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Diabetes Mellitus, Type 2NCT02613897

ESR-15-11293 - Saxa/Dapa, Safety and Efficacy Study

A study testing Saxagliptin and Dapagliflozin in people with Diabetes Mellitus, Type 2, run by The University of Texas Health Science Center at San Antonio at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This is a 16-week, single center, randomized, double-blind, active-controlled, parallel-group, Phase 3b efficacy and safety study of simultaneous administration of saxagliptin 5 mg plus dapagliflozin 10 mg once daily (QD) compared with dapagliflozin plus placebo for saxagliptin, and placebo for saxagliptin plus… Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Diabetes Mellitus, Type 2
What is being tested?
Saxagliptin and Dapagliflozin
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
56 participants
Where
1 siteUnited States
Study dates
Jan 2016to 30 Jun 2018
Phase
Interventional
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Provision of informed consent prior to any study-specific procedures.
  • Is able to read, understand, and sign the Informed Consent Forms (ICFs) and, if applicable, an Authorization to Use and Disclose Protected Health Information form (consistent with Health Insurance Portability and Accountability Act of 1996 legislation), communicate with the Investigator, and understand and comply with protocol requirements, including the use of diary and glucose meter measurements.
  • Age = 18-70 years.
  • Has a diagnosis of T2DM.
  • Has HbA1c ≥7.5% and ≤11.0% obtained at Screening.
  • Treated with a stable dose of metformin ≥1000 mg/day or stable dose of metformin (≥ 1000 mg/day) plus sulfonylurea (glipizide, ≥ 5 mg/day; glyburide, ≥ 5 mg/day; glimepiride, ≥ 4 mg/day) for at least 8 weeks prior to Screening.
Show all 11Show fewer
  • Has a BMI of 20 to 45 kg/m2 (inclusive) at Screening.
  • Is male, or is female, and meets all the following criteria:
  • Not pregnant or breastfeeding.
  • Negative pregnancy test result at Visit 1 (Screening).
  • Women of childbearing potential (WOCBP; [including perimenopausal women who have had a menstrual period within 1 year]) must practice and be willing to continue to practice appropriate birth control (defined as a method that results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as implants, injectables, hormonal contraceptives [pills, vaginal rings, or patches], some intrauterine contraceptive devices [levonorgestrel-releasing or copper-T], tubal ligation or occlusion, or a vasectomized partner) during the entire duration of the study. As applicable, all methods must be in effect prior to receiving the first dose of study medication.

