinogen, TNF-alpha, soluble TNF-alpha receptors) in AZD9668
or placebo-treated obese, insulin-resistant T2D subjects.
v) Assessment of biomarkers to Determine the Expression of Functional Pharmacologic Activity of
AZD9668: Desmosine 
levels in serum and urine.
o Desmosine is released during matrix degradation by NE and cleared by the kidney,
although it can also be detected in serum. Results from animal models and human
disease studies have indicated that NE activity 
in vivo is associated with the release of
desmosine, resulting in increased serum and urinary desmosine [127,133,147,151-153].
Thus, desmosine levels in serum and urine are relevant indirect biomarkers of the
efficacy of AZD9668 on NE activity, and they will be measured in urine of the study
subjects at the specified visits of the study.
Exploratory measures will include: 
i) To investigate whether or not delayed AZD9668administration 
(at 6 months) is inferior to the
early AZD9668 treatment (at trial start) on IR improvements 
in insulin sensitivity, metabolic 
measures, and beta cell function; 
ii)To assess the effects of AZ9668 and placebo on the frequency and absolute cell numbers of
neutrophils, T-cells, B-cells, dendritic cells (DC) as well as other peripheral blood leukocytes 
(PBL) over the entire study period of both trial stages; 
iii)To determine the molecular signatures in PBL and purified neutrophils in AZ9668 and placebo
recipients over the entire study period of both trial stages including HLA and TCR levels; 
iv)To determine the changes in neutrophil cell surface phenotype over the duration of the study in
placebo and AZD9668-treated subjects; 
v) To identify cellular and molecular signatures of responder versus non-responder status and/or
of effect of therapy in AZD9668 or placebo recipients over the entire study period of both trial 
stages; 
vi)To correlate changes in neutrophil absolute numbers with activation of TCR and HLA-specific
PBLs over time. 
1.8.1 STUDY ENDPOINTS 
1.8.1.1 Primary Endpoint: Improvement of insulin sensitivity by 40% or greater at 6 months compared to 
baseline, assessed by the 80 mU/m2 min-1 hyperinsulinemic-euglycemic clamp method. 
1.8.1.2 Secondary Endpoints: We are basing these endpoints on the minimum statistically-meaningful 
improvements of either MET alone or MET+a DPPIV inhibitor [154-162]: 


Clinical protocol AZD9668 dated 06/13/2017  
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i) Improvement in glycated HbA1c levels (range=0.2 – 1.5 or better) at 6 months compared to
baseline;
ii)Improvement OGTT-derived measurements, namely: glucose tolerance, glucose AUC, Matsuda
Index of insulin resistance [6-8], insulinogenic 
index using C-peptide [1-5], and the product of
Matsuda index times the insulinogenic index; bone density/total fat mass corrected 
insulin
sensitivity 
indices as well.
iii)Improvement in fasting plasma glucose by 6% or better at 6 months compared to baseline;
iv)decreased concentrations of serum/plasma IL-6, high sensitivity-C-reactive 
protein, fibrinogen,
TNF-alpha, soluble TNF-alpha receptors at 6 months compared to baseline.
1.8.1.3 Primary Efficacy Endpoint: Improvement of insulin sensitivity by 40% or greater at 6 months 
compared to baseline, assessed by the 80 mU/m2 min-1 hyperinsulinemic-euglycemic clamp method. 
1.8.1.4 Secondary Efficacy Endpoints: 
i) Improvement in glycated HbA1c levels (range=0.2 – 1.5 or better) at 6 months compared to
baseline; 
ii)Improvement OGTT-derived measurements, namely: glucose tolerance, Matsuda Index of
insulin resistance [6-8], insulinogenic index using C-peptide [1-5]; bone density/total fat mass 
corrected 
insulin sensitivity indices as well. 
iii)Improvement in fasting plasma glucose by 6% or better at 6 months compared to baseline;
1.8.1.5 Safety Endpoints: Identification of AEs: 
i) rate and severity of all adverse events including hypoglycemia
ii)rate and severity of known AEs of AZD9668
iii)rate and severity of known AEs of SAXA
iv)rate and severity of known AEs of Metformin
1.8.1.6 Exploratory Endpoints: To investigate whether or not delayed AZ9668 administration (at 6 
months) is inferior to the early AZ9668 treatment (at trial start) on IR improvements in insulin 
sensitivity, metabolic measures, and beta cell function 
1.8.1.7 Mechanistic Endpoints 
i) To assess the effects of AZ9668 and placebo on the frequency and absolute cell numbers of
neutrophils, T-cells, B-cells, dendritic cells (DC) as well as other peripheral blood leukocytes 
(PBL) over the entire study period of both trial stages; 
ii)To determine the molecular signatures in PBL and purified neutrophils in AZ9668 and placebo
recipients over the entire study period of both trial stages including HLA and TCR levels; 
iii)To determine the changes in neutrophil cell surface phenotype over the duration of the study in
placebo and AZD9668-treated subjects; 
iv)To identify cellular and molecular signatures of responder versus non-responder status and/or
of effect of therapy in AZ9668 or placebo recipients over the entire study period of both trial 
stages; 
v) To correlate changes in neutrophil absolute numbers with activation of TCR and HLA-specific
PBLs over time. 


Clinical protocol AZD9668 dated 06/13/2017  
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2.0 RESEARCH DESIGN 
2.1 STUDY AGENTS 
1)Saxagliptin (saxagliptin HCl) 5 mg
2)Metformin 
(metformin 
HCl) 500-2000 mg
Saxagliptin and metformin will comprise the basal drug combination to which AZD9668 or AZD9668 
placebo will be added. 
3)AZD9668 60 mg (achieved by two tablets each of 30 mg)
4)AZD9668 placebo
2.2 STUDY AGENT DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN 
Metformin will be administered as oral tablets at a daily dose of no more than 2000 mg; all patients will 
continue on their stable dose of metformin throughout the course of the study. Saxagliptin will be 
administered as oral tablets at a dose of 5 mg qd. AZD9668 will be administered as oral tablets at a 
dose of two tablets of 30 mg bid. AZD9668 placebo will be administered as oral tablets bid. Refer to 
Sections 4.5 for detailed information regarding the run-in and in-study periods. 
2.2.1 Labeling,  Packaging,  Storage, Dispensing, and Return of Clinical  Supplies 
2.2.2 Product  Descriptions 
Investigational materials (excluding metformin) will be provided by Astra Zeneca. 
Saxagliptin will be provided in tablet form at 5 mg active pharmaceutical ingredient per tablet. 
AZD9668 will be provided in tablet form at 30 mg active pharmaceutical ingredient per tablet. 
AZD9668 placebo will be provided in tablet form. 
Metformin HCl (generic) will be sourced from the designated trial dispensing pharmacy at AHN. 
The pharmacist and/or study coordinator will record the lot number, expiration date, and drug 
dispensed. 
2.2.3 Packaging  Information 
All study subjects will receive drug based upon the dispensing schedule described in the Visit 
Schematic (Figure 4, Section 4.5). Supplies will be affixed with a clinical label in accordance with 
regulatory requirements. 
2.2.4 Clinical  Supplies  Disclosure 
The investigator’s site personnel are not blinded to the basal drug treatment (saxagliptin+metformin) 
as 
all study subjects will take these agents. Drug identity (name, strength) is included in the label text; 
disclosure envelopes are not provided. However, the investigator’s site personnel will be blinded to the 
study agents (AZD9668 or placebo). Only the dispensing pharmacy will know the identity of the study 
agent and will maintain a detailed record of the date of dispensing, the lot numbers, any control 


Clinical protocol AZD9668 dated 06/13/2017  
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numbers and identifiers as the pharmacy will transmit these data to the AHN research staff (data entry, 
storage, and management center as well as the liaison between the PI and the trial study coordinator as 
well as the study physicians). 
2.2.5 Storage and Handling  Requirements 
The storage conditions for the saxagliptin 5 mg and the metformin 500 mg tablets will be indicated on 
the product 
label. The study agents AZD9668 and placebo will be stored at 15-25 degrees Celcius.. 
Upon receipt at the investigational site, the study agents should be removed from the outer secondary 
shipping box and stored immediately. 
The clinical supplies storage area at the site must be monitored by the site staff for temperature 
consistency with the acceptable storage temperature range specified in this protocol or in the product 
label attached to the protocol. Documentation of temperature monitoring should be maintained. 
Supplies should be stored in the original nested box with the lid closed to minimize exposure to light. 
The study agents must NOT be frozen. 
A temperature log must be maintained at the site. All subjects will receive storage 
instructions for the 
study drugs 
2.3 Standard Policies/Return of Clinical  Supplies 
Investigational clinical supplies must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the participating research 
pharmacist, the investigator and designated assistants have access. Study drugs are to be dispensed by 
the research pharmacist only in accordance with the protocol. Non-drug clinical supplies, like the 
glucose monitor and the glucose monitor test strips can be dispensed by the study physicians and/or the 
study coordinator. The research pharmacist and the site clinical investigators are responsible for 
keeping accurate records of the clinical supplies received from Astra Zeneca, the amount dispensed to 
and returned by the patients, and the amount remaining at the conclusion of the study. In accordance 
with Good Pharmacy Practices, gloves should always be worn by study personnel if directly handling 
tablets or capsules that are returned (i.e., when counting returns). At the end of the study, all clinical 
supplies including partial and empty containers must be returned to the pharmacy who will store the 
study agents returned according to the study subject identifier until the end of the trial. The site clinical 
investigators or designated assistant(s) should not open individual clinical supply containers and count 
tablets/capsules, etc., before dispensing to the patients. Any deviation from this must be discussed with 
the PI and Astra Zeneca. 
2.4 Distributing 
to Site and Dispensing to Patients 
The designated research staff will allocate patients based on the randomization outcome, will assign 
study agents to the patients, will coordinate with Astra Zeneca and the pharmacy to ensure timely 
reception of the study agents. 
2.5 Known and Potential  Risks of Study Medications 
DRUG 
COMMON RISKS 
LESS COMMON RISKS 
RARE RISKS 
Metformin 
Abdominal or 
stomach 
discomfort, 
Anxiety, blurred vision, chest 
discomfort, cold sweats, coma, 
confusion, cool, pale skin, 
Behavior change similar 
to being drunk, difficulty 
with concentrating, 


Clinical protocol AZD9668 dated 06/13/2017  
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decreased appetite, 
diarrhea, 
depression, difficult or labored 
breathing, dizziness, 
fast/irregular, pounding or 
racing heartbeat or pulse, 
feeling of warmth, headache, 
increased hunger, increased 
sweating, nausea, 
nervousness, nightmares, 
redness of the face, neck, 
arms, and occasionally, upper 
chest, seizures, shakiness, 
shortness of breath, slurred 
speech, tightness in the chest, 
unusual tiredness or 
weakness, wheezing cough or 
hoarseness. fast or shallow 
breathing, fever or chills, 
general feeling of discomfort, 
lower back or side pain, 
muscle pain or cramping, 
painful or difficult urination, 
sleepiness 
drowsiness, lack or loss 
of strength, restless 
sleep, unusual 
sleepiness 
Saxagliptin 
headache, nasal 
congestion, runny 
nose, sneezing, 
sore throat, 
Diarrhea, joint pain, pain or 
tenderness around the eyes 
and cheekbones, redness of 
the skin, weakness, welts 
Anxiety, bladder pain, bloating 
or swelling of the face, arms, 
hands, lower legs, or feet, 
bloody or cloudy urine, blurred 
vision, body aches or pain, 
chills, cold sweats, coma, 
confusion, cool, pale skin, 
cough, depression, difficult, 
burning, or painful urination, 
difficulty with breathing, 
dizziness, ear congestion, fast 
heartbeat, fever, frequent urge 
to urinate, increased hunger, 
loss of voice, lower back or 
side pain, nausea, 
nervousness, nightmares, 
rapid weight gain, seizures, 
shakiness, slurred speech, 
tingling of the hands or feet, 
unusual tiredness or 
weakness, unusual weight gain 
or loss 
Constipation, darkened 
urine, difficulty with 
swallowing, flaking or 
peeling of the skin, 
hives, indigestion, large, 
hive-like swelling on the 
face, eyelids, lips, 
tongue, throat, hands, 
legs, feet, or sex 
organs, loss of appetite, 
pains in the stomach, 
side, or abdomen, 
possibly radiating to the 
back, puffiness or 
swelling of the eyelids or 
around the eyes, face, 
lips, or tongue, 
shortness of breath, skin 
rash, tightness in the 
chest, vomiting, 
wheezing, yellow eyes 
or skin 


Clinical protocol AZD9668 dated 06/13/2017  
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AZD9668 
Headache, dyspepsia 
Raised liver enzymes, 
slow heart rate, 
AZD9668 
placebo 
Headache 
Dyspepsia, dysgeusia, 
pneumonia, pulmonary 
exacerbation, non- 
cardiac chest pain 
2.6 Risks of study procedures 
2.6.1 Oral glucose tolerance test (OGTT): 
There are minimal risks associated with this procedure. The oral glucose drink may cause the following 
rare but known adverse reactions: nausea, vomiting, abdominal bloating, and potentially headache. In 
addition, there is a rare incidence of hypoglycemia. Other risks include pain and phlebitis associated with 
venipuncture and hyperglycemia, which is transient and self-limited. 
2.6.2 Hyperinsulinemic-euglycemic clamp (Clamp): 
The clamp infusion uses regular insulin (Humulin-R) and therefore there is a theoretical risk of 
hypoglycemia. This is extremely unlikely to occur since plasma glucose concentration is monitored every 
5-10 mins and fixed at approximately 5 mmol/l by a variable infusion of glucose 20%. Another potential 
risk is self-limited pain and phlebitis associated with venipuncture and peripheral catheter placement. 
2.6.3 Venipuncture: 
At the OGTT and the Clamp tests as well as during collection of peripheral blood-Common risk - 
include pain, bruising, inflammation or excessive bleeding at the venipuncture site and 
faintness/lightheadedness. Also, multiple punctures might be required to identify the veins. Rare risks 
include- hematoma, infection. 
2.6.4 DEXA total body scan: 
The low doses of ionizing radiation encountered in a standard scan are considered insignificant when 
compared to natural background radiation that one encounters everyday (approximately 7 microsieverts 
per day). DEXA scans result in radiation of the order of 0.1 – 0.4 microsieverts. This dose for total body 
scan is lower than that of lumbar spine and proximal femur scans as total body scans use a lower x-ray 
current setting, the transverse passes of the scan arm do not overlap, and the scan arm moves more 
quickly down the length of the scan table. 
3.0 STUDY POPULATION 
Forty two (42) type 2 diabetic subjects will be recruited, see Section 6.5 for details regarding sample 
size. 
3.1. INCLUSION CRITERIA 
1.Patients 21-75 years of age inclusive who meet the American Diabetes Association standard
criteria for type 2 diabetes mellitus (T2D).
2.Subjects are currently on metformin (at least 1000 mg per day) for a minimum period of 4 weeks
prior to screening visit alone, or in combination with any of the following diabetes medications or
combinations:
a. DPPIV inhibitor (any dose level/frequency)
b. Sulfonylurea (any dose level/frequency)
c. GLP1 agonist (any dose level/frequency)


Clinical protocol AZD9668 dated 06/13/2017  
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d. Sulfonylurea (any dose level/frequency) + GLP1 agonist (any dose level/frequency)
e. Meglitinide (any dose level/frequency)
f. SGLT2 inhibitor (any dose level/frequency)
3.Patients must have a body-to-mass index (BMI) of greater than or equal to 27 kg/m2.
4.Patients exhibit glycated HbA1c between 7.3-11.0 during eligibility screening and then <=8.5 at final
run-in visit.
5.Willingness to replace current diabetes therapies (listed in inclusion 2) with metformin and
saxagliptin and to adjust metformin dose during run-in period.
6.Subjects present adequate immune competence as assessed by immunoreactivity to viral antigens
(CEF Pool Assay) in vitro at the time of screening.
7.Participants of childbearing potential must agree to practice an effective form of birth control which
may include any one of the following: barrier method, oral contraception, or surgery. These
measures must be maintained throughout the study.
8.Subjects must have good peripheral venous access for the hyperinsulinemic-euglycemic clamp and
the 3-hr. OGTT procedures.
9.Patients understand the study procedures, alternative treatments available, risks involved in the
study, and voluntarily agree to participate by giving informed and signed written consent for
screening and enrollment.
10.Participants can be on anti-inflammatory therapies that are not diabetes-focused (e.g. non-salicylate
anti-inflammatory therapies, non-salicylate NSAIDs) and/or anti-hypertensive medicaments or
statins.
3.2 EXCLUSION CRITERIA 
1.Patients with type 1 diabetes mellitus as defined by the American Diabetes Association criteria or a
history of ketoacidosis, or the patients are assessed by the study team as possibly having type 1
diabetes mellitus confirmed with the presence of at least one of the typical autoantibodies (insulin,
GAD65, IA-2, ZnT8) AND a serum C-peptide level of <0.7 ng/mL.
2.Patients have been treated with any therapies specific for their diabetes (other than those listed in
the inclusion criteria) within 4 weeks of the screening visit.
3.Patients have been treated with insulin within 2 months of the screening visit.
4.Patients are currently participating in or have participated in another study with an investigational
compound or device within the prior 12 weeks of signing the informed consent or do not agree to
refrain from participating in any other study while participating in this study.
5.Patients have a history of hypersensitivity or any contraindication to DPPIV inhibitors, including
saxagliptin (Onglyza), or metformin based upon the labels of the USA.
6.Patients are on a weight loss medication (such as orlistat, phentermine, Qsymia, or Belviq) within the
prior 6 weeks.
7.Patients are required by treating physicians to remain on any one of these agents during the trial:
macrolide antibiotics, cisapride, anti-arrhythmics, steroids, rifampicin, phenobarbital, phenytoin,
secobarbital, carbamazepine, norethindrone, isoniazid. AZD9668 is metabolized by CYP3A4, 3A5,
and 2B6. SAXA is metabolized by CYP3A4 and 3A5, potentially leading to drug-drug interactions
with hypothetical adverse events in patients on the above agents. Also, AZD9668 causes weak
inhibition of CYP2C9 and therefore patients on fluconazole, amiodarone, fenofibrate, fluvoxamine,
phenylbutazone, probenecid, sertraline, will also be excluded to avoid the hypothetical adverse
events due to this effect.
8.Patients have undergone major surgery within the 6 weeks prior to signing consent or have any type
or form of major surgery planned during the study (at the discretion of the physician).
9.Patients are on or are likely to require treatment with 14 consecutive days or repeated courses of
pharmacologic doses of corticosteroids or any other immunomodulatory agent. For example,


Clinical protocol AZD9668 dated 06/13/2017  
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patients requiring chronic systemic corticosteroids (does not include topical or inhaled 
corticosteroids). Exceptions are over the counter non-salicylate NSAIDs. 
10.
Enrollment or history of enrollment in a drug, or biologic therapy clinical trial that affects the
immune system within the past 12 months (e.g., systemic immunosuppressive 
pharmacologics, 
immunosuppressive 
cytokines, therapeutic immunomodulating 
antibodies, therapeutic 
immunomodulating 
fusion proteins and/or cytokine receptor decoys as well as any intervention 
and/or non-intervention induced immunodeficiencies). 
11.Prior history of coronary artery disease (defined as myocardial infarction, angina, bypass surgery, or
angioplasty) 
12.Prior history of arrhythmia (excludes premature beats)
13.Prior history of heart failure defined as i) symptomatic OR ii) pulmonary edema, leg edema or low
ejection fraction (<40%)
14.Evidence of refractory chronic migraine (defined in ICHD-3 and Martelletti et al. [9,10] ).
15.History of persistent bradycardia within the last year prior screening visit (more than three episodes in
a calendar year of a heart rate <60 beats per minute that required hospitalization on each of these
occasions).
16.Leukopenia (<3000 leukocytes/microliter), 
neutropenia (1500 neutrophils/microliter), 
lymphopenia
(<800 lymphocytes/microliter), 
or thrombocytopenia (<125000 platelets/microliter),. 
any other
clinically relevant abnormal hematology value.
17.Positivity for HIV, active CMV, chlamydia, any evidence of serious fungal infection, active HSV1,
HSV2, hepatitis B or C, or history of HSV1 or HSV2 at screening. Minor skin fungus, or minor
candidiasis is not an enrollment or treatment exclusion criterion. Also, with the exception of HIV
history, hepatitis B and C, successfully-treated, 
disease-free individuals (> 6 months between time of
successful treatment confirmation and time at screening) would be eligible for enrollment in this trial.
18.Patients are required by treating physician to remain on any medications listed in inclusion #2 that
directly affect glucose metabolism such as, but not limited to thiazolidinediones, pramlintide, or
amylin.
19.Vaccination with any form of live vaccine product within the last 3 months prior to initiation of study
agent administration.
20.Any chronic disease that in the opinion of the investigators would affect the patient’s safety and/or
the integrity of the study outcome. This does not include dyslipidemia, patients on statin or anti- 
hypertension treatment, or patients with well-controlled hypo- or hyperthyroidism
21.Any other disease or disorder requiring chronic drug therapy except for treated hypothyroidism (T4
and TSH should be within the normal reference range adjusted for age), celiac disease, or statin- 
maintained, uncomplicated lipidemia.
22.Evidence of liver dysfunction, with ALT or AST> 1.5 times the upper limit of normal.
23.Evidence of renal insufficiency as indicated by blood creatinine of > 2 times the upper limit of normal
at baseline screening OR an eGFR < 45 mL/min. OR A past history or current clinical evidence of
renal failure or low creatinine clearance at screening.
24.Females who are pregnant at the time of screening or unwilling to defer pregnancy during the study
period.
25.Lactating women.
26.Poor accessibility to veins for the 3-hour OGTT and hyperinsulinemic-euglycemic clamp
procedures.
27.The following therapies cannot be administered while patients are undergoing treatment on this
protocol: i) radiation therapy; ii) chemotherapy; iii) corticosteroids (except for very short courses of
topical or inhaled); iv) agents used to treat attention deficit and hyperactivity disorder (ADHD); v)
rifampicin or phenytoin; vi) other protein, particle or cell vaccine immunomodulation 
therapies. If
these therapies are essential for treatment of other conditions, participation in this study will be
terminated.


Clinical protocol AZD9668 dated 06/13/2017  
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28.A condition which interferes with the ability to accurately determine glycated HbA1c. Examples
include: Genetic variants (e.g. HbS trait, HbC trait), elevated fetal hemoglobin (HbF) and chemically
modified derivatives of hemoglobin (e.g. carbamylated Hb in patients with renal failure); Any
condition that shortens erythrocyte survival or decreases mean erythrocyte age (e.g., recovery from
acute blood loss, hemolytic anemia); Iron deficiency anemia, iron replacement therapy
29. 
Subjects who cannot tolerate at least 1000 mg daily of immediate or extended release metformin by the 
time of final run-in will be excluded from further participation. 
30.Subjects who do not exhibit a glycated HbA1c level <=8.5 by the end of the run-in period.
3.3 STOPPING RULES 
The trial wi
l
l
: 
a) stop enrolling 
study
subjects; AND
b) request the study subjects in-trial  to stop study agent administration
(AZD9668 or placebo);
IF ANY OF THE FOLLOWING OCCUR: 
1. The FDA, the IRB, NCATS or the DSMB requires termination of the study upon review of the
safety data.
2. Any death occurs that is possibly or definitely related to AZD9668
3. If within the first three months of their first dose, three or more of the first (initial) 6 participants
treated with AZD9668 experience a study-related adverse event resulting in the permanent
discontinuation of the treatment (as defined in Section 4.7.2).
4. Infection that persists for > 2 weeks from expected time of mean clearance (clear of
symptomatic evidence of disease) in the general population. Fingernail mycosis, athlete’s foot,
minor candidiasis, limited cutaneous warts and clinically insignificant, minor infections of this
type and category allowable.
5. Any expected adverse event considered possibly or definitely related to AZD9668 that occurs at
a greater severity than previously observed or listed in the study documents and is therefore
considered unexpected and classified as an AE of special interest (AESI).
The DSMB will be notified of any of the above events within 5 days of study team becoming aware. In 
addition, any events that meet FDA or IRB reporting requirements will be reported within the respective 
required timeframes. 
In the event of trial stop or termination, all study subjects will return to their standard-of-care diabetes 
management plan that was in place prior to trial enrollment which will include pre-trial medication. 
Resumption of enrollment and study agent (AZD9668 or placebo) treatment is contingent upon a 
favorable IRB and DSMB safety review. 


Clinical protocol AZD9668 dated 06/13/2017  
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3.4 STUDY TIMELINE AND MILESTONE PLAN 
The below Go/No Go points will be reviewed by the PI, study DSMB and Medical Monitor as they 
evaluate study progress. Our primary milestones are primarily based on detecting AEs and then making 
Go/No Go decisions based on those along the statistical parameters established by Simon, Gonin and 
Lazaridis [163-167]. 
3.4.1 Go/No Go Points: (See Figure 1)– It is important to note that the Go/No Go decisions will be 
based on an evaluation of AEs/SAEs and these decisions will be carefully made taking into account 
chiefly what the DSMB believes to be due to the therapeutic intervention. We will evaluate these points 
at the following timeframes following the start of treatment with study drug: 
i)
Month 1 after start of AZD9668 treatment: if no unexpected AE considered related to the
study treatment or procedures of grade >2 (as defined by the NCI Common Terminology
Criteria for Adverse Events version 4.0 [http://ctep.cancer.gov/reporting/ctc.html]) is seen in
3 of the first 6 study subjects enrolled we will continue enrollment
ii)
Month 3 after start of AZD9668 treatment: Again, if no unexpected AE considered related to
the study treatment or procedures of grade >2 are seen in 6 of the first 12 study subjects
enrolled we will continue enrollment
iii)
Month 6 after start of AZD9668 treatment: If, again, no unexpected AE considered related to
the study treatment or procedures of grade >2 are seen in 9 of the first 18 study subjects
enrolled we will continue enrollment as necessary.
The secondary milestones are based on enrollment rate; A Go/No Go point will be evaluated if <25% of 
the total study subject population is enrolled by 6 months of the start of the trial. A second Go/No Go 
point will be evaluated if <50% of the study population is enrolled by 1 year following the start of the trial. 
Given the safety record of AZD9668, we do not anticipate any particular regulatory impediments. 
3.4.2 Procedure  and Pace of Enrollment 
and Study Duration 
We plan to enroll 42 subjects in this trial. The subject’s complete participation in this trial will last 
approximately 15 months (up to 66 weeks). 
3.4.3 Milestone  Grid (Figure 1) – REMOVED DUE TO MODIFIED SCHEDULE 


Clinical protocol AZD9668 dated 06/13/2017  
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4.0 COMPLETE PROTOCOL 
4.1 Overview 
This is a trial to be conducted in the USA. Potential study subjects must be either on MET monotherapy, 
GLP-1 analog monotherapy, or a combination of MET+(either a DPPIV inhibitor, OR a sulfonylurea OR a 
GLP-1 analog) prior to enrollment. These drugs will be substituted by the combination of MET+SAXA as 
background drugs (also describing the “placebo” arm) for the purpose of the trial. The trial consists of a 
2-arm, randomized, double-blinded, placebo-controlled, 
crossover study in 42 T2D subjects (n=38 + 4 to 
account for a possible 10% drop-off; refer to power analyses in Section 
6.5; between 21-75 years of age, inclusive, with a monitoring period of 12 months following a 1:1 
randomization into AZD9668:placebo 
arms. 
A 3-month run-in period will precede baseline assessments. With the inclusion/exclusion criteria 
proposed herein and based on past experience in T2D clinical trials, we estimate that we can enroll one 
subject for every 4 screened and every 2 that enter the run-in period. Randomization will take place 
after baseline assessments. The run-in period is aimed at achieving/maintaining 
an HbA1c level <= 8.5 
using an optimized regimen of MET+SAXA. During the run-in, MET dosing will be according to the MET 
titration information in Section 4.6.2 and Figure 6. 
SAXA will replace the DPPIV inhibitor in subjects on another DPPIV inhibitor and will be administered at 
a dose of 5 mg qd, which is the most common SAXA regimen in published clinical trials[138-146] for the 
run-in and study period. Subjects will then receive AZ9668 or placebo as adjunctive treatment to the 
MET+SAXA for a 6 month period. AZD9668 will be administered bid at two tablets of 30 mg bid for 6 
months, in line with other AZD9668 clinical trials where the agent was well-tolerated [127- 
129,131,132,147]. After the 6 month evaluation point of insulin sensitivity, assessed by the 80 mU/m2 
min-1 hyperinsulinemic-euglycemic clamp method [148-150], those on placebo will be crossed over 
and assigned to AZ9668 and those on AZD9668 will be crossed over into the placebo arm 
(MET+SAXA+”placebo 
pill”) for comparison of efficacy. All study subjects will remain on MET+SAXA 
throughout the entire 15 months. 
There is no need for a washout period due to the crossover design of the trial. 
Insulin sensitivity and AE monitoring of all arms will continue to 12 months. The hyperinsulinemic- 
euglycemic clamp technique is the gold standard for assessing insulin sensitivity in humans [149,150]. 
The choice in this trial is for a dose of insulin of 80 mU/m2/min which will provide sufficient stimulation of 
glucose uptake by skeletal muscle and completely suppress endogenous glucose production. In addition, 
this study will also conduct glucose tolerance tests to assess the effect of AZD9668 on 
glucose tolerance and secondary parameters of glucose metabolism such as insulin secretory 
response using the 3-hr. OGTT. The OGTT and clamp procedures will be separated by at least a week 
in the 6- and 12 month assessment points. The subject’s complete participation in this trial will last 
approximately 15 months (up to 66 weeks). 
The trial will be conducted under an intent-to-treat design such that all randomized subjects will 
continue follow-up and complete all outcome assessments until they complete participation in the trial. 
Otherwise, analyses of all outcomes would be susceptible to a healthy survivor effect where the only 
subjects evaluated at out years would be those who have not yet experienced primary failure of the 
assigned regimen. 


