Efficacy and Safety of Dapagliflozin

Principal Investigator: Debra Simmons
Keywords: Type 1 Diabetes , ellitus , Insulin , Dapagliflozin Department: Endocrinology/Diabetes Researc
IRB Number: 00077405 Co Investigator:  
Specialty: Endocrinology and Metabolism
Sub Specialties: Type 1 Diabetes and Intensive Insulin Therapy
Recruitment Status: Recruiting

Contact Information

Zachary Mitchell
zachary.mitchell@hsc.utah.edu
801-587-7467

Brief Summary

This trial is a randomized, double-blinded, three-arm, parallel-group, placebo-controlled, multicenter trial to evaluate the efficacy and safety of dapagliflozin, when added to ongoing insulin therapy, in subjects with Type 1 diabetes (T1DM) and inadequate glycemic control.

The primary objective of the study is to compare the change from baseline in HbA1c after 24 weeks of double-blinded treatment with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin.

Secondary Objectives:

Efficacy

  • Six secondary efficacy objectives are identified for special consideration in this study, in addition to the primary objective:
  1. Compare the percent change from baseline in total daily insulin dose with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment 
  2. Compare the percent change from baseline in body weight with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  3. Compare the change from baseline in the mean value of 24-hour glucose readings obtained from continuous glucose monitoring (CGM) with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  4. Compare the change from baseline in mean amplitude of glucose excursion (MAGE) of 24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  5. Compare the chasd baseline in the percent of 24-hour glucose readings obtained from CGM that falls within the target range of >  70 mg/dL and < 180 mg/dL with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  6. Compare dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin for the proportion of subjects achieving an HbA1c reduction from baseline to Week 24 visit > 0.5% without severe hypoglycemia events Safety

Safety

  1. To assess the proportion of subjects with hypoglycemia events and the frequency and severity of the hypoglycemia events with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin
  2. To evaluate the safety and tolerability by assessment of adverse events (AE), vital signs, diabetic ketoacidosis events (DKA), physical examination findings, ECGs, and laboratory values.

Other/Exploratory Objectives: 

  1. Assess the proportion of subjects with HbA1c reduction of at least 0.5% (0.5%) from baseline with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  2. Assess the proportion of subjects with HbA1c< 7.0% with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  3. Assess the change from baseline in fasting plasma glucose (FPG) with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  4. Assess the change from baseline in the percent of 24-hour glucose readings obtained from CGM that is within the hypoglycemic range of < 70 mg/dL with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  5. Assess the change from baseline in seated systolic blood pressure with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment among subjects with hypertension at baseline, defined as seated SBP 140 mmHg and/or seated DBP 90 mmHg.
  6. Assess the change from baseline in average glucose values measured by 6-point self monitor blood glucose (SMBG) with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after24 weeks of double-blinded treatment
  7. Assess the change from baseline in postprandial glucose values measured by 6-point SMBG with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  8. Assess the change from baseline in postprandial glucose values measured by CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  9. Assess the change from baseline in standard deviation of 24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  10. Assess the change from baseline to Week 24 in health status, as measured by the EQ-5D-3L questionnaire, between dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment by using the EQ-5D-3L questionnaire
  11. Assess the changes from baseline to Week 24 in the summary score for treatment satisfaction and scores for perceived frequency of hyperglycemia and perceived frequency of hypoglycemia, respectively, as measured by the Diabetes Treatment Satisfaction Questionnaire status (DTSQs) between the dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
  12. To explore the relationship between observed and/or model estimated pharmacokinetic measures of exposure (eg, AUCss, Cmax, Cmin) and efficacy and/or safety endpoints by using model-based approaches. This analysis will be provided in a separate report.
  13. Compare the number of non-severe hypoglycemic events per subject in those achieving an HbA1c reduction of >0.5% on dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin from baseline to Week 24 visit.

Inclusion Criteria

Inclusion Criteria

1) Signed Written Informed Consent

  • a) Subjects must be willing and able to give signed and dated written informed consent.

2) Target Population

  • Diagnosis of T1DM. In addition, the following criteria also needs to be met;
  • Central laboratory test of C-peptide < 0.7 ng/ml(or < 0.23 nmol/L)
  • Not applicable per Protocol Amendment 03
  • Subject Re-enrollment: This study does not permit the re-enrollment of a subject who has discontinued the study as a screen or lead-in failure. However any subject previously excluded for any of the criteria changed in Amendment 03 will be allowed to be rescreened.
  • Subjects who did not fail any of the screening or lead-in criteria and are not subsequently randomized within the applicable study visit windows (eg, due to a planned medical procedure, vacation plans, or employment commitments) may rescreen after discussion and approval by the Sponsor.

3) Insulin use for at least 12 months per subject report or medical records and

  • Method of insulin administration (MDI or CSII) must have been unchanged for at least 3 months prior to the screening visit per subject reported or medical records. Subjects must be on a total insulin dose of > 0.3 U/kg/day for at least 3 months prior to the screening visit.
  • If on MDI insulin administration subject must be on > 3 injections per day.

4) A1C eligibility criteria include:

  • Screening Visit: Central laboratory A1C > 7.7% and < 11.0%
    • Note: A one-time repeat A1C test for subjects in screening is allowed if their initial test result was an A1C +/- 0.2% of the cut off values
  • Week -1 Visit: Central laboratory A1C > 7.5% and < 10.5% ​
    • Note: A one-time repeat A1C test for subjects at week -1is allowed if their tests result is within +/- 0.2% of the cut off values.
    • To ensure adequate time is given to complete the repeat week -1 AIC, a 7 day window (added to the current lead-in period window of 56 +/- 5 days) will be allowed

5) Body Mass Index (BMI) > 18.5 kg/m²

6) Age and Reproductive Status

  • Men and women, ages 18 to 75 years, inclusive
  • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
  • Women must not be breastfeeding.
  • WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with dapagliflozin plus 4 days (> 5 half-lives of dapagliflozin) plus 30 days (duration of ovulatory cycle) for a total of 34 days post-treatment completion
  • Males who are sexually active with WOCBP must agree to the following instructions for the duration of treatment with dapagliflozin plus 4 days (>5 half-lives of dapagliflozin) plus 90 days (duration of sperm turnover) for a total of 94 days post-treatment completion.

Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% per year when used consistently and correctly.

At a minimum, subjects must agree to the use of one method of highly effective contraception listed below:

  • Male condoms with spermicide
  • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject’s WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug
  • Non hormonal IUDs, such as ParaGard®
  • Tubal ligation (not considered surgically sterile)
  • Vasectomy
  • Complete Abstinence*

*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence.

  • Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, females must still undergo pregnancy testing as described in this section.

Exclusion Criteria

Target Disease Exceptions

a) History of T2DM or maturity onset diabetes of young (MODY), pancreatic surgery, or chronic pancreatitis or other pancreatic disorders that could result in decreased beta cell capacity (eg, pancreatogenous diabetes).

  • Note: Subjects with a previous misdiagnosis of T2DM in their medical history must have one of the following in order to be eligible for this trial:
    • Positive autoantibodies for GAD65, phosphatase IA-2/IA2beta, or zinc transporter 8 (ZnT8) (i.e. autoimmune diabetes)
      • Note: If additional time is needed to confirm positive autoantibodies, it can be granted by the Sponsor.
    • Fasting c-peptide value below the lower limit of detection performed by local or central laboratory

b) Previous use of dapagliflozin and/or any other SGLT-2 inhibitors.

c) Not applicable per Protocol Amendment 03

d) any non-insulin, any antihyperglycemic agent use within 1 month prior to the screening visit

e) History of diabetes ketoacidosis (DKA) requiring medical intervention (eg, emergency room visit and/or hospitalization) within 1 month prior to the screening visit

f) History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia) within 1 month prior to the screening visit

g) Frequent episodes of severe hypoglycemia as defined by more than one episode requiring medical assistance, emergency care (paramedics or emergency room care), and/or glucagon therapy administered by a third-party individual within 1 month prior to the screening visit

h) Symptoms of poorly controlled diabetes that would preclude participation in this trial including but not limited to marked polyuria and polydipsia with greater than 10% weight loss during the three months prior to screening, or other signs and symptoms of poor glycemic control.

I) History of Addison’s disease or chronic adrenal insufficiency

J) History of diabetes insipidus

K) Use of any GLP-1 receptor agonist within the following timeframe prior to the screening visit:

i. 1 month for once or twice daily administration (eg. liraglutide)

ii. 2 months for once weekly administration

L) Use of insulin-sensitizing agents, such as metformin and/or thiazolidinediones, within 2 months prior to the screening visit

2) Medical History and Concurrent Diseases

a) Any of the following CV/Vascular Diseases within 6 months of the screening visit:

1. Myocardial infarction

2. Cardiac surgery or revascularization (coronary artery bypass surgery [CABG]/percutaneous transluminal coronary angioplasty [PTCA])

3. Unstable angina

4. Unstable congestive heart failure (CHF)

5. CHF New York Heart Association (NYHA) Class III or IV

6. Transient ischemic attack (TIA) or significant cerebrovascular disease

7. Unstable or previously undiagnosed arrhythmia

b) Renal Disease:

1. History of unstable or rapidly progressing renal disease

2. Conditions of congenital renal glucosuria

3. Renal allograft

c) Hepatic Diseases:

1. Significant hepatic disease, including, but not limited to, chronic active hepatitis

and/or severe hepatic insufficiency

d) Hematological and Oncological Disease/Conditions:

1. History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or chronic or recurrent hemolysis

2. Known immunocompromised status, including but not limited to, individuals who have undergone organ transplantation or who are positive for the human immunodeficiency virus

3. Donation of blood or blood products to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of > 400 mL of blood during the 8 weeks prior to the screening visit

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

5. History of bladder cancer

6. History of radiation therapy to the lower abdomen or pelvis at any time

3) Physical and Laboratory Test Findings

a) Aspartate Aminotransferase (AST) > 3X Upper limit of normal (ULN)

b) Alanine aminotransferase (ALT) > 3X ULN

c) Serum Total Bilirubin (TB) > 2X ULN unless exclusively caused by Gilbert’s Syndrome

d) Calculated Creatinine Clearance <60 ml/min. The renal function, creatinine clearance will be estimated by the Cockcroft-Gault formula, using laboratory measurements of serum creatinine collected at the screening visit [Creatinine Clearance = [[140 - age(yr)]*weight(kg)/[72*serum Cr(mg/dl)] (multiply by 0.85 for women)].

e) Hemoglobin £ 11.0 g/dL (110 g/L) for men; hemoglobin £ 10.0 g/dL (100 g/L) for women.

f) Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody

g) Abnormal Free T4

· Note: abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded. A one-time retest may be allowed, as determined by the investigator, after a minimum of 6 weeks following the adjustment of thyroid hormone replacement therapy in subjects who have had a prior diagnosis of a thyroid disorder and who are currently receiving thyroid replacement therapy. Such cases should be discussed with the Sponsor prior to re-testing. The subject must have all enrollment procedures and laboratory assessments performed as part of this re-test, and all of these must meet enrollment eligibility criteria. The subject’s number will however remain the same as initially assigned.

4) Allergies and Adverse Drug Reaction

a) Allergies or contraindication to the contents of dapagliflozin tablets or insulin.

5) Sex and Reproductive Status

a) Women who are pregnant or breast feeding

6) Other Exclusion Criteria

a) Prisoners or subjects who are involuntarily incarcerate.

b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness

c) Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program.

d) History of bariatric surgery or lap-band procedure within 12 months prior to screening.

e) Replacement or chronic systemic corticosteroid therapy, therapy, (including local injections such as intramuscular or intra-articular,etc.), defined as any dose of systemic corticosteroid taken for > 4 weeks within 3 months prior to the Day 1 visit

NOTE: Topical (including drops) or inhaled corticosteroids are allowed

f) Any unstable endocrine, psychiatric or rheumatic disorders as judged by the Investigator

g) Volume depleted subjects. Subjects at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics who cannot carefully monitor their volume status should be excluded from the study.

h) Subject is, in the judgment of the Investigator, unlikely to comply with the protocol, or is unable to correctly self administer subcutaneous insulin injections and/or manage their insulin pump, or has any severe concurrent medical or psychological condition that may affect the interpretation of efficacy or safety data including during the lead-in period.

i) Subject with any condition which, in the judgment of the Investigator, may render the subject unable to complete the study or which may pose a significant risk to the subject.

j) Subject is currently abusing alcohol or other drugs or has done so within the last 6 months prior to the Day 1 visit

k) Subject is a participating investigator, study coordinator, employee of an investigator or immediate family member of any of the aforementioned.

l) Employee of BMS, AstraZeneca (AZ), or their relatives.

m) Administration of any other investigational drug within 30 days of the screening visit

n) No clinical conditions or clinically significant abnormalities, in any laboratory value(s) collected after screening and prior to randomization which, in the Investigator’s judgment, should preclude entry into the treatment period