Who cannot join

  • Target Disease Exceptions
  • Clinically diagnosed with Type I diabetes .
  • History of diabetic ketoacidosis, hyperosmolar nonketotic coma, or corticosteroid induced Type 2 diabetes.
  • Medical History and Concurrent Diseases
  • History of bariatric surgery or lap-band surgery, or either procedure is planned during the time period of the study.
  • History of any unstable endocrine, psychiatric, rapidly progressing, or unstable renal disease, or rheumatic disorder, as judged by the Investigator.
Show all 40Show fewer
  • Patients who, in the judgment of the Investigator, may be at risk for dehydration or volume depletion that may affect the patient's safety and/or the interpretation of efficacy or safety data.
  • Has evidence of current abuse of drugs or alcohol or a history of abuse within the past 52 weeks that, in the Investigator's opinion, would cause the individual to be noncompliant.
  • Cardiovascular Conditions
  • Cardiovascular disease within 3 months of Screening (i.e., MI, cardiac surgery, revascularization, unstable angina, stroke, transient ischemic attack, or arrhythmia).
  • Presence or history of severe congestive heart failure (New York Heart Association Class III and IV [CCNYHA 1994]), unstable or acute congestive heart failure, and/or known left ventricular ejection fraction of ≤40%.
  • Note: Eligible patients with congestive heart failure, especially those who are on diuretic therapy, should have careful monitoring of their volume status throughout the study.
  • Kidney Conditions
  • Estimated (eGFR) <60±5 mL/min/1.73 m2 or a measured serum creatinine of >1.4 mg/dL for female patients and >1.5 mg/dL for male patients. If the serum creatinine is ≤ 1.4 (female) or ≤ 1.5 (male) and the eGFR is ≥ 60±5 ml/min/1.73m2, the subject is eligible to participate in the study.
  • Congenital renal glucosuria. Hepatic Conditions
  • Significant hepatic disease, including, but not limited to, severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) of >3x upper limit of normal (ULN).
  • Serum total bilirubin (TB) >2 mg/dL.
  • History of, or currently have, acute or chronic pancreatitis or have triglyceride concentrations ≥500 mg/dL at Visit 1 (Screening).
  • Suspicion that the patient is infected with an infectious substance according to World Health Organization risk categories A and B (see Appendix C).
  • Known severe hepatic disease, including chronic active hepatitis.
  • Positive serologic evidence of current infectious liver disease, including patients positive for hepatitis B viral antibody IgM, hepatitis B surface antigen, and hepatitis C virus antibody.
  • Hematological/Oncological Conditions
  • Malignancy within 5 years of Visit 1 (Screening), with the exception of treated in situ basal cell or squamous cell carcinoma of the skin.
  • Hematocrit of <34% for both males and females. Prohibited Medications
  • Administration of any antihyperglycemic therapy, other than metformin or metformin/sulfonylurea, for more than 14 days (consecutive or not) during the 12 weeks prior to Visit 1 (Screening) and during the study unless per protocol for rescue.
  • Current treatment with potent cytochrome P450 3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).
  • Administration of any other investigational drug or participation in any interventional clinical studies 30 days prior to Visit 1 (Screening).
  • Treatment with systemic corticosteroids for the last 3 months prior to Visit 1 (Screening).
  • Prescription or over-the-counter weight loss medications within 3 months prior to Visit 1 (Screening).
  • Other
  • Patients with abnormal thyroid stimulating hormone (TSH) or free thyroxine (T4) values at Visit 1 (Screening) will be excluded.
  • Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being, as judged by the Investigator.
  • Has clinically significant abnormal laboratory test values (clinical chemistry, hematology, and urinalysis) as judged by the Investigator at Visit 1 (Screening).
  • Has known contraindications, allergies, or hypersensitivities to any study medication or excipient as outlined in the IBs or local package inserts for saxagliptin and dapagliflozin.
  • Has a contraindication to metformin use, including known metabolic or lactic acidosis, or any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis.
  • Is currently pregnant (confirmed with positive pregnancy test) or breast feeding.
  • Is on a commercial weight loss program with ongoing weight loss more than 5% over the last 3 months prior to Visit 1 (Screening), or is on an intensive exercise program.
  • Involvement in the planning and/or conduct of the study (applies to both the study sponsor staff and/or staff at the study site).
  • Patient with any condition that, in the judgment of the Investigator, may render the patient unable to complete the study or which may pose a significant risk to the patient or patient suspected or with confirmed poor protocol or medication compliance.
  • Previous randomization in the present study.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • The University of Texas Health Science Center at San Antonio

    San Antonio, Texas, 78229

Other trials in United States

About this study

Official title: A 16-wk, Uni-center, Randomized, Double-blind, Parallel, Phase 3b Trial to Evaluate Efficacy of Saxagliptin + Dapagliflozin vs.Dapagliflozin With Regard to EGP in T2DM With Insufficient Glycemic Control on Metformin+/-Sulfonylurea Therapy

This is a 16-week, single center, randomized, double-blind, active-controlled, parallel-group, Phase 3b efficacy and safety study of simultaneous administration of saxagliptin 5 mg plus dapagliflozin 10 mg once daily (QD) compared with dapagliflozin plus placebo for saxagliptin, and placebo for saxagliptin plus placebo for dapagliflozin in patients with Type 2 diabetes who have inadequate glycemic control on metformin or metformin/sulfonylurea.

Read the detailed description

The study is intended to demonstrate complimentary action of saxagliptin/dapagliflozin added to metformin versus dapagliflozin added to metformin with regard to EGP.

Many medications are approved for the treatment of T2DM; however, the challenge of achieving and maintaining treatment goals within the current sequential therapy approach is linked to shortcomings of older classes of drugs. Metformin is in the biguanide drug class that acts to decrease hepatic glucose output and subsequently, decreases fasting hyperglycemia. Metformin, the oral first-line gold standard agent, is recommended as the initial pharmacological therapy because of its glycemic efficacy, weight neutrality, low risk of hypoglycemia, and beneficial cardiovascular (CV) profile. Current sequential add-on second and third line oral therapy includes oral drugs such as sulfonylureas (SUs) and thiazolidinediones (TZDs). These therapies and insulin are associated with increased risks for weight gain and hypoglycemia; therefore, caution is recommended when using combination therapy with other agents known to cause hypoglycemia. Hypoglycemia is a clinically important issue in optimizing treatment and there is emerging evidence that hypoglycemia is associated with negative CV outcomes. Efforts by patients to lose weight as part of a therapeutic lifestyle program are undermined by therapies that lead to weight gain. The majority of patients with T2DM are overweight or obese, and additional weight gain often results in reduced treatment efficacy.

Over the past few years, it has been widely recognized that the management approach for each T2DM patients' needs to be personalized based on his or her clinical characteristics (e.g., the likelihood of weight gain, risk for hypoglycemia, and lifestyle preferences [e.g., many patients may be reluctant to use injections]) (Inzucchi et al 2012). Based on data from the National Health and Nutrition Examination Survey in 2007 to 2010, HbA1c is not appropriately controlled in approximately one-third of patients using even less stringent targets (Ali et al 2013).

Because of the challenge to achieve glycemic control in patients with T2DM, the progressive nature of the disease, and the limitations of available oral and non-oral therapies, there is a significant medical need for oral combination treatment options and dual add-on therapy in patients with high baseline HbA1c. Expert groups have increasingly suggested making use of combination therapy early after diagnosis to improve glycemic control (Inzucchi et al 2012, Rodbard et al 2009). In a recent study, initiating triple therapy (pathophysiological-based approach) in patients with new onset T2DM versus metformin followed by sequential addition of SUs and basal insulin (treat-to-fail approach) demonstrated a more durable HbA1c reduction over 24 months and less hypoglycemia with initial triple therapy (Abdul-Ghani et al 2014). Initial combination therapy with saxagliptin and dapagliflozin added to metformin may have similar potential for durable glucose lowering in combination with low risk of hypoglycemia.

Treatment with saxagliptin and dapagliflozin, both individually and in combination with metformin, have demonstrated a favorable safety and tolerability profile. These drugs had a low propensity for hypoglycemia, therefore addressing a potential key concern when adding 2 glucose lowering agents simultaneously. These drugs have demonstrated weight neutrality (saxagliptin) or moderate weight reduction (dapagliflozin). Dapagliflozin has also been shown to cause a persistent reduction in HbA1c and weight after 2 years of therapy. Dapagliflozin was recently shown to increase EGP, which, in part, may be mediated by increased plasma glucagon (Merovci et al). In contrast, saxagliptin has been demonstrated to reduce glucagon levels, e.g., in response to a meal (Sjöstrand et al 2014) and vildagliptin, also a DPP-4 inhibitor, has been shown to inhibit EGP (Balas et al 2007).

A second-line oral dual add-on therapy with saxagliptin co-administered with dapagliflozin could be a new option, as part of a triple therapy combination that includes drugs with complementary mechanisms of action, opposing effects on plasma glucagon concentration, and possibly EGP, low risk of hypoglycemia, and the potential for moderate weight loss, providing a more effective and patient-friendly approach to the treatment of T2DM.

Being tested
Saxagliptin, Dapagliflozin, Placebo
Medical subject headings
Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SaxagliptinDrug

    Also called Onglyza

    Saxagliptin (Onglyza™) is approved by the US FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. The 5 mg dose will be used for this study as it is the dose that is routinely used in the clinic. In addition, this dose is used in the pivotal studies in the saxagliptin/dapagliflozin clinical program.

  • DapagliflozinDrug

    Also called Farxiga

    Dapagliflozin (Farxiga) is approved by the FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Dapagliflozin (Farxiga) is also approved in the EU as an adjunct to diet and exercise to improve glycemic control in patients with T2DM for whom metformin use is considered inappropriate due to intolerance, and in combination with other glucose-lowering medicinal products when these, in combination with diet and exercise do not provide adequate glycemic control. The 10 mg dose was chosen for this study because it has been extensively studied in Phase 3 trials and has demonstrated a favorable benefit-risk profile. In addition, this dose is the most commonly used dose in most countries.

  • PlaceboDrug

    Placebo

Study groups in NCT02613897
Study groupRoleWhat they receive
DAPA/SAXA (dapagliflozin plus saxagliptin)Active comparatorDapagliflozin 10mg + Saxagliptin 5mg (plus standard of care treatment of metformin or metformin plus sulfonylurea).
Receives: Drug: Saxagliptin; Drug: Dapagliflozin
DAPA (Dapagliflozin plus placebo)Active comparatorDapagliflozin 10mg + Placebo (plus standard of care treatment of metformin or metformin plus sulfonylurea).
Receives: Drug: Dapagliflozin
PCB (Placebo plus placebo)Placebo comparatorPlacebo (for dapagliflozin) + placebo (for saxagliptin) (plus standard of care treatment of metformin or metformin plus sulfonylurea).
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Endogenous Glucose Production (EGP)

    All subjects received a Double-Tracer Oral Glucose Tolerance Test (OGTT) with 75g of glucose containing 14C-glucose together with intravenous primed-continuous infusion of 3(3H)-glucose for 240 minutes, at baseline (prior to) and after 16 weeks of therapy. Blood and urine samples were obtained during the OGTT to determine EGP.

