A Study of LGD-6972 in Patients With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the change from baseline in hemoglobin A1c (HbA1c) during 12 weeks of treatment with 3 dose levels of LGD-6972 compared to placebo in subjects with Type 2 Diabetes Mellitus (T2DM)

Detailed Description
-----------------
This will be a 12-week, randomized, double-blind, placebo-controlled, 4-arm, parallel group, multi-center study to evaluate the safety and efficacy of LGD-6972 in subjects with T2DM inadequately controlled on metformin monotherapy (a stable [≥12 weeks], daily dose of ≥1000mg at randomization). Subjects with T2DM will be treated with one of 3 dose levels of LGD-6972 (5 mg, 10 mg, or 15 mg) or placebo once daily (QD) for 12 weeks. Randomization will be stratified by HbAlc ≤8.5% or >8.5% at the Placebo Lead-in Visit. Qualified subjects who require adjustment or stabilization of their metformin dose will participate in a run-in period of up to 12 additional weeks prior to randomization. Subjects will have the option to participate in an oral glucose tolerance test (OGTT) at baseline and end of treatment for assessment of exploratory endpoints.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Safety and Efficacy of LGD-6972 in Patients With Type 2 Diabetes Mellitus

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

Intervention / Treatment
-----------------
* Drug: LGD-6972-5 mg
* Drug: LGD-6972-10 mg
* Drug: LGD-6972-15 mg
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female subjects must be surgically sterile (hysterectomy or bilateral oophorectomy or bilateral tubal ligation), or naturally post-menopausal for at least 12 months and with a follicle stimulating hormone (FSH) level in the post-menopausal range (if not taking hormone replacement therapy) Male subjects must either have a vasectomy or agree that they and any female partners will use 2 acceptable forms of contraception, one of which must be a condom, until 30 days after the last dose of study drug. Other acceptable forms of contraception include hormonal contraceptives that have been at stable dose for 12 weeks prior to randomization, intrauterine device, Depo-Provera®, Norplant® System Implants, bilateral tubal ligation, bilateral oophorectomy, hysterectomy, and contraceptive sponge, foam, or jelly. Also, male subjects must not donate sperm during the study and for 30 days after the last dose of study drug Willing and able to provide written informed consent Diagnosis of T2DM according to American Diabetes Association criteria Currently on stable metformin or metformin extended-release therapy (unchanged dose [minimum daily dose of 1000 mg] for ≥12 weeks prior to screening) Subjects must have an HbA1c value of ≥7.0% to ≤10.5% Subjects must have a fasting plasma glucose of ≤260 mg/dL Subjects must have a body mass index (BMI) between 25 kg/m2 and 40 kg/m2, inclusive, and must weigh more than 45 kg Exclusion Criteria: History of type 1 diabetes mellitus or history of diabetic ketoacidosis or persistent hypoglycemia or hypoglycemia unawareness Women of childbearing potential, lactating, or has a positive pregnancy test History or presence of alcoholism or drug abuse within 2 years prior to screening Unwilling to comply with study restrictions, including restrictions on strenuous exercise Presence of any of the following conditions: renal impairment (defined as history or estimated glomerular filtration rate at screening of <45 mL/min using the Modification of Diet in Renal Disease equation), diabetic proliferative retinopathy, severely symptomatic diabetic neuropathy requiring treatment, diabetic gastroparesis, active liver disease (other than asymptomatic nonalcoholic fatty liver disease), cirrhosis, symptomatic gall bladder disease, or pancreatitis Serum triglyceride level > 400 mg/dL at screening Liver transaminase levels (AST or ALT) >150% ULN, total bilirubin >2 ULN, or creatine kinase (CK) levels > 3 × ULN at screening History or evidence of clinically significant cardiovascular, pulmonary, renal, endocrine (other than T2DM), hepatic, neurologic, psychiatric, immunologic, hematologic, gastrointestinal, or metabolic disease or surgical intervention (eg, bariatric surgery) or allergic conditions (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) Myocardial infarction, unstable angina, arterial revascularization, stroke, symptomatic peripheral artery disease, deep vein thrombosis, New York Heart Association Functional Class III or IV heart failure, or transient ischemic attack within 6 months prior to screening History of malignant hypertension or a recent history of uncontrolled high blood pressure or at screening has a seated systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg after at least a 5 minute rest. Blood pressure is determined as the mean of triplicate measurements collected at 2- minute intervals after the subject has been sitting quietly for at least 5 minutes. Therapy for hypertension (beta blockers excluded) that has been stable for at least 8 weeks prior to screening is permitted Arm size in excess of the maximum limit of the largest cuff provided with the study blood pressure monitor History of malignancy (except adequately treated basal or squamous cell skin cancer or cervical carcinoma in situ) within 5 years prior to screening History or evidence of QT prolongation or clinically significant QT prolongation (QTcF >450 msec) at screening, or other significant ECG findings at screening that may place the subject at increased risk by participating in the study Treatment with any type of insulin (injected or inhaled) for > 6 consecutive days within 6 months prior to screening or any insulin therapy within 12 weeks prior to screening Treated with peroxisome proliferator-activated receptor-gamma agonists (thiazolidinediones [TZDs]), incretin therapy (GLP-1 agonists). or amylin mimetics within 12 weeks prior to screening Taking any of the following prohibited medications Antidepressants, antipsychotics, anti-epileptics, hormone replacement therapies (estrogen, progestin), testosterone therapies, and thyroid replacement medications that are not at a stable dose for at least 12 weeks prior to screening Lipid-modifying medications and anti-hypertensive medications that have not been at a stable dose for at least 8 weeks prior to the Screening Visit (excluding bile acid sequestrants, ezetimibe, and beta blockers, which are prohibited Over-the-counter herbal medications and supplement (aside from once daily multivitamins) Treatment with systemic corticosteroids, which must be discontinued at least 4 weeks prior to screening. Note: Inhaled, intraarticular, intranasal and topical corticosteroids are permitted Currently treated with weight-loss medications. These must be discontinued ≥12 weeks prior to screening History or evidence of intravenous illicit drug use, active hepatitis B virus (HBV), hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV) infection Known hypersensitivity or idiosyncratic reaction to glucagon receptor (GCGR) antagonists or LGD-6972 Participation in another interventional clinical trial within 30 days prior to dosing or treatment with an investigational product with 14 days or 5 half-lives of the Screening Visit (whichever is longer) Donated ≥ 450 mL of blood within 56 days of screening or has donated blood products within 30 days of screening Inability to comply with study procedures or to adhere to study-required restrictions

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 70 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LGD-6972-5 mg<br>5 mg LGD-6972 QD | Drug: LGD-6972-5 mg<br>* 5 mg LGD-6972 QD<br>* Other names: LGD-6972 sodium salt capsules;|
| Active Comparator: LGD-6972-10 mg<br>10 mg LGD-6972 QD | Drug: LGD-6972-10 mg<br>* 10 mg LGD-6972 QD<br>* Other names: LGD-6972 sodium salt capsules;|
| Active Comparator: LGD-6972-15 mg<br>15 mg LGD-6972 QD | Drug: LGD-6972-15 mg<br>* 15 mg LGD-6972 QD<br>* Other names: LGD-6972 sodium salt capsules;|
| Placebo Comparator: Placebo<br>Placebo QD | Other: Placebo<br>* Placebo QD<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in HbA1c |  | 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in HbA1C |  | Baseline to Weeks 2,4,8 | 
| Change from baseline in fasting glucose |  | Baseline to Weeks 2,4,8 and 12 | 
| Change from baseline values for fasting glucagon |  | Baseline to Weeks 2,4,8 and 12 | 
| Change from baseline values for fasting GLP-1 (total and active) |  | Baseline to Weeks 2,4,8 and 12 | 
| Change from baseline values for fasting insulin |  | Baseline to Weeks 2,4,8 and 12 | 
| Change from baseline values for fasting lipids (total, LDL, and HDL cholesterol and triglycerides) |  | Baseline to Weeks 2,4,8, and 12 | 
| Change from baseline in blood pressure (systolic and diastolic) |  | Baseline to Weeks 2,4,8, and 12 | 
| Change from baseline in body weight |  | Baseline to Weeks 2,4,8 and 12 |