PRECISE: A Study to Investigate How Common Pancreatic Exocrine Insufficiency (PEI) is in Patients With Type 2 Diabetes and Also to Investigate the Uptake of a Single Dose of EPANOVA® or OMACOR® in Patients With Different Degrees of PEI
Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT02370537
Collaborator
(none)
490
22
2
8
22.3
2.8
Study Details
Study Description
Brief Summary
This study is a 2-part open-label, randomized, crossover, multicenter, non-therapeutic Phase II study to investigate the presence of pancreatic exocrine insufficiency (PEI) in patients with Type 2 diabetes mellitus (T2DM), and to investigate the pharmacokinetics (PK) of EPANOVA® (omega-3 carboxylic acids) and omega-3-acid ethyl esters (OMACOR®, Abbott Healthcare Products Ltd) following a single oral dose in patients with different degrees of PEI.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
490 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Two-part, Open-label, Randomised, Crossover, Multicentre, Phase II Study to Investigate the Presence of Pancreatic Exocrine Insufficiency (PEI) in Patients With Type 2 Diabetes Mellitus, and to Investigate the Pharmacokinetics of EPANOVA® and OMACOR® Following a Single Oral Dose in Patients With Different Degrees of PEI
Study Start Date
:
Mar 1, 2015
Actual Primary Completion Date
:
Nov 1, 2015
Actual Study Completion Date
:
Nov 1, 2015
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Sequence AB A single dose of EPANOVA® 4 g (administered as 4 x 1 g capsules) at Visit 4, followed by 10 to 14 days washout, followed by a single dose of OMACOR® 4 g (administered as 4 x 1 g capsules) at Visit 7. |
Drug: Epanova® (omega-3 carboxylic acids)
4 g (administered orally as 4 x 1 g capsules)
Other Names:
Drug: Omacor® (omega-3-acid ethyl esters)
4 g (administered orally as 4 x 1 g capsules)
Other Names:
|
| Experimental: Sequence BA A single dose of OMACOR® 4 g (administered as 4 x 1 g capsules) at Visit 4, followed by 10 to 14 days washout, followed by a single dose of EPANOVA® 4 g (administered as 4 x 1 g capsules) at Visit 7. |
Drug: Epanova® (omega-3 carboxylic acids)
4 g (administered orally as 4 x 1 g capsules)
Other Names:
Drug: Omacor® (omega-3-acid ethyl esters)
4 g (administered orally as 4 x 1 g capsules)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Part A: Serum TG Level. [7 days after enrollment.]
For Part A, the distribution of serum TG levels by the degree of pancreatic exocrine insufficiency (PEI) was assessed in patients with Type 2 Diabetes Mellitus (T2DM).
- Part B: Baseline Corrected Area Under the Plasma Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) for Total Eicosapentaenoic Acid (EPA) Following Administration of EPANOVA® and OMACOR®. [Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose.]
Baseline corrected AUC(0-last) was measured for total EPA following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI.
- Part B: Baseline Corrected AUC(0-last) for Total Docosahexaenoic Acid (DHA) Following Administration of EPANOVA® and OMACOR®. [Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose.]
Baseline corrected AUC(0-last) was measured for total DHA following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI.
- Part B: Baseline Corrected AUC(0-last) for Total EPA+DHA Following Administration of EPANOVA® and OMACOR®. [Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose.]
Baseline corrected AUC(0-last) was measured for the sum of EPA and DHA (total EPA+DHA) following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI.
- Part B: Baseline Corrected Maximum Plasma Drug Concentration (Cmax) for Total EPA Following Administration of EPANOVA® and OMACOR®. [Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose.]
Baseline corrected Cmax was measured for total EPA following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI.
- Part B: Baseline Corrected Cmax for Total DHA Following Administration of EPANOVA® and OMACOR®. [Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose.]
Baseline corrected Cmax was measured for total DHA following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI.
- Part B: Baseline Corrected Cmax for Total EPA+DHA Following Administration of EPANOVA® and OMACOR®. [Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose.]
Baseline corrected Cmax was measured for the sum of EPA and DHA (total EPA+DHA) following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 70 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Male or female aged ≥18 years and ≤70 years, with suitable veins for cannulation or repeated venipuncture.
-
Clinically diagnosed Type 2 diabetics (American Diabetes Association guidelines;), on oral antibiotic drug use ≥3 months and HbA1c value ≥6.5% and ≤9.0% at Visit 1.