Clinical protocol AZD9668 dated 06/13/2017 
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Metformin has been selected as the foundation therapy based on the same rationale and 
characteristics as were used in the recently developed consensus algorithm (S41-Pharmacological 
Therapy for Type 2 Diabetes, in: http://professional.diabetes.org/admin/UserFiles/0%20- 
%20Sean/Documents/January%20Supplement%20Combined_Final.pdf): namely, its long-term clinical 
experience; effectiveness in lowering glycemia over a wide range of HbA1c levels without causing 
hypoglycemia; its weight-neutral or weight-loss effect; probable cardiovascular risk reduction (10, 11, 
23); safety profile; side-effect profile; high level of patient tolerance; and its low cost. Recent studies 
have shown that a large majority of patients with recent-onset T2DM are treated with metformin, 
making this design both practical and clinically relevant. 
4.2 STUDY PROTOCOL DIAGRAM/FLOW CHART 
Figure 2 


Clinical protocol AZD9668 dated 06/13/2017  
Page 44 of 93 
N=19-21 
N=19-21 
N=19-21 
N=19-21 
Figure 3 


Clinical protocol AZD9668 dated 06/13/2017  
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4.3 RECRUITMENT 
Potential subjects will be recruited after protocol approval by local IRBs. The combined diabetes clinics of 
the Allegheny Health Network [AHN] and AHN/Joslin Diabetes Clinics as well as the University of 
Pittsburgh Medical Center [UPMC] currently follow more than 2000 unique T2D subjects. Also, the two 
clinics combined diagnose approximately 500 new cases annually. Industry-sponsored and federal 
government-supported clinical trials are ongoing in all clinics with dedicated resources and personnel. 
Based on a very recent search of the proposed trial site patient databases (AHN/Joslin and UPMC), there 
are currently >2000 patients who entered the clinics as of the 1st of January 2011 for treatment of T2D. 
Potential recruitment approaches include:  
i)
Trial brochures/flyers in the clinics
ii)
Web-site/Facebook/Twitter
iii)
Advertising on local radio and public transportation
iv)
Advertising and advocacy through the local American Diabetes Association Chapters
We will aim to recruit as much representation as possible from racial and ethnic minority groups that are 
disproportionately affected by type 2 diabetes, encouraging the clinical centers to pay particular attention 
to these populations during recruitment. Clinical centers were selected to ensure an adequate distribution 
by race/ethnicity and age. 
4.4 INFORMED CONSENT 
Before study initiation, the investigator must have written and dated approval from the IRB for the protocol, 
consent form, and any other materials to be provided to subjects. All participants capable of providing 
informed consent must read, sign, and date the IRB-approved consent form and HIPAA authorization 
before entering the study, receiving study agent, or undergoing any study-specific procedures. Individuals 
interested in participating in the study will be offered information as well as the study consent forms. There 
are two consent forms; one for the procedures being conducted at AHN and the other for the procedures 
conducted at UPMC.  
The clinical study investigators will review the consent form and answer questions and the subject will be 
given ample time to review and decide whether or not to participate. The prospective study subject will be 
told that being in the trial is voluntary and that he or she may withdraw from the study at any time, for any 
reason.  The investigator must obtain documented consent from each potential patient prior to participating 
in a clinical trial. Consent must be documented by the patient’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion. A copy of the signed and dated 
consent form should be given to the patient before participating in the trial. 
The initial informed consent form and any subsequent revised written informed consent form and any 
written information provided to the patient must receive IRB approval in advance of use. The patient  
should be informed in a timely manner if new information becomes available that may be relevant to the 
patient’s willingness to continue participation in the study. The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form that 
captures the patient’s dated signature. 


Clinical protocol AZD9668 dated 06/13/2017  
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4.4.1 Consent and Collection of Specimens for Genetic and Other Biomedical Research 
In the informed consent, it will be made clear that one of the tests in the peripheral blood leukocytes will 
involve transcriptomic/epigenotype analyses, and even though these tests and their objective is not 
intended for “genetic analysis” in the strict definition of the term, the outcome data could in theory be 
extrapolated to deduce potential genetic risks of disease. The consent form will be clear that such 
extrapolations are not the objective of the trial, nor will they be pursued. Given the mandatory nature of this 
testing, if the study subject does not consent, they cannot be enrolled in the trial. 
In the informed consent, the study subject will also be made aware that any left-over blood samples are 
subject for storage and for future research on T2D (de-identified samples). This is contingent upon their 
consent explicit for this storage purpose. Only those subjects who have consented to allow storage of left-
over samples will have those samples stored. The investigator or designate is responsible for explaining 
the optional nature of the storage of biosamples and that participation in the associated clinical study is not 
dependent upon giving consent for such storage or any future research use of these samples.  
4.5 STUDY APPROACH 
All subjects will follow the study procedures outlined in the Visit Schematic (Figure 4, Section 4.5).  Unless 
otherwise noted, all study visits will take place within facilities in the Allegheny Health Network and all 
procedures and tests will be conducted as approved by AHN IRB.   
Every effort should be made to adhere to the visit schedule.  Visits should be scheduled ± 7 days of the 
designated time-point and phone calls within ± 4 days. If unavoidable, a visit may be scheduled at a time 
outside of this recommended range, but the schedule for subsequent visits must be maintained so that the 
total duration of the treatment period is as close as possible to 12 months. If a visit is scheduled at a time 
other than the protocol designated time, careful consideration must be given to the amount of study 
medication the subject has available. 
Patients should be counseled to fast (no food or drink except water and non-study medications as 
prescribed) for at least 8 hours prior to all study visits where blood and/or urine will be collected or for the 
OGTT and clamp procedures. 
4.5.1 SCREENING 
The information collected during the screening visit will allow us to assess eligibility inclusion/exclusion 
criteria and identify the study subjects to be further considered. Once eligibility has been confirmed, 
subjects will proceed to the run-in period to determine suitability for randomization. No more than two 
weeks will elapse between Visit 1 and the Run-in Visit (Visit 2). 


FIGURE 4 – VISIT SCHEMATIC 
VISIT # 
1 
2 
TC6
3 
4 
5 
5p 
6 
6p 
7 
8 
8p 
9 
9p 
10 
11 11p 
WEEK # 
-2 
0 
1-11 10 
12 
14 
18 
24 
30 
36 
38 
42 
48 
54 
60 
62 
64 
Consent 
x 
Diet/exercis
e 
counseling
x 
x 
x 
x 
Complete 
physi
cal exam
1
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medical history 
x 
Review adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Review medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Health status update
5
x 
x 
x 
x 
x 
x 
Collection of 
glucose meter data 
x 
x 
x 
x 
x 
Dispense MET 
x 
x 
x 
x 
x 
Dispense SAXA 
x 
x 
x 
x 
x 
MET titration 
(review & 
adjust MET dosing) 
x 
x 
x 
Dispense study agent 
x 
x 
x 
x 
Assessment of 
drug compliance 
x 
x 
x 
x 
x 
Randomization
 
x 
Crossover 
x 
Return of study drug & 
equipment 
x 
3hr OGTT and C- 
peptide 
x 
x 
x 
Euglycemic cl
amp
3
x 
x 
x 
DEXA
3
x 
x 
x 
Virology & Pregnancy 
x 
Hematology 
& 
Coagulation
4
x 
x 
x 
x 
x 
x 
Chemistry 
x 
x 
x 
x 
x 
x 
HgbA1c
 2
x 
x 
x 
x 
x 
x 
x 
C-peptide 
2
x 
x 
x 
x 
x 
Urine 
x 
x 
x 
x 
x 
x 
Immunology 
flow cytom 
x 
x 
x 
x 
x 
x 
Immunology luminex 
x 
x 
x 
x 
x 
x 
Immunology 
neutrophils 
x 
x 
x 
x 
x 
Genomi
cs 
x 
x 
Immunology Urine 
x 
x 
x 
x 
x 
p-indicates phone call 
1 – includes height (first visit only), weight and vital signs, 
2 – all blood samples collected will be fasting samples 
3- occurring at Univ of Pittsburgh site 
4- total blood draw volume per visit will not exceed 6 tab (with the exception of clamp visits) 
5- Health status update includes discussion of doctor visits/hospitalizations, 
recent glucose readings, current medication doses, pregnancy status, diet, and exercise 
6-TC defined as titration contact to be completed weekly (via phone or email) and will include assessment of subject glucose levels and MET dose as described in Section 4.6.2 
Clinical protocol AZD9668 dated 06/13/2017  
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Clinical protocol AZD9668 dated 06/13/2017  
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4.5.2 RUN-IN 
All subjects who meet eligibility criteria following the screening visit will enter a run-in period (minimum 
approximately 6 weeks, maximum approximately 12 weeks, depending on metformin exposure). 
Potential subjects who are at the study-specified maximum dose (2000 mg per day) of metformin can 
complete the run-in period in less time (as little as 6 weeks), whereas potential subjects who need to 
adjust metformin to achieve the study-specified dose can complete the run-in in as little as 8 weeks and 
a maximum target of 12 weeks. 
The goals of the run-in period include the following: adjustment of metformin dose to a goal of no higher 
than 2000 mg daily (minimum 1000 mg daily); achievement of a glycated HbA1c target of <=8.5 by the 
time of the final run-in visit; and demonstration of adherence to study procedures (visit attendance, 
medication taking) and of willingness to perform self-monitoring of blood glucose.. During run-in, 
Subjects will adjust MET according to the MET titration information in Section 4.6.2. 
During the run-in period, the diabetes medications of all participants will be changed to study supplied 
metformin and saxagliptin (5 mg qd) 
Study subjects must also not have at any time during run-in, reported instances (verified by the study 
team) of persistent arthralgia (i.e. at least twice in 7 days, for at least two weeks, of intense pain at any 
of the body joints, along with sudden joint swelling or an inability to move the joint(s)). As noted in 
Section 1.7.2, verified persistent arthralgia deemed by the medical monitor and the DSMB to be 
saxagliptin-related, 
in a study subject during the run-in phase at any time, will be grounds for their 
withdrawal and discontinuation in the trial (Refer to Section 4.7.2 for Discontinuation). 
4.5.3 RANDOMISATION 
At the end of run-in, if fasting plasma glucose is >140 mg/dL AND if the glycated HbA1c level is >8.5 
the study subject will not be eligible to continue in the trial. 
If fasting plasma glucose is <=140 mg/dL AND if the glycated HbA1c level is <=8.5 the study subject 
will be requested to maintain the current dose and dose frequency of metformin and will be eligible to 
proceed in the trial. 
Eligible study participants will be randomized following the end of the run-in period and will be assigned 
to a randomization code and will be thus randomized to receive either AZD9668 (60 mg bid) or AZD9668 
placebo starting at Study Visit 9. 
It is formally possible that some study subjects could meet the run-in glycemia targets by 8, or 10, or 12 
weeks into the run-in period. If so, they will be randomized without requiring addition time in the run-in 
period. 
Randomization will be conducted via a central web-based system. The participant, the clinical 
investigator, and clinical personnel will be masked to the treatment assignment. Laboratories performing 
assays for this protocol will be masked to the treatment assignment and the identity of each participant 
whose biological material is to be studied. The AHN research staff will have the only access to the 
identity of the study subject and the treatment arm they are randomized into. 
Research staff authorized to conduct randomization as specified in the site delegation log will be 
assigned an individual unique identifier code. They must use only their assigned identifier code to 
access the patient information system and must not share their assigned identifier code with anyone. 


Clinical protocol AZD9668 dated 06/13/2017  
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Randomization of allocation numbers will be performed via a computer-generated 
allocation schedule. 
Subject treatment assignment will follow the entry of a unique subject identifier in order to be 
randomized. The unique subject identifier will preclude a single patient/subject assigned more than 1 
randomization number. 
4.5.4 TREATMENT PERIOD A 
i)The AZD9668 arm will remain on the optimized MET+SAXA as established during the run-in period
and will be treated with two tablets of 30 mg AZ9668 bid as adjunctive treatment for a 6 month period; 
ii)The placebo arm will remain on the optimized MET+SAXA as established during the run-in period
and will be treated with a color- and size- matched placebo tablet bid as adjunctive treatment for a 6 
month period. 
4.5.5 WASHOUT 
The crossover design obviates the requirement of a washout period, since the AZD9668 arm will go on 
placebo (i.e. the background drugs) and vice versa. 
4.5.6 TREATMENT PERIOD B 
i)At the start of month 7, subjects originally in the placebo arm will be crossed over into the AZD9668
arm. These subjects will remain on the optimized MET+SAXA as established during the run-in period 
and will be treated with two tablets of 30 mg AZD9668 bid as adjunctive treatment for a 6 month period; 
ii)At the start of month 7, subjects originally in the AZD9668 arm will be crossed over into the placebo
arm. These subjects will remain on the optimized MET+SAXA as established during the run-in period 
and will be treated with oral placebo (two tablets bid) that is size- and color- matched to the 30 mg 
AZD9668 as adjunctive treatment for a 6 month period. 
The first crossover dose of AZD9668 (two tablets of 30 mg) or placebo will be administered in the clinic 
as a witnessed dose. 
4.5.7 UNSCHEDULED VISITS 
In addition to the scheduled visits, it is possible that subjects may need to complete an unscheduled visit 
if they experience an event that the clinical PI believes to warrant follow-up. The unscheduled visit will 
include a full physical examination and blood sample collection (less than 3 tab) based upon the event. 
4.5.8 END OF STUDY PROCEDURES 
After study treatment ends, questions concerning the next steps in the management of diabetes will be 
answered and the subject will then be discharged from the trial. At this point, the study subject will be 
asked to return all the trial study medication (MET, SAXA, AZD9668, and placebo) to the nurse/study 
coordinator and will be transferred to their normal diabetes management physician provider for their 
diabetes treatment and care. 
Poststudy Telephone Follow-Up 
Approximately 28 days following Visit 10 or two weeks following a trial discontinuation visit, subjects will 
be contacted by telephone to assess for any AEs that occurred after the administration of the last dose 
of study medication (see Visit 11p as described in Figure 4.5). 
4.6 STUDY PROCEDURES 
4.6.1 LABORATORY MONITORING 


