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 Overview
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Brief Summary
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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 115 countries worldwide including the USA and Europe. Saxagliptin (alone or in combination with other antidiabetic drugs) is available for use in adults in approximately 100 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 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. 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 day1 visit after the lead in phase the subject will be randomly assigned to receive one of 3 treatments: dapagliflozin 5mg, saxagliptin 2.5mg or placebo in a blinded manner.This treatment will continue up to week 14. After week 14, the subject will be assigned to receive one of the following 5 treatments: dapagliflozin 5mg,dapagliflozin 10mg,saxagliptin 2.5 mg, saxagliptin 5 mg compared with 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 rand withdrawal of background medication a randomized switch to active treatment. Short/ 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(+7 days). A window period of -28 days to +7 days from the original scheduled date will be allowed for the Week-104 visit.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

Detailed Description
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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, 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, 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), [all doses and regimens combined] or saxagliptin (2.5 mg and 5 mg) [all doses and regimens combined]) 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 (+7 days). A window period of -28 days to +7 days from the original scheduled date will be allowed for the Week 104 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.This visit should be completed without delay (at 104 weeks (- + 7 days) from Day 1, 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. No comparisons between dapagliflozin and saxagliptin will be performed. The sample size for this study is based on the ability to detect a 0.75% improvement over placebo for dapagliflozin or saxagliptin in change from baseline in HbA1c at Week 26 (ST) with approximately 80% power for each comparison at a 2 sided alpha level of 0.05. If 243 pediatric subjects are randomized and analyzed, and each treatment compared to placebo at a 2 sided alpha=0.05 level, this will provide approximately 80% power for each comparison to detect a 0.75% reduction in HbA1c change from baseline versus placebo assuming a standard deviation of 1.7%. Day 1 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 standard deviation estimate of data 1.7% is based on a blinded review of the ongoing study Analyses: Dapagliflozin and saxagliptin will be summarized separately. A common placebo group will be included in each summary. In addition, within the analyses of dapagliflozin and 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 dapagliflozin and saxagliptin regimens within each treatment will be combined into one subgroup and compared to the corresponding (common) placebo subgroup. 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 comparison vs placebo will be tested at a two sided alpha level of 0.05. The primary efficacy analysis will be performed using an analysis of covariance (ANCOVA). For this analysis, all dose levels for a treatment will be combined into one treatment group for each drug 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. 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/high dose and low dose treatment regimens and placebo, separately for both dapagliflozin and saxagliptin . In addition, up titrating to high-dose and continuing on low-dose will be compared in the subset of dapagliflozin and saxagliptin 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 (dapagliflozinand saxagliptin). 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/high-dose treatment regimen and placebo 2. Comparison of mean reduction in HbA1c from baseline at Week 26 between the low-dose treatment regimen and placebo 3.Comparison of mean reduction in FPG from baseline at Week 26 between overall drug treatment (all doses and regimens combined) and placebo 4.Comparison of mean reduction in FPG from baseline at Week 26 between the low dose/high-dose treatment regimen and placebo 5.Comparison of mean reduction in FPG from baseline at Week 26 between the low dose treatment regimen and placebo 6.Comparison of the percentage of subjects with baseline HbA1c ≥7% who achieve an HbA1c level < 7.0% at Week 26 between overall drug treatment (all doses and regimens combined) 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/high-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 the low-dose treatment regimen 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 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/high-dose treatment regimen. For this analysis, all dapagliflozin and saxagliptin subjects who had HbA1c < 7% at Week 12 and remained on the low-dose will get a weight of 1. The dapagliflozin and saxagliptin 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. 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 dapalgiflozin and saxagliptin subjects who had HbA1c < 7% at Week 12 and remained on the low-dose will get a weight of one. The daplagliflozin and saxagliptin 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 1. For subjects on dapagliflozin and saxagliptin 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. This analysis will be based on the Up -titration Randomized Subjects Data Set. 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 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 unweighted and 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 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.

