A Study to Examine the Efficacy, Safety and Tolerability, and Pharmacokinetics of Exenatide Once Monthly Suspension

Study Overview
=================
Brief Summary
-----------------
The purpose of Study BCB111 is to collect efficacy, pharmacokinetic, pharmacodynamic, safety, and tolerability data in patients with type 2 diabetes to assess the feasibility of once monthly dosing of the exenatide suspension formulation.

Official Title
-----------------
A Randomized, Multi-dose, Controlled Trial Investigating the Efficacy, Safety and Tolerability, and Pharmacokinetics of Exenatide Once Monthly Suspension.

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: exenatide once weekly
* Drug: exenatide once monthly suspension
* Drug: exenatide once monthly suspension
* Drug: exenatide once monthly suspension


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Is at least 18 years old at study start Has been diagnosed with type 2 diabetes mellitus Has HbA1c of 7.1% to 11.0%, inclusive, at study start Has been treated with diet and exercise alone or with a stable regimen of metformin, pioglitazone, or a combination of metformin and pioglitazone, for a minimum of 2 months prior to study start Either is not treated with or has been on a stable treatment regimen with any of the following medications for a minimum of 2 months prior to study start: hormone replacement therapy (female subjects); antihypertensive agents; thyroid replacement therapy; or antidepressant agents Exclusion Criteria: Clinically significant medical condition that could potentially affect study participation including: Acute or chronic pancreatitis Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) type 2 Active cardiovascular disease within 3 months of study start Underlying hepatic or renal disease Inflammatory bowel disease, or other severe gastrointestinal diseases (particularly those that may affect gastric emptying, such as gastroparesis, pyloric stenosis, and metabolic surgery) Has had > 2 episodes of major hypoglycemia in the preceding 6 months before study start Has received any investigational drug within 30 days (or 5 half-lives of the investigational drug, whichever is greater) prior to study start Has been treated, is currently being treated, or is expected to require or undergo treatment with any of the following treatment excluded medications: Any exposure to exenatide (BYETTA®, exenatide once weekly, or exenatide suspension), liraglutide (Victoza®), or any GLP-1 receptor agonist Any DPP-IV inhibitor, sulfonylurea (SU), or rosiglitazone (Avandia®) within 3 months prior to study start Alpha glucosidase inhibitor, meglitinide, nateglinide, or pramlintide (SYMLIN®) within 30 days prior to study start Insulin within 2 weeks prior to study start, or for more than 1 week within 3 months prior to study start Systemic corticosteroids by oral, intravenous, intra-articular, or intramuscular route; or potent, inhaled, or intrapulmonary (including ADVAIR®) steroids known to have a high rate of systemic absorption Prescription or over-the-counter weight loss medications within 3 months prior to study start