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All laboratory tests will be performed according to the Visit Schematic (Figure 4) either by the central 
laboratory of the Allegheny Health Network or the PI laboratory within the AHN Institute for Cellular 
Therapeutics. The specific tests to be completed are detailed in Appendices A and B. 
Fasting Prior to Scheduled Study Visits: Subjects should be counseled to fast (no food or drink except 
water and non-study medications as prescribed) for at least 8 hours prior to all study visits where blood 
and/or urine will be collected or for the OGTT and clamp procedures. 
No laboratory test results will be masked to the research staff for this study. Subjects with elevations 
greater than 3-times upper limit of normal (ULN) in liver transaminases (i.e., ALT and AST) will be 
flagged by the central laboratory and subjects will be retested. 
NOTE ON SHARING OF LAB RESULTS WITH STUDY SUBJECTS: With the exception of the test 
results for HIV, CMV, HSV, hepatitis B or C, none of the other lab results will be available for the study 
subject. Release of lab result data to the study subject will be made only if the study physicians and/or 
the medical monitor in consultation with the DSMB and the IRB deem there is a medically-necessary 
reason to do so. 
The clinically relevant measurements such as fasting glucose, HbA1c, blood pressure, and lipid levels, 
may be shared with the subjects’ health care provider. 
4.6.2 METFORMIN TITRATION AND DOSING 
Subjects’ diabetes medication will be replaced with metformin 500 mg and will be dispensed from the 
pharmacy. Metformin will be adjusted as follows: The study subjects will be requested to not take their 
diabetes medications on the day of Visit 2, in order to transition all participants to study supplied 
metformin. If already taking 2000 mg per day (1000 twice per day) of metformin and tolerating that dose, 
no further changes will be made. If taking more than 2000 mg per day of metformin, their dose will be 
reduced to 1000 mg twice per day. If taking less than 2000 mg per day, the potential participants will 
increase the dose approximately weekly by 500 mg, with doses taken with meals (usually breakfast and 
dinner) to a target dose of 2000 mg daily, as tolerated. If potential participants develop gastrointestinal 
intolerance during metformin titration, metformin XR can be used to try to get them to 2000 mg daily or to 
a minimum of 1000 mg daily. Potential participants who do not tolerate at least 1000 mg per day of 
metformin will not be eligible for randomization. Metformin or Metformin XR will be provided free-of- 
charge to study participants. Subjects who enter run-in but are not randomized will be provided with 
study metformin as they transition their diabetes care back to their primary care provider and the pre- 
run-in diabetes medication. The first dose of metformin 500 mg will be administered in the clinic as a 
witnessed dose. At drug dispensing visits, subjects will return the MET to the pharmacy and procure a 
new supply until the next scheduled drug dispensing. 
METFORMIN TITRATION DURING RUN-IN (to be co-ordinated between study subject and trial study 
staff: Prior to up-titrating metformin, subjects must call or email study staff requesting up-titration as per 
schedule shown immediately below. Study staff must confirm the up-titration in response and record the 
new dose level). Also described in FIGURE 6 
1. Begin with low-dose metformin (500 mg) taken once per day with meals (breakfast and/or
dinner).
2. After 5-7 days, if fasting blood glucose levels are <= 140 mg/dL, maintain the metformin dose
until the next week.
3. If fasting blood glucose is >140 mg/dL, increase the metformin dose by 500 mg per day taken
once per day with meals (breakfast and/or dinner).


Clinical protocol AZD9668 dated 06/13/2017  
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4. If gastrointestinal side effects appear (stomach cramps, abdominal or stomach discomfort,
stomach upset, stomach acidity, heartburn, indigestion, nausea, diarrhea), decrease metformin
to previous lower dose.
5. 5-7 days later, measure fasting blood glucose. If >140 mg/dL increase the metformin dose by
500 mg per day taken once per day with meals (breakfast and/or dinner). If fasting blood
glucose levels are <= 140 mg/dL, maintain the metformin dose until the next week.
6. If gastrointestinal side effects appear (see above) as doses advanced, decrease to previous
lower dose.
7. 5-7 days later, measure fasting blood glucose. If >140 mg/dL increase the metformin dose by
500 mg per day taken once per day with meals (breakfast and/or dinner). If fasting blood
glucose levels are <= 140 mg/dL, maintain the metformin dose until the next week.
8. If gastrointestinal side effects appear as doses advanced, decrease to previous lower dose.
9. 5-7 days later, measure fasting blood glucose. If >140 mg/dL increase the metformin dose by
500 mg per day taken once per day with meals (breakfast and/or dinner). If fasting blood
glucose levels are <= 140 mg/dL, maintain the metformin dose until the next week (Run-in
Study Visit 2).
10.If gastrointestinal side effects appear as doses advanced, decrease to previous lower dose.
Do not go over 2000 mg metformin per day. 
If fasting plasma glucose is >140 mg/dL AND if the glycated HbA1c level is >8.5 the study subject will 
be instructed to titrate the metformin dose upward by 500 mg per day to no more than 2000 mg per day. 
If fasting plasma glucose is <=140 mg/dL AND if the glycated HbA1c level is <=8.5 the study subject 
will be requested to maintain the current dose and dose frequency of metformin. 
If fasting plasma glucose is >140 mg/dL AND if the glycated HbA1c level is <=8.5 the study subject will be 
instructed to titrate the metformin dose upward by 500 mg per day to no more than 2000 mg per day. 
Subjects who meet their glycemic and HbA1c targets at Visit 3 will proceed to Visit 4 to be randomized. 
If glycemia targets have not been met by visit 3, we will reassess at Visit 4 and determine if subject is 
able to randomized at that point. 


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FIGURE 6 METFORMIN TITRATION 


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4.6.3 SAXAGLIPTIN DOSING 
Subjects’ diabetes medication will be replaced with saxagliptin 5 mg qd and will be dispensed from the 
pharmacy. The study subjects will be requested to not take their diabetes medications on the day of Visit 
2, in order to transition all participants to study supplied saxagliptin. Saxagliptin 5 mg will be 
administered qd and maintained at that dose level throughout the trial study. Given the warnings 
concerning the possibility of arthralgia, noted for the DPP-IV inhibitors as a class, saxagliptin included 
(see Section 1.7.2, earlier), especially in study subjects without a history or recent evidence of persistent 
arthralgia (Grade 3 per NCI-CTCAE criteria), the study team will ask study subjects to report all 
instances of arthralgia. If arthralgia becomes persistent, the guidelines for reporting and discontinuation 
in Section 4.7.2 and 5.0 will be followed. The first dose of saxagliptin 5 mg will be administered in the 
clinic as a witnessed dose. At drug dispensing visits, subjects will return the SAXA to the pharmacy and 
procure a new supply until the next scheduled drug dispensing. 
4.6.4 AZD9668 OR PLACEBO DOSING 
Subjects should be instructed to withhold their morning doses of AZD9668 or placebo on the days of 
the study visits. The last dose of study medications should be administered on the day before Visit 10 
(final end-point-related study visit). No study medications will be administered on the day of Visit 10. 
The first dose of AZD9668 (two tablets of 30 mg) or placebo will be administered in the clinic as a 
witnessed dose. The subjects will be instructed to take two tablets of 30 mg AZD9668 or the placebo 
(twice a day) until the crossover and to maintain their metformin and saxagliptin for the duration of the 
study. 
4.6.5 STANDARD DIABETES EDUCATION 
All participants will be provided standard diabetes education during the run-in period and at some of the 
scheduled visits thereafter, which will provide basic knowledge about T2D, including skills and 
behaviors that are important for successful management such as medication taking, healthy eating and 
weight loss, increased physical activity, and smoking cessation. Standardized printed materials on 
diabetes management (diet, exercise) will be made available to patients who can discuss them in more 
depth with the study physicians. This printed information will include information on the pathophysiology 
of diabetes, prevention of complications, reduction of cardiovascular risk factors, diet/nutrition, exercise 
goals, and self-care such as foot care and medication taking. The importance of eating a healthy diet, 
losing weight if overweight or obese, and being physically active will be stressed. These materials will 
be consistent with the aims of the Look AHEAD (Action for Health in Diabetes) program (full list of 
bibliography in: https://www.lookaheadtrial.org/public/Bibliography.pdf). 
The patient will receive printed information on a weight-maintaining diet and exercise approaches 
consistent with American Diabetes Association (ADA) recommendations from the study physician or 
other qualified health professional. 
The recommended diet, consistent with ADA and other standard diabetes guideline recommendations 
should contain approximately 45 to 65% carbohydrate, 10 to 35% protein, and 20 to 35% fat 
Patients will receive information (printed) on how to maintain a medically appropriate, routine exercise 
program; consistency in physical activity levels will be encouraged throughout the study. 
4.6.6 GLUCOSE MONITORING 


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Glucose treatment decisions will be driven by protocol and controlled solely by the study staff. 
Medications that are titrated in usual care and consistent with their labeling will be titrated to achieve 
fasting glucose levels 70-140 mg/dl based on self-monitoring of blood glucose without symptomatic 
hypoglycemia or to the maximum tolerated dose, whichever dose is lower. 
Study staff will communicate directly with participants’ primary care providers (PCPs) so that it is clear 
that glycemic management will be assumed by the study staff through the entire course of the study. 
Similar strategies in the Diabetes Control and Complications Trial (DCCT), United Kingdom Prospective 
Diabetes Study (UKPDS) and in the ongoing Look AHEAD study resulted in almost no interference with 
the study implemented interventions and have promoted good retention. Subjects will be scheduled to be 
seen as shown in the Visit Schematic (Figure 4, Section 4.5). 
Glycemic management for participants will follow an established titration protocol based on self- 
monitoring of blood glucose, aiming for fasting glucose between 70 and 140 mg/dl and a glycated 
HbA1c levels of <=8.5 without symptomatic hypoglycemia.. 
Although consideration was given to masking HbA1c values, in order to limit potential bias in the 
application of the medications and treatment strategies in this unmasked trial, we chose to share 
HbA1c values with the participants as it more closely resembles usual care. Moreover, although 
glucose treatment decisions will be driven by protocol and controlled solely by the study staff, patients 
are likely to have HbA1c levels drawn outside of the study, so that masking of levels would be 
impractical. 
Self-monitoring of blood glucose (SMBG) will be performed for safety (to prevent hypoglycemia) 
according to usual care recommendations. Metformin will be titrated between visits based on results of 
SMBG as is common in the course of usual care. SMBG will also be performed for safety reasons by all 
participants in the presence of symptoms that suggest hypoglycemia, hyperglycemia, or during inter- 
current illness likely to affect glucose control substantially. 
All participants will be followed until the end of their participation in this study. 
All participants, including those who have reached the primary and/or secondary outcomes, will 
continue to be followed until their participation in the study concludes, under the intention-to-treat 
principle. After the primary outcome has been reached, randomly assigned study drugs and 
metformin+saxagliptin 
will be continued and supplied free-of-charge until the subject’s participation in 
the trial ends. 
Subjects will: 1) be provided with a glucose meter and receive training in performing SBGM 
measurements; and 2) receive instructions on hypoglycemia symptoms and hypoglycemia 
management. 
Electronic glucose meters will be supplied to all patients at Visit 2 in order to standardize the procedure 
for blood glucose measurements. Patients will be instructed on the procedure to perform fingerstick 
glucose measurements. Following alcohol swab sterilization of a finger, a lancet will be used to pierce 
the skin in order to draw a single drop of blood onto a glucose. Patients will monitor their fingerstick 
glucose concentrations with a frequency determined appropriate by the investigator (based upon 
his/her assessment of the patient’s risk of increasing glucose concentrations) with a minimum of 1 
fasting determinationper two days. Throughout the duration of the entire trial, patients will be instructed 
to contact the site if the fingerstick glucose values are 70 mg/dL or less. Furthermore, in order to assess 
for exclusion/discontinuation criteria, patients should be instructed to contact the study coordinator if the 
fingerstick glucose values are >140 mg/dL at any time during the trial. 


Clinical protocol AZD9668 dated 06/13/2017  
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4.6.6.1 ASSESSMENT AND MANAGEMENT OF HYPOGLYCEMIA 
At Visit  2, the site will review the symptoms and management of hypoglycemia with the subject. The 
site will counsel the subject to immediately perform a fingerstick glucose measurement if any symptoms 
occur that may be related to hypoglycemia (e.g., weakness, dizziness, shakiness, increased sweating, 
palpitations, or confusion), but also to avoid delay in treating these symptoms. Subjects should be 
instructed to contact the investigational site to report: any episode of possible hypoglycemia resulting in 
symptoms, any episode of hypoglycemia for which assistance was required (i.e., severe hypoglycemia), 
any episode of fingerstick glucose 
less than 70 mg/dL with or without symptoms. 
The subject will be instructed to complete the Hypoglycemia Assessment Log (HAL) for any 
symptomatic episodes he or she believes may represent hypoglycemia. In addition, subjects will be 
instructed to record in the HAL any fingerstick glucose values less than 70 mg/dL regardless of the 
presence of clinical symptoms. 
Each episode should be evaluated by the investigator and recorded on the Hypoglycemia Assessment 
(HA) case report form (CRF). The investigator will determine if the event should be considered an 
adverse event. For episodes determined to be hypoglycemia (symptomatic or asymptomatic), and for 
all glucose values less than 70 mg/dL, regardless of whether they are considered an adverse event, the 
HA CRF must also be completed. 
4.6.6.2 Management of procedure-associated 
in-clinic hypoglycemia 
In subjects with diabetes, hypoglycemia is defined as all episodes of an abnormally low plasma glucose 
concentration (with or without symptoms) that expose the individual to harm. Hypoglycemia is also 
defined as a self-monitored blood glucose (SMBG) level ≤70 mg/dL. While that value is higher than the 
value used to diagnose hypoglycemia 
in people without diabetes, it approximates the lower limit of the 
physiological fasting nondiabetic range, the normal glycemic 
threshold for glucose counterregulatory 
hormone secretion, and the highest antecedent low glucose level reported to reduce sympathoadrenal 
responses to subsequent hypoglycemia. 
Common symptoms: dizziness, weakness, delirium, confusion, tremors, and sweating. 
4.6.6.3 Treatment of hypoglycemia 
In order to treat early symptoms of hypoglycemia, subjects should be certain that fast-acting 
carbohydrate (such as glucose tablets, hard candy, or sweetened fruit juice) is available at all times. 
Fifteen to 20 grams is usually sufficient to raise the blood glucose into a safe range without inducing 
hyperglycemia. This can be followed by long-acting carbohydrate to prevent recurrent symptoms. 
Alternatively, 25 g of 50 percent glucose (dextrose) intravenously can be given for rapid treatment. A 
subsequent glucose 
infusion (or food, if subject is able to eat) is often needed, depending upon the 
cause of the hypoglycemia. 
Unconscious subjects: A subcutaneous or intramuscular injection of 0.5 to 1.0 mg of glucagon will 
usually lead to recovery of consciousness within 10 to 15 minutes, although it may be followed by 
marked nausea or even vomiting. 


