Safety and Efficacy of Dapagliflozin in Asian T2DM Subjects With Inadequate Glycemic Control on Metformin/Saxagliptin

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Asian Subjects With T2DM and Inadequate Glycemic Control on Metformin and Saxagliptin (DS Navigation)

This is a 24-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel group, phase 3 study designed to evaluate if the safety and efficacy of dapagliflozin 5 mg or 10 mg added to saxagliptin 5 mg plus metformin is superior to placebo added to saxagliptin 5 mg plus metformin in reducing hemoglobin A1c (HbA1c).

Study Overview

• Status: Terminated
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Dapagliflozin 10 mg; Drug: Dapagliflozin 5 mg placebo to match; Drug: Saxagliptin 5 mg; Drug: Metformin; Drug: Dapagliflozin 5 mg; Drug: Dapagliflozin 10 mg placebo to match

Detailed Description

This study will be conducted in approximately 36 sites in Asian countries. Approximately 1004 subjects will be screened and 342 randomized. Prior to the screening, subjects of Stratum A should have a stable dose of metformin (≥1500 mg/day or a maximal tolerated dose) for at least 8 weeks. And subjects of Stratum B should have a stable dose of metformin (≥1500 mg/day or a maximal tolerated dose) AND a dipeptidyl peptidase-4 inhibitor at maximum approved dose for at least 8 weeks prior to the screening. Eligible subjects who complete the screening visit will enter the lead-in period, which includes open-label saxagliptin 5 mg and metformin treatment for 16 weeks in Stratum A or 8 weeks in Stratum B. At randomization visit, eligible subjects will be randomized into 1 of 3 treatment groups in a 1:1:1 ratio, receiving blinded dapagliflozin 5 mg, 10 mg or placebo plus metformin and saxagliptin 5 mg treatment for 24 weeks.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 3

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10330
    • Research Site
  • Bangkok, Thailand, 10400
    • Research Site
• Vietnam
  • Ho Chi Minh, Vietnam, 700000
    • Research Site
  • Ho Chi Minh, Vietnam, 10000
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Provision of informed consent before participating in the study
2. Diagnosed with type 2 diabetes mellitus

3. Inadequate glycemic control defined as below:

   • HbA1c ≥ 8.0% and ≤ 11.5% for Stratum A and HbA1c ≥ 7.5% and ≤ 10.5% for Stratum B at screening visit
   • HbA1c ≥ 7.0 and ≤ 10.5% for both strata at Week -2 visit
4. Body mass index ≤ 40.0 kg/m^2

Exclusion Criteria:

1. Women of childbearing potential unable or unwilling to use acceptable birth control, or women who are pregnant or breastfeeding
2. History of diabetes insipidus and type 1 diabetes
3. History of diabetic ketoacidosis requiring medical intervention within 1 month prior to screening
4. Subjects with moderate to severe renal impairment (defined as estimate glomerular filtration rate calculated by the MDRD Formula < 60mL/min/1.73 m^2 or serum creatinine ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females) or end-stage renal disease
5. History of unstable or rapidly progressing renal disease
6. Subjects with significant hepatic disease or severe hepatic impairment, or positive serologic evidence of current infectious liver disease

