Study of MEDI0382 in Combination With Dapagliflozin and Metformin in Overweight/Obese Participants With Type 2 Diabetes
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Overweight
Intervention: MEDI0382; Placebo; Dapaglifozin; Metformin
Intervention description: Subcutaneous dose of MEDI0382 (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 300 μg for 14 days).; Subcutaneous dose of placebo matched to MEDI0382.; Oral dose of dapaglifozin 10 mg tablet.; Oral dose of metformin tablet (maximum tolerated dose [MTD] > 1 g).
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Efficacy and Safety of MEDI0382 versus Placebo in Overweight/Obese Participants with Type 2 Diabetes Mellitus Treated with Dapagliflozin and Metformin
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Randomized, Placebo-controlled, Double-blind Study
Enrollment: 49.0
Sex: All
Minimum age: 18 Years
Maximum age: 115 Years
Healthy volunteers: No
Keywords: 0382; T2DM

Summary:

      A Phase 2 study Comparing the effects on glucose control of MEDI0382 in combination with
      Dapagliflozin and Metformin compared to placebo in combination with Dapagliflozin and
      Metformin in overweight/obese participants with Type 2 Diabetes Mellitus (T2DM).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male and female participants aged >= 18 years at screening.

          2. Provision of signed and dated informed consent form (ICF) prior to any study specific
             procedures.

          3. Body mass index between 25 kg/m^2 and 40 kg/m^2 (inclusive) at screening.

          4. Hemoglobin A1c range between 7.0% and 10.0% (inclusive) at the time of screening.

          5. Diagnosed with T2DM and treated with of metformin monotherapy (MTD > 1 g) at least 8
             weeks prior to screening or treated with stable, oral doses of dapagliflozin 10 mg and
             metformin (MTD > 1 g) for at least 3 months prior screening.

          6. Participants prescribed oral dual therapy with sulphonylurea, glitinide, or dipeptidyl
             peptidase-4 inhibitor (in addition to metformin) may be eligible to enter the study
             following a washout period of these medications totaling at least 28 days before
             initial screening evaluations have been completed.

          7. Participants treated with stable doses of metformin (MTD > 1 g) with canagliflozin
             (maximum dose of 300 mg/day), or metformin (MTD > 1 g) with empaglifozin (maximum dose
             of 25mg/day) for at least 3 months prior to screening may be eligible to enter the
             study after switching to dapagliflozin.

          8. Female participants of childbearing potential must have a negative pregnancy test at
             screening and randomization and must not be lactating.

          9. Females of childbearing potential who are sexually active with a nonsterilized male
             partner must use at least one highly effective method of contraception from screening
             and must agree to continue using such precautions through to the end of the study. It
             is strongly recommended for the male partner of a female participant to also use male
             condom plus spermicide throughout this period. Cessation of contraception after this
             point should be discussed with a responsible physician. Periodic abstinence, the
             rhythm method, and the withdrawal method are not acceptable methods of contraception.

        Exclusion Criteria:

          1. History of, or any existing condition that in the opinion of the investigator would
             interfere with evaluation of the investigational product, put the participant at risk,
             influence the participant's ability to participate, or affect the interpretation of
             the results of the study and/or any participant unable or unwilling to follow study
             procedures.

          2. Any participant who has received another investigational product not included in the
             protocol as part of a clinical trial or a glucagon-like peptide-1 (GLP-1) analogue or
             sodium-glucose cotransporter-2 (SGLT2)-containing preparation (excluding
             dapagliflozin, canagliflozin, empagliflozin) within the last 30 days or 5 half-lives
             of the drug (whichever is longest) at the time of screening.

          3. Any participant who has received any of the following medications prior to the start
             of the screening period (Visit 1) or prior to the study start period (Visit 4):

               -  Concurrent use of any medicinal products, or herbal or over-the-counter (OTC)
                  preparations licensed for control of body weight or appetite at the time of
                  screening (Visit 1)

               -  Concurrent or previous use of drugs approved for weight loss (eg, orlistat,
                  bupropion-naltrexone, phentermine-topiramate, phentermine, lorcaserin) within the
                  last 30 days or 5 half-lives of the drug (whichever is longest) at the time of
                  screening (Visit 1)

               -  Concurrent use of aspirin (acetylsalicylic acid) at a dose greater than 150 mg
                  once daily and within the last 72 hours prior to the start of the study (Visit 4)