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Glucose gel (eg, Insta-Glucose) or cake frosting in the space between the teeth and buccal mucosa, 
keeping the subject
's head tilted slightly to the side. 
4.6.7 COMPLETE PHYSICAL EXAM 
The complete physical exam will include demographics, smoking status, height, weight, BMI, waist 
circumference, physical examination, auscultation, eye, ear, nose, throat, blood pressure, temperature, 
other vital signs. 
4.6.8 MEDICAL HISTORY 
Medical history assessment will include review of pre-existing conditions, treatments, prior./concomitant 
medications check. 
4.6.9 DEXA SCAN 
Study subjects will remove all objects from clothing (wallet, phones, jewelry, underwire bras) and will be 
asked to lie supine on the scan table. The scanner operator will ensure that the subject is lying straight 
by looking at the body alignment. A radiolucent pillow will be placed under the study subject’s head and 
under the paper on the table. A large square cushion will then be placed under the lower legs with the 
thighs as close to a 90 degree angle to the body as possible. The study subject should rest their arms 
comfortably at their sides. The operator will then begin the scan process on the computer system. The 
whole scan is on average between 15-30 minutes depending on the height of the subject. 
Once the DEXA scan is complete, after a 30 minute rest period, the subject will begin the clamp test in 
another clinical suite. NOTE: Even though every effort will be made to conduct the clamp and DEXA 
scan on the same day, scheduling reasons might require the two procedures to be conducted on 
separate days (separated by no more than 7 days). 
4.6.10 80 mU/m2  min-1  HYPERINSULINEMIC- EUGLYCEMIC CLAMP TEST 
Subjects will be studied in the supine position. During the procedure, the participants are only allowed to 
drink water. An intravenous catheter will be placed in an antecubital vein for infusion of insulin (Humulin-
R)and dextrose. A second catheter will be placed retrograde in a dorsal vein of the contralateral hand for
blood draws. The hand will be gently warmed with a heating pad that has a timer). The other catheter is 
used for infusion of dextrose 20% (prepared by the hospital’s pharmacy) and continuous insulin at 80 
mU/m2 min-1. 
After fasting baseline blood samples are collected, the hyperinsulinemic clamp will start with a primed- 
continuous infusion of insulin (Humulin-R) at a rate of 80 mU/m2 body surface area per minute for 4 hr. 
Plasma glucose is measured every 5-10 min to ensure glucose is maintained at a target range of 90- 
100 mg/dl with a variable 20% dextrose infusion controlled by the investigator. 
During the last 30 min of the clamp (steady-state), blood samples are collected for determination of 
glucoregulatory factors (e.g. insulin, C-peptide, FFA). The glucose disposal rate is calculated based on 
the mean glucose infusion rate at the steady-state phase. Approximately 250 mL of blood per clamp will 
be drawn. 
Thereafter insulin infusion is discontinued and participants will be offered a carbohydrate-rich meal. The 
dextrose infusion is gradually tapered during the course of the meal. Bedside glucose monitoring will 
occur before determination that the participant is safe to be discharged. The subject will remain in the 


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investigator’s watch until ready for discharge to ensure no procedure-associated 
emergent AE. 
4.6.11 3-hour MULTI-POINT ORAL GLUCOSE TOLERANCE TEST (OGTT) 
The study subject will will have the OGTT panel (see Appendix A) samples collected as follows: 
- 0 minutes: baseline blood draw 
- Subject will then consume 100mg of a oral glucose containing drink within 5 minutes 
- 30 minutes: blood draw 
- 60 minutes: blood draw 
- 120 minutes: blood draw 
- 180 minutes: blood draw 
. 
Each sample will be collected as a separate needle stick within ± 5 minutes of the scheduled time point. 
The study subject will be monitored for an additional hour for signs of hypoglycemia and then 
discharged. The OGTT will be stopped if the study subject exhibits signs and symptoms of hypoglycemic 
attack; hypoglycemia will be treated according to Section 4.6.6. 
4.6.12 SAFETY ASSESSMENTS 
Subjects will be interviewed regarding adverse events throughout the course of the study according to 
the Visit Schematic (Figure 4, Section 4.5). We will monitor hematologic parameters (e.g., hemoglobin, 
serum vitamin B12 concentrations) throughout the trial duration. 
In particular, subjects will also be asked if they have recent experience of any recurring arthralgia 
(given the DPP-IV-related warnings as described in the background, earlier). This will be relevant in 
determining if any instance of in-trial arthralgia could be due to an underlying chronic condition that is 
not an exclusion criterion, or saxagliptin-related. 
In order to detect concurrent illness, we will evaluate applicable blood markers for evidence of 
ketoacidosis or lactic acidosis. Temporary withdrawal of metformin therapy and administration of 
insulin may be required to maintain glycemic control during periods of stress. We will observe patient 
closely for evidence of altered glycemic control when such drugs are added to or withdrawn from 
therapy. 
4.6.13 CONCOMITANT MEDICATIONS/TREATMENTS 
Subjects will be interviewed regarding any concomitant medications taken during the course of the study. 
If necessary, concurrent lipid lowering, antihypertensive, and thyroid hormone medications are 
permitted. It is preferable that doses of these medications remain stable after the run-in period and then 
for the duration of the trial. 
If necessary, hormone replacement therapy and birth control medications are allowed, but patients 
should be on stable regimens, and are expected to remain on that stable regimen during the run-in and 
the duration of the trial. At no time during trial should any over-the-counter salicylates, 
NSAIDs or prescription salicylates or NSAIDs be used (e.g. no salicylic acid or derivatives, or COX-2 
inhibitors). 
4.6.13.1 PROHIBITED MEDICATIONS 


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1. 
Other Anti-hyperglycemic Medications: Except for medication given as part of the study protocol,
no other anti-hyperglycemic 
medication (such as GLP-1 analogues, sulfonylureas, glitazones, 
glimepiride, meglitinides, other biguanides, glucosidase inhibitors, PPAR< 
agonists, insulin) may 
be taken during the study. 
2. 
Antiretroviral Drugs: The use of antiretroviral drugs (e.g., protease inhibitors, reverse
transcriptase inhibitors) is prohibited. 
3. 
Corticosteroids: The use of 14 consecutive days of systemic corticosteroids (oral,
injectable/parenteral) 
is prohibited. However, oral corticosteroids used for physiologic 
replacement therapy (i.e., in patients with adrenal insufficiency) and inhaled, nasal, and topical 
corticosteroids are allowed. 
4. At no time during  trial should  any over-the-counter salicylates,NSAIDs 
or
prescription salicylates 
or NSAIDs be used (e.g. no salicylic acid or derivatives, or
COX-2 inhibitors).
5. Macrolide antibiotics
6. Cisapride
7. Anti-arrhythmics
8. Rifampicin
9. Phenobarbital
10.Phenytoin
11.Secobarbital
12.Carbamazepine
13.Norethindrone
14.Isoniazid
15.Fluconazole
16.Amiodarone
17.Fenofibrate
18.Fluvoxamine
19.Phenylbutazone
20.Probenecid
21.Sertraline
22.Amphetamines, dextroamphetamines, 
lisdexamfetamine, 
methylphenidate
23.Atomoxetine, Clonidine, Guanfacine
Use or need for use of excluded medications will require consultation with the study investigator. 
4.7 INTERRUPTION OF STUDY MEDICATION OR DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
Randomized subjects who discontinue due to an adverse event or for any other reason will have a 
discontinuation visit (mirroring the procedures listed in Visit 10, Figure 4) scheduled. 
Subjects may withdraw at any time or be dropped from the study at the discretion of the investigator 
should any untoward effects occur. In addition, a subject may be withdrawn by the investigator or the if 
he/she violates the study plan or for administrative and/or other safety reasons. The investigator or study 
coordinator will follow local applicable IRB reporting guidelines for subjects being discontinued/ 
withdrawn due to a serious adverse event. When a subject discontinues/withdraws 
prior to study 
completion, all applicable activities scheduled for the final study visit should be performed at the time of 
discontinuation. Any adverse experiences which are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 5.0.  


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Subjects may withdraw, at any time, consent for participation in this research study without penalty or 
loss of benefits to which they are otherwise entitled. Subjects who optionally consent to having left-over 
blood samples stored for future research on T2D may also request that their specimen(s) be removed 
from storage and destroyed in accordance with the terms outlined in the associated consent form. 
Requests for withdrawal and destruction of the optional stored samples should be made in writing to the 
principal investigator. The principal investigator will be informed when the associated specimens are 
destroyed and should notify the subject that specimen destruction is complete. 
The Medical Monitor and the IRB will be notified according to local IRB reporting requirements 
regarding subject discontinuation or interruption in study medication due to an AE/SAE or laboratory 
safety test abnormality. Given the warnings concerning the possibility of arthralgia, noted for the DPP- 
IV inhibitors as a class, saxagliptin included (see Section 2.6.1.2.9, earlier), the study team will closely 
document and monitor all instances of arthralgia. If arthralgia becomes a Grade 3 persistent arthralgia 
per NCI-CTCAE criteria (i.e. at least twice in 7 days, for at least two weeks, of intense pain at any of the 
body joints, along with sudden joint swelling or an inability to move the joint(s)), the medical monitor 
and DSMB will be notified within 5 days and can recommend to withdraw the study subject from 
saxagliptin (and therefore from the trial). The study subject will be requested to withdraw from the study 
and discontinue saxagliptin if the medical monitor and DSMB concur that the arthralgia is saxagliptin- 
related. If required, these events will also be reported to the FDA and or IRB based upon their reporting 
guidelines. 
4.7.1 Metformin and/or saxagliptin interruption 
Since all subjects will be receiving treatment with metformin and saxagliptin, if a subject undergoes an 
imaging study requiring the use of radiocontrast dye (for example, an intravenous pyelogram or 
computerized tomography study with contrast), treatment with metformin should be temporarily 
discontinued for the time of the radiocontrast dye study. The subject’s renal function should be 
reassessed 48 hours after the procedure, and metformin should be reinstituted (at the same dose prior 
to interruption) only after renal function has been evaluated and found not to have been reduced by the 
dye study. In a subject requiring an imaging study, if considered clinically appropriate, studies not using 
radiocontrast dye (e.g., ultrasound-based studies, MRI with gadolinium contrast, or non- contrast CT 
studies) should be performed instead of radiocontrast dye studies, so as to avoid the interruption of 
metformin. 
4.7.2 Reasons for protocol-specified discontinuation from the study 
All subjects will be followed until resolution (i.e., return to baseline values or diagnosis determined or 
new stable state established, based upon investigator and study sponsor assessment) for any 
laboratory safety test abnormality resulting in discontinuation. 
1. Informed consent withdrawn or subject requests discontinuation from the study.
2. Hypoglycemia: Repeated (2 or more episodes) FPG or fingerstick glucose <50 mg/dL with
or without symptoms of hypoglycemia or FPG or fingerstick glucose less than 70 mg/dL with
symptoms of hypoglycemia and without a reasonable explanation (such as increased
physical activity and/or skipped meal) occurring after a subject has had their
metformin/saxagliptin 
interrupted. Note: Subjects who experience hypoglycemia should
have their dose of metformin down-titrated to avoid further hypoglycemia. If hypoglycemia
persists despite down-titration of metformin to zero mg (i.e., until dosing of metformin
interrupted), then the subject should be discontinued.
3. Hyperglycemia. criteria are as follows:
i) -FPG (with value repeated and confirmed within 7 days from initial report):


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ii)>270 mg/dL after Visit 2 through Visit 4. FPG (with value repeated and confirmed within 7
days from initial report)
iii)>240 mg/dL after Visit 4 through Visit 6. FPG (with value repeated and confirmed within 7
days from initial report)
iv)>200 mg/dL at any other period after Visit 6, through the remainder of the study.
4. Elevation in ALT and/or AST (3X).
5. Blood serum creatinine is consistently 1.5 mg/dL (133 mmol/L) in men and 1.4 mg/dL (124
mmol/L) in women. Note: Serum creatinine values meeting discontinuation criteria must be
repeated and confirmed within 7 to 10 days of initial measurement.
6. Requirement for one of the excluded medications listed in Section 4.6.13.1.
7. Run-in period or in-trial persistent arthralgia as described in Section 4.6.12.
8. Pregnancy. Note: If the subject reports pregnancy after randomization and has a positive serum
pregnancy test, study medication will be immediately interrupted Subject must be permanently
discontinued and followed per Section 4.12.
9. Any medical condition or personal circumstance which, in the opinion of the investigator,
exposes the subject to risk by continuing in the study or does not allow the subject to adhere to
the requirements of the protocol.
4.8 MEDICATION COMPLIANCE 
Adherence to treatment will be assessed by subject report which may be facilitated by tablet counts for 
saxagliptin, metformin, AZD9668 or AZD9668 placebo remaining in the specific bottles. Every effort will 
be made to maintain adherence as close to 100% as possible. If a subject is found to have reduced 
compliance (<75%), site personnel should begin frequent contacts with the subject to remind the subject 
to take the study medication. 
Overdosages will be managed as described in Section 5.2. In the event that the study agents are 
depleted prior to the next scheduled pharmacy visit, the research staff will communicate with the 
subject and coordinate re-supply. 
4.9 UNBLINDING 
The study code should only be broken for valid medical or safety reasons, e.g. in the case of a severe 
adverse event where it is necessary for the study team or treating health care professional to know 
which treatment the subject is receiving before the participant can be treated. This decision should 
made in consultation with the clinical PI and Medical Monitor, and reported to the DSMB. 
4.10 EFFICACY MEASUREMENTS 
Efficacy measurements include laboratory assessment of insulin sensitivity as measured by the 
hypersinsulinemic-euglycemic clamp, beta cell function as assessed by the oral glucose tolerance test, 
glycemic control as assessed by the glycated HbA1c level, fasting plasma glucose, and lipid panel. 
4.11 SAFETY MEASUREMENTS 
Safety assessments will include collection of AEs, physical examination, vital signs, body weight, and 
laboratory safety studies. For further details refer to Section 5.0. 