7. Prohibited Treatment and Therapies

   • Administration of any anti-hyperglycemic therapy [other than metformin, or Dipeptidyl peptidase-4 (DPP-4) inhibitors] for more than 14 days (consecutive or not) during the 8 weeks prior to screening
   • Any use of Sodium glucose cotransporter 2 (SGLT2) inhibitor within 8 weeks prior to screening
   • Prescription and over-the-counter weight loss medications within 3 months prior to screening
   • Current treatment with potent cytochrome P450 3A4/5 inhibitors
8. Malignancy within 5 years of the screening
9. History of hemoglobinopathy
10. Hematuria (by microscopy) positive at screening visit
11. FPG > 270 mg/dL obtained at open-label period
12. An abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin 10 mg; Dapagliflozin 10 mg and dapagliflozin 5 mg placebo to match added to saxagliptin 5 mg and metformin	Drug: Dapagliflozin 10 mg; 10 mg, oral tablet, once daily for 24 weeks of double-blind treatment period; Drug: Dapagliflozin 5 mg placebo to match; 5 mg, oral tablet, once daily for 24 weeks of double-blind treatment period; Drug: Saxagliptin 5 mg; 5 mg, oral tablet, once daily for 24 weeks of double-blinded treatment period, and for 16 weeks of open-label treatment period in Stratum A or 8 weeks of open-label treatment period in Stratum B; Drug: Metformin; Stable dose of metformin immediate release/extended release (≥ 1500 mg/day or at a maximal tolerated dose) throughout the whole study period
Experimental: Dapagliflozin 5 mg; Dapagliflozin 5 mg and dapagliflozin 10 mg placebo to match added to saxagliptin 5 mg and metformin	Drug: Saxagliptin 5 mg; 5 mg, oral tablet, once daily for 24 weeks of double-blinded treatment period, and for 16 weeks of open-label treatment period in Stratum A or 8 weeks of open-label treatment period in Stratum B; Drug: Metformin; Stable dose of metformin immediate release/extended release (≥ 1500 mg/day or at a maximal tolerated dose) throughout the whole study period; Drug: Dapagliflozin 5 mg; 5 mg, oral tablet, once daily for 24 weeks of double-blind treatment period; Drug: Dapagliflozin 10 mg placebo to match; 10 mg, oral tablet, once daily for 24 weeks of double-blind treatment period
Placebo Comparator: Placebo; Dapagliflozin 5 mg placebo to match and dapagliflozin 10 mg placebo to match added to saxagliptin 5 mg and metformin	Drug: Dapagliflozin 5 mg placebo to match; 5 mg, oral tablet, once daily for 24 weeks of double-blind treatment period; Drug: Saxagliptin 5 mg; 5 mg, oral tablet, once daily for 24 weeks of double-blinded treatment period, and for 16 weeks of open-label treatment period in Stratum A or 8 weeks of open-label treatment period in Stratum B; Drug: Metformin; Stable dose of metformin immediate release/extended release (≥ 1500 mg/day or at a maximal tolerated dose) throughout the whole study period; Drug: Dapagliflozin 10 mg placebo to match; 10 mg, oral tablet, once daily for 24 weeks of double-blind treatment period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from baseline in HbA1c at Week 24	To compare the mean change from baseline in HbA1c achieved with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin versus placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from baseline in fasting plasma glucose (FPG) at Week 24	To compare the mean change from baseline in FPG achieved with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin versus placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment	Baseline to Week 24
Mean change in 2-hour postprandial glucose during a meal tolerance test (2-hour MTT) at Week 24	To compare the mean change from baseline in 2-hour postprandial glucose from a meal tolerance test (2-hour MTT) achieved with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin versus placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment	Baseline to Week 24
Mean change from baseline in total body weight at Week 24	To compare the mean change from baseline in total body weight achieved with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin versus placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment	Baseline to Week 24
Percent of subjects achieving a therapeutic glycaemic response of HbA1c <7.0% at Week 24	To compare the proportion of subjects achieving a therapeutic glycaemic response of HbA1c < 7.0% with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin vs. placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment	At week 24

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Linong Ji, Professor, People's Hospital of Peking Universty

Publications and helpful links

Helpful Links

• Clinical Study Results on trialsummaries.com

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2019
• Primary Completion (Actual): August 4, 2020
• Study Completion (Actual): August 4, 2020

Study Registration Dates

• First Submitted: July 11, 2018
• First Submitted That Met QC Criteria: July 24, 2018
• First Posted (Actual): July 31, 2018

Study Record Updates

• Last Update Posted (Actual): May 31, 2022
• Last Update Submitted That Met QC Criteria: May 25, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: HbA1c; Dapagliflozin; Incretin; DPP-4 inhibitor
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Dapagliflozin; Metformin; Saxagliptin
• Other Study ID Numbers: D1683C00008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No