               -  Concurrent use of paracetamol (acetaminophen) or paracetamol-containing
                  preparations at a total daily dose of greater than 3000 mg and within the last 72
                  hours prior to the start of the study (Visit 4)

               -  Concurrent use of ascorbic acid (vitamin C) supplements at a total daily dose
                  greater than 1000 mg and within the last 72 hours prior to the start of the study
                  (Visit 4)

               -  Concurrent use of opiates, domperidone, metoclopramide, or other drugs known to
                  alter gastric emptying and within the last 72 hours prior to the start of the
                  study (Visit 4)

          4. Concurrent participation in another study of any kind and repeat randomization in this
             study is prohibited.

          5. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients.

          6. Diagnosis of type 1 diabetes mellitus, maturity-onset diabetes of the young, or latent
             autoimmune diabetes of adulthood or presence of anti-glutamic acid decarboxylase,
             anti-islet cell, or anti-insulin antibodies.

          7. Symptoms of acutely decompensate blood glucose control (eg, thirst, polyuria, weight
             loss) at screening or randomization, a history of diabetes ketoacidosis (DKA), or
             hyperosmolar nonketotic coma or treatment with daily subcutaneous insulin within 90
             days prior to screening.

          8. Fasting hyperglycemia (> 250 mg/dL/ > 13.9 mmol/L) prior to randomization.

          9. C-peptide level < lower limit of normal (LLN).

         10. History of acute or chronic pancreatitis or pancreatectomy.

         11. Hypertriglyceridemia (> 400 mg/dL) at screening.

         12. Significant inflammatory bowel disease, gastroparesis, or other severe disease or
             surgery affecting the upper gastrointestinal (GI) tract (including weight-reducing
             surgery and procedures) which may affect gastric emptying or could affect the
             interpretation of safety and tolerability data.

         13. Significant hepatic disease (except for nonalcoholic steatohepatitis or nonalcoholic
             fatty liver disease without portal hypertension or cirrhosis) and/or participants with
             any of the following results at screening:

               -  Aspartate transaminase (AST) >= 3 × upper limit of normal (ULN)

               -  Alanine transaminase (ALT) >= 3 × ULN

               -  Total bilirubin (TBL) >= 2 × ULN

         14. Impaired renal function defined as estimated glomerular filtration rate (eGFR) <= 60
             mL/minute/1.73m^2 at screening (eGFR according to Modification of Diet in Renal
             Disease [MDRD] using the isotope dilution mass spectrometry-traceable MDRD Study
             Equation (SI units).

         15. Use of loop diuretics within 1 month prior to screening.

         16. Poorly controlled hypertension as defined below:

               -  Systolic blood pressure (BP) > 160 mm Hg

               -  Diastolic BP or >= 100 mm Hg After 10 minutes of supine rest and confirmed by
                  repeated measurement at screening (Visit 1 for all participants).

         17. Unstable angina pectoris, myocardial infarction, transient ischemic attack, or stroke
             within 3 months prior to screening, or participants who have undergone percutaneous
             coronary intervention or a coronary artery bypass graft within the past 6 months or
             who are due to undergo these procedures at the time of screening.

         18. Severe congestive heart failure (New York Heart Association Class III and IV)

         19. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary
             thyroid carcinoma or multiple endocrine neoplasia.

         20. Hemoglobinopathy, hemolytic anemia, or chronic anemia (hemoglobin concentration < 11.5
             g/dL [115 g/L] for males and < 10.5 g/dL [105 g/L] for females) at screening or any
             other condition known to interfere with interpretation of HbA1c measurement.

         21. History of neoplastic disease within 5 years prior to screening, except for adequately
             treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer.

         22. Any positive results for serum hepatitis B surface antigen, hepatitis C antibody, and
             human immunodeficiency virus antibody.

         23. Recent viral infection or illness requiring the use of antibiotics in the month prior
             to screening (Visit 1) for participants on dual therapy or prior to run-in period
             (Visit 2) for participants on monotherapy.

         24. History of recurrent (at least 2) urinary tract and/or genital tract infections
             (including mycotic infections such as thrush) within 6 months prior to screening.

         25. Substance dependence likely to impact participant safety or compliance with study
             procedures.

         26. Involvement of any AstraZeneca, MedImmune, contract research organization, or study
             site employees and their close relatives.