Trial Outcomes & Findings for Safety, Tolerability, and Pharmacodynamics of IONIS-DGAT2Rx in Adult Patients With Type 2 Diabetes (NCT NCT03334214)

Last Updated: 2020-01-27

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

44 participants

Primary outcome timeframe

Baseline to Week 15

Results posted on

2020-01-27

Participant Flow

44 participants were randomized at multiple study centers in Canada, Hungary, and Poland.

A total of 173 participants were screened for the study and 44 participants were randomized and received study drug.

Participant milestones

Participant milestones
Measure	Placebo Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.	IONIS DGAT2Rx 250 mg Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Overall Study STARTED	15	29
Overall Study COMPLETED	14	27
Overall Study NOT COMPLETED	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.	IONIS DGAT2Rx 250 mg Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Overall Study Adverse Event or Serious Adverse Event	0	1
Overall Study Withdrawal by Subject	0	1
Overall Study Other	1	0

Baseline Characteristics

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.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=15 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.	IONIS DGAT2Rx 250 mg n=29 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.	Total n=44 Participants Total of all reporting groups
Age, Continuous	63 years STANDARD_DEVIATION 6 • n=15 Participants	62 years STANDARD_DEVIATION 7 • n=29 Participants	62 years STANDARD_DEVIATION 7 • n=44 Participants
Sex: Female, Male Female	8 Participants n=15 Participants	14 Participants n=29 Participants	22 Participants n=44 Participants
Sex: Female, Male Male	7 Participants n=15 Participants	15 Participants n=29 Participants	22 Participants n=44 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=15 Participants	0 Participants n=29 Participants	0 Participants n=44 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants n=15 Participants	29 Participants n=29 Participants	44 Participants n=44 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=15 Participants	0 Participants n=29 Participants	0 Participants n=44 Participants
Race/Ethnicity, Customized White	15 Participants n=15 Participants	29 Participants n=29 Participants	44 Participants n=44 Participants
Liver Fat Percentage (Randomized Population)	19.54 fat percentage STANDARD_DEVIATION 5.68 • n=15 Participants	18.48 fat percentage STANDARD_DEVIATION 6.04 • n=29 Participants	18.84 fat percentage STANDARD_DEVIATION 5.88 • n=44 Participants
Liver Fat Percentage (Per Protocol Population)	19.77 fat percentage STANDARD_DEVIATION 6.03 • n=12 Participants • 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.	18.22 fat percentage STANDARD_DEVIATION 6.05 • n=25 Participants • 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.	18.72 fat percentage STANDARD_DEVIATION 6.00 • n=37 Participants • 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.

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=26 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Absolute Change in Liver Fat Percentage (Randomized Population)	-0.04 liver fat percentage Standard Deviation 5.82	-5.37 liver fat percentage Standard Deviation 5.41

PRIMARY outcome

Timeframe: 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.

Absolute change in liver fat percentage as quantified by MRI-PDFF from baseline to post-treatment MRI.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=25 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Absolute Change in Liver Fat Percentage (Per Protocol Population)	-0.64 liver fat percentage Standard Deviation 6.11	-5.15 liver fat percentage Standard Deviation 5.40

PRIMARY outcome

Timeframe: Up to 176 days

Population: The safety set included all randomized participants who received at least one dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=29 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Percentage of Participants With Adverse Events That Were Related to Treatment With IONIS DGAT2Rx	13.3 percentage of participants	48.3 percentage of participants

PRIMARY outcome

Timeframe: Up to 176 days

Population: The safety set included all randomized participants who received at least one dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=29 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx Mild	6.7 percentage of participants	37.9 percentage of participants
Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx Moderate	6.7 percentage of participants	6.9 percentage of participants
Percentage of Participants With Adverse Events, Graded by Severity, That Were Related to Treatment With IONIS DGAT2Rx Severe	0.0 percentage of participants	3.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 15

Relative percent change in liver fat percentage from baseline to post-treatment MRI.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=25 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Percent Change in Liver Fat Percentage	-2.4 percent change Standard Deviation 28.8	-25.5 percent change Standard Deviation 26.5

SECONDARY outcome

Timeframe: Week 15

Percentage of participants with ≥ 30% relative reduction in liver fat percentage from baseline to post-treatment.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=25 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Percentage of Participants With ≥ 30% Relative Reduction in Liver Fat Percentage	16.7 percentage of participants	48.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 15

