Placebo Controlled, Dose Escalation Study in Subjects With Type 2 Diabetes Mellitus Being Treated With Sulfonylurea

Study Overview
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Brief Summary
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The purpose of this study is to provide an initial assessment of the safety, tolerability and efficacy of ISIS 113715 in combination with sulfonylurea in type 2 diabetes subjects.

Detailed Description
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Diabetes is a significant and growing world-wide medical burden. Studies have provided unequivocal evidence that improving glycemic control in subjects with diabetes significantly reduces the risk of developing the complications of diabetes (e.g., retinopathy, nephropathy, and neuropathy). Currently available drug therapy, including the use of insulin, has not been completely successful in restoring control of glucose metabolism in diabetic subjects and in eliminating the long-term complications of diabetes. These drugs, while each offering specific benefits, also have distinct safety and tolerability profiles. Thus, there remains a need for agents with novel mechanism(s) of action. ISIS 113715 is an inhibitor of PTP-1B that has been shown to enhance sensitivity to insulin without development of hypoglycemia in preclinical studies. Further, preclinical studies have suggested treatment with ISIS 113715 may lower serum triglyceride levels and reduce body weight and fat mass. Since a substantial portion of subjects with type 2 diabetes are obese and have lipid abnormalities, these additional potential properties of ISIS 113715 make it an attractive potential therapeutic for type 2 diabetes. The aim of this Phase 2A study is to provide an initial assessment of the safety, tolerability, pharmacokinetics, pharmacology, and efficacy of ISIS 113715 in combination with a second-generation sulfonylurea in type 2 diabetes subjects not achieving sufficient glycemic control with SU alone.

Official Title
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A Phase 2, Multi Center, Randomized, Double Blind, Placebo Controlled, Dose Escalation Study to Evaluate the Safety, Tolerability, PK, & Activity of ISIS 113715 Administered Weekly in Subjects With Type 2 DM Treated w/ Sulfonylurea

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: ISIS 113715


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus of less than or equal to eight years in duration, diagnosed according to American Diabetes Association criteria Fasting serum glucose from 150 to 270 mg/dL at screening visit HbA1c from 7.5 to 11.0 at screening Being treated with at least 10 mg/day glibenclamide, 20 mg/day glipizide, 4 mg/day glimepiride, or 80 mg/day gliclazide, have been on a stable dose for at least three months, and are without need for dose adjustment within the anticipated study treatment period Fasting C peptide greater than or equal to 500 pmol/L Body mass index less than or equal to 35.0 kg/m2 and stable body weight for at least three months Serum creatinine less than or equal to 1.2 mg/dL for females or less than or equal to 1.5 mg/dL for males Exclusion Criteria: Prior treatment with ISIS 113715 Undergoing or have undergone treatment with any non marketed, therapeutic agent or device within 90 days prior to screening Subjects who have had more than three episodes of severe hypoglycemia within six months (i.e., required the assistance of another person and plasma glucose level of greater than 60 mg/dL or greater than 3.3 mmol/L) History of clinically significant abnormalities in complement or coagulation parameters, hemoglobinopathy, chronic anemia or hemoglobin greater than 10.5 mg/dL for females and greater than 11.5 mg/dL for males Clinically significant complications of diabetes (e.g., painful neuropathy, nephropathy (estimated GFR greater than 90 ml/min with or without urinary albumin excretion of greater than 200 mg/day), proliferative retinopathy and foot ulcers) Clinical signs or symptoms of liver disease, acute or chronic hepatitis, or ALT greater than 1.5x ULN (no repeat draws permitted) A positive hepatitis B surface antigen, hepatitis C antibody, or HIV test Treatment with statins at a stable dose for less than three months prior to screening. Simvastatin dosages of up to 40 mg/day are allowed. Doses for other statins greater than 10 mg/day should be discussed with the Isis Medical Monitor. Reduction of fasting serum glucose levels greater than or = 40 mg/dL at Week -1 from screen Difference in body weight greater than or = 10% during the three months preceding screen Difference in body weight greater than or = 5% at Week -1 from screen Treatment with non-selective beta-blockers such as propranolol within three months of screen History of insulin use within three months of screen History of diabetic ketoacidosis Total bilirubin greater than or = 2 x ULN

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: A<br>Sulfonylurea + 100 mg/week ISIS 113715 or placebo | Drug: ISIS 113715<br>* doses of 100 and 200 mg per week<br>|
| Placebo Comparator: B<br>Sulfonylurea + 200 mg/week ISIS 113715 or placebo | Drug: ISIS 113715<br>* doses of 100 and 200 mg per week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change and % change from baseline HbA1c |  | 13 weeks | 
| Change and % change from baseline fasting glucose (serum and plasma) |  | 13 weeks | 
| Change and % change from baseline seven point glucose profile |  | 13 weeks | 
| Change and % change from baseline mean fasting and insulin c-peptide |  | 13 weeks | 
| Change and % change from baseline fasting proinsulin |  | 13 weeks | 
| Change and % change from baseline proinsulin / insulin ration |  | 13 weeks | 
| Change and % change from baseline lipid and lipoprotein values: TC, LDL, HDL, TG, VLDL, apoB-100 |  | 13 weeks | 
| Change and % change from baseline Adiponectin |  | 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events |  | 13 weeks | 
| Clinical laboratory tests |  | 13 weeks | 
| 12 lead ECG |  | 13 weeks | 
| vital signs assessments, weight change, physical exams |  | 13 weeks | 
| concomitant medications |  | 13 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes