Hepatic Steatosis
Conditions
Keywords
Hepatic Steatosis, IONIS-DGAT2Rx, Type 2 Diabetes
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.
Interventions
DRUGIONIS DGAT2Rx
Single Dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks
DRUGPlacebo
Saline 0.9%
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Liver Fat Percentage (Randomized Population) | 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. |
| Absolute Change in Liver Fat Percentage (Per Protocol Population) | Baseline to Week 15 | Absolute change in liver fat percentage as quantified by MRI-PDFF from baseline to post-treatment MRI. |
| Percentage of Participants With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx | 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. |
| Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx | 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
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Parameters of Insulin Resistance (IR) | 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. |
| Percent Change in Liver Fat Percentage | Baseline to Week 15 | Relative percent change in liver fat percentage from baseline to post-treatment MRI. |
| Absolute Change in Hemoglobin A1C (HbA1C) | Week 14 | Absolute change in HbA1C from baseline to post-treatment. |
| Percentage of Participants With ≥ 30% Relative Reduction in Liver Fat Percentage | Week 15 | Percentage of participants with ≥ 30% relative reduction in liver fat percentage from baseline to post-treatment. |
| Percent Change in Liver Volume | Baseline to Week 15 | Assessed from Baseline MRI to Post-Treatment MRI. |
| Percent Change in Plasma Lipoprotein Profile | 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). |
Countries
Canada, Hungary, Poland, United Kingdom
Participant flow
Recruitment details
44 participants were randomized at multiple study centers in Canada, Hungary, and Poland.
Pre-assignment details
A total of 173 participants were screened for the study and 44 participants were randomized and received study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks. | 15 |
| IONIS DGAT2Rx 250 mg Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks. | 29 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event or Serious Adverse Event | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | IONIS DGAT2Rx 250 mg | Total |
|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 6 | 62 years STANDARD_DEVIATION 7 | 62 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 29 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Liver Fat Percentage (Per Protocol Population) | 19.77 fat percentage STANDARD_DEVIATION 6.03 | 18.22 fat percentage STANDARD_DEVIATION 6.05 | 18.72 fat percentage STANDARD_DEVIATION 6 |
| Liver Fat Percentage (Randomized Population) | 19.54 fat percentage STANDARD_DEVIATION 5.68 | 18.48 fat percentage STANDARD_DEVIATION 6.04 | 18.84 fat percentage STANDARD_DEVIATION 5.88 |
| Race/Ethnicity, Customized White | 15 Participants | 29 Participants | 44 Participants |
| Sex: Female, Male Female | 8 Participants | 14 Participants | 22 Participants |
| Sex: Female, Male Male | 7 Participants | 15 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 29 |
| other Total, other adverse events | 10 / 15 | 20 / 29 |
| serious Total, serious adverse events | 0 / 15 | 4 / 29 |
Outcome results
Primary
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.
Time frame: Baseline to Week 15
Population: The per protocol set included all randomized participants who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Liver Fat Percentage (Per Protocol Population) | -0.64 liver fat percentage | Standard Deviation 6.11 |
| IONIS DGAT2Rx 250 mg | Absolute Change in Liver Fat Percentage (Per Protocol Population) | -5.15 liver fat percentage | Standard Deviation 5.4 |
p-value: 0.026ANOVA
Primary
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.
Time frame: Baseline to Week 15
Population: The randomized population included all participants who are randomized into the study regardless of whether they received the study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Liver Fat Percentage (Randomized Population) | -0.04 liver fat percentage | Standard Deviation 5.82 |
| IONIS DGAT2Rx 250 mg | Absolute Change in Liver Fat Percentage (Randomized Population) | -5.37 liver fat percentage | Standard Deviation 5.41 |
p-value: 0.003ANOVA
Primary
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.
Time frame: Up to 176 days
Population: The safety set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx | Mild | 6.7 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx | Moderate | 6.7 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx | Severe | 0.0 percentage of participants |
| IONIS DGAT2Rx 250 mg | Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx | Mild | 37.9 percentage of participants |
| IONIS DGAT2Rx 250 mg | Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx | Moderate | 6.9 percentage of participants |
| IONIS DGAT2Rx 250 mg | Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx | Severe | 3.4 percentage of participants |
Primary
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.
Time frame: Up to 176 days
Population: The safety set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx | 13.3 percentage of participants |
| IONIS DGAT2Rx 250 mg | Percentage of Participants With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx | 48.3 percentage of participants |
Secondary
Absolute Change in Hemoglobin A1C (HbA1C)
Absolute change in HbA1C from baseline to post-treatment.
Time frame: Week 14
Population: The per protocol set included all randomized participants who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Hemoglobin A1C (HbA1C) | -0.2 percentage of total hemoglobin | Standard Deviation 0.7 |
| IONIS DGAT2Rx 250 mg | Absolute Change in Hemoglobin A1C (HbA1C) | -0.2 percentage of total hemoglobin | Standard Deviation 0.6 |
p-value: 0.933ANOVA
Secondary
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.
