T2 Diabetes and Fatty Liver Disease (Non-alcoholic Origin)
Conditions
Keywords
omega-3 carboxylic acid
Brief summary
This study is a double-blind randomized, placebo-controlled, parallel-group, 12 week study performed in up to 5 centres in Sweden to assess the effect of Omega-3 carboxylic acids and dapagliflozin on liver fat in patients with Type 2 diabetes with fatty liver (\>5.5% as measured with magnetic resonance imaging (MRI))
Interventions
DRUGplacebo
Placebo matching to Omega-3 carboxylic acids (olive oil)
DRUGOmega-3 carboxylic acids
4 g administered as 4 x 1 g capsules
DRUGDapagliflozin
10 mg administered as 10 mg tablet
DRUGPlacebo
Placebo matching to dapagliflozin 10 mg
Sponsors
Uppsala Clinical Research, Uppsala, Sweden
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Provision of informed consent prior to any study specific procedures; Men or women ≥40 years and ≤75 years with suitable veins for cannulation or repeated venepuncture; Have liver fat content as assessed by MRI \>5.5%; Diagnosis of Type 2 diabetes since at least 6 months in accordance with WHO criteria.
Exclusion criteria
Any condition when MRI is contraindicated such as, but not limited to, having a pacemaker or claustrophobia; Diagnosis or signs of Type 1 diabetes (e.g. history of positive islet antibodies); Creatinine clearance \<60 mL/min at screening (Cockcroft-Gault formula).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in % Liver Fat as Assessed by MRI (Comparison Versus Placebo) | 12 weeks | To evaluate the efficacy of the combination therapy (Epanova + Dapagliflozin) when compared to placebo with respect to reduction in liver fat content (%) at the end of 12 weeks of double-blinded treatment. Treatment effect in liver fat reduction (%) was assessed using a mixed linear model with the change from baseline on logarithmic scale as response variable and the logarithm of the baseline value as covariate, treatment as fixed effect, and center as random effect. The treatment effect was then back-transformed to original scale as Geometric mean ratio and presented as percentage change from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in % Liver Fat (Comparison Between Active Treatment Groups) | 12 weeks | To evaluate the relative efficacy of the combination of Epanova and dapagliflozin versus Epanova alone and dapagliflozin alone with respect to reduction in % liver fat at the end of 12 weeks of double-blind treatment. Treatment effect in liver fat reduction (%) was assessed using a mixed linear model with the change from baseline on logarithmic scale as response variable and the logarithm of the baseline value as covariate, treatment as fixed effect, and center as random effect. The treatment effect was then back-transformed to original scale as Geometric mean ratio and presented as percentage change from baseline. |
Countries
Sweden
Participant flow
Recruitment details
This study was conducted in 5 centers in Sweden between 20 January 2015 and 11 December 2015.
Pre-assignment details
The study duration was up to 15 weeks: an screening period of up to 2 weeks, a 12-week treatment period, and a follow-up visit 1 week after the last dose of study drug. A total of 223 patients signed informed consent; data was not recorded for 1 patient and 18 were screened twice. Therefore, 204 patients were screened, and 84 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Epanova + Dapagliflozin Epanova 4 g/day + Dapagliflozin 10 mg/day | 22 |
| Epanova Epanova 4 g/day + placebo to Dapagliflozin | 20 |
| Dapagliflozin Dapagliflozin 10 mg/day + placebo to Epanova | 21 |
| Placebo Placebo to Epanova and placebo to Dapagliflozin | 21 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 2 | 0 |
| Overall Study | Couldn't swallow IP; noncompliance | 0 | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Epanova + Dapagliflozin | Epanova | Dapagliflozin |
|---|---|---|---|---|---|
| Age, Continuous | 65.6 Years STANDARD_DEVIATION 6.1 | 65.5 Years STANDARD_DEVIATION 5.92 | 65.0 Years STANDARD_DEVIATION 5.42 | 66.2 Years STANDARD_DEVIATION 5.94 | 65.0 Years STANDARD_DEVIATION 6.54 |
| Age, Customized <50 | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Customized >=50 - <65 | 6 Participants | 27 Participants | 9 Participants | 6 Participants | 6 Participants |
| Age, Customized >=65 | 15 Participants | 56 Participants | 13 Participants | 14 Participants | 14 Participants |
| Race/Ethnicity, Customized Black Or African American | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 21 Participants | 82 Participants | 21 Participants | 20 Participants | 20 Participants |
| Sex: Female, Male Female | 4 Participants | 25 Participants | 7 Participants | 9 Participants | 5 Participants |
| Sex: Female, Male Male | 17 Participants | 59 Participants | 15 Participants | 11 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 22 | 12 / 20 | 8 / 21 | 7 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 20 | 1 / 21 | 1 / 21 |
Outcome results
Primary
Change From Baseline to Week 12 in % Liver Fat as Assessed by MRI (Comparison Versus Placebo)
To evaluate the efficacy of the combination therapy (Epanova + Dapagliflozin) when compared to placebo with respect to reduction in liver fat content (%) at the end of 12 weeks of double-blinded treatment. Treatment effect in liver fat reduction (%) was assessed using a mixed linear model with the change from baseline on logarithmic scale as response variable and the logarithm of the baseline value as covariate, treatment as fixed effect, and center as random effect. The treatment effect was then back-transformed to original scale as Geometric mean ratio and presented as percentage change from baseline.
Time frame: 12 weeks
Population: The Full Analysis Set included all randomized patients, regardless of whether they took trial medication or not. In this set, patients were analyzed according to their randomized treatment assignment.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Epanova + Dapagliflozin | Change From Baseline to Week 12 in % Liver Fat as Assessed by MRI (Comparison Versus Placebo) | 0.79 ratio of % liver fat |
| Placebo | Change From Baseline to Week 12 in % Liver Fat as Assessed by MRI (Comparison Versus Placebo) | 0.97 ratio of % liver fat |
p-value: 0.04695% CI: [0.7, 1]Mixed Models Analysis
Secondary
Change From Baseline to Week 12 in % Liver Fat (Comparison Between Active Treatment Groups)
To evaluate the relative efficacy of the combination of Epanova and dapagliflozin versus Epanova alone and dapagliflozin alone with respect to reduction in % liver fat at the end of 12 weeks of double-blind treatment. Treatment effect in liver fat reduction (%) was assessed using a mixed linear model with the change from baseline on logarithmic scale as response variable and the logarithm of the baseline value as covariate, treatment as fixed effect, and center as random effect. The treatment effect was then back-transformed to original scale as Geometric mean ratio and presented as percentage change from baseline.
Time frame: 12 weeks
Population: The Full Analysis Set included all randomized patients, regardless of whether they took trial medication or not. In this set, patients were analyzed according to their randomized treatment assignment.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Epanova + Dapagliflozin | Change From Baseline to Week 12 in % Liver Fat (Comparison Between Active Treatment Groups) | 0.79 ratio of % liver fat |
| Placebo | Change From Baseline to Week 12 in % Liver Fat (Comparison Between Active Treatment Groups) | 0.87 ratio of % liver fat |
| Epanova | Change From Baseline to Week 12 in % Liver Fat (Comparison Between Active Treatment Groups) | 0.85 ratio of % liver fat |
p-value: 0.50295% CI: [0.75, 1.11]Mixed Models Analysis
p-value: 0.56295% CI: [0.73, 1.13]Mixed Models Analysis