Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus Aged 10 to Below 18 Years Old

In pediatric Type 2 Diabetes Mellitus (T2DM) subjects on diet and exercise and metformin, or
insulin, or metformin and insulin:

The primary research hypothesis for dapagliflozin is whether addition of dapagliflozin,
including up-titration if needed, results in a greater mean reduction from baseline in
glycosylated hemoglobin (HbA1c) as compared to placebo when each are administered over 26
weeks of oral double-blind add-on treatment.

The primary research hypothesis for saxagliptin is whether addition of saxagliptin, including
up-titration if needed, results in a greater mean reduction from baseline in HbA1c as
compared to placebo when each are administered over 26 weeks of oral double-blind add-on
treatment.

Study Design: The proposed study is a 26-week Phase 3b, multicenter, randomized,
placebo-controlled, double-blind, parallel group study with a 26-week safety extension period
to evaluate the safety and efficacy of dapagliflozin (5 mg and 10 mg), and, separately,
saxagliptin (2.5 mg and 5 mg) in pediatric subjects with T2DM, and an additional post study
visit at Week 104 for assessment of measures of growth and maturity. Approximately 243
pediatric subjects will be randomized in a 1:1:1 ratio to receive dapagliflozin 5 mg,
saxagliptin 2.5 mg, or placebo. Approximately 81 subjects will be randomized to each
treatment arm.

After a 26-week, double-blind, ST treatment period, the primary efficacy endpoint will be
assessed. This will be followed by a 26-week, site- and subject-blind LT safety extension
period. Dapagliflozin and, separately, saxagliptin will be compared against the single shared
placebo comparator.

Measures of growth and maturity will be assessed at the Week 104 post study visit.

Subjects will be required to have been treated with diet and exercise and a stable dose of at
least 1000 mg metformin (IR or XR) for a minimum of 8 weeks, or a stable baseline dose of
insulin for a minimum of 8 weeks, or a stable combination of at least 1000 mg metformin and
insulin for a minimum of 8 weeks prior to randomization. At least 50% of subjects will be on
a stable baseline dose of metformin, with or without concurrent insulin therapy. At least 30%
of total subjects will be between the ages of 10 and 14 years and at least one third, but no
more than two thirds, female subjects.

During the 2-week lead-in period, subjects will be instructed on a diet and exercise program
(in accordance with the American Diabetes Association [ADA] or similar local guidelines) to
be followed for the study duration. Subjects will maintain their baseline types and/or doses
of antidiabetic therapy throughout the study (2-week lead-in, 26-week double-blind ST
treatment period, and the 26-week blinded safety extension LT treatment period). If
applicable, investigators will encourage subjects to keep their insulin doses stable.
Down-titration of insulin will be allowed only as necessary to prevent hypoglycemia and will
be at the discretion of the Investigator. Home glucose meters to monitor glucose control will
be dispensed to subjects and self-blood glucose monitoring (SBGM) requirements and procedures
will be explained. Subjects will also be instructed on the use of the subject diary to record
self-monitored glucose levels and daily insulin dose, if applicable. Subjects will also
receive a blood ketone meter for testing when DKA is suspected.

After the lead-in period, eligible subjects with HbA1c of 6.5% to 10.5% at screening will be
randomized 1:1:1 to receive oral, double-blind, dapagliflozin 5 mg (approximately 81
subjects), saxagliptin 2.5 mg (approximately 81 subjects), or placebo (approximately 81
subjects). Randomization will be stratified based on baseline anti-diabetes treatment regimen
(stable baseline dose of metformin (IR or XR), a stable baseline dose of insulin, or a stable
combination of metformin and insulin), gender, and age (10 to below 15 years of age, 15 to
below 18 years of age).