-
Have a body mass index ≥18 kg/m2 and ≤40 kg/m2 and weigh at least 50 kg.
Exclusion Criteria:
-
Intolerance to Omega-3 fatty acids, ethyl esters or fish.
-
On insulin therapy or treated with injectable Glucagon-like peptide-1 (GLP-1).
-
Treated with bile acid sequestrants.
-
Serum levels of TGs >10 mmol/L at any time during the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Frederiksberg | Denmark | ||
| 2 | Research Site | København NV | Denmark | ||
| 3 | Research Site | Århus | Denmark | ||
| 4 | Research Site | Balatonfüred | Hungary | ||
| 5 | Research Site | Budapest | Hungary | ||
| 6 | Research Site | Létavértes | Hungary | ||
| 7 | Research Site | Daugavpils | Latvia | ||
| 8 | Research Site | Jekabpils | Latvia | ||
| 9 | Research Site | Riga | Latvia | ||
| 10 | Research Site | Białystok | Poland | ||
| 11 | Research Site | Puławy | Poland | ||
| 12 | Research Site | Staszów | Poland | ||
| 13 | Research Site | Zamość | Poland | ||
| 14 | Research Site | Bardejov | Slovakia | ||
| 15 | Research Site | Bratislava | Slovakia | ||
| 16 | Research Site | Lubochna | Slovakia | ||
| 17 | Research Site | Göteborg | Sweden | ||
| 18 | Research Site | Linköping | Sweden | ||
| 19 | Research Site | Lund | Sweden | ||
| 20 | Research Site | Malmo | Sweden | ||
| 21 | Research Site | Stockholm | Sweden | ||
| 22 | Research Site | Uppsala | Sweden |
Sponsors and Collaborators
- AstraZeneca
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02370537
Other Study ID Numbers:
- D5881C00006
- 2014-003511-11
First Posted:
Feb 25, 2015
Last Update Posted:
Jan 20, 2017
Last Verified:
Nov 1, 2016
Keywords provided by AstraZeneca
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | First patient enrolled: 7 April 2015. Last patient completed Part B: 17 November 2015. This study was performed in 23 centres across 6 countries in Europe. |
|---|---|
| Pre-assignment Detail | A total of 490 patients were screened and of these, 315 patients met all inclusion and none of the exclusion criteria and completed the first part of the study. 51 patients were randomised to treatment in the second part of the study. |
| Arm/Group Title | Low FEC (EPANOVA® and OMACOR®) | Intermediate FEC (EPANOVA® and OMACOR®) | Normal FEC (EPANOVA® and OMACOR®) |
|---|---|---|---|
| Arm/Group Description | Part A investigated serum lipids, especially triglycerides (TGs) and faecal elastase-1 concentration (FEC) as a measure of pancreatic exocrine function in the study population. Patients in the Low FEC group were determined to have FEC levels <100 microgram per gram (mcg/g). No treatment was administered in Part A which was a recruitment phase for Part B. In Part B, study treatment was administered at Visit 4 and Visit 7 with a randomised crossover design to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | Part A investigated serum lipids, especially TGs and FEC as a measure of pancreatic exocrine function in the study population. Patients in the Intermediate FEC group were determined to have FEC levels ≥100 mcg/g to <200 mcg/g. No treatment was administered in Part A which was a recruitment phase for Part B. In Part B, study treatment was administered at Visit 4 and Visit 7 with a randomised crossover design to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | Part A investigated serum lipids, especially TGs and FEC as a measure of pancreatic exocrine function in the study population. Patients in the Normal FEC group were determined to have FEC levels ≥200 mcg/g. No treatment was administered in Part A which was a recruitment phase for Part B. In Part B, study treatment was administered at Visit 4 and Visit 7 with a randomised crossover design to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). |
| Period Title: Part A (Open-label Recruitment) | |||
| STARTED | 16 | 16 | 283 |
| COMPLETED | 16 | 15 | 282 |
| NOT COMPLETED | 0 | 1 | 1 |
| Period Title: Part A (Open-label Recruitment) | |||
| STARTED | 16 | 15 | 282 |
| Eligible for Randomisation | 15 | 13 | 23 |
| Period 1 Sequence AB | 8 | 6 | 11 |
| Period 1 Sequence BA | 7 | 7 | 12 |
| Period 2 Sequence AB | 8 | 5 | 11 |
| Period 2 Sequence BA | 7 | 7 | 12 |
| COMPLETED | 15 | 12 | 23 |
| NOT COMPLETED | 1 | 3 | 259 |
Baseline Characteristics
| Arm/Group Title | Low FEC (EPANOVA® and OMACOR®) | Intermediate FEC (EPANOVA® and OMACOR®) | Normal FEC (EPANOVA® and OMACOR®) | Total |
|---|---|---|---|---|
| Arm/Group Description | Patients had low levels (<100 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. | Patients had intermediate levels (≥100 to <200 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. | Patients had normal levels (≥200 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. | Total of all reporting groups |