    Measured: Baseline and 16 weeks

Secondary outcomes (8)

  1. Change in Body Weight

    Change in body weight from baseline to 16 weeks

    Measured: Baseline to 16 weeks

  2. Change in BMI

    Change in BMI (body mass index) from study start to 16 weeks

    Measured: Change from baseline to 16 weeks

  3. HBA1c

    Change in blood glucose level measured over a 3 month period from study start to 16 weeks

    Measured: Change from baseline to 16 weeks

  4. Mean Oral Glucose Tolerance Test (OGTT)

    Measure of change in OGTT from study start to 16 weeks

    Measured: Change from baseline to 16 weeks

  5. Change in Lipid Oxidation

    Change in lipid oxidation percentage from baseline to 16 weeks

    Measured: Change from baseline to 16 weeks

  6. Change in Glucose Oxidation

    Change in percentage of glucose oxidation from study start to 16 weeks

    Measured: Change from baseline to 16 weeks

  7. Change in Fasting Plasma Glucagon (FPG)

    A measure of the change in fasting plasma glucagon from study start to 16 weeks

    Measured: Change from baseline to 16 weeks

  8. Change in Free Fatty Acids (FFA)

    Measure of change in Free Fatty Acids from study start to 16 weeks

    Measured: Change from baseline to 16 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Nov 2015 (estimated)
  2. Study startJan 2016
  3. Primary completion30 Jun 2018
  4. Study completion30 Jun 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
56 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02613897
Sponsor's protocol ID
HSC20150742H
Status last verified
Jun 2019
First submitted
12 Nov 2015
Last updated
14 Aug 2019
Data monitoring committee
Yes

Publications

  • Rodbard HW, Blonde L, Braithwaite SS, Brett EM, Cobin RH, Handelsman Y, Hellman R, Jellinger PS, Jovanovic LG, Levy P, Mechanick JI, Zangeneh F; AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007 May-Jun;13 Suppl 1:1-68. doi: 10.4158/EP.13.S1.1. No abstract available.

    PubMed 17613449

  • Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011 Aug;32(4):515-31. doi: 10.1210/er.2010-0029. Epub 2011 May 23.

    PubMed 21606218

  • Abdul-Ghani MA, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, DeFronzo RA. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015 Mar;17(3):268-75. doi: 10.1111/dom.12417. Epub 2015 Jan 7.

    PubMed 25425451

  • Ali MK, Bullard KM, Gregg EW. Achievement of goals in U.S. Diabetes Care, 1999-2010. N Engl J Med. 2013 Jul 18;369(3):287-8. doi: 10.1056/NEJMc1306652. No abstract available.

    PubMed 23863067

  • Balas B, Baig MR, Watson C, Dunning BE, Ligueros-Saylan M, Wang Y, He YL, Darland C, Holst JJ, Deacon CF, Cusi K, Mari A, Foley JE, DeFronzo RA. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007 Apr;92(4):1249-55. doi: 10.1210/jc.2006-1882. Epub 2007 Jan 23.

    PubMed 17244786

  • The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. 1994; 253-256.

  • Centers for Disease Control and Prevention (CDC). Prevalence of overweight and obesity among adults with diagnosed diabetes--United States, 1988-1994 and 1999-2002. MMWR Morb Mortal Wkly Rep. 2004 Nov 19;53(45):1066-8.

    PubMed 15549021

  • CHMP 2009 European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Guideline on Clinical Development of Fixed Combination Medicinal Products. CHMP/EWP/240/95 Rev. 1. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003686.pdf. Published 19 February 2009. Accessed 19 June 2014.

  • CHMP 2012 European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. CPMP/EWP/1080/00 Rev. 1. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Published 14 May 2012. Accessed 19 June 2014.

  • Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009 Apr;58(4):773-95. doi: 10.2337/db09-9028. No abstract available.

    PubMed 19336687

  • Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011 Mar;13(3):258-67. doi: 10.1111/j.1463-1326.2010.01350.x.

    PubMed 21205122

  • Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011 May;34 Suppl 2(Suppl 2):S276-8. doi: 10.2337/dc11-s229. No abstract available.

    PubMed 21525468

  • Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.

    PubMed 8366922

  • Ferrannini E, Bjorkman O, Reichard GA Jr, Pilo A, Olsson M, Wahren J, DeFronzo RA. The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes. 1985 Jun;34(6):580-8. doi: 10.2337/diab.34.6.580.

    PubMed 3891471

  • Goke B, Hershon K, Kerr D, Calle Pascual A, Schweizer A, Foley J, Shao Q, Dejager S. Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naive patients with type 2 diabetes: comparison with metformin. Horm Metab Res. 2008 Dec;40(12):892-5. doi: 10.1055/s-0028-1082334. Epub 2008 Aug 22.

    PubMed 18726829

Questions about this trial

What is this clinical trial studying?

A study testing Saxagliptin and Dapagliflozin in people with Diabetes Mellitus, Type 2, run by The University of Texas Health Science Center at San Antonio at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Endogenous Glucose Production (EGP) (time frame: Baseline and 16 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02613897, which also lists 35 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2019.

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