An Exploratory Study on the Effects of Repeat Doses of Albiglutide Compared to Exenatide on Gastric Myoelectrical Activity and Gastric Emptying in Type 2 Diabetes Mellitus Subjects
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Exenatide; Albiglutide
Intervention description: Supplied as SC injection containing 250 mcg/mL of exenatide, provided in the following dose regimens: Part A: 10 mcg taken twice daily for 5 days; Part B: 5 mcg twice daily taken for 4 weeks followed by uptitration to 10 mcg for 4 weeks In both parts, it will be administered within 60-minute period before morning and evening meals (or before 2 meals with approximate >=6 hours apart); Part B: Albiglutide will be supplied as follows:30 mg SC injection pen containing 40.3 mg lyophilized albiglutide and 0.65 mL; 50 mg SC injection pen contains 67 mg lyophilized albiglutide and 0.65 mL water; Starting dose will be 30 mg weekly for 4 weeks and then uptitrated to 50 mg weekly for 4 weeks; Administered as a single SC injection once a week in the morning
Intervention MeSH terms: Exenatide; rGLP-1 protein
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: gastric emptying; albiglutide; GMA; exenatide; type 2 diabetes mellitus

Summary:

      The primary objective of this study is to compare the effect of albiglutide and exenatide on
      gastric myoelectrical activity (GMA), gastric emptying (GE) and nausea (as measured by visual
      analogue scale [VAS]) in subjects with type 2 diabetes mellitus (T2DM). The study is divided
      in two parts. Part A will characterize the GMA, GE and nausea response to exenatide and
      confirm exenatide as a positive control for Part B. Part B will compare the effects of
      albiglutide and exenatide on GMA, GE and nausea.

      Part A is a single arm, open-label design and all subjects will receive 10 microgram (mcg)
      subcutaneous exenatide twice daily for 5 days. This part will comprise 3 study periods: a
      3-week screening/wash-out, 5-day treatment, and follow-up (within 7 days after the last dose
      of exenatide). The total duration of a subject's participation in Part A will be
      approximately 5 weeks. Once Part A is complete, data will be reviewed and a decision to
      progress to Part B will be made.

      In Part B, subjects will be randomized 1:1 to receive either albiglutide (starting dose of 30
      milligrams [mg] once weekly for 4 weeks, followed by 50 mg once weekly for 4 weeks) or
      exenatide (starting dose of 5 mcg twice daily for 4 weeks, followed by 10 mcg twice daily for
      4 weeks). The total duration of a subject's participation in the study will be approximately
      15 weeks.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female, aged between 18 and 60 years of age at the time of signing the
             informed consent.

          -  Type 2 diabetes mellitus diagnosed at least 6 months prior to screening.

          -  Subjects treated with diet and exercise alone or stable dose of single oral
             antihyperglycemic medication (OAM) of metformin, sulfonylurea (except chlorpropamide),
             sodium glucose co-transporter 2-inhibitor, or meglitinide for at least 2 months prior
             to screening

          -  Glycated hemoglobin A1C (HbA1c) >6.5% and <=9.0% at screening. If the first HbA1c
             value does not meet eligibility criterion, the HbA1c may be rechecked once during
             screening. If the average of these determinations meets the criterion, the subject is
             eligible.

          -  Fasting plasma glucose (FPG) <=210 mg/deciliter (dL; central lab) at screening. If the
             first FPG value does not meet eligibility criterion, the FPG may be rechecked once
             during screening.

          -  Patient assessment of upper GI symptom severity index at screening:

        Overall score <=20 (if score is >=21 and <=25, subjects can be re-evaluated 2 weeks later)
        Total score of items 1-9 is <=9 Score from any of single item <=2

          -  Body mass index (BMI) >20 kilograms (kg)/meter (m)^2 and <35 kg/m^2 and a stable
             weight (no more than 5% reported change within 3 months prior to screening).

          -  A female subject is eligible to participate if she is not pregnant (as confirmed by a
             negative serum human chorionic gonadotrophin [hCG] test for females of reproductive
             potential [FRP] only), not breastfeeding, and at least one of the following conditions
             applies:

        Reproductive potential and agrees to follow one of the options listed in the Modified List
        of Highly Effective Methods for Avoiding Pregnancy in FRP (eg., combined oral contraceptive
        pill) from 30 days prior to the first dose of study medication and until after the last
        dose of study medication and completion of the follow-up visit.