| Overall Participants | 16 | 16 | 283 | 315 |
| Age, Customized (Number) [Number] | ||||
| From 18 - 64 years |
11
68.8%
|
11
68.8%
|
171
60.4%
|
193
61.3%
|
| From 65 - 84 years |
5
31.3%
|
5
31.3%
|
112
39.6%
|
122
38.7%
|
| Over 85 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Gender (Count of Participants) | ||||
| Female |
5
31.3%
|
5
31.3%
|
123
43.5%
|
133
42.2%
|
| Male |
11
68.8%
|
11
68.8%
|
160
56.5%
|
182
57.8%
|
Outcome Measures
| Title | Part A: Serum TG Level. |
|---|---|
| Description | For Part A, the distribution of serum TG levels by the degree of pancreatic exocrine insufficiency (PEI) was assessed in patients with Type 2 Diabetes Mellitus (T2DM). |
| Time Frame | 7 days after enrollment. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Per Protocol Analysis Set included all enrolled patients without an important protocol deviation. |
| Arm/Group Title | Low FEC (EPANOVA® and OMACOR®) | Intermediate FEC (EPANOVA® and OMACOR®) | Normal FEC (EPANOVA® and OMACOR®) |
|---|---|---|---|
| Arm/Group Description | Part A investigated serum lipids, especially TGs and FEC to assess the relationship between serum TGs and degree of pancreatic exocrine function (as measured by FEC) in the study population. Patients in the Low FEC group were determined to have FEC levels <100 mcg/g. No treatment was administered in Part A which was a recruitment phase for Part B. | Part A investigated serum lipids, especially TGs and FEC to assess the relationship between serum TGs and degree of pancreatic exocrine function (as measured by FEC) in the study population. Patients in the Intermediate FEC group were determined to have FEC levels ≥100 mcg/g to <200 mcg/g. No treatment was administered in Part A which was a recruitment phase for Part B. | Part A investigated serum lipids, especially TGs and FEC to assess the relationship between serum TGs and degree of pancreatic exocrine function (as measured by FEC) in the study population. Patients in the Normal FEC group were determined to have FEC levels ≥200 mcg/g. No treatment was administered in Part A which was a recruitment phase for Part B. |
| Measure Participants | 15 | 16 | 278 |
| Mean (Standard Deviation) [millimole per litre (mmol/L)] |
2.07
(0.63)
|
1.68
(0.57)
|
2.00
(1.16)
|
| Title | Part B: Baseline Corrected Area Under the Plasma Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) for Total Eicosapentaenoic Acid (EPA) Following Administration of EPANOVA® and OMACOR®. |
|---|---|
| Description | Baseline corrected AUC(0-last) was measured for total EPA following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI. |
| Time Frame | Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Pharmacokinetic (PK) Analysis Set included all randomised patients who received at least one dose of study treatment in Part B and had at least one post-dose PK measurement without any important protocol deviations. 3 subjects were excluded from the analysis for AUC(0-last) due to missing sample results at 48 hours. |
| Arm/Group Title | Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) |
|---|---|---|---|---|---|---|
| Arm/Group Description | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). |
| Measure Participants | 15 | 14 | 13 | 12 | 21 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [hours*mcg per millilitre (h*mcg/mL)] |
2170
(65.2)
|
1650
(31.3)
|
2000
(82.8)
|
946
(96.0)
|
2070
(36.1)
|
1260
(126)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Low FEC (EPANOVA® and OMACOR®), Intermediate FEC (EPANOVA® and OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of least-square means (LSmeans) for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% Confidence Intervals (CIs) by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric least-squares (GLS) Mean Ratio |
| Estimated Value | 0.75 | |
| Confidence Interval |
(2-Sided) 90% 0.52 to 1.10 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA® and OMACOR®), Intermediate FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean ratio |
| Estimated Value | 0.48 | |
| Confidence Interval |
(2-Sided) 90% 0.32 to 0.72 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA®), Normal FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.6 | |
| Confidence Interval |
(2-Sided) 90% 0.44 to 0.82 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
| Title | Part B: Baseline Corrected AUC(0-last) for Total Docosahexaenoic Acid (DHA) Following Administration of EPANOVA® and OMACOR®. |
|---|---|
| Description | Baseline corrected AUC(0-last) was measured for total DHA following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI. |
