Clinical trial NCT02793154: 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
Official title: A Randomized, Open-label, Active-Controlled, Parallel-Group, Exploratory Study on the Effects of Repeated Doses of Albiglutide Compared to Exenatide on Gastric Myoelectrical Activity and Gastric Emptying in Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Keywords: gastric emptying
albiglutide
GMA
exenatide
type 2 diabetes mellitus
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Wake Forrest Baptist Health
First posted: 2016-06-08
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Part A: Distribution of Average Power by Frequency Region
timeFrame: Up to Day 4
measure: Part A: Ratios of Average Power Post- WLT/Pre-WLT by Frequency Region
timeFrame: Up to Day 4
measure: Part A: Percentage of Time With the Dominant EGG Frequencies in the Four Frequency Ranges of Bradygastria, Normal, Tachygastria and Duodenal
timeFrame: Up to Day 4
measure: Part A: Number of Par. With Shifts in Gastric Rhythm Status
timeFrame: Up to 12 days
measure: Part A: Number Par. by Gastric Rhythm Status
timeFrame: Up to 12 days
measure: Part A: Average Dominant Frequency
timeFrame: Up to Day 4
measure: Part A: Assessment of Nausea by Visual Analogue Scale (VAS) Score
timeFrame: Day 4
measure: Part A: Time to Half-gastric Emptying
timeFrame: Up to Day 5
measure: Part A: Rate of [13]C Dose Excreted in Breath
timeFrame: Day 5
measure: Part A: Gastroparesis Cardinal Symptom Index -Daily Diary (GCSI-DD) Score
timeFrame: Up to Day 5
measure: Part A: The Volume of Water Ingested During EGG
timeFrame: Up to Day 4
measure: Part A: Assessment of Stomach Fullness, Hunger, Bloating and Abdominal Pain by VAS Score
timeFrame: Day 4
measure: Part A: Assessment of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) as a Measure of Safety
timeFrame: Up to 12 days
measure: Part A: Assessment of Heart Rate (HR) as a Measure of Safety
timeFrame: Up to 12 days
measure: Part A: Basophils, Eosinophil, Lymphocytes, Monocytes, Platelet Count, Total Neutrophils, White Blood Cell (WBC) Level at Indicated Time Points
timeFrame: Day 5
measure: Part A: Red Blood Cell (RBC) Count at Indicated Time Points
timeFrame: Day 5
measure: Part A: Hemoglobin Level at Indicated Time Points
timeFrame: Day 5
measure: Part A: Hematocrit Level at Indicated Time Points
timeFrame: Day 5
measure: Part A: Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Gamma Glutamyl Transferase (GGT) Levels at Indicated Time Points
timeFrame: Day 5
measure: Part A: Glucose, Calcium, Magnesium, Potassium, Sodium, Phosphorus Inorganic, Chloride, Urea/Blood Urea Nitrogen (BUN) Levels
timeFrame: Day 5
measure: Part A: Creatinine, Direct Bilirubin, Total Bilirubin, Indirect Bilirubin Levels at Indicated Time Points
timeFrame: Day 5
measure: Part A: Estimated Glomerular Filtration Rate at Indicated Time Points
timeFrame: Day 5
measure: Part A: Total Protein, Albumin Levels at Indicated Time Points
timeFrame: Day 5
measure: Part A: Albumin Level in Urine at Indicated Time Points
timeFrame: Day 5
measure: Part A: Concentration of Creatinine in Urine at Indicated Time Points
timeFrame: Day 5
measure: Part A: Number of Par. With Presence of Ketones, Occult Blood, Glucose, Nitrates and Leukocyte Esterase in Urine at Indicated Time Points
timeFrame: Day 5
measure: Part A: Presence RBC and WBC in Urine Assessed by Microscopy
timeFrame: Day 5
measure: Part A: Specific Gravity of Urine at Indicated Time Points
timeFrame: Day 5
measure: Part A: Potential of Hydrogen (pH) of Urine at Indicated Time Points
timeFrame: Day 5
measure: Part A: Number of Par. With Adverse Events (AEs) and Serious AEs (SAEs)
timeFrame: Up to 12 days
measure: Part A: Number of Par. With Nausea AEs Presenting Outside the Timing of the WLT and GCSI-DD
timeFrame: Up to 12 days
measure: Part B: Distribution of Average Power by Frequency Region
timeFrame: Up to 8 weeks
measure: Part B: Ratios of Average Power Post- WLT/Pre-WLT by Frequency Region
timeFrame: Up to 8 weeks
measure: Part B: Percentage of Time With the Dominant EGG Frequencies in the Four Frequency Ranges of Bradygastria, Normal, Tachygastria and Duodenal
timeFrame: Up to 8 weeks
measure: Part B: Assessment of Nausea by VAS Score
timeFrame: Up to 8 weeks
Secondary outcomes:
measure: Part B: Time to Half-gastric Emptying
timeFrame: Up to 8 weeks
measure: Part B: Rate of [13]C Dose Excreted in Breath
timeFrame: Up to 8 weeks
measure: Part B: The Volume of Water Ingested During EGG
timeFrame: Up to 8 weeks
measure: Part B: Assessment of Stomach Fullness, Hunger, Bloating and Abdominal Pain by VAS Score
timeFrame: Up to 8 weeks
measure: Part B: Number of Par. With Abnormal Values for Vital Signs
timeFrame: Up to 12 weeks
measure: Part B: Number of Par. With Abnormal Values for Hematology Parameters
timeFrame: Up to 8 weeks
measure: Part B: Number of Par. With Abnormal Values for Clinical Chemistry Parameters
timeFrame: Up to 8 weeks
measure: Part B: Number of Par. With Abnormal Values for Urinalysis
timeFrame: Up to 8 weeks
measure: Part B: Number of Par. With AEs and SAEs
timeFrame: Up to 12 weeks
measure: Part B: Assessment of GCSI-DD Score
timeFrame: Up to 8 weeks
measure: Part B: Number of Par. With Nausea AEs Presenting Outside the Timing of the WLT and GCSI-DD
timeFrame: Up to 12 weeks
Other outcomes:
Locations:
city: Louisville
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: