Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus Aged 10 to Below 18 Years Old
Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus Aged 10 to Below 18 Years Old
The purpose of this research study is to evaluate the efficacy and safety of the drugs
 dapagliflozin and saxagliptin in patients with Type 2 Diabetes who are aged 10 to below 18
 years old and are currently taking metformin, insulin, or both drugs.

 Dapagliflozin and saxagliptin are both approved for use in patients with Type 2 Diabetes aged
 18 years or older. Dapagliflozin (alone or in combination with other antidiabetic drugs) is
 available for use in adults in approximately 40 countries worldwide including the USA and
 Europe. Saxagliptin (alone or in combination with other antidiabetic drugs) is available for
 use in adults in approximately 90 countries worldwide. This study will assess how well
 dapagliflozin and saxagliptin work by finding out how these treatments affect blood glucose
 (sugar) levels compared to placebo (a pill that contains no active drug), in children and
 adolescents. Dapagliflozin and saxagliptin are considered investigational products in this
 study since while they have been approved for use in adults (patients 18 years or older),
 they haven't been approved for children and adolescents due to lack of clinical studies in
 this specific population.

 Patients with Type 2 Diabetes have higher levels of blood glucose (sugar) than patients who
 do not have this disease. The high level of sugar in the blood can lead to serious short-term
 and long-term medical problems. The main goal of treating diabetic patients is to lower blood
 glucose to a normal level. Lowering and controlling blood glucose help prevent or delay
 complications of diabetes, such as heart disease, kidney, eye and nerve diseases, and the
 possibility of amputation.

 Dapagliflozin is a drug that helps to reduce blood glucose (sugar) levels by helping the
 kidneys to remove excess glucose from the blood and excrete it in the urine. It prevents the
 kidneys from returning glucose from the urine back into the bloodstream.

 Saxagliptin increases insulin production when blood glucose levels are high. Insulin is a
 hormone made by the pancreas that allows the body to use sugar (glucose) from the food that
 is eaten for energy or to store glucose for future use. Saxagliptin helps to improve blood
 sugar levels in response to a meal and between meals if blood glucose levels are not lowered
 effectively. Saxagliptin does not work when the blood glucose is low. Saxagliptin also helps
 to decrease the amount of sugar made by the body. Together, these processes reduce blood
 glucose levels and help to control Type 2 Diabetes.

 The subject will either receive one of the active study drugs or a placebo (a pill that looks
 identical but contains inactive drug). This study will be double blind; this means that
 neither the subject, nor the study doctor will know which treatment the subject will receive.

 Which treatment the subject receives is decided by a computer, purely by chance; this is
 called a "random assignment".

 For this study, there will first be a screening phase of up to 6 months if Investigator
 thinks that some of the screening tests can be repeated, followed by a 2 week lead in phase.
 Thereafter there will be a 26W short-term treatment phase (W1-26), and a 26 W long-term
 treatment phase (W27-52). Following this there will be a follow-up telephone call on week 56
 and a post study visit at W104. At day 1 visit after the lead in phase the subject will be
 randomly assigned to receive one of 3 treatments: dapagliflozin 5 mg, saxagliptin 2.5 mg or
 placebo in a blinded manner. This treatment will continue up to week 14. Then after week 14,
 and until the end of the study, the subject will be assigned to receive one of the following
 5 treatments: dapagliflozin 5 mg, dapagliflozin 10 mg, saxagliptin 2.5 mg, saxagliptin 5 mg
 or placebo in a blinded manner. The drugs assigned after week 14 will be the same drugs as at
 Day 1, but some of the groups will receive them at a higher dose.Starting at W32 or W40,
 i.e., after the end of the primary endpoints, patients with background medication of
 metformin only, and an HbA1c value < 7.5% at W26 or W32, will undergo a third randomization.
 Eligible subjects from the treatment arms will undergo the randomized withdrawal of
 background medication, while eligible patients from the placebo arm will undergo, in addition
 to randomized withdrawal of background medication a randomized switch to active treatment.

 Short- and long-term period study visits can be delayed by a maximum of 11 months in total.
 If the duration of investigational product administration is longer than 52 (+1) weeks, the
 safety follow-up period should be shortened such that the complete study duration does not
 exceed 104 weeks. The W104 visit should not be delayed.If more than 12 weeks elapse between
 the HbA1c collection at W26 and the third rand at W32, or the HbA1c collection at W32 and the
 third rand at W40, the subject should not go through this rand as the HbA1c value would no
 longer be reliable to ascertain eligibility for the third rand
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 assessments at Week 26, a subset of eligible subjects who
 are receiving background medication with metformin only will undergo a third randomization
 (randomized withdrawal of background medication) at either Week 32 or Week 40. Eligibility
 for randomized withdrawal from background medication will be restricted to subjects who are
 receiving background treatment with metformin only, and who have HbA1c < 7.5% at Week 26 or
 Week 32 provided they have not initiated rescue glycemic control therapy or been withdrawn
 from study drug. Subjects who are receiving background medication with metformin only, who do
 not qualify for the third randomization at Week 32 due to an HbA1c ≥ 7.5% at Week 26, may
 qualify for the third randomization at Week 40 if HbA1c < 7.5% at Week 32. Subjects who have
 passed Week 40 will not be included in the randomized withdrawal of background medication

 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.In case a visit is delayed for any reason, subsequent
 visits should be scheduled such that an interval of at least 12 weeks is maintained between
 the:

 -  Week 14 visit and the Week 26 visit.

 -  Third randomization (for subjects undergoing third randomization; occurring at the Week
 32 or the Week 40 visit) and the Week 52 visit.

 If more than 12 weeks elapse between the HbA1c collection at Week 26 and the third
 randomization at Week 32, or the HbA1c collection at Week 32 and the third randomization at
 Week 40, the subject should not go through this randomization as the HbA1c value would no
 longer be reliable to ascertain eligibility for the third randomization. Short- and long term
 period study visits can be delayed by a maximum of 11 months in total. If the duration of IP
 administration is longer than 52 (+1) weeks, the safety follow-up period should be shortened
 such that the complete study duration does not exceed 104 weeks.

 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.This visit should be completed without
 delay (at 104 weeks from Day 1 + 7 days), regardless of whether any other study visits were
 delayed.

 If scheduled visits at clinical sites will be significantly impacted by the COVID-19 pandemic
 (e.g., there is a risk that the subject may be exposed to COVID-19 when visiting the site),
 home visits by study site personnel/vendor are allowed in countries where this is
 logistically feasible and considered acceptable. Before such a visit, a risk assessment that
 considers the potential risks to both the subject and the study personnel has to be
 performed.

 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.Samples may be collected at additional time points during the study if
 warranted and agreed upon between the investigator and the Sponsor, eg, for safety reasons.

 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 subjectsdo not have a primary endpoint, 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. All subjects who do not undergo 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. All subjects who do not undergo 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.Off-site
 monitoring visits and remote source data verification are allowed when restrictions due to
 the COVID-19 pandemic prevent on site visits (e.g., monitors may not be able to access the
 sites in a timely manner). Should this occur, it should be documented and the reasons be
 available for review by the Sponsor and during inspections by any Regulatory Authorities 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). Except where the IP has to be sent directly to the subjects'
 homes due to the coronavirus disease 2019 (COVID 19) pandemic. Any unused IP sent directly to
 subjects' homes should be returned to the site at the next on-site visit.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.Data entered in the eCRF that are transcribed from
 source documents must be consistent with the source documents or the discrepancies must be
 explained.

 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