| Time Frame | Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK Analysis Set included all randomised patients who received at least one dose of study treatment in Part B and had at least one post-dose PK measurement without any protocol deviations. 3 subjects were excluded from the analysis for AUC(0-last) due to missing sample results at 48 hours. |
| Arm/Group Title | Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) |
|---|---|---|---|---|---|---|
| Arm/Group Description | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). |
| Measure Participants | 15 | 14 | 13 | 12 | 21 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [h*mcg/mL] |
801
(55.7)
|
1040
(47.1)
|
719
(85.0)
|
567
(70.7)
|
625
(90.2)
|
810
(105)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Low FEC (EPANOVA® and OMACOR®), Intermediate FEC (EPANOVA® and OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 1.28 | |
| Confidence Interval |
(2-Sided) 90% 0.84 to 1.93 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA® and OMACOR®), Intermediate FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.80 | |
| Confidence Interval |
(2-Sided) 90% 0.51 to 1.25 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA®), Normal FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 1.29 | |
| Confidence Interval |
(2-Sided) 90% 0.92 to 1.82 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
| Title | Part B: Baseline Corrected AUC(0-last) for Total EPA+DHA Following Administration of EPANOVA® and OMACOR®. |
|---|---|
| Description | Baseline corrected AUC(0-last) was measured for the sum of EPA and DHA (total EPA+DHA) following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI. |
| Time Frame | Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK Analysis Set included all randomised patients who received at least one dose of study treatment in Part B and had at least one post-dose PK measurement without any protocol deviations. 3 subjects were excluded from the analysis for AUC(0-last) due to missing sample results at 48 hours. |
| Arm/Group Title | Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) |
|---|---|---|---|---|---|---|
| Arm/Group Description | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). |
| Measure Participants | 15 | 14 | 13 | 12 | 21 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [h*nanomole/mL (h*nmol/mL)] |
9700
(57.7)
|
8780
(32.9)
|
8990
(72.4)
|
5130
(80.6)
|
8890
(43.8)
|
6690
(112)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Low FEC (EPANOVA® and OMACOR®), Intermediate FEC (EPANOVA® and OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.90 | |
| Confidence Interval |
(2-Sided) 90% 0.63 to 1.28 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA® and OMACOR®), Intermediate FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.58 | |
| Confidence Interval |
(2-Sided) 90% 0.39 to 0.85 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA®), Normal FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.75 | |
| Confidence Interval |
(2-Sided) 90% 0.55 to 1.00 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
| Title | Part B: Baseline Corrected Maximum Plasma Drug Concentration (Cmax) for Total EPA Following Administration of EPANOVA® and OMACOR®. |
|---|---|
| Description | Baseline corrected Cmax was measured for total EPA following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI. |
| Time Frame | Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK Analysis Set included all randomised patients who received at least one dose of study treatment in Part B and had at least one post-dose PK measurement without any important protocol deviations. |
| Arm/Group Title | Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) |
|---|---|---|---|---|---|---|
| Arm/Group Description | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). |
| Measure Participants | 15 | 15 | 13 | 12 | 22 | 23 |
| Geometric Mean (Geometric Coefficient of Variation) [mcg/mL] |
137
(70.5)
|
71.5
(64.0)
|
116
(53.3)
|
53.9
(70.1)
|
131
(36.2)
|
69.3
(76.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Low FEC (EPANOVA® and OMACOR®), Intermediate FEC (EPANOVA® and OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.52 | |
| Confidence Interval |
(2-Sided) 90% 0.37 to 0.73 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA® and OMACOR®), Intermediate FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.46 | |
| Confidence Interval |
(2-Sided) 90% 0.32 to 0.67 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA®), Normal FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.53 | |
| Confidence Interval |
