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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03334214
Recruitment Status : Completed
First Posted : November 7, 2017
Results First Posted : January 27, 2020
Last Update Posted : January 27, 2020
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

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.

Condition or disease Intervention/treatment Phase
Hepatic Steatosis Drug: IONIS DGAT2Rx Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : November 3, 2017
Actual Primary Completion Date : November 28, 2018
Actual Study Completion Date : November 28, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: IONIS DGAT2Rx
Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks
Drug: IONIS DGAT2Rx
Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks

Placebo Comparator: Placebo (sterile saline 0.9)
Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks
Drug: Placebo
Saline 0.9%




Primary Outcome Measures :
  1. Absolute Change in Liver Fat Percentage (Randomized Population) [ Time Frame: Baseline to Week 15 ]
    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.

  2. Absolute Change in Liver Fat Percentage (Per Protocol Population) [ Time Frame: Baseline to Week 15 ]
    Absolute change in liver fat percentage as quantified by MRI-PDFF from baseline to post-treatment MRI.

  3. Percentage of Participants With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx [ Time Frame: Up to 176 days ]
    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.

  4. Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx [ Time Frame: Up to 176 days ]
    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.


Secondary Outcome Measures :
  1. Percent Change in Liver Fat Percentage [ Time Frame: Baseline to Week 15 ]
    Relative percent change in liver fat percentage from baseline to post-treatment MRI.

  2. Percentage of Participants With ≥ 30% Relative Reduction in Liver Fat Percentage [ Time Frame: Week 15 ]
    Percentage of participants with ≥ 30% relative reduction in liver fat percentage from baseline to post-treatment.

  3. Percent Change in Liver Volume [ Time Frame: Baseline to Week 15 ]
    Assessed from Baseline MRI to Post-Treatment MRI.

  4. Percent Change in Plasma Lipoprotein Profile [ Time Frame: Week 15 ]
    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).

  5. Percent Change in Parameters of Insulin Resistance (IR) [ Time Frame: Week 14 ]
    Percent change in parameters of IR (fasting plasma glucose [FPG], homeostatic model assessment - insulin resistance [HOMA-IR], and insulin) from baseline to post-treatment.

  6. Absolute Change in Hemoglobin A1C (HbA1C) [ Time Frame: Week 14 ]
    Absolute change in HbA1C from baseline to post-treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03334214


Locations
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Canada, Nova Scotia
Ionis Investigational Site
Halifax, Nova Scotia, Canada, B3H 2Y9
Canada, Quebec
Ionis Investigational Site
Chicoutimi, Quebec, Canada, G7H 7K9
Hungary
Ionis Investigational Site
Budapest, Hungary, 1036
Ionis Investigational Site
Budapest, Hungary, 1083
Ionis Investigational Site
Budapest, Hungary, 1088
Ionis Investigational Site
Hatvan, Hungary, 3000
Ionis Investigational Site
Miskolc, Hungary, 3529
Ionis Investigational Site
Szekesfehervar, Hungary, 8000
Poland
Ionis Investigational Site
Bydgoszcz, Poland, 85-863
Ionis Investigational Site
Bytom, Poland, 41-902
Ionis Investigational Site
Chełm, Poland, 22-100
Ionis Investigational Site
Katowice, Poland, 40-752
Ionis Investigational Site
Kraków, Poland, 31-501
Ionis Investigational Site
Kraków, Poland, 31-530
Ionis Investigational Site
Mysłowice, Poland, 41-400
Ionis Investigational Site
Wierzchosławice, Poland, 33-122
Ionis Investigational Site
Wrocław, Poland, 50-127
Ionis Investigational Site
Wrocław, Poland, 50-220
Ionis Investigational Site
Wrocław, Poland, 50-349
Ionis Investigational Site
Łódź, Poland, 93-509
United Kingdom
Ionis Investigational Site
Dundee, United Kingdom, DD1 9SY
Ionis Investigational Site
Nottingham, United Kingdom, NG7 2UH
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
Investigators
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Study Director: Sanjay Bhanot Ionis Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Ionis Pharmaceuticals, Inc.:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03334214    
Other Study ID Numbers: ISIS 484137-CS2
2017-003197-13 ( EudraCT Number )
First Posted: November 7, 2017    Key Record Dates
Results First Posted: January 27, 2020
Last Update Posted: January 27, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Ionis Pharmaceuticals, Inc.:
Hepatic Steatosis
IONIS-DGAT2Rx
Type 2 Diabetes
Additional relevant MeSH terms:
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Fatty Liver
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liver Diseases
Digestive System Diseases