A blinded HbA1c assessment will be performed at Week 12. All subjects with Week 12 HbA1c
values < 7% will remain on previously assigned randomized treatment (dapagliflozin 5 mg, or
saxagliptin 2.5 mg, or placebo) after the Week 12 assessment. Subjects assigned to the
dapagliflozin treatment arm at Day 1 Randomization with Week 12 HbA1c values >= 7% will be
re-randomized in a 1:1 ratio to continue on the low-dose treatment (dapagliflozin 5 mg) or
up-titrate to the high-dose treatment (dapagliflozin 10 mg) after the Week 12 assessment.
Similarly, subjects assigned to the saxagliptin treatment arm at Day 1 Randomization with
Week 12 HbA1c values >= 7% will be re randomized in a 1:1 ratio to continue on the low-dose
treatment (saxagliptin 2.5 mg) or up-titrate to the high-dose treatment (saxagliptin 5 mg)
after the Week 12 assessment. Subjects assigned to the placebo treatment arm at Day 1
Randomization with Week 12 HbA1c values >= 7% will continue on placebo treatment. To maintain
the blinding of treatments as well as HbA1c results, all placebo subjects and all subjects
taking saxagliptin or dapagliflozin with an HbA1c < 7% at week 12 will go through a dummy 2nd
randomization process that will be indistinguishable (for the subjects and site personnel)
from the actual 2nd randomization. During the Week 14 visit, blinded study drug will be
dispensed to all subjects in accordance with new treatment assignments based on Week 12 HbA1c
assessments.

After completion of the ST treatment period, all subjects will enter the LT treatment period.
All subjects, including those randomized to receive placebo, will continue with their
randomized study medication assigned after the Week 12 assessment in the site- and subject
blind LT treatment period. Adverse events (AEs) and serious adverse events (SAEs) will be
assessed during a Week 56 phone visit.

Subjects who discontinue study drug before the end of the study treatment period will enter a
non-treatment, follow up phase, in which subjects will follow their visit schedules with
modified assessments until study completion. Subjects will attend a post-study visit at Week
104, for assessment of measures of growth and maturity.

Discontinued subjects will not be replaced. Samples for analysis of plasma levels of
dapagliflozin, saxagliptin and its metabolite 5-Hydroxy saxagliptin (5 OH saxagliptin) will
be collected pre-dose and approximately 2 hours post-dose (+/- 1 hour) during the Week 6, 12,
20, and 26 visits.

Samples for analysis of plasma glucose will be collected pre-dose during the Day 1 visit, and
pre-dose and approximately 2 hours post-dose (+/- 1 hour) during the Week 6, 12, 20, and 26
visits.

Plasma samples for analysis of dipeptidyl peptidase-4 (DPP-4) activity will be collected
pre-dose during the Day 1 visit, and at 2 (+/-1) hours post-dose during the Week 6, 12, 20,
and 26 visits.

All plasma samples will be drawn in the fasting condition. During the course of the trial,
subjects may be eligible for the addition of open-label rescue medication to their blinded
treatment regimen in order to treat ongoing hyperglycemia. Insulin may be used as rescue, at
the Investigator's discretion.

Pre-specified glycemic criteria, based upon self-monitored blood glucose (SMBG) FPG, or
single central laboratory FPG and repeat confirmatory FPG have been established during the
treatment period, starting at Week 6, and up to but not including the Week 52 visit, to
determine eligibility for open-label rescue medication.

Sample Size:

The sample size for this study was selected to be consistent with the research hypotheses.

Dapagliflozin and saxagliptin will be compared with placebo separately. The Bonferroni method
to control the type 1 error rate across two comparisons with respect to the two groups of
research hypotheses (dapagliflozin vs placebo and saxagliptin vs placebo) will be used. No
comparisons between saxagliptin and dapagliflozin will be performed.

The sample size for this study is based on the ability to detect a 0.5% improvement over
placebo for dapagliflozin and saxagliptin in change from baseline in HbA1c at Week 26 (ST)
with at least 80% power for each comparison at a two sided alpha level of 0.025. Assuming a
standard deviation of 0.9% for change from baseline HbA1c at Week 26, a total of 237
pediatric subjects will be randomized in a 1:1:1 ratio to receive dapagliflozin 5 mg (79
subjects), saxagliptin 2.5 mg (79 subjects), or placebo (79 subjects) respectively. Assuming
that 2% of subjects do not have a baseline and at least one post-baseline assessment, a total
of approximately 243 subjects will be randomized. Randomization will be stratified based on
the baseline anti-diabetic treatment regimen (stable baseline dose of metformin [IR or XR]),
a stable baseline dose of insulin, or a stable combination of metformin [IR or XR] and
insulin), gender, and age (10 to below 15 years of age, 15 to below 18 years of age).

The anticipated difference of 0.5% between each study drug (saxagliptin and dapagliflozin)
and placebo used in sample size estimation is consistent with estimates that were obtained in
adult clinical trials with saxagliptin or dapagliflozin as add on to anti-diabetic medication
where the primary endpoint was improvement in HbA1c after 24 weeks treatment. The standard
deviation estimate of 0.9% is consistent with estimates obtained in these adult studies as
well as with published estimates from pediatric trials of other anti-diabetic medications.

Analyses:

Dapagliflozin and saxagliptin will be summarized separately. A common placebo group will be
included in each summary.

In addition, within the analyses of saxagliptin, the overall (combined low-dose and
high-dose) efficacy and safety analyses will be repeated for the subgroup of subjects on a
stable baseline dose of metformin (IR or XR) (with or without insulin). For these analyses,
the saxagliptin treatment regimens will be combined into one group and compared to the
(common) placebo group. P values corresponding to subgroup comparisons will be reported for
the primary and secondary efficacy endpoints, and will be reported at the nominal
significance level.

All efficacy analyses will be performed using the Randomized Subjects Data Set (all
randomized subjects who receive at least one dose of study medication during the treatment
period) unless otherwise specified.

The following treatment regimens are considered for analysis:

- Low-dose/high-dose: Initial treatment of the low-dose followed by up-titrating to the
high-dose for those who do not achieve the glycemic target of HbA1c <7% at week 12

- Low-dose: Initial treatment of the low-dose followed by continuing treatment on the
low-dose drug for those who do not achieve the glycemic target of HbA1c <7% at week 12
For each drug, the primary comparison between the low-dose/high-dose and placebo
regimens will be tested at a two sided alpha level of 0.025.

The primary efficacy analysis will be performed using a weighted analysis of covariance
(ANCOVA). Separate models will be used for saxagliptin and dapagliflozin analyses, and each
analysis will include the (common) placebo control. Each model will have terms for baseline
value, treatment group, and randomization strata.

For the comparison of the low-dose/high-dose treatment regimen versus placebo, all subjects
who had HbA1c<7% at Week 12 and remained on the low-dose will get a weight of one. The
subjects who had HbA1c >= 7% at Week 12 and continued on the low-dose will get a weight of 0.
The subjects who had HbA1c>= 7% at Week 12 and received the high-dose will have a weight of
2. The subjects who withdrew from the study entirely before the second randomization and all
placebo subjects will get a weight of one.

The intent-to-treat (ITT) estimand will be evaluated as the primary estimand. Missing values
for Week 26 will be imputed using the multiple imputation method. The details of the
imputation method will be presented in the statistical analysis plan. Point estimates and 95%
confidence intervals will be calculated based on maximum likelihood for the adjusted mean
changes within each treatment group as well as for the differences in adjusted mean changes
between treatment groups.

To assess the robustness of the primary efficacy analysis for the change in HbA1c from
baseline to Week 26, additional sensitivity analysis may be performed using the Evaluable
Subjects Data Set if > 10% of the subjects in any treatment group in the Randomized Subjects
Data Set have relevant protocol deviations.

The primary endpoint will also be compared between the low-dose treatment regimen and
placebo. In addition, up titrating to high-dose and continuing on low-dose will be compared
in the subset of saxagliptin and dapagliflozin subjects who had HbA1c >= 7% at Week 12. These
analyses are described under secondary efficacy analyses.

Secondary efficacy analyses will also be performed separately for each drug (saxagliptin and
dapagliflozin). For each drug, the following sequential testing order will be employed to
control multiplicity of testing for the secondary objectives.

1. Comparison of mean reduction in HbA1c from baseline at Week 26 between the low-dose
treatment regimen and placebo

2. Comparison of mean reduction in HbA1c from baseline at Week 26 between overall drug
treatment and placebo

3. Comparison of mean reduction in FPG from baseline at Week 26 between the low
dose/high-dose treatment regimen and placebo

4. Comparison of mean reduction in FPG from baseline at Week 26 between the low-dose
treatment regimen and placebo

5. Comparison of mean reduction in FPG from baseline at Week 26 between overall drug
treatment and placebo

6. Comparison of the percentage of subjects with baseline HbA1c>= 7% who achieve an HbA1c
level < 7.0% at Week 26 between the low-dose/high-dose treatment regimen and placebo

7. Comparison of the percentage of subjects with baseline HbA1c >= 7% who achieve an HbA1c
level < 7.0% at Week 26 between the low-dose treatment regimen and placebo

8. Comparison of the percentage of subjects with baseline HbA1c >= 7% who achieve an HbA1c
level < 7.0% at Week 26 between overall drug treatment and placebo

9. Comparison of mean reduction in HbA1c from baseline at Week 26 between the high dose and
the low-dose in subjects who do not achieve an HbA1c < 7% at Week 12

10. Comparison of mean reduction in FPG from baseline at Week 26 between the high dose and
the low-dose in subjects who do not achieve an HbA1c < 7% at Week 12

11. Comparison of the percentage of subjects with baseline HbA1c >= 7% who achieve an HbA1c
level < 7.0% at Week 26 between the high-dose and the low-dose in subjects who do not
achieve an HbA1c < 7% at Week 12 When the sequential testing stops for non-significance,
nominal p-values and adjusted means will be provided for the remaining comparisons.

For each drug, weighted ANCOVA analysis will be performed for the change from baseline in
HbA1c at Week 26 to compare the placebo and the low-dose treatment regimen. For this
analysis, all subjects who had HbA1c < 7% at Week 12 and remained on the low-dose will get a
weight of one. The subjects who had HbA1c >= 7% at Week 12 and continued on the low-dose will
get a weight of 2. The subjects who had HbA1c >= 7% at Week 12 and received the high-dose
will have a weight of 0. The subjects who withdrew from the study entirely before the second
randomization and all placebo subjects will get a weight of one.

For subjects on saxagliptin and dapagliflozin and who had HbA1c >= 7% at Week 12, the change
from baseline HbA1c at Week 26 (ST) will be compared between the subjects re-randomized to
remain on the low-dose and the subjects who are re-randomized to the high- dose using an
ANCOVA.

Change from baseline of HbA1c at Week 26 (ST) will be compared also using a repeated measures
analysis between overall drug and placebo. For this analysis, both treatment regimens will be
combined into one treatment group for each drug.

Change from baseline at Week 26 (ST) in FPG will be analyzed similar to the primary weighted
analyses of change from baseline in HbA1c at Week 26.

The proportion of subjects achieving HbA1c < 7.0% at Week 26 (ST) will be analyzed using
weighted logistic regression with adjustment for the baseline HbA1c measurement and the
randomization strata. Weighting for the subjects will be applied similarly to a weighting in
the analysis of change from baseline in HbA1c. Subjects with missing a response at Week 26
will be imputed by dichotomizing the imputed values of HbA1c at Week 26.

The assessment of safety will be based on the analyses of AEs, vital signs, physical
examinations, electrocardiograms, hypoglycemia, DKA, safety laboratory evaluations, and
measures of growth and maturity. All safety analyses will be performed using the Treated
Subjects Data Set. Dapagliflozin and saxagliptin will be summarized separately. Treatment
regimens (low-dose or low-dose/high-dose) will be combined for saxagliptin and dapagliflozin
to provide the safety summary for overall saxagliptin and overall dapagliflozin compared to
placebo. A common placebo group will be included in each summary.

Measures of growth, bone and maturation markers will also be summarized for the combined ST +
LT + additional post study visit at Week 104.

Monitoring The Sponsor/designee representatives will review data centrally to identify
potential issues to determine a schedule of on-site visits for targeted review of study
records.

Representatives of the Sponsor (or designee) must be allowed to visit all study site
locations periodically to assess the data quality and study integrity. On site they will
review study records and directly compare them with source documents, discuss the conduct of
the study with the Investigator, and verify that the facilities remain acceptable.

