WO2016073335A1

WO2016073335A1 - Methods of treatment

Info

Publication number: WO2016073335A1
Application number: PCT/US2015/058574
Authority: WO
Inventors: Karl Erik Goeran GANNEDAHL; Jan Peter Mikael OSCARSSON; Robert Eugene WARD
Original assignee: Omthera Pharmaceuticals Inc.
Priority date: 2014-11-05
Filing date: 2015-11-02
Publication date: 2016-05-12

Abstract

A method for treating patients with pancreatic exocrine insufficiency and suitable compositions for carrying out the method are claimed. method of treating hypertriglyceridemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, b administration of an omega-3 fatty acid composition to said human being, wherein the omega-3 fatty acids in the composition are substantially in free fatty acid form.

Description

METHODS OF TREATMENT

The present invention relates to methods for treating lipid disorders such as hypertriglyceridemia or mixed dyslipidemia in patients with pancreatic exocrine insufficiency, including patients who also have Type II diabetes. The methods comprise administration of an effective amount of an omega-3 fatty acid composition, where the fatty acids are in free fatty acid form, such as in Epanova®.

Pharmaceutical compositions rich in omega-3 polyunsaturated fatty acids have been developed to treat a variety of clinical indications, including various disorders of blood lipids, including hypertriglyceridemia and mixed dyslipidemia.

Omega-3 (OM3) fatty acids are generally naturally derived mixtures from sources such as fish, which may then be subject to further processing, and will often be present in conjunction with other fatty acids such as omega-6 fatty acids. The exact composition of the fatty acid mixture may depend on the source of the acids and the extent and nature of the further processing. Typically, such mixtures are rich in eicosapentaenoic acid (C20:5 n- 3) ("EPA," also known as timnodonic acid), Docosahexaenoic acid (C22:6 n-3) ("DHA," also known as cervonic acid) and/or docosapentaenoic acid (C22:5 n-3) ("DP A," also known as clupanodonic acid) may typically also be present in some proportion.

Several prescription omega-3 products have been approved for human use, for example the Food and Drug Administration (FDA) -approved omega-3 ethyl ester drugs. The US FDA first approved an omega-3 fatty acid ethyl ester mixture (Lovaza®, omega-3 - acid ethyl esters, GlaxoSmithKline, Research Triangle Park, NC) as a dietary adjunct to reduce TG levels in adults with very high (>500 mg/dL) TG levels in 2004. The active ingredient of Lovaza® comprises fatty acid ethyl esters (EEs), predominantly EPA-EE (approximately 465 mg / lg capsule) and DHA-EE (approximately 375 mg / lg capsule). Lovaza® has a recommended dose of 4 g/day.

More recently, a generic equivalent to Lovaza® by Teva Pharmaceuticals (Petah Tikva, Central District) as well as drugs with a similar EE mixture such as Omtryg® (omega-3-acid ethyl esters A, Trygg Pharmaceuticals, Oslo, Norway), have also been granted marketing authorization in various countries. Other trademarks may also be used for some of these products in various countries. Reference herein to a "bio-equivalent version" of a composition is intended to refer to a version of the composition which has, or could be, granted marketing authorization by a regulatory body on the basis of being bio-equivalent to the composition.

Vascepa® (icosapent ethyl, Amarin Pharma Inc., Bedminster, NJ), comprises purified EPA-EE and has a recommended dose of 4g /day.

Epanova® (USAN omega-3 carboxylic acids) was approved by the FDA in May 2014 as 2g or 4g dose as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (>500mg/dL) hypertriglyceridemia and comprises a mixture of free fatty acids (FFA), with EPA-FFA and DHA-FFA as the most abundant omega-3 species; the active ingredient is encapsulated in a soft gelatin capsule coated with polyacrylate material. The manufacturing of this free fatty acid product requires an additional step compared with that of the available OM3-EE drugs. This consists of the hydrolysis and distillation of the EE to produce the omega-3 free fatty acids.

The Epanova® composition contains EPA and DHA in concentrations of approximately 50-60 wt% of fatty acids and 15-25 wt% of fatty acids, respectively.

Epanova® contains approximately 75 wt% EPA + DHA per 1 gram capsule and is a complex mixture comprising a plurality of species of omega-3 -FAs and a plurality of species of omega-6 -FAs, each present substantially in free acid form. One of these other omega-3 FA species is DPA which is present in about 1-8 wt% fatty acids. Examples of the free fatty acid compositions used for Epanova® are described in WO2013/103902, such as in Example 7 therein, and such as Table 10 therein, which is reproduced for convenience as Table 1 below.

Table 1

Final (free acid) API Batches

Batch Batch Batch Batch Batch Batch Batch Batch Batch Batch 1 2 3 4 5 6 7 8 9 10

API Batch 36355 36395 37225 37289 38151 38154 38157 38300 38303 38306

#

Intermediate 1 1 2 3 4 4 5 7 8 6 Batch #

Identity Common area area area area area area area area area area name % % % % % % % % % %

C18:2(n-6) Linoleic acid 0.55 0.49 0.59 0.55 0.60 0.61 0.78 0.62 0.53 0.72

C18:3(n-6) Gamma- 0.15 0.14 0.12 0.12 0.17 0.16 0.16 0.22 0.15 0.15 linolenic acid

C18:3(n-3) a-Linolenic 0.39 0.34 0.38 0.37 0.45 0.45 0.55 0.41 0.44 0.50 acid

C18:4(n-3) Moroctic acid 1.70 1.67 1.16 1.26 1.37 1.37 1.87 1.65 1.77 1.81

C20:2(n-6) Eicosadienoic 0.10 0.13 0.12 0.09 0.10 0.10 0.27 0.12 0.11 0.12 acid

C20:3(n-6) Dihomo- 0.35 0.39 0.45 0.42 0.42 0.45 0.52 0.51 0.42 0.51 gamma- linolenic acid

C20:4(n-6) Arachidonic 2.43 2.45 2.84 2.86 3.50 3.50 3.64 4.02 2.57 3.60 acid

C20:3(n-3) Eicosatrienoic 0.15 0.25 0.22 0.16 0.20 0.17 0.25 0.18 0.17 0.23 acid

C20:4(n-3) Eicosatetrae- 2.18 2.02 2.11 2.09 1.96 1.90 2.64 2.13 2.34 2.54 noic acid

C20:5(n-3) EPA 57.25 57.64 55.81 57.08 56.25 56.38 56.88 56.30 56.72 57.15

C21:5(n-3) Heneicosape- 2.79 2.75 2.72 2.78 2.68 2.60 2.15 2.57 2.88 2.18 ntaenoic acid

C22:5(n-6) Docosapenta- 0.20 0.17 0.72 0.71 0.61 0.62 0.66 0.63 0.71 0.66 enoic acid

C22:5(n-3) DPA 6.23 6.22 5.46 5.49 6.12 5.97 3.41 5.15 5.59 3.43

C22:6(n-3) DHA 19.58 19.65 19.45 20.00 19.16 18.79 20.60 20.10 20.97 21.01

Another omega-3 fatty acid composition, MAT9001, is under development by Matinas BioPharma Inc. This was described in a poster at the 2015 NLA Scientific

Sessions, June 11^th to June 14^th 2015, Chicago, as containing predominantly DPA and EPA. The same company has filed a number of patent applications, including

WO2013/192109. A challenge in designing an optimal composition of PUFAs is variation in bioavailability of orally administered PUFA compositions. Absorption of PUFAs in the form of ethyl esters is known, for example, to depend on the presence of pancreatic lipase, which is released in response to ingested fats. Absorption of PUFA ethyl esters is therefore inefficient, and is subject to substantial variation, both among subjects and in any individual subject, depending on dietary intake of fat. See Lawson et al., "Human absorption of fish oil fatty acids as triacylglycerols, free acids, or ethyl esters," Biochem Biophys Res Commun. 152:328-35 (1988); Lawson et al., Biochem Biophys Res Commun. 156:960-3 (1988). Absorption is particularly reduced in subjects on low-fat diets, a diet advocated for subjects with elevated serum triglyceride levels or cardiovascular disease.