Time frame: Week 15
Population: The per protocol set included all randomized participants who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With ≥ 30% Relative Reduction in Liver Fat Percentage | 16.7 percentage of participants |
| IONIS DGAT2Rx 250 mg | Percentage of Participants With ≥ 30% Relative Reduction in Liver Fat Percentage | 48.0 percentage of participants |
p-value: 0.0774Cochran-Mantel-Haenszel
Secondary
Percent Change in Liver Fat Percentage
Relative percent change in liver fat percentage from baseline to post-treatment MRI.
Time frame: Baseline to Week 15
Population: The per protocol set included all randomized participants who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change in Liver Fat Percentage | -2.4 percent change | Standard Deviation 28.8 |
| IONIS DGAT2Rx 250 mg | Percent Change in Liver Fat Percentage | -25.5 percent change | Standard Deviation 26.5 |
p-value: 0.024ANOVA
Secondary
Percent Change in Liver Volume
Assessed from Baseline MRI to Post-Treatment MRI.
Time frame: Baseline to Week 15
Population: The per protocol set included all randomized participants who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change in Liver Volume | -1.9 percent change | Standard Deviation 7.2 |
| IONIS DGAT2Rx 250 mg | Percent Change in Liver Volume | -6.3 percent change | Standard Deviation 9.8 |
p-value: 0.183ANOVA
Secondary
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.
Time frame: Week 14
Population: The per protocol set included all randomized participants who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations. Number analyzed were the participants with analysis values at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change in Parameters of Insulin Resistance (IR) | FPG | -6.3 percent change | Standard Deviation 23.1 |
| Placebo | Percent Change in Parameters of Insulin Resistance (IR) | HOMA-IR | -16.9 percent change | Standard Deviation 29.7 |
| Placebo | Percent Change in Parameters of Insulin Resistance (IR) | Insulin | -10.3 percent change | Standard Deviation 21.7 |
| IONIS DGAT2Rx 250 mg | Percent Change in Parameters of Insulin Resistance (IR) | FPG | -6.9 percent change | Standard Deviation 16.1 |
| IONIS DGAT2Rx 250 mg | Percent Change in Parameters of Insulin Resistance (IR) | HOMA-IR | 2.6 percent change | Standard Deviation 46.8 |
| IONIS DGAT2Rx 250 mg | Percent Change in Parameters of Insulin Resistance (IR) | Insulin | 10.1 percent change | Standard Deviation 44.8 |
Comparison: FPGp-value: 0.902ANOVA
Comparison: HOMA-IRp-value: 0.267Van Elteren test
Comparison: Insulinp-value: 0.2Van Elteren test
Secondary
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).
Time frame: Week 15
Population: The per protocol set included all randomized participants who received at least 10 of the prescribed doses and received the first 4 doses in the first 5 weeks, not missing 3 consecutive weekly doses and having no significant protocol deviations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change in Plasma Lipoprotein Profile | ApoB | -8.1 percent change | Standard Deviation 9.5 |
| Placebo | Percent Change in Plasma Lipoprotein Profile | LDL-C | -8.8 percent change | Standard Deviation 14.9 |
| Placebo | Percent Change in Plasma Lipoprotein Profile | Total cholesterol | -4.4 percent change | Standard Deviation 9.6 |
| Placebo | Percent Change in Plasma Lipoprotein Profile | Triglycerides | -0.8 percent change | Standard Deviation 20.3 |
| Placebo | Percent Change in Plasma Lipoprotein Profile | HDL | 1.0 percent change | Standard Deviation 6.3 |
| Placebo | Percent Change in Plasma Lipoprotein Profile | VLDL-C | -0.7 percent change | Standard Deviation 20.3 |
| Placebo | Percent Change in Plasma Lipoprotein Profile | Non-HDL | -7.1 percent change | Standard Deviation 13.4 |
| IONIS DGAT2Rx 250 mg | Percent Change in Plasma Lipoprotein Profile | VLDL-C | 2.0 percent change | Standard Deviation 18.5 |
| IONIS DGAT2Rx 250 mg | Percent Change in Plasma Lipoprotein Profile | Non-HDL | -3.8 percent change | Standard Deviation 18.7 |
| IONIS DGAT2Rx 250 mg | Percent Change in Plasma Lipoprotein Profile | Total cholesterol | -2.9 percent change | Standard Deviation 14.2 |
| IONIS DGAT2Rx 250 mg | Percent Change in Plasma Lipoprotein Profile | ApoB | -6.7 percent change | Standard Deviation 15.3 |
| IONIS DGAT2Rx 250 mg | Percent Change in Plasma Lipoprotein Profile | HDL | 2.2 percent change | Standard Deviation 11.6 |
| IONIS DGAT2Rx 250 mg | Percent Change in Plasma Lipoprotein Profile | LDL-C | -3.8 percent change | Standard Deviation 24.1 |
| IONIS DGAT2Rx 250 mg | Percent Change in Plasma Lipoprotein Profile | Triglycerides | 2.8 percent change | Standard Deviation 20.1 |
Comparison: Total Cholesterolp-value: 0.682ANOVA
Comparison: ApoBp-value: 0.716ANOVA
Comparison: HDLp-value: 0.717ANOVA
Comparison: LDL-Cp-value: 0.463ANOVA
Comparison: Non-HDLp-value: 0.555ANOVA
Comparison: Triglyceridesp-value: 0.619ANOVA
Comparison: VLDL-Cp-value: 0.698ANOVA