Safety of Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus Treated With Thiazolidinedione Alone or Thiazolidinedione in Combination With Metformin

Conditions

Type 2 Diabetes

Keywords

Amylin, Lilly, exenatide once weekly, thiazolidinedione, metformin

Brief summary

This study will examine the safety of exenatide once weekly (2.0 mg) in approximately 134 patients receiving treatment with thiazolidinedione alone or thiazolidinedione in combination with metformin. Patients are expected to be treated with exenatide once weekly for at least 52 weeks.

Norwood P, Liutkus JF, Haber H, Pintilei E, Boardman MK, Trautmann ME.

2012-09-2921 citations

10.1016/j.clinthera.2012.09.007

Interventions

DRUGexenatide

subcutaneous injection, 2.0mcg, once weekly

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Have type 2 diabetes * At least 18 years of age at screening. * Have HbA1c of 7.1% to 10.0%, inclusive, at screening. * Have a body mass index (BMI) of 25 kg/m2 to 45 kg/m2, inclusive. * Have been treated with a stable dose of TZD (≥4 mg/day rosiglitazone or ≥30 mg/day pioglitazone) for at least 120 days prior to Visit 1 OR Have been treated with a stable dose of TZD (≥4 mg/day rosiglitazone or ≥30 mg/day pioglitazone) for at least 120 days PLUS a stable dose of metformin for at least 90 days prior to Visit 1. * Have a history of stable body weight (not varying by \>10% for at least 3 months prior to screening). * If female of child-bearing potential (not surgically sterilized and between menarche and 1-year postmenopause) only. * Are not breastfeeding. * Test negative for pregnancy at the time of screening based on a serum pregnancy test. * Intend not to become pregnant during the study. * Have practiced a reliable method of birth control (e.g., use of oral contraceptives or approved hormonal implant; diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices; partner with vasectomy; or abstinence) for at least 6 weeks prior to screening. * Agree to continue to use a reliable method of birth control (see above) during the study.

Exclusion criteria

* Have had a clinically significant history of cardiac disease or presence of active cardiac disease within the year prior to inclusion in the study, including myocardial infarction, clinically significant arrhythmia, unstable angina, coronary artery bypass surgery, angioplasty. * Is expected to require coronary artery bypass surgery or angioplasty during the course of the study. * Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis * Have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine ≥135 μmol/L for males and ≥110 μmol/L for females. * Have active or untreated malignancy, or have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years. * Have known hemoglobinopathy or chronic anemia (hemoglobin concentration \<11.5 g/dL \[115 g/L\] for males, \<10.5 g/dL \[105 g/L\] for females). * Have clinically significant history or presence of severe gastrointestinal disease, particularly those which may impact gastric emptying, such as gastroparesis, pyloric stenosis, or gastric bypass surgery. * Have a history of pancreatitis. * Have had greater than three episodes of major hypoglycemia within 6 months prior to screening. * Have any contraindication for the OAD(s) which they use, according to local label requirements. * Are known to have active proliferative retinopathy. * Are receiving chronic (\>2 weeks) systemic glucocorticoid therapy (excluding topical or inhaled preparations) or have received systemic glucocorticoid therapy for \>2 weeks within the 4 weeks immediately preceding screening. * Have been treated with drugs that promote weight loss (e.g., Xenical® \[orlistat\], Meridia® \[sibutramine\], Acomplia® \[rimonabant\], Acutrim® \[phenylpropanolamine\], or similar over-the-counter medications) within 3 months of screening. * Have previously been treated with glucagon-like peptide 1 analogs or liraglutide. * Have been treated for longer than 2 weeks with any of the following excluded medications within 3 months prior to screening: Insulin; Sulfonylureas; Alpha-glucosidase inhibitors (e.g., Glyset® \[miglitol\] or Precose® \[acarbose\]); Meglitinides (e.g., Prandin® \[repaglinide\] or Starlix® \[nateglinide\]); Dipeptidyl peptidase (DPP)-4 inhibitors (e.g., Januvia™ \[sitagliptin\], Galvus® \[vildagliptin\]); Symlin® (pramlintide acetate). * Have had an organ transplant. * Have donated blood within 30 days of screening. * Have previously completed or withdrawn from this study or any other study investigating exenatide once weekly. * Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. * Are currently participating in an interventional medical, surgical, or pharmaceutical study (a study in which an experimental, drug, medical, or surgical treatment is given). Patients completing the final visit of a study examining safety/efficacy of exenatide BID may enter this study on the same day if they meet other eligibility criteria.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients Experiencing Adverse Events	Baseline to Week 52	Percentage of patients experiencing treatment-emergent adverse events over 52 weeks
Assessment of Event Rate of Treatment-Emergent Hypoglycemic Events	Baseline to Week 52	Major hypoglycemia: any episode with symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure with prompt recovery in response to administration of glucagon or glucose OR documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) and required the assistance of another person. Minor hypoglycemia: any sign or symptom associated with hypoglycemia that is either self-treated by the patient or resolves on its own AND has a concurrent finger stick blood glucose \<3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia. Mean event rate = total number of events for all subjects in a treatment regimen / the total number of subject years of exposure for all subjects in that treatment. Standard error = square root of (total number of events / (subject years of exposure)\\2).

Secondary

Measure	Time frame	Description
Percentage of Patients Achieving HbA1c <=6.5% at Week 52	Baseline, Week 52	Percentage of patients achieving HbA1c \<=6.5% at endpoint (for patients with HbA1c \>6.5% at baseline)
Change in Fasting Serum Glucose From Baseline to Week 52	Baseline, Week 52	Change in fasting serum glucose from baseline to endpoint
Change in Body Weight From Baseline to Week 52	Baseline, Week 52	Change in body weight from baseline to endpoint
Change in HbA1c From Baseline to Week 52	Baseline, Week 52	Change in HbA1c from baseline to endpoint
Change in High-density Lipoprotein (HDL) From Baseline to Week 52	Baseline, Week 52	Change in HDL from baseline to endpoint
Change in Triglycerides From Baseline to Week 52	Baseline, Week 52	Change in Triglycerides from baseline to endpoint
Change in Blood Pressure From Baseline to Week 52	Baseline, Week 52	Change in Systolic and Diastolic Blood Pressure from baseline to endpoint
Change in Total Cholesterol From Baseline to Week 52	Baseline, Week 52	Change in Total Cholesterol from baseline to endpoint
Percentage of Patients Achieving HbA1c <=7% at Week 52	Baseline, Week 52	Percentage of patients achieving HbA1c \<=7% at endpoint (for patients with HbA1c \>7% at baseline)

Countries

Canada, Mexico, Romania, South Africa, United States

Participant flow

Participants by arm

Arm	Count
Exenatide Once Weekly Subcutaneous injection, 2.0mcg, once weekly.	134
Total	134

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	4
Overall Study	Death	1
Overall Study	Entry Criteria Not Met	4
Overall Study	Lost to Follow-up	2
Overall Study	Protocol Violation	1
Overall Study	Withdrawal by Subject	4

Baseline characteristics

Characteristic	Exenatide Once Weekly
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	20 Participants
Age, Categorical Between 18 and 65 years	114 Participants
Age, Continuous	55.0 years STANDARD_DEVIATION 9.74
Background Oral Antidiabetic Agent Metformin + Thiazolidinedione (TZD)	118 participants
Background Oral Antidiabetic Agent TZD	16 participants
Glycosylated hemoglobin (HbA1c)	7.2 percentage of total hemoglobin STANDARD_DEVIATION 0.95
Sex: Female, Male Female	60 Participants
Sex: Female, Male Male	74 Participants
Weight	98.1 kg STANDARD_DEVIATION 18.71

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	67 / 134
serious Total, serious adverse events	9 / 134

Outcome results

Primary

Assessment of Event Rate of Treatment-Emergent Hypoglycemic Events

Major hypoglycemia: any episode with symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure with prompt recovery in response to administration of glucagon or glucose OR documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) and required the assistance of another person. Minor hypoglycemia: any sign or symptom associated with hypoglycemia that is either self-treated by the patient or resolves on its own AND has a concurrent finger stick blood glucose \<3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia. Mean event rate = total number of events for all subjects in a treatment regimen / the total number of subject years of exposure for all subjects in that treatment. Standard error = square root of (total number of events / (subject years of exposure)\*\*2).

Time frame: Baseline to Week 52

Population: All enrolled patients who had taken at least one dose of study drug. Sample size based on FDA recommendation for safety exposure: a minimum of 100 patients completing at least 52 weeks of treatment is sought to assess long-term safety associated with exposure to exenatide once weekly.

Arm	Measure	Group	Value (MEAN)	Dispersion
Exenatide Once Weekly	Assessment of Event Rate of Treatment-Emergent Hypoglycemic Events	Major Hypoglycemia	0.00 events per subject-year	Standard Error 0
Exenatide Once Weekly	Assessment of Event Rate of Treatment-Emergent Hypoglycemic Events	Minor Hypoglycemia	0.02 events per subject-year	Standard Error 0.014

Primary

Percentage of Patients Experiencing Adverse Events

Percentage of patients experiencing treatment-emergent adverse events over 52 weeks

Time frame: Baseline to Week 52

Population: All enrolled patients who had taken at least one dose of study drug. Sample size based on FDA recommendation for safety exposure: a minimum of 100 patients completing at least 52 weeks of treatment is sought to assess long-term safety associated with exposure to exenatide once weekly.

Arm	Measure	Value (NUMBER)
Exenatide Once Weekly	Percentage of Patients Experiencing Adverse Events	73.1 percentage of patients

Secondary