Official Title
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A 26 Week, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Parallel Group, Phase 3 Trial With a 26 Week Safety Extension Period Evaluating the Safety and Efficacy of Dapagliflozin 5 and 10 mg, and Saxagliptin 2.5 and 5 mg in Pediatric Patients With Type 2 Diabetes Mellitus Who Are Between 10 and Below 18 Years of Age

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Saxagliptin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible subjects with HbA1c of 6.5% to 10.5% at screening will be randomized 1:1:1 to receive dapagliflozin 5 mg, saxagliptin 2.5 mg, or placebo. Blinded HbA1c assessment will be performed at Week 12. All subjects with Week 12 HbA1c < 7% will remain on previously assigned randomized treatment. Subjects taking dapagliflozin with Week 12 HbA1c ≥ 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). Subjects taking saxagliptin with Week 12 HbA1c ≥ 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). Subjects taking placebo with Week 12 HbA1c ≥ 7% will continue on placebo treatment. All placebo subjects and all subjects taking saxagliptin or dapagliflozin with HbA1c < 7% at Week 12 will go through a dummy 2nd randomization process for maintaining the blinding.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose Dapagliflozin<br>Oral route. Start with a low dose of dapagliflozin administered once daily and remain on the low dose regardless of your HbA1c at week 12. | Drug: Dapagliflozin<br>* Tablets, Oral, 5mg , Once daily Tablets, Oral, 10mg, Once daily<br>* Other names: Forxiga;|
| Experimental: Low dose/high dose Dapagliflozin<br>Oral route. Start with a low dose of Dapagliflozin administered once daily and up titrate to the high dose Dapagliflozin administered once daily if HbA1c >= 7% at week 12 | Drug: Dapagliflozin<br>* Tablets, Oral, 5mg , Once daily Tablets, Oral, 10mg, Once daily<br>* Other names: Forxiga;|
| Experimental: Low dose Saxagliptin<br>Oral route. Start with a low dose of saxagliptin administered once daily and remain on the low dose regardless of your HbA1c at week 12 | Drug: Saxagliptin<br>* Tablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily<br>* Other names: Onglyza;|
| Experimental: Low dose/high dose Saxagliptin<br>Oral route. Start with a low dose of saxagliptin administered once daily and up titrate to the high dose if HbA1c >= 7% at week 12 | Drug: Saxagliptin<br>* Tablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily<br>* Other names: Onglyza;|
| Placebo Comparator: Placebo arm<br>Oral route. Placebo tablets administered for 52 weeks | Drug: Placebo<br>* Matching placebo to dapagliflozin 5mg and 10 mg/saxagliptin 2.5 mg and 5 mg, Tablets, oral, Once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in HbA1c at Week 26 | To determine if there will be a greater mean reduction from baseline in HbA1c achieved after 26 weeks of oral double-blind add-on therapy ofdapagliflozin (5 mg or 10 mg [all doses and regimens combined]) or saxagliptin (2.5 mg or 5 mg [all doses and regimens combined]) compared to placebo in pediatric T2DM subjects with HbA1c levels of 6.5 to 10.5% on diet and exercise and metformin (IR or XR), insulin, or metformin (IR or XR) plus insulin. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Fasting Plasma Glucose at Week 26 | To determine if there will be a greater mean reduction from baseline in Fasting Plasma Glucose (FPG) achieved after 26 weeks of oral double-blind add-on therapy of dapagliflozin (5 mg or 10 mg [all doses and regimens combined]) or of saxagliptin 2.5 mg or 5 mg [all doses and regimens combined]) compared to placebo in pediatric T2DM subjects with HbA1c of 6.5 to 10.5% on diet and exercise and metformin (IR or XR), insulin, or metformin (IR or XR) plus insulin | 26 weeks | 
| Percentage of subjects with baseline HbA1c ≥ 7%, who achieve an HbA1c level < 7.0% at Week 26 | To compare the percentage of subjects with baseline HbA1c ≥ 7% who achieve an HbA1c level < 7.0% after 26 weeks of oral double-blind add-on therapy of dapagliflozin (5 mg or 10 mg [all doses and regimens combined]) or of saxagliptin (2.5 mg or 5 mg [all doses and regimens combined]) compared to placebo in pediatric T2DM subjects with HbA1c levels of 6.5 to 10.5% on diet and exercise and metformin (IR or XR), insulin, or metformin (IR or XR) plus insulin | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus