A study to investigate effects of Omega-3 carboxylic acids and dapagliflozin on liver fat content in diabetic patients - EFFECTII

Study identifier:D5883C00004

ClinicalTrials.gov identifier:NCT02279407

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A double-blind randomized placebo-controlled, parallel-group 12 week study to investigate the effects of Omega-3 carboxylic acids and dapagliflozin on liver fat content in type 2 diabetic patients; EFFECT II

Medical condition

T2 diabetes and fatty liver disease (non-alcoholic origin)

Phase

Phase 2

Healthy volunteers

Study drug

placebo, Omega-3 carboxylic acids, Dapagliflozin, Placebo

Sex

All

Actual Enrollment

223

Study type

Interventional

Age

40 Years - 75 Years

Date

Study Start Date: 01 Jan 2015

Primary Completion Date: 01 Dec 2015

Study Completion Date: 01 Dec 2015

Study design

Allocation: Randomized
Endpoint Classification: Efficacy
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Feb 2017 by AstraZeneca

Collaborators

Uppsala Clinical Research, Uppsala Sweden

Inclusion and exclusion criteria

Location

Research Site

Uppsala, Sweden

Location

Research Site

Stockholm, Sweden

Location

Research Site

Göteborg, Sweden

Location

Research Site

Örebro, Sweden

Location

Research Site

Linkoping, Sweden

Arms	Assigned Interventions
Placebo Comparator: placebo	Drug: placebo Placebo matching to Omega-3 carboxylic acids (olive oil) Drug: Placebo Placebo matching to dapagliflozin 10 mg
Experimental: Omega-3 carboxylic acids 4g / day	Drug: Omega-3 carboxylic acids 4 g administered as 4 x 1 g capsules
Experimental: Dapagliflozin, 10mg / day	Drug: Dapagliflozin 10 mg administered as 10 mg tablet
Experimental: Omega-3 carboxylic acids 4g/day+Dapagliflozin 10mg/day	Drug: Omega-3 carboxylic acids 4 g administered as 4 x 1 g capsules Drug: Dapagliflozin 10 mg administered as 10 mg tablet

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted in 5 centers in Sweden between 20 January 2015 and 11 December 2015.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Epanova + Dapagliflozin	Epanova 4 g/day + Dapagliflozin 10 mg/day
Dapagliflozin	Dapagliflozin 10 mg/day + placebo to Epanova
Epanova	Epanova 4 g/day + placebo to Dapagliflozin
Placebo	Placebo to Epanova and placebo to Dapagliflozin

Participant Flow: Overall Study

	Epanova + Dapagliflozin	Dapagliflozin	Epanova	Placebo
STARTED	22	21	20	21
COMPLETED	20	20	15	20
NOT COMPLETED	2	1	5	1
Couldn't swallow IP; noncompliance	0	0	2	0
Withdrawal by Subject	1	0	1	1
Adverse Event	1	1	2	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Epanova + Dapagliflozin	Epanova 4 g/day + Dapagliflozin 10 mg/day
Epanova	Epanova 4 g/day + placebo to Dapagliflozin
Dapagliflozin	Dapagliflozin 10 mg/day + placebo to Epanova
Placebo	Placebo to Epanova and placebo to Dapagliflozin

Baseline Measures

	Epanova + Dapagliflozin	Epanova	Dapagliflozin	Placebo	Total
Number of Participants [units: Participants]	22	20	21	21	84
Age Continuous [units: Years] Mean ± Standard Deviation	65.0 ± 5.42	66.2 ± 5.94	65.0 ± 6.54	65.6 ± 6.10	65.5 ± 5.92
Age, Customized [units: Participants]
<50	0	0	1	0	1
>=50 - <65	9	6	6	6	27
>=65	13	14	14	15	56
Gender, Male/Female [units: Participants]
Female	7	9	5	4	25
Male	15	11	16	17	59
Race, Customized [units: Participants]
Black Or African American	1	0	1	0	2
White	21	20	20	21	82

Outcome Measures

1. Primary Outcome Measure: Change from Baseline to Week 12 in % liver fat as assessed by MRI (comparison versus placebo) [ Time Frame: 12 weeks ]

Measure Type	Primary
Measure Name	Change from Baseline to Week 12 in % liver fat as assessed by MRI (comparison versus placebo)
Measure Description	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
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Epanova + Dapagliflozin	Epanova 4 g/day + Dapagliflozin 10 mg/day
Placebo	Placebo to Epanova and placebo to Dapagliflozin

Measured Values

	Epanova + Dapagliflozin	Placebo
Number of Participants Analyzed [units:participants]	20	19
Change from Baseline to Week 12 in % liver fat as assessed by MRI (comparison versus placebo) [units: ratio of % liver fat] Geometric Mean (95% Confidence Interval)	0.79 (0.69 to 0.90)	0.97 (0.90 to 1.04)

Statistical Analysis 1 for Change from Baseline to Week 12 in % liver fat as assessed by MRI (comparison versus placebo)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.046
Other^[5]	0.83
95% Confidence Interval	( 0.70 to 1.00 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Hypotheses tested using Dunnett’s multiple testing procedure with a family-wise error rate of 5%, adjusting for 3 pairwise comparisons versus a single control (placebo).
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Change from Baseline to Week 12 in % liver fat (comparison between active treatment groups) [ Time Frame: 12 weeks ]

Measure Type	Secondary
Measure Name	Change from Baseline to Week 12 in % liver fat (comparison between active treatment groups)
Measure Description	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
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Epanova + Dapagliflozin	Epanova 4 g/day + Dapagliflozin 10 mg/day
Dapagliflozin	Dapagliflozin 10 mg/day + placebo to Epanova
Epanova	Epanova 4 g/day + placebo to Dapagliflozin

Measured Values

	Epanova + Dapagliflozin	Dapagliflozin	Epanova
Number of Participants Analyzed [units:participants]	20	19	15
Change from Baseline to Week 12 in % liver fat (comparison between active treatment groups) [units: ratio of % liver fat] Geometric Mean (95% Confidence Interval)	0.79 (0.69 to 0.90)	0.87 (0.77 to 0.99)	0.85 (0.78 to 0.92)

Statistical Analysis 1 for Change from Baseline to Week 12 in % liver fat (comparison between active treatment groups)

Groups^[1]	Epanova + Dapagliflozin, Dapagliflozin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.502
Other^[5]	0.91
95% Confidence Interval	( 0.75 to 1.11 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Conditional upon rejection of at least 1 of the 3 hypotheses for the primary analysis, secondary hypotheses are tested using Tukey's multiple testing procedure with a family-wise error rate of 5%, adjusting for 3 pairwise comparisons.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from Baseline to Week 12 in % liver fat (comparison between active treatment groups)

Groups^[1]	Epanova + Dapagliflozin, Epanova
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.562
Other^[5]	0.91
95% Confidence Interval	( 0.73 to 1.13 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Conditional upon rejection of at least 1 of the hypotheses for the primary analysis, secondary hypotheses are tested using Tukey's multiple testing procedure with a family-wise error rate of 5%, adjusting for 3 pairwise comparisons.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Reporting Groups

	Description
Epanova + Dapagliflozin	Epanova 4 g/day + Dapagliflozin 10 mg/day
Epanova	Epanova 4 g/day + placebo to Dapagliflozin
Dapagliflozin	Dapagliflozin 10 mg/day + placebo to Epanova
Placebo	Placebo to Epanova and placebo to Dapagliflozin

Serious Adverse Events

Epanova + Dapagliflozin

Epanova

Dapagliflozin

Placebo

Total, serious adverse events

# participants affected / at risk

0/22 (0.00%)

0/20 (0.00%)

1/21 (4.76%)

Infections and infestations

Sepsis¹,^†

# participants affected / at risk

0/22 (0.00%)

0/20 (0.00%)

0/21 (0.00%)

1/21 (4.76%)

# events

Renal and urinary disorders

Hydronephrosis¹,^†

# participants affected / at risk

0/22 (0.00%)

0/20 (0.00%)

1/21 (4.76%)

0/21 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.1

Other Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Epanova + Dapagliflozin	Epanova 4 g/day + Dapagliflozin 10 mg/day
Epanova	Epanova 4 g/day + placebo to Dapagliflozin
Dapagliflozin	Dapagliflozin 10 mg/day + placebo to Epanova
Placebo	Placebo to Epanova and placebo to Dapagliflozin

Other Adverse Events

Epanova + Dapagliflozin

Epanova

Dapagliflozin

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

14/22 (63.64%)

12/20 (60.00%)

8/21 (38.10%)

7/21 (33.33%)

Gastrointestinal disorders

Abdominal pain upper¹,^†

# participants affected / at risk

3/22 (13.64%)

2/20 (10.00%)

0/21 (0.00%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

0/22 (0.00%)

1/20 (5.00%)

2/21 (9.52%)

1/21 (4.76%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

11/22 (50.00%)

7/20 (35.00%)

1/21 (4.76%)

0/21 (0.00%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

2/22 (9.09%)

3/20 (15.00%)

0/21 (0.00%)

2/21 (9.52%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

2/22 (9.09%)

2/20 (10.00%)

1/21 (4.76%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

2/22 (9.09%)

1/20 (5.00%)

5/21 (23.81%)

1/21 (4.76%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/22 (4.55%)

0/20 (0.00%)

0/21 (0.00%)

2/21 (9.52%)

# events

Renal and urinary disorders

Pollakiuria¹,^†

# participants affected / at risk

2/22 (9.09%)

1/20 (5.00%)

2/21 (9.52%)

1/21 (4.76%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Stefan Carlsson
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Jan Eriksson

Uppsala University Hospital, Uppsala, SE

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Trial Results Summaries