Pancreatic Exocrine Insufficiency, PEI, can be defined as a reduction in pancreatic enzyme activity in intestinal lumen to a level below the threshold required to maintain normal digestion. It is an important cause of maldigestion and a major complication in chronic pancreatitis (Lundkvist, World journal of Gastroenterology, 2013, 19(42), 7258- 7266). PEI is associated with impaired production and secretion of gastric enzymes such as lipase and amylase and results in an impaired hydrolysis of fatty acids in the natural triglyceride or esterified form. So treatment of blood lipid disorders, such as

hypertriglyceridemia or mixed dyslipidemia, in patients with PEI using omega-3 fatty acid compositions may be particularly effective if the omega-3 fatty acids are administered in free fatty acid form (for example as Epanova®) rather than in ester or triglyceride form (which require lipase in order to be hydrolysed to free fatty acid form for absorption).

Diabetes Mellitus results from a mismatch between the demand and the supply of insulin resulting in increased glucose levels. Long term, and particularly, poorly controlled diabetes leads to a number of complications, for example of the cardiovascular system, some of which can become life threatening. One potential complication is increased triglycerides, such that many diabetic patients have triglyceride levels above recommended guidelines. PEI is more common among patients with Diabetes Mellitus.

Specific preferred embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.

In a first aspect, there is provided a method of treating severe hypertriglyceridemia (TGs > 500 mg/dL) in patients with PEI, by administration of an omega-3 fatty acid composition wherein the omega-3 fatty acids are substantially in free fatty acid form. In another aspect, there is provided a method of treating hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in patients with PEI by administration of an omega-3 fatty acid composition wherein the omega-3 fatty acids are substantially in free fatty acid form.

In one embodiment, the omega-3 fatty acid composition is in the form of an encapsulated oil.

Detailed Description

In particular embodiments, the omega-3 fatty acid composition comprises EPA, substantially in free acid form, DHA, substantially in free acid form and docosapentaenoic acid (DPA) substantially in free acid form. The omega-3 fatty acid composition may comprise EPA in an amount of at least 50 wt% of fatty acids, DHA in an amount of at least 15 wt% of fatty acids and DPA in an amount of at least 1 wt% of fatty acids, wherein each of EPA, DHA and DPA are substantially in free acid form. The omega-3 fatty acid composition may comprise EPA in an amount of about 50 wt% to about 60 wt% of fatty acids, DHA in an amount of about 17 wt% to about 23 wt% of fatty acids and DPA in an amount of about 1 wt% to about 8 wt% of fatty acids, wherein each of EPA, DHA and DPA are substantially in free acid form. In particular embodiments, DPA is present in an amount of at least about 1.5 wt% of fatty acids, such as at least about 2 wt% of fatty acids, such as at least about 2.5 wt% of fatty acids, such as at least about 3 wt% of fatty acids, such as at least about 3.5 wt% of fatty acids, such as at least about 4 wt% of fatty acids, such as at least about 4.5 wt% of fatty acids.

The omega-3 fatty acids in the omega-3 fatty acid composition for use in the present invention are suitably in free fatty acid form. Suitable omega-3 free fatty acid mixtures for use in the present invention are disclosed in WO2013/103902, the contents of which are hereby incorporated by reference in its entirety. In one embodiment of this aspect, the free fatty acid composition is provided as Epanova® or a bio-equivalent version thereof. In another embodiment of this aspect, the free fatty acid composition is provided as Epanova®.

In another embodiment, the omega-3 fatty acid compositions for use in the present invention are in free fatty acid form and are provided as MAT9001.

In the above aspects, the omega-3 fatty acids are described as being substantially in a particular form, it will be understood to mean that the omega-3 fatty acids are at least 70%, such as at least 80%>, such as at least 90%>, such as at least 95%, such as at least 98%> in the specified form.

The omega-3 fatty acid composition may comprise one or more excipients or diluents. For example alpha-tocopherol may be present.

In another aspect, the omega-3 fatty acid composition is usefully packaged in unit dosage forms for oral administration.

In particular embodiments, the dosage form comprising an omega-3 fatty acid composition is a capsule. In certain embodiments, the dosage form is a hard gelatin capsule. In other embodiments, the dosage form is a soft gelatin capsule.

In various embodiments, the capsule comprises Type A gelatin. In certain embodiments, the capsule comprises Type B gelatin. In some embodiments, the capsule comprises both Type A and Type B gelatin. Sources of collagen for the production of either type A or type B gelatin include, but are not limited to, cows, pigs and fish.

In various embodiments, the capsule is a soft gelatin capsule in which at least about 1% (w/w) of the gelatin is Type A gelatin. In certain embodiments, at least about 2% (w/w), 3% (w/w), 4%, (w/w), 5% (w/w), 6% (w/w), 7% (w/w), 8% (w/w), 9% (w/w), or at least about 10%> (w/w) of the gelatin is Type A gelatin. In selected embodiments, at least about 15% (w/w), 20% (w/w), 25% (w/w), 30% (w/w), 35% (w/w), 40% (w/w), 45% (w/w), even at least about 50% (w/w), 55% (w/w), 60% (w/w), 65% (w/w), 70% (w/w), 75% (w/w), 80% (w/w), 85% (w/w), 90% (w/w), 95% or more of the gelatin is Type A gelatin.

In particular embodiments, the gelatin of the capsule consists essentially of type A gelatin.

In particular embodiments, the Type A gelatin is porcine Type A gelatin.

In some embodiments, the capsule is a reduced cross-linked gelatin capsule, such as those described in U.S. Pat. No. 7,485,323, incorporated herein by reference in its entirety. In a variety of embodiments, capsules are made from substances that are not animal byproducts, such as alginate, agar-agar, carrageenan, pectin, konjak, guar gum, food starch, modified corn starch, potato starch, and tapioca. Non-animal sources of materials that can be used to make capsules are described in U.S. Patent Publication No. 2011/0117180, incorporated herein by reference in its entirety. In some embodiments, Vegicaps® Capsules (Catalent) are used. In some embodiment the capsule can be a combination of non-animal product such as alginate and type A or B gelatin.

In certain embodiments, the capsule comprises a chemically-modified gelatin. In various embodiments, the chemically-modified gelatin is a succinylated gelatin.

In certain capsular oral unit dosage form embodiments, the capsule is uncoated. In a variety of embodiments, the capsule is coated.

In certain coated capsule embodiments, the capsule is coated with a coating on the exterior of the capsule that causes the encapsulated pharmaceutical composition to be released in a time-dependent manner. In various embodiments, release of the

pharmaceutical composition is delayed for at least 15 minutes after ingestion. In particular embodiments, release of the pharmaceutical composition is delayed for at least 30 minutes after ingestion. In other embodiments, release of the fatty acid composition is delayed for about 30 minutes - about 60 minutes after ingestion. In various coated embodiments, the coating is selected from cellulose acetate trimellitate, cellulose acetate phthalate and poly(ethylacrylate-methylacrylate). In some embodiments, such as in Epanova®, the coating is a neutral polyacrylate such as poly(ethylacrylatemethylmethacrylate), such as Eudragit NE 30-D (Evonik Industries AG), which has an average molecular weight of about 800,000.

In certain embodiments, capsules are coated as described in U.S. Pat. Nos.

