The Potential of Dapagliflozin Plus Exenatide in Obese Insulin-resistant Patients

Sponsor

Universitätsklinikum Hamburg-Eppendorf (Other)

Overall Status

Terminated

CT.gov ID

NCT03419624

Collaborator

AstraZeneca (Industry)

Enrollment

Locations

Arms

17.5

Actual Duration (Months)

3.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a 28-week, multi-center, randomized, double-blind, placebo-controlled trial to study a potential synergistic effect of Dapagliflozin plus Exenatide once-weekly in combination with high-dose intensive insulin therapy compared to Placebo in obese insulin-resistant patients with Type 2 Diabetes mellitus (T2DM) and inadequate glycemic control (HbA1c≥8.0% and ≤ 11.0%).

Condition or Disease	Intervention/Treatment	Phase
Obesity Diabetes Mellitus, Type 2	Drug: Dapagliflozin 10mg Drug: Exenatide 2 mg [Bydureon] Drug: Placebo Oral Tablet Drug: Placebo injection Drug: Insulin Drug: Metformin, if taken before	Phase 3

Detailed Description

In this proof-of-concept study the potential of treatment with Dapagliflozin plus Exenatide added to high-dose intensive insulin therapy compared to Placebo added to high-dose intensive insulin with active insulin up-titration for change in HbA1c from baseline to week 28 shall be explored and generate initial data on the primary outcome. We hypothesize that SGLT-2 inhibition and GLP-1 receptor agonism may be a rational combination therapy that addresses a broad range of pathophysiological defects associated with T2DM in obesity and may reduce HbA1c levels in patients with severe insulin resistance. In a third treatment arm, patients will be treated with Exenatide monotherapy added to high-dose intensive Insulin therapy to study additive effects of Dapagliflozin and Exenatide.

Study Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A 28-week, Multi-center Randomized, Double-blind, Placebo-controlled Study to Evaluate the Potential of Dapagliflozin Plus Exenatide in Combination With High-dose Intensive Insulin Therapy Compared to Placebo in Obese Insulin-resistant Patients With Type 2 Diabetes Mellitus (Proof-of-concept Study)

Actual Study Start Date :

Feb 19, 2018

Actual Primary Completion Date :

Apr 1, 2019

Actual Study Completion Date :

Aug 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin plus Exenatide Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy	Drug: Dapagliflozin 10mg Dapagliflozin 10 mg tablet once daily Drug: Exenatide 2 mg [Bydureon] Exenatide 2 mg injection once weekly Drug: Insulin daily Insulin injections Drug: Metformin, if taken before If the Patient has taken Metformin prior to enrollment, he or she will continue to take it.
Placebo Comparator: Placebo plus Placebo Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy	Drug: Placebo Oral Tablet Placebo oral tablet once daily Drug: Placebo injection Placebo injection once weekly Drug: Insulin daily Insulin injections Drug: Metformin, if taken before If the Patient has taken Metformin prior to enrollment, he or she will continue to take it.
Active Comparator: Placebo plus Exenatide Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy	Drug: Exenatide 2 mg [Bydureon] Exenatide 2 mg injection once weekly Drug: Placebo Oral Tablet Placebo oral tablet once daily Drug: Insulin daily Insulin injections Drug: Metformin, if taken before If the Patient has taken Metformin prior to enrollment, he or she will continue to take it.

Arm

Intervention/Treatment

Experimental: Dapagliflozin plus Exenatide

Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy

Drug: Dapagliflozin 10mg

Dapagliflozin 10 mg tablet once daily

Drug: Exenatide 2 mg [Bydureon]

Exenatide 2 mg injection once weekly

Drug: Insulin

daily Insulin injections

Drug: Metformin, if taken before

If the Patient has taken Metformin prior to enrollment, he or she will continue to take it.

Placebo Comparator: Placebo plus Placebo

Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy

Drug: Placebo Oral Tablet

Placebo oral tablet once daily

Drug: Placebo injection

Placebo injection once weekly

Drug: Insulin

daily Insulin injections

Drug: Metformin, if taken before

If the Patient has taken Metformin prior to enrollment, he or she will continue to take it.

Active Comparator: Placebo plus Exenatide

Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy

Drug: Exenatide 2 mg [Bydureon]

Exenatide 2 mg injection once weekly

Drug: Placebo Oral Tablet

Placebo oral tablet once daily

Drug: Insulin

daily Insulin injections

Drug: Metformin, if taken before

If the Patient has taken Metformin prior to enrollment, he or she will continue to take it.

Outcome Measures

Primary Outcome Measures

Change in HbA1c from baseline (week 0) to week 28 [28 weeks]
To compare the absolute change from baseline in HbA1c at week 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy

Secondary Outcome Measures

Change in HbA1c from baseline (week 0) to week 14 [14 weeks]
To compare the absolute change in HbA1c from baseline at week 0 to week 14 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Change in total body weight from baseline (week 0) to week 14 and 28 [28 weeks]
To compare the change in total body weight from baseline at week 0 to week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Change in BMI from baseline (week 0) to week 14 and 28 [28 weeks]
To compare the change in BMI from baseline at week 0 to week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Change in FPG from baseline (week 0) to week 14 and 28 [28 weeks]
To compare the change in fasting plasma glucose (FPG) from baseline at week 0 to week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Change in TDID from baseline (week 0) to week 14 and 28 [28 weeks]
To compare the change in total daily insulin dose (TDID) from baseline at week 0 to week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Proportion of patients achieving HbA1c of ≤ 7% at week 28 compared to baseline [28 weeks]
To compare the number of patients achieving HbA1c of ≤ 7% at week 28 compared to baseline at week 0 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

For inclusion in the study patients should fulfill the following key criteria:

Informed Consent can be obtained prior to any study procedures.
Patient is able to read, understand and sign the Informed Consent.
HbA1c ≥ 8.0% and ≤ 11.0% based on laboratory results
Currently treated with a stable TDID ≥ 80 U at least 3 months prior to enrolment
Patients who are receiving metformin must be on a stable total daily dose ≥ 1500 mg or the maximum tolerated dose of metformin within 3 months prior to enrolment
BMI of ≥ 30 kg/m2 at enrolment
Male or female and ≥18 and ≤75 years old at time of informed consent
For female patients:

Not breastfeeding.
Negative pregnancy test result (human chorionic gonadotropin, beta subunit [βhCG]) at Visit 0 (Screening) and Visit 1 (randomization) -not applicable to hysterectomized and post-menopausal females.
If of childbearing potential (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 which results in a low failure rate, ie, 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.
Must practice appropriate birth control as stated above for 10 weeks after the last dose of study medication.

Patients who are receiving the following medications must be on a stable treatment regimen for a minimum of 2 months prior to Visit 0 (Screening):

Antihypertensive agents
Thyroid replacement therapy
Antidepressant agents

Exclusion Criteria:

Diagnosis of Type 1 Diabetes
History of diabetic ketoacidosis, hyperosmolar coma or corticosteroid-induced Type 2 diabetes
Patients with significant thyroid disease
Patients with history of acute or chronic pancreatitis
Clinically significant cardiovascular disease or procedure within 3 months prior to enrolment or expected to require coronary revascularization procedure
Presence of history of severe congestive heart failure (NYHA III and IV)
Creatinin-Clearance of < 60 ml/min based on local laboratory results
Concomitant medication with loop diuretics
Patients who, as judged by the investigator, may be at risk for dehydration or volume depletion that may affect the patient's safety (including e.g. patients with a history of Diabetes insipidus)
Pregnant women
Administration of any other antidiabetic therapy, other than insulin (see inclusion criterion no.4 and 5) and metformin with a stable total daily dose ≥ 1500 mg or the maximum tolerated dose of metformin within 3 months prior to enrolment
History of, or currently have, acute or chronic pancreatitis, or have triglyceride concentrations ≥ 700 mg/dL (≥ 7.98 mmol/L) at Visit 0 (Screening).
History or presence of inflammatory bowel disease or other severe GI diseases, particularly those which may impact gastric emptying, such as gastroparesis or pyloric stenosis.
History of gastric bypass surgery or gastric banding surgery, or either procedure is planned during the time period of the study. Current use of gastric balloons is also excluded.
Significant hepatic disease, including, but not limited to, acute hepatitis, chronic active hepatitis, or severe hepatic insufficiency, including patients with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or total bilirubin (TB) >2 mg/dL (>34.2 μmol/L) (patients with TB >2 mg/dL [>34.2 μmol/L] and documented Gilbert's syndrome will be allowed to participate).
Known history of hepatotoxicity with any medication
Known history of severe hepatobiliary disease.
Positive serological test for hepatitis B or hepatitis C.
Known or suspected human immunodeficiency virus (HIV) infection.
History of organ transplantation.
Presence or history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2) OR a family history of medullary thyroid carcinoma or MEN 2.
Malignancy (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 0 (Screening).
Hemoglobinopathy, hemolytic anemia, or chronic anemia (haemoglobin concentration <11.5 g/dL [115 g/L] for males, <10.5 g/dL [105 g/L] for females) or any other condition known to interfere with the HbA1c methodology.
Patients with abnormal test results of hematocrit (hematocrit > 50% for men; hematocrit > 47% for women)
Has donated blood or had a significant blood loss within 2 months of first dose of study medication or is planning to donate blood during the study.
Has donated plasma within 7 days prior to first dose of study medication.
Any exposure to Exenatide (including BYETTA®, BYDUREON, or exenatide suspension).
Any exposure to Dapagliflozin or any SGLT-2 inhibitor.
Has been treated, is currently being treated, or is expected to require or undergo treatment with any of the following treatment excluded medications:

Any DPP-4 inhibitor within 3 months prior to Visit 0 (Screening).
Any GLP-1 analog within 1 year prior to Visit 0 (Screening).
Systemic corticosteroids within 3 months prior to Visit 0 (Screening) by oral, intravenous, intra-articular, or intramuscular route; or potent, inhaled, or intrapulmonary (including ADVAIR) steroids known to have a high rate of systemic absorption. For examples of excluded steroids, refer to Section 7.7.
Prescription or over-the-counter weight loss medications within 3 months prior to Visit 0 (Screening).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Diabeteszentrum Oldenburg	Oldenburg	Lower Saxony	Germany	23758
2	University Medical Center Hamburg-Eppendorf	Hamburg		Germany	20246
3	Diabetologische Schwerpunktpraxis Harburg	Hamburg		Germany	21073
4	Gemeinschaftspraxis für Innere Medizin und Diabetologie	Hamburg		Germany	22607