(2-Sided) 90% 0.40 to 0.70 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
| Title | Part B: Baseline Corrected Cmax for Total DHA Following Administration of EPANOVA® and OMACOR®. |
|---|---|
| Description | Baseline corrected Cmax was measured for total DHA following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI. |
| Time Frame | Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK Analysis Set included all randomised patients who received at least one dose of study treatment in Part B and had at least one post-dose PK measurement without any protocol deviations. |
| Arm/Group Title | Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) |
|---|---|---|---|---|---|---|
| Arm/Group Description | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). |
| Measure Participants | 15 | 15 | 13 | 12 | 22 | 23 |
| Geometric Mean (Geometric Coefficient of Variation) [mcg/mL] |
59.0
(58.6)
|
60.5
(47.3)
|
56.0
(40.6)
|
51.0
(52.0)
|
53.8
(41.8)
|
59.7
(53.9)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Low FEC (EPANOVA® and OMACOR®), Intermediate FEC (EPANOVA® and OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of least-squares LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 1.02 | |
| Confidence Interval |
(2-Sided) 90% 0.77 to 1.36 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA® and OMACOR®), Intermediate FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS mean Ratio |
| Estimated Value | 0.92 | |
| Confidence Interval |
(2-Sided) 90% 0.67 to 1.25 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA®), Normal FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 1.11 | |
| Confidence Interval |
(2-Sided) 90% 0.88 to 1.40 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
| Title | Part B: Baseline Corrected Cmax for Total EPA+DHA Following Administration of EPANOVA® and OMACOR®. |
|---|---|
| Description | Baseline corrected Cmax was measured for the sum of EPA and DHA (total EPA+DHA) following administration of single oral doses of EPANOVA® 4 g (A) and OMACOR® 4 g (B) (2-way crossover design) to patients with T2DM and different degrees of PEI. |
| Time Frame | Blood samples for analysis were taken at 1, 0.5, and 0.05 hours pre-dose, to be used as baseline, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 24 and 48 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK Analysis Set included all randomised patients who received at least one dose of study treatment in Part B and had at least one post-dose PK measurement without any protocol deviations. |
| Arm/Group Title | Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) |
|---|---|---|---|---|---|---|
| Arm/Group Description | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with low FEC, <100 mcg/g were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with intermediate FEC, ≥ 100 to <200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). | In Part B, study treatment was administered at Visit 4 (Day 21+5) and Visit 7 (10 to 14 days after Visit 4) with a randomised crossover design. Patients with normal FEC, ≥ 200 mcg/g, were randomised in Part B to a treatment sequence: AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). |
| Measure Participants | 15 | 15 | 13 | 12 | 22 | 23 |
| Geometric Mean (Geometric Coefficient of Variation) [nmol/mL] |
622
(69.7)
|
421
(54.0)
|
553
(47.0)
|
328
(57.2)
|
592
(36.6)
|
413
(61.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Low FEC (EPANOVA® and OMACOR®), Intermediate FEC (EPANOVA® and OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean |
| Estimated Value | 0.68 | |
| Confidence Interval |
(2-Sided) 90% 0.49 to 0.92 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA® and OMACOR®), Intermediate FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.60 | |
| Confidence Interval |
(2-Sided) 90% 0.42 to 0.84 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Normal FEC (EPANOVA®), Normal FEC (OMACOR®) |
|---|---|---|
| Comments | Back transformed results are based on the analysis of natural log-transformed data with a Linear Mixed Model containing the terms of FEC classification, treatment, FEC x treatment, sequence, and period as fixed effects and patient nested within sequence as random effect. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The exposure of a single dose of EPANOVA® 4 g (reference) relative to OMACOR® 4 g (test) was estimated by degree of pancreatic exocrine function using level of FEC. Natural log estimates of LSmeans for each treatment and differences of the LSmeans (OMACOR®-EPANOVA®) along with 90% CIs by degree of pancreatic exocrine function using level of FEC were exponentiated. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | GLS Mean Ratio |