In addition, the study may be evaluated by the Sponsor (or designee) internal auditors and
government inspectors who must be allowed access to Case Report Forms (CRFs), source
documents, other study files, and study facilities. The Sponsor (or designee) audit reports
will be kept confidential.

The investigator must notify the Sponsor (or designee) promptly of any inspections scheduled
by regulatory authorities, and promptly forward copies of inspection reports to the
Sponsor/designee.

Records Retention The investigator must retain all study records and source documents for the
maximum period required by applicable regulations and guidelines, or institution procedures,
or for the period specified by the Sponsor/designee, whichever is longer. The investigator
must contact the Sponsor/designee prior to destroying any records associated with the study.

The Sponsor/designee will notify the Investigator when the study records are no longer
needed.

If the Investigator withdraws from the study (e.g., relocation, retirement), the records
shall be transferred to a mutually agreed upon designee (e.g., another investigator, IRB).
Notice of such transfer will be given in writing to the Sponsor/designee.

Study Drug Records

It is the responsibility of the Investigator to ensure that a current disposition record of
study drug (inventoried and dispensed) is maintained at the study site to include
Investigational Products (IPs). Records or logs must comply with applicable regulations and
guidelines and should include:

- Amount received and placed in storage area

- Amount currently in storage area

- Label identification number or batch number

- Amount dispensed to and returned by each subject, including unique subject identifiers

- Amount transferred to another area/site for dispensing or storage

- Non study disposition (e.g., lost, wasted)

- Amount destroyed at study site, if applicable

- Amount returned to the Sponsor/designee

- Retain samples for bioavailability/bioequivalence, if applicable

- Dates and initials of person responsible for IP dispensing/accountability, as per the
Delegation of Authority Form The Sponsor/designee will provide forms to facilitate
inventory control if the investigational site does not have an established system that
meets these requirements.

Case Report Forms An investigator is required to prepare and maintain adequate and accurate
case histories designed to record all observations and other data pertinent to the
investigation on each individual treated or entered as a control in the investigation. Data
that are derived from source documents and reported on the CRF must be consistent with the
source documents or the discrepancies must be explained. Additional clinical information may
be collected and analyzed in an effort to enhance understanding of product safety. Case
report forms may be requested for AEs and/or laboratory abnormalities that are reported or
identified during the course of the study.

For sites using the Sponsor/designee's Electronic Data Capture (EDC) tool, electronic CRFs
will be prepared for all data collection fields except for fields specific to SAEs and
pregnancy, which will be reported on the electronic SAE form and Pregnancy Surveillance Form,
respectively. If electronic SAE form is not available, a paper SAE form can be used. Spaces
may be left blank only in those circumstances permitted by study-specific CRF completion
guidelines provided by the Sponsor/designee.

The confidentiality of records that could identify subjects must be protected, respecting the
privacy and confidentiality rules in accordance with the applicable regulatory
requirement(s).

The investigator will maintain a signature sheet to document signatures and initials of all
persons authorized to make entries and/or corrections on CRFs.

The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly
reviewed, signed, and dated by the Investigator or qualified physician who is a
co-investigator and who is delegated this task on the Delegation of Authority Form. For
electronic CRFs, review and approval/signature is completed electronically through the
Sponsor/designee's EDC tool. The investigator must retain a copy of the CRFs including
records of the changes and corrections.

Each individual electronically signing electronic CRFs must meet Sponsor/designee training
requirements and must only access the Sponsor/designee's EDC tool using the unique user
account provided by the Sponsor/designee. User accounts are not to be shared or reassigned to
other individuals.

Inclusion Criteria:

- Signed Written Informed Consent

- Target Population

- Previously diagnosed with Type 2 Diabetes Mellitus by World Health Organization/ADA
criteria

- HbA1c between 6.5% and 10.5% obtained at screening.

- Currently on diet and exercise and stable dose of at least 1000 mg metformin (IR or
XR) for a minimum of 8 weeks, or stable dose of insulin for a minimum of 8 weeks, or a
stable combination of at least 1000 mg metformin (IR or XR) and insulin for a minimum
of 8 weeks prior to randomization. For those children on insulin, investigators will
confirm that attempts at removing insulin from the subject's therapeutic regimen had
been previously made but had not been successful.