Assessed from Baseline MRI to Post-Treatment MRI.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=25 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Percent Change in Liver Volume	-1.9 percent change Standard Deviation 7.2	-6.3 percent change Standard Deviation 9.8

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=25 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Percent Change in Plasma Lipoprotein Profile ApoB	-8.1 percent change Standard Deviation 9.5	-6.7 percent change Standard Deviation 15.3
Percent Change in Plasma Lipoprotein Profile HDL	1.0 percent change Standard Deviation 6.3	2.2 percent change Standard Deviation 11.6
Percent Change in Plasma Lipoprotein Profile Non-HDL	-7.1 percent change Standard Deviation 13.4	-3.8 percent change Standard Deviation 18.7
Percent Change in Plasma Lipoprotein Profile Total cholesterol	-4.4 percent change Standard Deviation 9.6	-2.9 percent change Standard Deviation 14.2
Percent Change in Plasma Lipoprotein Profile LDL-C	-8.8 percent change Standard Deviation 14.9	-3.8 percent change Standard Deviation 24.1
Percent Change in Plasma Lipoprotein Profile Triglycerides	-0.8 percent change Standard Deviation 20.3	2.8 percent change Standard Deviation 20.1
Percent Change in Plasma Lipoprotein Profile VLDL-C	-0.7 percent change Standard Deviation 20.3	2.0 percent change Standard Deviation 18.5

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=25 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Percent Change in Parameters of Insulin Resistance (IR) FPG	-6.3 percent change Standard Deviation 23.1	-6.9 percent change Standard Deviation 16.1
Percent Change in Parameters of Insulin Resistance (IR) HOMA-IR	-16.9 percent change Standard Deviation 29.7	2.6 percent change Standard Deviation 46.8
Percent Change in Parameters of Insulin Resistance (IR) Insulin	-10.3 percent change Standard Deviation 21.7	10.1 percent change Standard Deviation 44.8

SECONDARY outcome

Timeframe: Week 14

Absolute change in HbA1C from baseline to post-treatment.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks	IONIS DGAT2Rx 250 mg n=25 Participants Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Absolute Change in Hemoglobin A1C (HbA1C)	-0.2 percentage of total hemoglobin Standard Deviation 0.7	-0.2 percentage of total hemoglobin Standard Deviation 0.6

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

IONIS DGAT2Rx 250 mg

Serious events: 4 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=15 participants at risk Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.	IONIS DGAT2Rx 250 mg n=29 participants at risk Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
Cardiac disorders Cardiac arrest	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Investigations Blood triglycerides increased	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Nervous system disorders Ischaemic cerebral infarction	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Vascular disorders Deep vein thrombosis	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.

Other adverse events

Additional Information

Ionis Pharmaceuticals, Inc.

Phone: 800-679-4747

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo n=15 participants at risk Calculated volume to match active comparator administered subcutaneously once weekly for 13 weeks.	IONIS DGAT2Rx 250 mg n=29 participants at risk Single dose of DGAT2Rx administered subcutaneously once weekly for 13 weeks.
General disorders Injection site erythema	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	34.5% 10/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
General disorders Injection site bruising	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	13.8% 4/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
General disorders Injection site swelling	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	17.2% 5/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
General disorders Injection site pain	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	13.8% 4/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
General disorders Injection site pruritus	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	13.8% 4/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
General disorders Fatigue	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	6.9% 2/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
General disorders Oedema peripheral	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	20.0% 3/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	6.9% 2/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Constipation	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	6.9% 2/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Gastrooesophageal reflux disease	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Infections and infestations Nasopharyngitis	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	10.3% 3/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Infections and infestations Urinary tract infection	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	6.9% 2/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Infections and infestations Vulvovaginal mycotic infection	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	6.9% 2/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	10.3% 3/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Myalgia	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Joint swelling	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Nervous system disorders Carotid arteriosclerosis	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Nervous system disorders Headache	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Nervous system disorders Carpal tunnel syndrome	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Investigations Alanine aminotransferase increased	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	3.4% 1/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Investigations Blood creatine phosphokinase increased	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Investigations Weight decreased	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hypoglycaemia	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	10.3% 3/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Decreased appetite	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Foot fracture	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Joint dislocation	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	13.3% 2/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Reproductive system and breast disorders Vulvovaginal pruritus	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Erythema	6.7% 1/15 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.	0.00% 0/29 • Up to 176 days The safety set included all randomized participants who received at least one dose of study drug.