5,792,795 and 5,948,818, the disclosures of which are incorporated herein by reference in its entirety. In certain embodiments, such as Epanova®, the dosage form is a coated soft gelatin capsule comprising porcine type A gelatin, as described in U.S. Patent No.

7,960,370, incorporated herein by reference in its entirety.

In various embodiments, the oral unit dosage form contains from about 100 mg to about 2000 mg of the pharmaceutical composition described herein. In some embodiments, the oral dosage form contains about 250 mg of the pharmaceutical composition. In some embodiments, the oral dosage form contains about 500 mg of the pharmaceutical composition. In certain embodiments, the oral dosage form contains about 750 mg of the pharmaceutical composition. In some embodiments, the oral dosage form contains about 1000 mg of the pharmaceutical composition. In other embodiments, the oral dosage form contains about 1500 mg of the pharmaceutical composition. In certain embodiments, the unit dosage form contains nonintegral weight amounts of pharmaceutical composition, typically between 100 mg and 2000 mg.

In some embodiments, the dosage form encapsulates PUFAs in an amount of about 50 mg to about 2000 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg.

In various embodiments, the pharmaceutical composition present in the unit dosage form is stable at room temperature (about 23 °C to 27 °C, or about 25 °C) and about 60% relative humidity for a period of at least six months, at least one year, or at least two years.

The omega-3 fatty acid composition is conveniently administered as a capsule, preferably a coated capsule as hereinbefore described. In certain embodiments, at least about 2g of the omega-3 fatty acid composition is administered per day. In some embodiments, at least about 3g of the omega-3 fatty acid composition is administered per day. In certain embodiments, at least about 4g of the omega-3 fatty acid composition is administered per day. In certain embodiments, at least about lg of the omega-3 fatty acid composition is administered per day. Typically, the omega-3 fatty acid composition is administered as a plurality of unit dosage forms, such as those described above. Thus, in certain embodiments, at least 2 unit dosage forms, each comprising lg of the omega-3 fatty acid composition, are administered per day. In various embodiments, at least 3 unit dosage forms, each comprising lg of omega-3 fatty acid composition, are administered per day. In particular embodiments, at least 4 unit dosage forms, each comprising lg of the omega- 3 fatty acid composition are administered per day. In one aspect, in the above

embodiments, the omega-3 fatty acid composition is provided as Epanova®.

In another aspect, a plurality of unit dosage forms as above-described may usefully be packaged together in a dosage kit to increase ease of use and patient compliance.

In certain embodiments, the dosage kit is a bottle. In other embodiments, the plurality of dosage forms is packaged in blister packs, a plurality of which blister packs may optionally be packaged together in a box or other enclosure. Typically, whether in a bottle or one or more blister packs, the plurality of unit dosage forms is sufficient for 30 days, 60 days, or 90 days of dosing. Thus, in selected embodiments, in which the unit dosage form is a capsule that encapsulates approximately one gram of the pharmaceutical composition as described herein above, the dosage kit comprises 30, 60, 90, 120, 150, 180, 240, 270, 300, 330 or 360 such capsules. In various embodiments, the plurality of unit dosage forms is packaged under an inert gas, such as nitrogen or a noble gas, or is packaged under vacuum.