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>2 mg exenatide once weekly subcutaneous (SC). This arm is used as a reference arm in the study. | Drug: exenatide once weekly<br>* subcutaneous injection, 2 mg, once a week<br>|
| Experimental: Group B<br>Low dose 5 mg exenatide once monthly suspension SC. | Drug: exenatide once monthly suspension<br>* subcutaneous injection, low dose, once a month<br>|
| Experimental: Group C<br>Medium dose 8 mg exenatide once monthly suspension SC. | Drug: exenatide once monthly suspension<br>* subcutaneous injection, medium dose, once a month<br>|
| Experimental: Group D<br>High dose 11 mg exenatide once monthly suspension SC. | Drug: exenatide once monthly suspension<br>* subcutaneous injection, high dose, once a month<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in HbA1c From Baseline to End of Treatment (Week 20) - Evaluable Population | HbA1c was measured as a percent of total hemoglobin at screening, Baseline, and during treatment on Weeks 4, 8, 12, 16, and 20. Baseline was Day 1, or last measurement prior to first dose of study drug. The Evaluable population was defined as participants who completed study procedures in compliance with the protocol and had adequate exposure to the study drug. | Baseline (Day 1) to 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving HbA1c Target Values at Week 20 - Evaluable Population | HbA1c was measured as a percent (%) of total hemoglobin. The Target values for HbA1c were <7% and ≤ 6.5% at Week 20. Evaluable population was defined as participants who completed study procedures in compliance with the protocol and had adequate exposure to the study drug. | Week 20 | 
| Mean Change in Body Weight From Baseline to Week 20 - Evaluable Population | Body weight was measured in kilograms (kg) at Baseline, and during treatment at Weeks 2, 4, 6, 8, 9-11, 12, 13, 14, 15, 16, 17-19, and 20. Baseline was Day 1, or last measurement prior to first dose of study drug. Evaluable population was defined as all participants who completed study procedures in compliance with the protocol and had adequate exposure to the study drug. | Baseline (Day 1) to Week 20 | 
| Mean Change in Fasting Glucose From Baseline to Week 20 - Evaluable Population | Fasting glucose was measured in milligrams per deciliter (mg/dL) at screening, Baseline, and during treatment at Weeks 2, 4, 6, 8, 9-11, 12, 13, 14, 15, 16, 17-19, and 20. Baseline was Day 1, or last measurement prior to first dose of study drug. Evaluable population was defined as all participants who completed study procedures in compliance with the protocol and had adequate exposure to the study drug. | Baseline (Day 1) to Week 20 | 
| Time Weighted Average Concentration and Peak to Trough of Exenatide From Week 12 Through Week 16 - Pharmacokinetic Evaluable - Steady State Population | All participants received an initial blood draw prior to the first dose and a single blood sample was collected at all other subsequent visits, for plasma exenatide assessments and the characterization of pharmacokinetic (PK) parameters following multiple monthly doses over the study period. Exenatide was measured using a validated enzyme-linked immunosorbent assay (ELISA). Time weighted average concentration (Cave (2016-2688 h) and Peak to Trough were measured in picograms per milliliter (pg/mL). | Day 1 to Week 20 | 
| Mean Change From Baseline in Diastolic and Systolic Blood Pressure at Week 20 - Intent to Treat (ITT) Population | Baseline was Day 1, or last measurement prior to first dose of study drug. Vital signs were measured after the participant had rested for approximately 5 minutes and with the participant in a sitting position. Measurement was recorded in millimeters of mercury (mmHg). The blood pressure measurement was repeated after at least 30 seconds and the average of the two readings recorded. ITT population was defined as all participants who received at least one dose of the study drug. | Baseline (Day 1), Week 20 | 
| Mean Change From Baseline in Heart Rate at Week 20 - Intent to Treat (ITT) Population | Baseline was Day 1, or last measurement prior to first dose of study drug. Heart rate was measured after the participant had rested for approximately 5 minutes and with the participant in a sitting position. Measurement was recorded in beats per minute (bpm). The measurement was repeated after at least 30 seconds and the average of the two readings recorded. ITT population was defined as all participants who received at least one dose of the study drug. | Baseline (Day 1), Week 20 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and AEs Leading to Discontinuation - ITT Population | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. All participants who received at least one dose of study drug were included in the ITT analysis. Treatment-emergent (TE) adverse events were defined as those with onset at or after initiation of study medication on Day 1 through study termination or early termination. | Day 1 to Study Termination (24 Weeks) or early Termination | 
| Number of Participants With Injection Site Reaction Treatment Emergent Adverse Events - ITT Population | AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Injection site related adverse events were defined as the adverse events with 'injection site' phrase in preferred term excluding 'injection site nodule'. The following events were Injection Site Reaction AEs: erythema, hematoma, hemorrhage, site pain, site papule, site pruritus, site warmth. Participants receiving study drug monthly received 5 injections with last injection at Week 16; Participants receiving study drug weekly received 20 injections with last injection at Week 19. . | Day 1 through study termination (Week 24) or early termination. | 
| Participants Negative or Positive for Anti-exenatide Antibodies - ITT Population | Serum titers of antibodies to exenatide were evaluated using a validated enzyme-linked immunosorbent assay (Covance Method No. ELISA-0308). Positive antibody to exenatide titer: observed at the indicated visit following a negative or missing titer at baseline, or a positive titer that has increased by at least 3 dilutions at the indicated visit from a detectable baseline. Baseline=Day 1. | Day 1 to Study Termination (24 weeks) or early termination | 
| Number of Hematology Laboratory Values of Potential Clinical Importance Observed During Treatment Period - ITT Population | Potential clinical importance are the following: Hematocrit values for males less than (<) 36%, females < 30%; hemoglobin for males <12 grams per deciliter (g/dL), females < 10 g/dL; low platelet values <75,000/micro liter (µL), high values greater than (>) 500,000 µL. Laboratory samples were obtained at baseline (Day 1 or if unavailable, last measurement prior to first study drug dose), Weeks 6, 12, 20, and at study termination (Week 24) or early termination. Number of laboratory values of potential clinical importance presented for Weeks 6 - Week 24 or early termination. | Day 1 to study termination (24 weeks) or early termination | 
| Number of Chemistry Laboratory Values of Potential Clinical Importance Observed During Treatment Period - ITT Population | Potential clinical importance (PCI): triacylglycerol lipase high values were > 3* upper limit of normal (ULN); creatinine high values in males >1.6 mg/dL, females >1.4 mg/dL; gamma glutamyl transferase (GGT) high value >3* ULN; bilirubin high value > 2 mg/dL; Urate high values > 10 (males), >8 (females) mg/dL; potassium low value < 3 milliequivalents per liter (mEq/L), high value >5.5 mEq/L; calcium low value < 8 mg/dL and high value > 11 mg/dL. Laboratory samples were obtained at baseline (Day 1 or if unavailable, last measurement prior to first study drug dose), Weeks 6, 12, 20, and at study termination (Week 24) or early termination. Number of laboratory values of potential clinical importance (values could be either low or high) are presented for Weeks 6 - Week 24 or early termination. Note: those tests with no values meeting the PCI criteria, ie, 0 values observed across all treatment arms, are not presented. | Day 1 to Study Termination (Week24) or early termination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Exenatide, Amylin, Lilly, Byetta, Exenatide Once Weekly