Safety, Tolerability, and Pharmacodynamics of IONIS-DGAT2Rx in Adult Patients With Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
The purpose is to assess the Safety, Tolerability, and Pharmacodynamics effect of IONIS DGAT2Rx in up to 45 Adult Patients with Type 2 Diabetes.

Detailed Description
-----------------
This short-term study will assess changes in hepatic steatosis over a 13-week treatment period in a patient population with higher risk for development of Nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic steatohepatitis (NASH), obese type 2 diabetes mellitus (T2DM) with elevated HbA1c.

Official Title
-----------------
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability and Pharmacodynamics of ISIS 484137 (IONIS-DGAT2Rx, an Antisense Inhibitor of Diacylglycerol Acyltransferase 2) Administered Once-Weekly for 13 Weeks in Adult Patients With Type 2 Diabetes

Conditions
-----------------
Hepatic Steatosis

Intervention / Treatment
-----------------
* Drug: IONIS DGAT2Rx
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must have given written informed consent and be able to comply with all study requirements. Males or females aged 18-75, inclusive, at the time of Informed Consent. Females must be non-pregnant and non-lactating, and either surgically sterile or post- menopausal. Males must be surgically sterile, abstinent or using an acceptable contraceptive method. Body mass index (BMI) ≥ 27.0 - ≤ 39.0 kilograms per square meter (kg/m^2). Diagnosis of Type 2 Diabetes Mellitus with an Hemoglobin A1C (HbA1c) ≥7.3% and ≤9.5% at screening. Must have been on a stable dose of Oral Antidiabetic Therapy for a minimum of 3 months prior to Screening. ≥ 10% liver fat prior to randomization assessed by MRI-PDFF. Stable body weight for at least 3 months before screening. Exclusion Criteria: Clinically-significant abnormalities in medical history or physical examination. Clinically-significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion, per Sponsor. Evidence of uncorrected hypothyroidism or hyperthyroidism results at Screening. History of solid organ transplantation or renal dialysis. Clinically-significant complications of diabetes. Treatment with another Study Drug, biological agent, or device within one-month of screening. Known history or evidence of liver disease with a positive test for human immunodeficiency virus (HIV), Hepatitis C virus (HCV), or chronic Hepatitis B virus (HBV), or chronic liver disease other than NASH. Recent history of, or current drug or alcohol abuse. Current use of concomitant medications known to significantly impact body weight or that may cause liver toxicity, per Investigator Use of anticoagulant/Antiplatelet agents unless the dose has been stable for 4 weeks prior to the first dose of study drug] Use of non-steroidal anti-inflammatory drug nimesulide or any other drug influencing coagulation (except lose-dose aspirin). Use of obeticholic acid or ursodeoxycholic acid Considered unsuitable for inclusion by the Principal Investigator

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Experimental: IONIS DGAT2Rx<br>Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks | Drug: IONIS DGAT2Rx<br>* Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks<br>|
| Placebo Comparator: Placebo (sterile saline 0.9)<br>Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks | Drug: Placebo<br>* Saline 0.9%<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Liver Fat Percentage (Randomized Population) | Absolute change in liver fat percentage as quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) from baseline to post-treatment MRI. | Baseline to Week 15 | 
| Absolute Change in Liver Fat Percentage (Per Protocol Population) | Absolute change in liver fat percentage as quantified by MRI-PDFF from baseline to post-treatment MRI. | Baseline to Week 15 | 
| Percentage of Participants With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx | An adverse event (AE) is any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. | Up to 176 days | 
| Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx | AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, June 2010. Grades: mild - the event is easily tolerated by the participant and does not affect the participant's usual daily activities; moderate - the event causes the participant more discomfort and interrupts the participant's usual daily activities; severe - the event is incapacitating and causes considerable interference with the participant's usual daily activities. | Up to 176 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Liver Fat Percentage | Relative percent change in liver fat percentage from baseline to post-treatment MRI. | Baseline to Week 15 | 
| Percentage of Participants With ≥ 30% Relative Reduction in Liver Fat Percentage | Percentage of participants with ≥ 30% relative reduction in liver fat percentage from baseline to post-treatment. | Week 15 | 
| Percent Change in Liver Volume | Assessed from Baseline MRI to Post-Treatment MRI. | Baseline to Week 15 | 
| Percent Change in Plasma Lipoprotein Profile | Percent change in plasma lipoprotein profile (total cholesterol, apolipoprotein B [ApoB], high density lipoprotein (HDL), low density lipoprotein cholesterol [LDL-C], non-HDL, triglycerides, and very low density lipoproteins [VLDL]) from baseline to the average of the post-treatment values assessed 1 and 2 weeks after the last dose (Post-Treatment 1 and Post-Treatment 2 visits). | Week 15 | 
| Percent Change in Parameters of Insulin Resistance (IR) | Percent change in parameters of IR (fasting plasma glucose [FPG], homeostatic model assessment - insulin resistance [HOMA-IR], and insulin) from baseline to post-treatment. | Week 14 | 
| Absolute Change in Hemoglobin A1C (HbA1C) | Absolute change in HbA1C from baseline to post-treatment. | Week 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatic Steatosis, IONIS-DGAT2Rx, Type 2 Diabetes