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4.12 Pregnancy  Testing and Contraception 
Pregnancy  Testing 
All pre-menopausal women who are not surgically sterilized participating in the study will have a blood 
(serum) pregnancy test at the screening visit (Figure 4). A positive serum pregnancy test prior to 
randomization requires exclusion. If the subject reports pregnancy after randomization and has a 
positive pregnancy test study medication will be immediately interrupted and the subject must be 
permanently discontinued and followed (see Section 4.7.2). 
Contraception 
Non-pregnant, non-breast-feeding women may be enrolled if they are considered highly unlikely to 
conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, 2) postmenopausal, 3) not 
heterosexually active for the duration of this study, or 4) heterosexually active and willing to use a birth 
control method. The birth control method can be either a barrier method or a hormonal method to 
prevent pregnancy, used throughout the study starting with Visit 2 through to 14 days after the last 
dose of study medication. 
The following are considered adequate barrier methods of contraception: diaphragm, condom, copper 
IUD, sponge, or spermicide. Appropriate hormonal contraceptives will include any registered and 
marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents). Postmenopausal is defined as 6 months of 
spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels in postmenopausal 
range as determined by the laboratory, or 12 months of spontaneous amenorrhea in women >45 years 
of age. 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study and agree that in order to participate in the 
study they must adhere to the contraception requirement (described above) for the 
duration 
of the study. If there is any question that a subject will not reliably comply with the 
requirements for contraception, she should not be entered into the study. 
Contraception does not apply to male study subjects; the short half life of AZD9668 is incompatible with 
accumulation of the molecule in the seminal fluid, or the germ line, to a concentration level that could 
be functionally relevant. 
4.12.1 Reporting of Pregnancy  to study team 
Although not considered an adverse experience, it is the responsibility of investigators or their 
designees to report any pregnancy in a subject (as reported by the subject to them) which occurs 
during the study or within 14 days of completing the study. All subjects who become pregnant must be 
followed to the completion/termination 
of the pregnancy. If the pregnancy continues to term, the 
outcome (health of infant) must also be reported to one of the individuals listed on the study team 
Contact Information page. 
4.13 Immune/immunomodulation assays 
4.13.1 Overview 
The scheduled immunological monitoring along with the mechanistic studies are aimed at ascertaining 
how neutrophil elastase inhibition might change the natural progression of T2D by alterations in 
peripheral blood cells including but not limited to neutrophils, regulatory T-cells, B-cells, M1 and M2 
macrophages, dendritic cells and signaling pathways in these cell populations, modulation of neutrophil 


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bioactivity, NET activity, and changes in the balance between TH1 and TH2 immunity. Also, markers of 
inflammation (e.g. hs-CRP, cytokines, adipokines) in serum can be correlated to changes in the cell 
populations and signaling in the specific cells. 
Upon consent to permit storage of left-over blood, this blood could be used in future studies and assays 
to re-evaluate and further explore biologic responses in the constituent leukocytes and serum as 
knowledge accumulates over time. 
Also, baseline, and in-trial gene expression profiling analysis will also be conducted using RNA isolated 
from PBL and purified neutrophils using microarrays and then high-throughput real-time quantitative 
polymerase chain reaction (RT-qPCR) for verification. Changes in gene expression may provide a 
signature of responder versus non-responder status and/or of effect of therapy. 
Of particular interest, and a novel research direction based on the proposed mechanistic studies, is the 
accumulating evidence supporting the existence of distinct neutrophil subsets that have diverse roles in 
infection, inflammation and cancer immunology [168-174]. For example, Kamp and colleagues, 
Fridlender et al. and Christoffersson et al. have described distinct immunostimulatory as well as 
putative immunosuppressive 
neutrophils [169,170,175]. Even though there are still questions about 
whether these cells represent truly distinct lineages or instead develop from a single plastic neutrophil 
precursor, it is formally possible that a dynamic ratio of “pro- inflammatory” and “anti-inflammatory” 
neutrophils might shape the course of the T2D chronic inflammation which might modulate insulin 
sensitivity and beta cell function, directly, or indirectly by other cells (e.g. affecting M1 and M2 
macrophages)[176]. 
Thus, among the PBL subset frequency and absolute numbers we intend to 
measure, we include neutrophils characterized by the surface expression of CD11b+ Gr-1+ CXCR4low 
(“pro-inflammatory”) 
and CD16bright CD62Ldim (“anti-inflammatory”) 
[170,175]. 
4.13.2 Peripheral  blood leukocyte cell multi-parameter/multi-color flow cytometry 
The effect of the study agents on the frequency and absolute cell numbers of T-cell, B-cell, dendritic 
cell, neutrophil, and macrophage cell populations relevant to the study (refer to Appendix B for details) 
will be assessed over time using flow cytometry. 
4.13.3 Peripheral  blood transcriptome 
studies 
There are observations indicating that marked changes in the gene expression of peripheral blood cells 
from pre-diabetic vs. recent-onset diabetic subjects can predict onset of complications based on immune 
activation [177,178]. Changes in gene expression of whole blood may provide a signature of 
treatment-responder 
versus non-responder status and/or of effect of therapy as has been demonstrated 
in other studies [179-184]. 
4.13.4 PBMC T-cell response  viral CEF pool 
The effect of the study agents on general immune competence will be measured in standard PBMC 
response to viral CEF pool (IFNgamma or TNFalpha or GranzymeB ELISPOT). 
4.14.5 Serum cytokine panel 
Serum will be collected at each of the visits designated for labs and monitoring. Levels of various 
immune cytokines will be measured to determine if cytokine levels correlate with clinical AEs and 
potential efficacy. 
4.13.6 Frozen peripheral blook leukocytes or PBL-derived cell assays 
Peripheral blood leukocytes and/or PBMC not used for monitoring from study subjects will be 
cryopreserved for assays that could identify progressors to complications as well as responders vs. 
non-responders to treatment. 


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5.0 ADVERSE EVENTS REPORTING 
5.1 SAFETY MONITORING 
5.1.1 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) that will include NIH NCATS and Astra-Zeneca 
representatives as non-voting members who attend open session in addition to at least two clinical 
experts in type 2 diabetes will monitor the study and will have the authority to suspend the trial if it 
determines that the risks to individuals exceed the originally described risks and/or that modifications to 
the protocol are needed to minimize the risks. The DSMB will receive and review safety data during 
their regular reviews as described in Sections 3.3 and 5.1.3. 
5.1.2 Definitions 
5.1.2.1 Adverse event 
An AE is any untoward or unfavorable medical occurrence associated with the subject’s participation in 
the research, whether or not considered related to the subject’s participation in the research (modified 
from the definition of adverse events in the 1996 International Conference on Harmonization E-6 
Guidelines for Good Clinical Practice) (from OHRP "Guidance on Reviewing and Reporting 
Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (1/15/07); 
http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2). 
5.1.2.2 Serious adverse event 
An AE or SAR is considered “serious” if, in the view of either the investigator, the DSMB, the FDA, IRB, 
NIH NCATS or Astra-Zeneca, it results in any of the following outcomes (21 CFR 312.32(a)): 
i)
Death. A death that occurs during the study or that comes to the attention of the investigator
during the protocol-defined follow-up after the completion of therapy must be reported
whether it is considered to be treatment-related or not.
ii)
A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either
the investigator or DSMB, the FDA, IRB, NIH NCATS or Astra-Zeneca, its occurrence places
the subject at immediate risk of death. It does not include an AE or SAR that, had it occurred
in a more severe form, might have caused death.
iii)
Inpatient hospitalization or prolongation of existing hospitalization.
iv)
Persistent or significant incapacity or substantial disruption of the ability to conduct normal
life functions.
v)
An event that requires intervention to prevent permanent impairment or damage. An
important medical event that may not result in death, be life threatening, or require
hospitalization may be considered serious when, based upon appropriate medical judgment,
it may jeopardize the participant and may require medical or surgical intervention to prevent
one of the outcomes listed above.
vi)
Congenital anomaly or birth defect.
vii)
Other conditions specified in the protocol.
Regardless of the relationship of the adverse event to study drug, the event must be reported as an 
SAE if it meets any of the above definitions. 
5.1.2.3 Unexpected  adverse event 
A SAR is considered “unexpected” if it is not listed in the available risk information on the article or test 
article. For example, in the investigator’s brochure, the product insert, or peer reviewed publications. 


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In addition, if  the specificity or severity has been previously observed, this meets the criteria for 
“unexpected”. (21 CFR 312.32(a)). 
5.1.2.4 Adverse reaction  and suspected adverse reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Suspected adverse reaction (SAR) means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of safety reporting, ‘reasonable possibility’ 
means there is evidence to suggest a causal relationship between the drug and the adverse event. A 
suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug (21 CFR 312.32(a)). Adverse events and treatment- 
emergent laboratory abnormalities, such as aminotransferase elevations, rises in BUN and/or creatinine, 
and abnormalities in hemoglobin, WBC count and differential, and/or platelets will be followed until they 
resolve or stabilize. 
5.1.2.4.1 Unanticipated Problems 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks 
to subjects or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
     -Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied; 
     -Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
     -Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
5.1.2.5 Collecting 
and reporting procedures 
All AEs will be recorded. Additionally, AEs that are classified as serious according to the definition set 
forth by the health authorities must be reported promptly to the IRBs, health authorities, investigators, 
and the DSMB according to their reporting requirements and timeframes. The next sections define the 
types of adverse events and outline the procedures for appropriately collecting, grading, recording, and 
reporting them. Information in this section complies with ICH Guideline E2A: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting and ICH E6: Guideline for Good 
Clinical Practice, and applies the standards set forth in the National Cancer Institute (NCI), Common 
Terminology Criteria for Adverse Events version 4.0 (http://ctep.cancer.gov/reporting/ctc.html). 
Adverse events will be collected from the time the study subject signs the informed consent until the 
time an event is resolved or until 30 days after the participant completes study treatment, whichever 
comes first. 
Adverse events may be discovered through any of these methods: 
i)
Observing the participant.


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ii)
Questioning the participant in an objective manner.
iii)
Receiving an unsolicited complaint from the participant.
An abnormal value or result from a clinical or laboratory evaluation (e.g., biochemistry, hematology, 
metabolic, immune testing) can also indicate an adverse event. If this is the case, then the evaluation 
that produced the value or result should be repeated until the value or result returns to normal or can be 
explained and the participant’s safety is not at risk. If an abnormal value or result is determined by the 
investigator to be clinically significant, it must be recorded as an adverse event on the appropriate 
laboratory evaluation form(s). 
Unanticipated problems will be recorded in the data collection system throughout the study. 
The PI will record all AEs with start dates occurring any time after informed consent is obtained until 7 
(for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study visit, 
the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be 
followed for outcome information until resolution or stabilization. 
5.1.2.6 Recording procedure 
Throughout the study the investigator will record AEs on the appropriate adverse event CRF regardless 
of their severity or relation to study medication or study procedure. All AEs will be recorded on the 
adverse event CRFs except those that are expected following treatment. The investigator will treat 
participants experiencing AEs appropriately and observe them at suitable intervals until their symptoms 
resolve or their status stabilises. Further, all AEs attributable to the study agent reported in the 
AZD9668 Investigator’s Brochure will be recorded. For Saxagliptin and/or Metformin, AEs attributable to 
those agents can be recorded and designated as such (attributable to saxagliptin and/or metformin). 
5.1.2.7 Grading and attribution of all adverse events 
5.1.2.7.1 Grading criteria 
The study site will grade the severity of AEs experienced by study subjects according to the criteria set 
forth in the National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). These criteria 
provide a common language to describe levels of severity, to analyze and interpret data, and to 
articulate the clinical significance of all AEs which will be graded on a scale from 1 to 5 according to the 
following standards in the NCI-CTCAE manual: 
Grade 1 = Mild adverse event. no intervention required; no impact on activities of daily living (ADL) 
Grade 2 = Moderate adverse event. minimal, local, or non-invasive intervention indicated; moderate 
impact on ADL 
Grade 3 = Severe and undesirable adverse event. significant symptoms requiring invasive intervention; 
subject seeks medical attention, needs major assistance with ADL 
Grade 4 = Life threatening or disabling adverse event. 


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Grade 5 = Death. 
All AEs will be reported and graded whether they are or are not related to disease progression or 
treatment. 
5.1.2.8 Definition of attribution 
Adverse events will be categorized for their relation to placebo, metformin, saxagliptin and/or AZD9668. 
The principal investigator will do the initial determination of the relation, or attribution, of an AE to study 
participation and will record the initial determination on the appropriate CRF and/or SAE reporting form. 
The relation of an AE to study participation will be determined using definitions in Table 2, below. Final 
determination of attribution for safety reporting will be decided by the DSMB. 
Table 2: Definition 
of Attribution 
Code 
Descriptor 
Relationship (to primary 
investigational product and/or 
other concurrent mandated 
study treatment) 
UNRELATED CATEGORIES 
1 
Unrelated 
The AE is clearly unrelated; 
Alternative etiology compelling 
2 
Unlikely 
The AE is unlikely related; Most of 
evidence supports an alternative 
etiology. 
RELATED CATEGORIES 
3 
Possible 
The AE has a reasonable 
possibility to be related; 
4 
Probable 
The AE is likely related;There is 
evidence to suggest a causal 
relationship 
5 
Definite 
The AE is clearly related; As 
demonstrated by dose-titre effect, 
rechallenge,compelling etiologic 
mechanism, etc. 
5.1.3 Event reporting procedures 
Adverse events, unanticipated problems (UP) and non-compliance will be collected from the time the 
study subject begins study treatment until 30 days after he or she completes study treatment or until 30 
days after he or she prematurely withdraws from the study. The following procedures for reporting 
ensure study compliance with 21CFR312 and ICH guidelines. 
All AEs/SAEs and Unanticipated Problems (UP) will be recorded in the subject study records and 
reviewed at minimum at quarterly study DSMB meetings and at the time of IRB annual review. These 
will also be forwarded to the Medical Monitor at the time of the above-mentioned reviews. 


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The IND holder will submit any applicable events to the FDA according to the following reporting 
requirements: 
i)Standard reporting (to be reported in the IND annual report). This option applies if the event is
classified as one of the following: 
a) Expected SAE
b) SAE unlikely to be or not related to study drug
ii)Expedited Safety Reporting. The following events will be reported on the standard FDA reporting
form according to the FDA timeframe requirements (15 calendar days, or 7 days for death of life- 
threatening events): 
a. SAE that is unexpected and possibly or definitely related to study drug
b. Aggregate analysis of SAEs when at least 5 SAEs suggest a causal relationship to the
study drug
c. Any findings from clinical or epidemiological studies, analysis of data pooled across
multiple studies, published or unpublished scientific papers, or from animal or in vitro
testing that would result in a safety-related change in the protocol, informed consent,
investigator brochure or other aspects of the overall conduct of the trial will be reported;
d. Any Unanticipated Problem or Non-compliance that suggests a significant risk of
subjects
Events that meet the FDA expedited reporting requirements will also be reported concurrently to the 
IRB (within 5 or 10 days based upon the event), Medical Monitor, and study DSMB. In cases of various 
reporting timeframes, the shortest timeframe will be followed. 
5.2 Definition 
of an Overdose for This Protocol 
An overdose must be reported if any of the following occur during the conduct of the study: 
1.Dosing with more than 1 tablets per day of saxagliptin (>5 mg).
2.Dosing with more than 4 tablets per day of metformin (>2000 mg) for more than 5 consecutive days.
3.Dosing with more than 4 tablets per day of AZD9668 (>120 mg)
For recommended management of acute overdose, please refer to the Investigator’s Brochure or the 
product insert/label for each of the above study agents. 
5.2.1 Reporting of Overdose 
If a dose of test drug meeting the protocol definition of overdose is taken without any associated clinical 
symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical 
Interest (ECI). 
All reports of overdose with and without an adverse experience must be reported to the Medical Monitor. 
If the event meets IRB or FDA reporting requirements, it will be reported per the timeframes described 
in Section 5.1, otherwise they will be reported within 15 calendar days. 


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5.3 Guidance on Adverse Events Related to Glycemia 
5.3.1 Guidance on Adverse Events Related to Hyperglycemia: An adverse event of hyperglycemia 
requires that a subject have one or more symptoms (e.g., increased thirst, polyuria) typically associated 
with an increased glucose level. At the discretion of the investigator, this may be captured as an 
adverse event of "hyperglycemia." This diagnosis may be supported by, but does not require, results 
from a glucose meter or the study central laboratory. Further, at the discretion of the investigator, an 
elevated blood glucose value without associated symptoms that is considered to be an adverse event 
may be reported as an adverse event of "increased blood glucose. 
General guidance regarding the 
determination as to whether an event is considered to be an adverse event should be followed (see 
Section 5.1.2). 
5.3.2 Guidance on Adverse Events Related to Hypoglycemia 
Documentation 
Regardless of whether an episode is considered an adverse event, the Hypoglycemia CRF must be 
completed for the following: 
-all episodes determined by the investigator to be hypoglycemia (symptomatic or asymptomatic) 
-all glucose values less than 70 mg/dL 
Guidance: All episodes considered as likely to represent symptomatic hypoglycemia by the investigator 
should be captured as an adverse event of symptomatic hypoglycemia. This diagnosis may be 
supported by, but does not require, confirmatory blood glucose results (such as those measured using a 
fingerstick or from a clinical laboratory sample). Further, at the discretion of the investigator, an 
asymptomatic blood glucose value less than 70 mg/dL may be reported as an adverse event of 
symptomatic hypoglycemia. General guidance regarding the determination as to whether an event is 
considered to be an adverse event should be followed (see Section 5.1.2). 
5.4 Guidance on Adverse Events Related to Arthralgia 
Given the warnings concerning the possibility of arthralgia, noted for the DPP-IV inhibitors as a class, 
saxagliptin included (see Section 1.7.2, earlier), the study team will ask study subjects to report all 
instances of arthralgia. If arthralgia becomes persistent the guidelines for reporting and discontinuation 
in Section 4.7.2 will be followed. 
5.5 Assessment of compliance with study 
drugs 
For the summary of subject compliance, a day within the post-randomisation Treatment Period will be 
considered a compliant day if the subject was compliant on that day with study medication, defined as 
follows: 
-For saxagliptin: a subject will be compliant if the subject took exactly 1 tablet. 
-For metformin: a subject will be compliant if the subject took at least 1 tablet, and no more than a total 
dose of 2000 mg; 
or
3


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0 tablets with an accompanying indication on the CRF that this occurred due to the Investigator’s 
decision to interrupt metformin. 
-For AZD9668 or placebo: a subject will be compliant if he/she took two tablets, but not less than one 
tablet. 
If the study medication CRF indicates general compliance problems with any study medication, the 
subject will be considered non-compliant for that day regardless of the number of tablets reported. 
For a subject who is followed for the entire study period, the "Number of Days in Treatment Period" is 
the total number of days from the post-randomisation 
first dose of study medication to the last scheduled 
day for treatment administration for that subject. For a subject who discontinues from the study 
prematurely, the "Number of Days in Treatment Period" is the total number of days from the post- 
randomisation first dose of study medication to the date of the last dose of study medication. 
For each subject, percent compliance will then be calculated using the following formula: 
Compliance = (Number of Compliant Days/Number of Days in Treatment Period) x 100% 
5.6 Protocol 
Non-Compliance 
Defined as any noncompliance with the clinical study protocol, Good Clinical Practice, or Manual of 
Procedures requirements. The noncompliance may be on the part of the subject, the investigator, or 
study staff. As a result of non-compliance, corrective actions are to be developed by the study staff and 
implemented promptly. 
These practices are consistent with investigator and sponsor obligations in ICH E6. 
All instances of protocol non-compliance will be documented in the study records. In cases where 
protocol non-compliance is considered to cause increased risk to study subjects, the event will be 
reported to the IRB and the study DSMB within 10 days and to the FDA within their Expedited 
Reporting timeframe. All other instances of protocol non-compliance will be reported to the IRB at 
continuing review and to the study DSMB at their quarterly meetings. 
5.6.1 Protocol Violations 
Protocol violations are any deviations from the protocol. The following rules define protocol violators 
during the study period of interest and will be used to identify such subjects prior to database lock. 
Subjects identified as protocol violators will be excluded from all time points in all analyses. 
5.6.1.1 Drug compliance <75%: Non-compliance will be assessed by prime therapy records as 
provided by the investigator in the CRF. Assessment will be based on a subject’s prime therapy records. 
-If a subject has a compliance rate < 75% during the study this will be considered protocol non- 
compliance and reported as detailed in Section 5.6. Compliance rate is defined in Section 5.5. 
5.6.1.2 Use of prohibited medications: 
The list of prohibited medications can be found in Section 
4.6.13.1. 


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-If a subject takes any prohibited/anti-hyperglycemic medications after randomization (Visit 5 and 
onwards)  for a total of 14 days or 7 consecutive days, he/she will be identified as a protocol violator. 
-A subject with pharmacological dose (as defined in protocol) corticosteroid use 14 days during the last 
90 days of the study period of interest is considered a protocol violator. 
5.6.1.3 
-If a subject receives incorrect study medication for a total of 14 days during the last 90 days of the 
study period of interest, then he/she will be identified as a protocol violator. 
The final determination on protocol violations, and thereby the composition of the study population, will 
be made prior to database lock and will be documented in a separate communication to the study team. 
5.7 Updating  source documentation 
Documents describing the safety profile of a study agent, such as the investigator’s brochure, will be 
amended as needed to ensure that the description of safety information adequately reflects any new 
clinical findings. Until these documents are updated, expedited reporting will be required for additional 
occurrences of a reaction. 


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6.0 STATISTICAL ANALYSIS PLANS 
6.1 General Analysis Strategies 
6.1.1 General Statistical Analysis: Descriptive data will be presented as mean +/- SD. Independent 
sample t tests and Mann-Whitney U tests will test group differences for continuous variables. GDR 
determined from the hyperinsulinemic-euglycemic clamp will be also adjusted for weight, BSA, FFM, or 
FFM+17.7 to determine insulin sensitivity. For the OGTT data, the statistical significance of differences 
between the same parameters calculated from different sampling schedules will be calculated using the 
Wilcoxon’s signed-rank test. Linear regression and Spearman rank correlation analyses will be used to 
examine the relationship between parameters. In all analyses, significance will be declared at P < 0.05. 
6.2 Primary Outcome 
6.2.1 Primary study endpoint: This study is designed to be a two-stage crossover experiment in which 
individuals are randomized to AZ9668 or placebo for six months, and then crossed-over to another 6 
months of protocol therapy on the other treatment arm. The cross-over design was chosen in order to 
reduce the overall target sample size, as well as to enable the study to investigate, in an exploratory 
fashion, whether or not delayed AZ9668 administration (at 6 months) is inferior to the upfront AZ9668 
treatment (at trial start) on IR improvement, metabolic measures, and beta cell function. A cross-over 
design is generally used when an intervention may have an effect, but not a cure. That is, typically after 
the treatment is removed, the subject returns to a baseline level of disease activity (insulin resistance, 
IR), assessed by the 80 mU/m2 min-1 hyperinsulinemic-euglycemic clamp method, and then the 
response to the second treatment is measured from this baseline. In this study, there will be a new 
baseline selected at the beginning of the second treatment period. Even though starting from a new 
baseline, it is assumed that the relative response in the second period is the same as it was in the first 
period. As others have found, that all participants will receive the intervention might make enrollment 
easier. As well, generally, a comparison of treatment effects on the same participant is more precise 
which translate into a smaller sample size.  
Hence, the sample size for this crossover design is about 
2/3 of the sample size of a design not employing a cross-over (e.g. 2-arm parallel design). 
The linear model for the standard 2x2 cross-over design is 
Yijk = m + Sik + Pj + F(j,k)  + C(j-1,k) + eijk
where i = 1-n, the number of subjects, j represents the treatment period (1 or 2), and k the sequence 
(first or second). S is the subject effect, P the period effect, F the treatment effect and C the carry-over 
effect. While the assumption is that there is no carry-over effect, this assumption can be tested using a 
t-test. The treatment effect (our main interest) is also tested using a t-test and, in a similar fashion we 
can test for period effects in the same way (i.e., does the result depend upon whether the intervention 
was received upfront or delayed) which is a secondary endpoint. 
6.3 Other Outcomes 
6.3.1 Secondary study endpoints: Secondary end points include 
i)
Improvement in glycated HbA1c levels by a minimum of 0.2 or better (range=0.2 – 1.5) at 6
months compared to baseline;


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ii)
Improvement in OGTT-derived measurements, namely: glucose tolerance, Matsuda
Index of insulin resistance [6-8], insulinogenic index using C-peptide [1-5];
iii)
Improvement in fasting plasma glucose by 6% or better at 6 months compared to
baseline; and
iv)
decreased concentrations of serum/plasma IL-6, high sensitivity-C-reactive 
protein,
fibrinogen, TNF-alpha, soluble TNF-alpha receptors at 6 months compared to baseline.
Based on the assumption 
that the individual within-treatment 
arm HbA1c level standard 
deviation would be no more than 1% after treatment,  that the difference in HbA1c levels 
between treatment  arms would be at least 0.6% in paired analyses;  at a power of .89 and at 
a two-si
ded 0.05 significance 
level, a total of 30 study subjects are needed. 
The proposed enrollment 
of 42 study subjects 
to account  for potential 
study dropout 
to 
achieve the primary  study aim fully powers this secondary objective.  If all 42 of the study 
subjects complete  the trial, the power increases  to > .96. All the other secondary 
measures are summarized  by their means and standard  deviations. 
The ratio of the difference in means to the standard deviation is a commonly accepted measure of the 
standard deviation to the mean defines the effect size in standard deviation units. While exact data from 
prior studies are not available for each of the secondary outcome measures, the analysis plan is the 
same and we would expect that if the study met the accrual projects for the primary stratum that it will 
produce sufficient numbers to detect a moderate effect size on the secondary outcome measures as 
well. As these are considered secondary, no special provision in the sample size target is made for 
multiple testing although caution will be exercised in interpreting significance levels close to 0.05. 
6.3.2 Exploratory Endpoints: To investigate whether or not delayed AZ9668 administration (at 6 months) 
is inferior to the upfront AZ9668 treatment (at trial start) on IR improvement, metabolic measures, and 
beta cell function, we will compare the groups using a 12 month endpoint. Hence, the planned analysis 
would not consider the 6 month endpoint that is observed for each stage of the cross- over design. In this 
context the study is one of a parallel design with approximately 20 participants on each arm. With this 
number of participants, the study would have 80% power to detect a 59% change in IR (effect size 0.662) 
at a significance level of 0.5, two-sided test. 
6.4 Interim Analyses 
There are no interim analyses planned. 
6.5 SAMPLE SIZE AND POWER 
Primary Outcome 
Table 3 
Based upon previous 
effect 
ranges of metformin+DPPIV 
inhibitor on insulin 
sensitivity/resistance 
(from  
10%-20% improvement over baseline at 6 months; 
[155,157,158,160-162,185,186], a two-sided 
T- test achieves 80% power to reject the null hypothesis (e.g., the ratio of the 6-month placebo vs. 
AZ9668 IR=1) in favor of the alternative hypothesis (the IR ratio is 1.15) when the total sample size of a 
2x2 cross-over design is 200 and the coefficient of variation (SD/M) is .528 (=2.3/5. 8). The sample size 


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requirement drops sharply when considering a larger effect size as Table 3 above demonstrates (all at 
80% power). 
From this, should the study be powered at 80% to detect a 48% effect size (which represents at least a 
a 20% improvement OVER the expected 10-20% improvement due to the MET+SAXA combination 
alone), the total sample size required would be 37. 
This compares quite favorably to a straight parallel design in which case the required sample size 
would be 64 to have 80% power to detect the same effect size. 
The above estimates do not include any provision for dropouts toward the end of the trial arms in 
Treatment Period B. Under ideal conditions, the target would be increased by 10% to provide for such a 
contingency. Should the dropout rate exceed this number, additional participants would be enrolled. 
Nevertheless, if end-of-trial dropout occurs, the primary analysis will be based on all participants enrolled 
(intent-to-treat). 
Considering 
all this, we propose  a total study population of 42 individuals 
in two arms 
(n=21 placebo and n=21 AZD9668). 
6.6 Secondary  Outcomes 
Based on the assumption that the individual within-treatment arm HbA1c level standard deviation would 
be no more than 1% after treatment, that the difference in HbA1c levels between treatment arms would 
be at least 0.6% in paired analyses; at a power of .89 and at a two-sided 0.05 significance level, a total 
of 30 study subjects are needed. 
The proposed enrollment of 42 study subjects to account for potential study dropout to achieve the 
primary study aim fully powers this secondary objective. If all 42 of the study subjects complete the 
trial, the power increases to > .96. 
All the other secondary measures are summarized by their means and standard deviations The ratio of 
the difference in means to the standard deviation is a commonly accepted measure of the standard 
deviation to the mean defines the effect size in standard deviation units. While exact data from prior 
studies are not available for each of the secondary outcome measures, the analysis plan is the same 
and we would expect that if the study met the accrual projects for the primary stratum that it will produce 
sufficient numbers to detect a moderate effect size on the secondary outcome measures as well. As 
these are considered secondary, no special provision in the sample size target is made for multiple 
testing although caution will be exercised in interpreting significance levels close to 0.05. 
6.7 Interim Analyses 
6.7.1 Interim Analysis of Efficacy  Data 
No formal interim analyses are planned. 


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6.7.2 Interim Analysis of Safety Data 
Safety results will be listed, tabulated using descriptive statistics, and plotted when appropriate. 
Parameters to be studied may include incidence of AEs, vital signs, laboratory parameters, physical 
examination findings, cytokine levels, and other safety analyses as deemed clinically appropriate. For 
some safety parameters, results may be summarized and plotted separately for obese vs. non-obese 
individuals (subjects who were obese at the time of randomization). Analyses of AEs may include 
special categories of AEs, such as bacterial/viral infections. Adverse events may also be summarized 
by time of onset. 
6.7.3 Futility 
Analysis
 
Since no formal efficacy analyses are planned, a futility analysis without a priori knowledge of effects on 
efficacy is unwarranted. 
6.8 Missing  Data 
The participating trial investigators are well aware of the problems caused by missing data, and 
subscribe to the credo that the best solution to the problems caused by missing data is the elimination 
or reduction of missing data. To prevent or minimize the amount of missing data, careful data 
collection, data management and quality control procedures must be implemented. These measures 
may include, among others, training and certification of all study personnel, careful design of data 
collection forms, clear and thorough documentation of all study procedures, the implementation of a 
data management system that minimizes the probability of data entry errors and reporting procedures 
that help track subjects in longitudinal studies. 
However, it is prudent to acknowledge up front that some loss to follow-up and some missing data may 
occur in any study. In this case, it is critical to understand what events or factors are responsible for data 
that are missing. That is, are the missing data: (1) missing completely at random (MCAR), (2) missing 
at random (MAR) or (3) non-ignorable. By knowing how the data are missing (e.g., MAR), the most 
appropriate analytic approach can be selected. To understand how those individuals with missing data 
differ from those without missing data, comparisons of the baseline characteristics and the last observed 
measurement of subjects with missing data will be made to those without missing data and tests for 
MAR and MCAR will be applied when applicable. 
6.9 Laboratory 
Values Below Limits  of Quantification 
and Repeat Testing 
Laboratory values below the level of quantification (BLQ) will be set to one-half the limit of quantification 
(unless noted otherwise) in computations for the aggregate analyses, but will be listed as BLQ in the 
listings. 
If a laboratory test is repeated because of an apparent error, the repeat test result will be used in place 
of the original test result. Both the original test result and the repeat test result will be shown in the 
listings. 


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7.0 Ethical considerations 
and compliance 
with good clinical practice 
7.1 Statement of compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for 
Industry: E6 Good Clinical Practice Consolidated Guidance, and according to the criteria specified in 
this study protocol. Before study initiation, the protocol and the informed consent documents will be 
reviewed and approved by the IRB. Any amendments to the protocol or to the consent materials will 
also be approved by the IRB before they are implemented. 
7.2 Privacy and confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study. All data and records 
generated during this study will be kept confidential in accordance with Institutional policies and HIPAA 
recommendations for subject privacy. Each participant will be assigned a study identification code and 
this code rather than names will be used to collect, store, and report study subject information. Any 
identifiable participant information will be kept in locked offices of study investigators and staff or on a 
password-protected, 
encrypted computer. This data will not be used for any other purpose than 
conducting the study. The only times when unblinding of the data will be requested is if an SAE has 
occurred that warrants the identity of the study subject to be known to the medical monitor, the study 
physician and/or the IRB for treatment of the SAE. Otherwise, data will be de-identified before analysis 
and before sharing with blinded study investigators and staff. 


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8.0 Identification 
and access to source data 
8.1 Identifying source data 
The investigator is required to keep accurate records to ensure that the conduct of the study is fully 
documented. The results of all clinical and clinical laboratory evaluations will be maintained in the 
participant’s medical records and the data will be transferred to clinical CRFs. 
Safety data will be recorded on CRFs specifically designed for this purpose. All the SAEs will be 
reported on an SAE report form as well as on individual CRFs. The DSMB and/or the IRB have the 
authority to withdraw any participants and/or terminate the study because of safety findings. 
8.2 Permitting 
access to source data 
The investigational site participating in this study will maintain the highest degree of confidentiality 
permitted for the clinical and research information obtained from the participants in this clinical trial. 
Medical and research records should be maintained at each site in the strictest confidence. However, 
as a part of the quality assurance and legal responsibilities of an investigation, the investigational site 
must permit authorized representatives of the sponsor(s) and health authorities to examine (and when 
required by applicable law, to copy) clinical records for the purpose of quality assurance reviews, audits, 
and evaluations of the study safety and progress. Unless required by the laws that permit copying of 
records, only the coded identity associated with documents or with other participant data may be copied 
(and all personally identifying information must be obscured). Authorized representatives as noted 
above are bound to maintain the strict confidentiality of medical and research information that is linked 
to identify individuals. The investigational site will normally be notified before auditing visits occur. 
8.3 Study Subject Confidentiality 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored within the research offices of the study team. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number that cannot be used to identify any individual subject. The study data 
entry and study management systems used by research staff will be secured and password protected. At 
the end of the study, all study databases will be de-identified and archived at AHN. 
8.4 Sample and Data Storage 
Data collected for this study will be analyzed and stored at AHN. After the study is completed, the de- 
identified, remaining blood samples could be available to other scientists for research purposes. 
The relevance of left-over samples being made available to the research community is that such samples 
could be used for research into the causes of diabetes and obesity, its complications and other 
conditions for which individuals with diabetes are at increased risk and to improve treatment. 
Per expert determination, the data collected for this study is deemed de-identified. Dates of laboratory 
values may be distinguishing, but they are rarely independently replicable, therefore, the risk of 
identification is low. In addition, at no point will the study sponsors have access to any data source that 
reveals the identity of the corresponding individuals. 
8.5 Preservation of the Integrity 
of the Study 


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The scientific integrity of the trial dictates that results be reported on a study-wide basis; thus, an 
individual site will not report the data collected from its site alone. All presentations and publications 
using trial study data must protect the main objectives of the trial. Specifically, all presentations and 
publications will be generated and coordinated so that the main objectives of the trial are not 
compromised, such as might occur by early or ill-timed publication of an ancillary study. Data that could 
be perceived as threatening the equipoise of the trial will not be disclosed prior to release of the primary 
study outcomes. Timing of presentations or publications of data and the venue where they will be 
presented or published will be determined or approved by the Steering Committee. Study results should 
be discussed with the news media only upon authorization of the Steering Committee, and never before 
the results are presented. Any written statements about this study that are shared with national media 
should be approved by the Steering Committee before release. 
8.6 Quality control 
and quality  assurance 
The site clinical investigators are required to keep accurate records to ensure that the conduct of the 
study is fully documented. 
The sponsor is responsible for regularly reviewing the conduct of the trial, for verifying adherence to the 
protocol, and for confirming the completeness, consistency, and accuracy of all documented data. 
Astra-Zeneca follows SOP QC and QA concerning the production, testing and validation of the study 
agents (placebo, AZD9668, and saxagliptin). 
8.7 Data handling 
The site clinical investigators are required to keep accurate records to ensure that the conduct of the 
study is fully documented. The investigators are required to ensure that all CRFs are completed for 
every participant entered in the trial. The PI and study team will regularly review the conduct of the 
trial, verifying adherence to the protocol, and confirming the completeness, consistency, and accuracy 
of all documented data. Study staff at the site will collect source information on paper CRFs and enter 
information into the electronic database. Data quality will be ensured through research team and 
database processes for detection and correction of errors. The database will be maintained on a 
secure, restricted access computer system. All paper CRFs will be maintained to provide an 
appropriate paper trail. 


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9.0 STUDY ADMINISTRATION 
9.1 STUDY LEADERSHIP AND GOVERNANCE 
9.2 The Steering Committee  will govern the conduct of the study. The Steering Committee will be 
composed of the Study Principal Investigator who will also be the Study Chairman, a representative of 
the Trial Coordinating Center, the clinical principal investigators with expertise in T2D, the 
Biostatistician, an independent Medical Monitor who may also be a representative of the DSMB, and a 
representative from NCATS. 
The Steering Committee will meet in person at least twice annually. 
9.3 The Executive  Committee  will consist of the Study Chairman, the representative of Trial 
Coordinating Center, the Biostatistician, the independent Medical Monitor, and a representative from 
NCATS. The Executive Committee will manage the day-to-day conduct of the study. It will meet by 
phone regularly, with administrative and other support staff in attendance to discuss the progress of the 
study and provide frequent guidance and supervision. Members of the Steering Committee as well as 
study staff who are managing specific areas of the protocol will also join the Executive Committee call, 
as needed. 


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9.4 RESEARCH CENTER AND CHAIRMAN’S OFFICE 
The trial research team will be located at Allegheny Health Network and specifically, the Institute of 
Cellular Therapeutics and the Allergy and Autoimmunity Institute of the Allegheny Health Network. 
It will be responsible for study subject management, clinical visit and study agent procurement 
coordination, visit scheduling, test scheduling, study support and management, and for data storage, 
and management. 
The Biostatistics Core will be under the leadership of Dr. Jeffrey Krischer at the University of South 
Florida and will interface with the AHN research staff on a frequent basis. It will be responsible for the 
randomization and the statistical analyses of the data. 
The Study Chairman’s Office is in the Institute of Cellular Therapeutics of the Allegheny Health Network 
under the direction of Dr. Nick Giannoukakis, the Study PI. He will provide overall administrative, 
clinical and scientific leadership for the conduct of this trial. He is also the designated PI for the NIH 
NCATS grant that supports this trial. 
9.5 DATA AND SAFETY MONITORING BOARD AND PLAN 
An independent physician familiar with clinical trials will be designated to serve as the Medical Monitor 
who will maintain regular contact with the TCC, the Study Site Clinical PI, the DSMB and IRB. (S)he will 
review all SAE reports that meet reporting requirements as described in Section 5.1.3.. 
Research staff will receive all the test results and medical reports in a timely manner, and enter into the 
database and will ensure that paper copies are stored in clearly labeled binders (with the study 
subject
's alphanumeric identifier code) which shall be placed in a locked room. 
The study site coordinators, the Study Site Clinical PIs and participating clinical staff will have regular 
communication with each study subject during the run-in and then the first 3 months of the trial as 
detailed in the study schematic above. The study subject will be encouraged to communicate with the 
study site coordinator should they experience any health anomaly. The Study Site Clinical PI will be 
responsible for determining whether the anomaly constitutes an AE, SAE, UP, or non-compliance and 
will proceed with safety reporting according to the process detailed in section 5.1.3. For events that 
meet FDA Expedited Safety Reporting requirements, the PI, clinical PI, Medical Monitor and DSMB 
Study Chair may determine whether the event requires a full meeting of the DSMB.  The Medical 
Monitor can also make suggestions to the Clinical PI regarding initiation of any therapeutic course of 
treatment for relief of SAEs as appropriate and in consultation with the study subject'
s regular 
physician. 
The DSMB will routinely meet approximately every 3 months following the point where the first subject 
enters the trial run-in and as needed to review indicators of safety. The DSMB will independently 
evaluate whether there are grounds to modify or discontinue the study. In all instances, the AHN 
research staff will ensure that the trial remains blinded, that no breach of identity has occurred, that all 
the data are protected in the database and that all primary records and test results are stored under 
controlled access. Unblinding could be requested by the Medical Monitor if needed to assess an event if 
subject management or safety requires it. Furthermore, the DSMB can request unblinded data at any 
time. Minutes of, as well as any data deliberated by the DSMB meetings will be available to the IRB at 


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the time of continuing review. 
10.0 Conflict 
of interest/duality 
of interest 
If any of the study team, including but not limited to the principal investigator, co-investigators, 
individual site-specific investigators and staff directly related to the conduct of this trial and data 
interpretation and publication has a real or potential conflict of industry/duality of interest relating 
directly to the study agents it will be disclosed on the consent and assent forms in a clear manner. 
The independence of this study from any actual or perceived influence by the pharmaceutical industry is 
critical and, therefore, the pharmaceutical industry will play a supportive and advisory role in the trial 
through its representative on the Steering Committee. The study leadership and their institutions in 
conjunction with the NIH/NCATS have established policies and procedures for all study group members 
to disclose all conflicts of interest and should any be disclosed, mechanisms for their management, in 
line with NIH policies, will be instituted. 
11.0 Publication policy 
The principal investigator
's institutional guidelines and policies on publication and public dissemination 
of study results will apply for this trial. 


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12.0 Literature 
cited/Bibliography 
1.Pacini G, Mari A (2003) Methods for clinical assessment of insulin sensitivity and beta-cell function.
Best Pract Res Clin Endocrinol Metab 17: 305-322. 
2.Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, et al. (2000) Use of the oral glucose
tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23: 295-301. 
3.Hanson RL, Pratley RE, Bogardus C, Narayan KM, Roumain JM, et al. (2000) Evaluation of simple
indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J 
Epidemiol 151: 190-198. 
4.Phillips DI, Clark PM, Hales CN, Osmond C (1994) Understanding oral glucose tolerance:
comparison of glucose or insulin measurements during the oral glucose tolerance test with 
specific measurements of insulin resistance and insulin secretion. Diabet Med 11: 286-292. 
5.Seltzer HS, Allen EW, Herron AL, Jr., Brennan MT (1967) Insulin secretion in response to glycemic
stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. 
J Clin Invest 46: 323-335. 
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13.0 APPENDICES 
Appendix A: Core labs 
Appendix B: Study labs 


Appendix 
A: Clinical  Laboratory 
Measures - Core Lab 
Performed as described in the Visit Schematic (Figure 4) in protocol Section 4.5 
Hematology/ 
Coagulation Panel 
Virology/Pregnancy 
Panel 
Chemistry Panel 
Urine Panel 
OGTT 
Panel 
Other labs 
(run 
indivi
dually) 
White Blood Cells (total 
leukocyte count) 
Cytomegalovirus IgM AB 
Blood Urea Nitrogen 
Bacteria 
C-peptide 
HgBA1C 
Neutrophils (absolute and 
%) 
Cytomegalovirus AB 
Serum Creatinine 
Bilirubin 
Glucose 
C-peptide 
Lymphocytes (absolute 
and %) 
Hepatitis B Surface AB 
Fasting  Plasma Glucose 
Blood 
Monocytes (absolute and 
%) 
Hepatitis B Surface AG 
EIA 
Sodium 
Calcium Oxalate 
Crystals 
Eosinophils (absolute and 
%) 
Hepatitis C AB 
Potassium 
Casts 
Basophils (absolute and 
%) 
HIV EIA 
Chloride 
Glucose 
Red Blood Cells 
IM Antibody 
Bicarbonate 
Ketones 
MCV 
Immunology Antibody 
Calcium 
Leukocyte, 
esterase 
Hematocrit 
Acute Hepatitis Panel 
Albumin 
Nitrites 
Hemoglobin 
HSV AB type 1 
Total Serum Protein 
pH 
Platelet (cell count) 
HSV AB type 2 
Alanine aminotransferase 
Protein 
Fibrinogen 
Serum Pregnancy (Visit 1 
only) 
Aspartate aminotransferase 
Red Blood Cells 
Lactic Acid Dehydrogenase 
Specific Gravity 
Total Bilirubin 
Urobilinogen 
Alkaline phosphatase 
White Blood 
Cells 
Total Cholesterol 
eGFR 
Triglycerides 
Low Density Lipoprotein 
High Density Lipoprotein 
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Appendix 
B: Exploratory Laboratory Measures  – Investigator 
Study Lab 
Performed as described in the Visit Schematic (Figure 4) in protocol Section 4.5 
Immunology Flow 
Cytometry 
Immunology 
Neutrophils 
Immunology Luminex Genomics 
Immunology 
Urine 
T-Cells 
NET formation 
Response to viral CEF 
pool 
Total genome 
expression analysis 
Desmosine 
CD4+ 
Neutrophil 
elastase activity 
in vitro 
Response to 
allostimulation in vitro – 
IFNgamma or 
TNFalpha or Granzyme 
B ELISPOT 
Total genome 
epigenotype – epG 
methylation and 
histone acetylation 
CD69+ 
Multi-cytokine panel 
CD8+ CD69+ 
hs-CRP 
CD25High 
Serum leptin 
Foxp3+ 
Serum adiponectin 
B-Cells 
IL-6 
CD19+ 
Insulin 
CD20+ 
CD 19+ IL-10+ 
CD19+ CD24+ 
CD38+ 
Dendritic Cells 
CD11c+/HLA-DR+ 
CD11c+ BDCA2+ 
BDCA-4+ 
ALDEFLUOR+ 
CD11c+ 
CD45+ 
CD11c+ 
CD103+ALDEFLUOR+ 
Neutrophils 
CD15+ CD16+ 
CD62L+ 
CD15+ CD16+ CD68+ 
Macrophages 
M1 
M2 
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