- Age and Reproductive Status

- Male and female patients eligible if 10 years of age, up to but not including 18 years
of age at the time of enrollment/screening. At least 30% of total subjects will be
between the ages of 10 and 14 years and at least one third, but no more than two
thirds, female subjects.

- Women of childbearing potential must have a negative pregnancy test within 24 hours
prior to the start of study drug.

- Women must not be breastfeeding.

- Women of childbearing potential must agree to follow instructions for method(s) of
contraception for the duration of treatment with study drugs: saxagliptin, and
dapagliflozin, plus 5 half-lives of study drugs or 30 days (whichever is longer), plus
30 days (duration of ovulatory cycle) for a total of 60 days post treatment
completion.

Exclusion Criteria:

- Target Disease Exceptions

- Presence of Type 1 diabetes, as demonstrated by Preexisting diagnosis of Type 1
diabetes,

- Previous diagnosis of monogenic etiology of Type 2 diabetes

- Diabetes ketoacidosis (DKA) within 6 months of screening

- Current use of the following medications for the treatment of diabetes, or use within
the specified timeframe prior to screening for the main study:

- Eight weeks: sulfonylureas, alpha glucosidase inhibitors, metiglinide, oral or
injectable incretins or incretin mimetics, other antidiabetes medications not
otherwise specified.

- Sixteen weeks: thiazolidinediones, DPP-4 inhibitors (with no reported medication
related AEs related to DPP-4 inhibitors), sodium glucose cotransporter-2 (SGLT-2)
inhibitors (with no reported medication related AEs related to SGLT-2 inhibitors)

- Initiation or discontinuation of prescription or non-prescription weight loss drugs
within 8 weeks of screening. Use of prescription or non-prescription weight loss drugs
must be stable during the study.

- Medical History and Concurrent Diseases

- Pregnant, positive serum pregnancy test, planning to become pregnant during the
clinical trials, or breastfeeding

- History of unstable or rapidly progressive renal disease

- History of unresolved vesico-ureteral reflux

- History of or current, acute or chronic pancreatitis

- History of hemoglobinopathy, with the exception of sickle cell trait or thalassemia
minor; or chronic or recurrent hemolysis

- Malignancy within 5 years of the screening visit (with the exception of treated basal
cell or treated squamous cell carcinoma)

- Replacement or chronic systemic corticosteroid therapy, defined as any dose of
systemic corticosteroid taken for > 4 weeks within 3 months prior to the Day 1 visit

- Physical and Laboratory Test Findings

- Abnormal renal function,

- An abnormal thyroid-stimulating hormone (TSH) value at enrollment will be further
evaluated for free T4. Subjects with abnormal free T4 values will be excluded.

- Hematuria (confirmed by microscopy at screening) with no explanation as judged by the
Investigator up to randomization.

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2× upper limit of
normal (ULN), or clinically significant hepatic disease.

- Serum total bilirubin (TB) > 2x ULN unless exclusively caused by Gilbert's syndrome

- Positive serologic evidence of current infectious liver disease including anti
hepatitis A virus (HAV) (IgM), hepatitis B surface antigen (HBsAg), or anti hepatitis
C virus (HCV). Patients who have isolated positive anti-hepatitis B surface antibodies
may be included.

- Anemia of any etiology

- Volume-depleted subjects.

- Allergies and Adverse Drug Reaction

- Known allergy, sensitivity or contraindication to any study drug or its
excipient/vehicle

- Other Exclusion Criteria

- Subject is currently abusing alcohol or other drugs or has done so within the last 6
months prior to the screening visit.

- Prisoners or subjects who are involuntarily incarcerated. (Note: under certain
specific circumstances a person who has been imprisoned may be included or permitted
to continue as a subject. Strict conditions apply and Sponsor/designee approval is
required.)

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness.

- Psychiatric or cognitive disorder that will, in the opinion of investigators, limit
the subject's ability to comply with the study medications and monitoring.

- Subjects who have contraindications to therapy as outlined in the saxagliptin and
dapagliflozin Investigator Brochure or local package inserts.

- Participation and receiving IP in another clinical study during the prior 3 months