Effect of Cycloset on Glycemic Control When Added to Glucagon-like Peptide 1 (GLP-1) Analogue Therapy

Effect of Cycloset on Glycemic Control in Type 2 Diabetic Patients Inadequately Controlled on GLP-1 Analogue Therapy

Purpose This study will examine the effect of the addition of Cycloset upon glucose metabolism (glycemic control including post prandial glucose metabolism) in individuals with inadequately controlled (HbA1c 7.5-10.0) type 2 diabetes (T2DM) who are already on Bydureon (exenatide once weekly) or Victoza (liraglutide once daily) as part of their standard care.

Both a mechanistic rationale and empirical experimental evidence implicate a beneficial interaction between bromocriptine and the incretin mimetics (GLP-1 analogs) upon postprandial hyperglycemia in insulin resistant states. One of the actions of the incretin mimetics such as the GLP-1 analogs is to stimulate postprandial beta cell insulin secretory response to plasma glucose (see drug labeling information; www.fda.gov). Thus the combination of Cycloset that is working as a post prandial insulin sensitizier with therapies that increase post prandial insulin would be expected to provide complimentary glucose lowering effects. To date, however, no such studies investigating the interactive effects of a GLP-1 analog and Bromocriptine-QR (QR=extended release) (Cycloset) have been conducted in humans.

Condition - Type 2 Diabetes. Intervention - Cycloset. Phase - Phase 4

Study Type: Interventional Study Design: Treatment, Single Group Assignment, Open Label, N/A, Safety/Efficacy Study

Official Title: Effect of Cycloset on Glycemic Control in Type 2 Diabetic Patients Inadequately Controlled on GLP-1 Analogue Therapy

This is a single-site, prospective, cohort study that will assess the effect of Cycloset as add-on therapy in adult subjects with T2DM that is inadequately controlled (HbA1c 7.5% to 10.0%) on GLP-1 analog therapy with either exenatide (Bydureon) once weekly or liraglutide (Victoza) once daily.

Entry criteria will be checked at the screening visit. All qualified subjects will undergo baseline studies including non-invasive hemodynamic testing for assessment of aortic stiffness and pulse wave velocity, assessment of body weight composition by dual-energy X-ray absorptiometry (DXA), assessment of endothelial function using the Endo-PAT device, measurement of cytokines and inflammatory biomarkers in the peripheral blood and urine, assessment of oxidative stress and inflammatory markers in white blood cells isolated from a peripheral whole blood sample, a 5-hour mixed meal tolerance test (MMT) for assessment of postprandial glucose metabolism and 24-hour ambulatory BP monitoring.

Following completion of all the baseline studies as above, subjects will be started on Cycloset, 0.8 mg/day in addition to their stable dose of Bydureon (exenatide) (2mg/week) or Victoza (liraglutide) (1.2-1.8 mg/day), and the dose will be increased by 0.8 mg/day every week to a maximum of 3.2 mg/day, or as tolerated to a minimum of 2.4 mg/day.

Subjects will return at months 1, 2, 3, and 4 for interim medical history, body weight, HbA1c, and FPG (Fasting plasma glucose). Postural blood pressure measurements will be obtained with the subject lying down and then after standing for 5 minutes at each of the visits. At month 4, all of the baseline studies detailed above will be repeated.

All tests will be performed in the Clinical Research Center at the Texas Diabetes Institute/University of Texas Health Science Center, San Antonio.

Inclusion Criteria:

• Type 2 diabetes male or female subjects between the ages of 30 and 70 years of age, inclusive, at Screening
• BMI = 24-40 kg/m2
• HbA1c = 7.5-10.0%
• Stable body weight (±3-4lbs) over the preceding 3 months
• Subjects currently receiving a stable dose of exenatide (2mg/week) or liraglutide (1.2-1.8 mg/day) for at least 90 days prior to determination of baseline HbA1C and eligibility for enrollment in the study protocol.
• Subjects with a daytime feeding/night time sleeping schedule
• Subjects with no evidence of major organ system disease as determined by physical exam, history, and screening laboratory data
• Women must be of non-childbearing potential as defined by one of the following:
• Women >45 and < 60 years of age at Screening, who have been amenorrheic for at least 2 years
• Women who have had a documented hysterectomy and/or bilateral oophorectomy
• Women > 60 years of age
• Females of childbearing potential with a negative pregnancy test at Screening and Treatment visits, using one of the following forms of contraception for the duration of participation in the study (i.e., until Follow-up 7-14 days post last dose): Oral contraceptive, Injectable progesterone, subdermal implant, spermicidal foam/gel/film/cream/suppository, diaphragm with spermicide, copper or hormonal containing IUD (intrauterine device), sterile male partner vasectomized > 6 month pre-dosing
• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study
• Subjects must be willing and able to comply with scheduled visits, treatment, laboratory tests and study procedures.

Exclusion Criteria:

• Recent (i.e., within three (3) months prior to Screening) evidence or medical history of unstable concurrent disease such as: documented evidence or history of clinically significant hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, immunological, or clinically significant neurological disease.
• No history of T2DM
• BMI of less 24 and greater 40 kg/m2
• Unstable body weight (change of greater than ±3-4lbs over the preceding 3 months
• Subjects not currently receiving exenatide or liraglutide
• Subjects participating in an excessively heavy exercise program
• Subject with a feeding/sleeping schedule different from a daytime feeding/night time sleeping schedule
• Subjects taking medications known to alter glucose metabolism (with the exception of metformin and/or pioglitazone) or which effect brain neuro synaptic function are excluded.
• Subjects with evidence of major organ system disease as determined by physical exam, history, and screening laboratory data
• Pregnant subjects or subjects unwilling to use birth control during their study enrollment
• Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening 12. Subjects that are allergic to bromocriptine or any of the other ingredients in Cycloset, or take ergot medicines, breastfeeding or have history of syncope or Type 1 diabetes mellitus
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results that, in the judgment of the investigator, would make the subject inappropriate for entry into this study subjects of reproductive potential