        Non-reproductive potential defined as either:

          -  Pre-menopausal with one of the following: documented tubal ligation; documented
             hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal
             occlusion; hysterectomy; or documented bilateral oophorectomy, or;

          -  Postmenopausal defined as 12 months of spontaneous amenorrhea and age appropriate
             (i.e., >50 years). In questionable cases, a blood sample with simultaneous follicle
             stimulating hormone >40 milli-International units/milliliters (mL) and estradiol <40
             picograms/mL (<140 picomoles/L) is confirmatory, depending on local laboratory ranges.
             Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt
             will be required to use one of the highly effective contraception methods if they wish
             to continue their HRT during the study. Otherwise, they must discontinue HRT to allow
             confirmation of post-menopausal status prior to study enrolment

               -  For the regular use of other medications (does not include protocol excluded
                  medications), subjects must be on a stable dose for at least 4 weeks before
                  screening

               -  Capable of giving signed informed consent; which includes compliance with the
                  requirements and restrictions listed in the consent form and in this protocol

        Exclusion Criteria:

          -  Type 1 diabetes mellitus

          -  Type 2 diabetes mellitus treated with more than one OAM or with chronic use of insulin
             within 3 months prior to screening

          -  Hemoglobin <11 grams (g)/dL (<110 g/L) for male subjects and <10 g/dL (<100 g/L) for
             female subjects at screening

          -  Fasting triglyceride level >500 mg/dL at screening

          -  Hemoglobinopathy that may affect proper interpretation of HbA1c

          -  History of cancer that has not been in full remission for at least 3 years before
             screening. (A history of squamous cell or basal cell carcinoma of the skin or treated
             cervical intra-epithelial neoplasia I or II is allowed).

          -  Personal or family history of medullary thyroid carcinoma or multiple endocrine
             neoplasia type 2

          -  History of acute or chronic pancreatitis.

          -  History or current severe lactose intolerance

          -  History of thyroid dysfunction or an abnormal (i.e., outside the normal reference
             range) thyroid function test assessed by thyroid stimulating hormone at screening.

          -  Alanine aminotransferase (ALT) >2.5x upper limit of normal (ULN).

          -  Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
             fractionated and direct bilirubin <35%).

          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or
             asymptomatic gallstones or otherwise stable chronic liver disease per investigator
             assessment).

          -  Clinical diagnosis of gastroparesis.

          -  History of significant GI medical conditions such as chronic esophagitis, peptic ulcer
             diseases, celiac disease, inflammatory bowel disease, unexplained abdominal pain or
             irritable bowel syndrome and/or history of surgery that in the opinion of the
             investigator is likely to significantly affect upper GI or pancreatic function (e.g.,
             gastric bypass, gastric banding, antrectomy, Roux en Y bypass, gastric vagotomy, small
             bowel resection, or surgeries thought to significantly affect upper GI function).

          -  History of hypoglycemia unawareness (i.e., the absence of autonomic warning symptoms
             before the development of neuroglycopenic symptoms such as blurred vision, difficulty
             speaking, feeling faint, difficulty thinking, and confusion).

          -  Diabetic complications (e.g., active proliferative retinopathy or severe diabetic
             neuropathy) or any other clinically significant abnormality (including a psychiatric
             disorder) that, in the opinion of the investigator, may pose additional risk in
             administering the investigational product or may influence data interpretation.

          -  Clinically significant cardiovascular and/or cerebrovascular disease at any time, such
             as prior myocardial infarction, unstable angina, stroke, transient ischemic attack or
             documented heart failure, before screening.

          -  Estimated glomerular filtration rate (eGFR) <=75 mL/min/1.73 m^2 (calculated using the
             MDRD formula) at screening.

          -  Lung diseases associated with pulmonary dysfunction (e.g. chronic obstructive
             pulmonary disease).

          -  A subject with a clinical abnormality or laboratory parameter(s) which is/are not
             specifically listed in the inclusion or exclusion criteria, outside the reference
             range for the population being studied should be excluded unless the investigator (in
             consultation with the Medical Monitor, if necessary) decides and documents that the
             finding is unlikely to introduce additional risk factors and will not interfere with
             the study procedures or ability to interpret study results

          -  Unable to refrain from medications that might modify GMA or GI motility, such as
             prokinetics (e.g., erythromycin), anti-emetics (e.g., metoclopromide), narcotics
             (e.g., morphine), anticholinergics (e.g.,domperidone), anti-acids (e.g., proton pump
             inhibitors, H2 blockers) and laxatives, received within 7 days prior to screening or
             high likelihood of a requirement during the study.

          -  Use of oral or systemically injected glucocorticoids within the 3 months prior to
             randomization or high likelihood of a requirement for prolonged treatment (>1 week) in
             the 4months following randomization. However, short courses of oral steroids (single
             dose or multiple doses for up to 7 days) may be permitted provided these cases are
             discussed with the Medical Monitor. Inhaled, intra-articular, epidural, and topical
             corticosteroids are allowed

          -  Known allergy to albiglutide, exenatide or any product components (including yeast and
             human albumin), any other glucagon-like receptor 1 analogue, or other study treatment
             excipients OR other contraindications (per the principal investigator) for the use of
             potential study treatment.

          -  Intolerance or allergy to any component of GE test meal

          -  Received any glucagon-like peptide 1 receptor agonist at any time

          -  Receipt of any investigational drug within the 30 days or 5 half-lives, whichever is
             longer, before screening, a history of receipt of an investigational antidiabetic drug
             within the 3 months before randomization.

          -  Exposure to more than 4 investigational medicinal products within 12 months prior to
             the first dosing day