| Estimated Value | 0.70 | |
| Confidence Interval |
(2-Sided) 90% 0.54 to 0.90 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | OMACOR®/EPANOVA® | |
Adverse Events
| Time Frame | All adverse events (AEs) were collected until the safety follow-up contact (Visit 10). Serious AEs were collected from Visit 1 (screening) onwards over a period of up to 13 weeks. Other AEs were recorded from Visit 2 over a period of 7 weeks. | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Regular investigator assessment at study sites. Population used was the Safety Analysis Set which included all patients who received at least 1 dose of study treatment in Part B. | |||||||||||
| Arm/Group Title | Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) | ||||||
| Arm/Group Description | Patients had low levels (<100 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. AEs with an onset date on or after the date of administration of EPANOVA® 4 g at Visit 4 were reported for this group. | Patients had low levels (<100 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. AEs with an onset date on or after the date of administration of OMACOR® 4 g at Visit 4 were reported for this group. | Patients had intermediate levels (≥100 to <200 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. AEs with an onset date on or after the date of administration of EPANOVA® 4 g at Visit 4 were reported for this group. | Patients had intermediate levels (≥100 to <200 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. AEs with an onset date on or after the date of administration of OMACOR® 4 g at Visit 4 were reported for this group. | Patients had normal levels (≥200 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. AEs with an onset date on or after the date of administration of EPANOVA® 4 g at Visit 4 were reported for this group. | Patients had normal levels (≥200 mcg/g) of FEC, as determined by the average of the FEC from 2 stool samples collected between Visit 2 and Visit 3 as a measure of pancreatic exocrine function. AEs with an onset date on or after the date of administration of OMACOR® 4 g at Visit 4 were reported for this group. | ||||||
All Cause Mortality |
||||||||||||
| Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||||
Serious Adverse Events |
||||||||||||
| Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/15 (0%) | 0/15 (0%) | 0/13 (0%) | 1/12 (8.3%) | 0/23 (0%) | 0/23 (0%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Rotator cuff syndrome | 0/15 (0%) | 0 | 0/15 (0%) | 0 | 0/13 (0%) | 0 | 1/12 (8.3%) | 1 | 0/23 (0%) | 0 | 0/23 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||||||
| Low FEC (EPANOVA®) | Low FEC (OMACOR®) | Intermediate FEC (EPANOVA®) | Intermediate FEC (OMACOR®) | Normal FEC (EPANOVA®) | Normal FEC (OMACOR®) | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/15 (6.7%) | 1/15 (6.7%) | 0/13 (0%) | 0/12 (0%) | 5/23 (21.7%) | 1/23 (4.3%) | ||||||
| Ear and labyrinth disorders | ||||||||||||
| Vertigo | 0/15 (0%) | 0 | 0/15 (0%) | 0 | 0/13 (0%) | 0 | 0/12 (0%) | 0 | 1/23 (4.3%) | 1 | 0/23 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||
| Nausea | 1/15 (6.7%) | 1 | 0/15 (0%) | 0 | 0/13 (0%) | 0 | 0/12 (0%) | 0 | 1/23 (4.3%) | 1 | 0/23 (0%) | 0 |
| Abdominal Pain | 0/15 (0%) | 0 | 0/15 (0%) | 0 | 0/13 (0%) | 0 | 0/12 (0%) | 0 | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 |
| Dry Mouth | 0/15 (0%) | 0 | 0/15 (0%) | 0 | 0/13 (0%) | 0 | 0/12 (0%) | 0 | 1/23 (4.3%) | 1 | 0/23 (0%) | 0 |
| Flatulence | 0/15 (0%) | 0 | 0/15 (0%) | 0 | 0/13 (0%) | 0 | 0/12 (0%) | 0 | 1/23 (4.3%) | 1 | 0/23 (0%) | 0 |
| General disorders | ||||||||||||
| Fatigue | 0/15 (0%) | 0 | 0/15 (0%) | 0 | 0/13 (0%) | 0 | 0/12 (0%) | 0 | 2/23 (8.7%) | 2 | 0/23 (0%) | 0 |
| Infections and infestations | ||||||||||||
| Nasopharyngitis | 1/15 (6.7%) | 1 | 0/15 (0%) | 0 | 0/13 (0%) | 0 | 0/12 (0%) | 0 | 0/23 (0%) | 0 | 0/23 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||
| Traumatic Ulcer | 0/15 (0%) | 0 | 1/15 (6.7%) | 1 | 0/13 (0%) | 0 | 0/12 (0%) | 0 | 0/23 (0%) | 0 | 0/23 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Each Principal Investigator has signed a Confidential Disclosure Agreement which does not allow them to disclose any study related information for 10 years unless it is publically available.
Results Point of Contact
| Name/Title | Stefan Carlsson |
|---|---|
| Organization | AstraZeneca AB |
| Phone | |
| Stefan.C.Carlsson@astrazeneca.com |
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02370537
Other Study ID Numbers:
- D5881C00006
- 2014-003511-11
First Posted:
Feb 25, 2015
Last Update Posted:
Jan 20, 2017
Last Verified:
Nov 1, 2016