In one aspect there is provided an omega-3 free fatty acid composition, wherein the omega-3 free fatty acids are substantially in free fatty acid form, for use as a medicament for the treatment of severe (TG >500mg/dL) hypertriglyceridemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided Epanova®, or a bio -equivalent version thereof, for use as a medicament for the treatment of severe (TG >500mg/dL) hypertriglyceridemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided Epanova® for use as a medicament for the treatment of severe (TG >500mg/dL) hypertriglyceridemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In one aspect there is provided an omega-3 free fatty acid composition, wherein the omega-3 free fatty acids are substantially in free fatty acid form, for use as a medicament for the treatment of hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided Epanova®, or a bio -equivalent version thereof, for use as a medicament for the treatment of hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided Epanova®, for use as a medicament for the treatment of hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In one aspect there is provided an omega-3 free fatty acid composition, wherein the omega-3 free fatty acids are substantially in free fatty acid form, for use as a medicament for the treatment of mixed dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided Epanova®, or a bio-equivalent version thereof, for use as a medicament for the treatment of mixed dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided Epanova®, for use as a medicament for the treatment of mixed dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In one aspect, there is provided a method of treating severe hypertriglyceridemia (TGs > 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of an omega-3 fatty acid composition to said human being, wherein the omega-3 fatty acids are substantially in free fatty acid form.

In another aspect, there is provided a method of treating severe

hypertriglyceridemia (TGs > 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of Epanova®, or a bio- equivalent version thereof to said human being.

In another aspect, there is provided a method of treating severe

hypertriglyceridemia (TGs > 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of Epanova® to said human being.

In one aspect, there is provided a method of treating hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of an omega-3 fatty acid composition to said human being, wherein the omega-3 fatty acids are substantially in free fatty acid form. In another aspect, there is provided a method of treating hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of Epanova®, or a bio-equivalent version thereof to said human being.

In another aspect, there is provided a method of treating hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of Epanova® to said human being.

In one aspect, there is provided a method of treating mixed dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of an omega-3 fatty acid composition to said human being, wherein the omega-3 fatty acids are substantially in free fatty acid form.

In another aspect, there is provided a method of treating mixed dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of Epanova®, or a bio-equivalent version thereof to said human being.

In another aspect, there is provided a method of treating mixed dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of Epanova® to said human being.

In one aspect, there is provided the use of an omega-3 fatty acid composition, wherein the omega-3 fatty acids are substantially in free fatty acid form, in the

manufacture of a medicament for the treatment of severe hypertriglyceridemia (TGs > 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided the use of Epanova®, or a bio-equivalent version thereof, in the manufacture of a medicament for the treatment of severe

hypertriglyceridemia (TGs > 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided the use of Epanova® in the manufacture of a medicament for the treatment of severe hypertriglyceridemia (TGs > 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

manufacture of a medicament for the treatment of hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided the use of Epanova®, or a bio-equivalent version thereof, in the manufacture of a medicament for the treatment of

hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided the use of Epanova® in the manufacture of a medicament for the treatment of hypertriglyceridemia (TG = 200 mg/dL - 500 mg/dL) in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

manufacture of a medicament for the treatment of mixed dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided the use of Epanova®, or a bio-equivalent version thereof, in the manufacture of a medicament for the treatment of mixed

dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided the use of Epanova® in the manufacture of a medicament for the treatment of mixed dyslipidemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In one aspect, the humans to be treated with the above omega-3 fatty acid compositions have also been diagnosed as suffering from Type II diabetes. In another aspect, the humans to be treated with the above compositions have not been diagnosed as suffering from Type II diabetes. In a further aspect, the humans to be treated with the above combinations are those that do not exhibit symptoms of diabetes and have a plasma glucose level below 11.1 mmol/L, have a fasting plasma glucose level below 7 mmol/L; or have a two-hour plasma glucose level of below 11.1 mmol/L during an oral glucose tolerance test.

In one aspect, the humans to be treated with the above omega-3 fatty acid compositions also have non-alcoholic fatty liver disease (NAFLD) as well as PEL In another aspect the humans to be treated with the above omega-3 fatty acid compositions do not also have non-alcoholic fatty liver disease (NAFLD). In one aspect, the humans to be treated with the above omega-3 fatty acid compositions also have non-alcoholic steato- hepatitis (NASH). In another aspect the humans to be treated with the above omega-3 fatty acid compositions do not also have non-alcoholic steato-hepatitis (NASH). In a further aspect, the humans to be treated treated with the above omega-3 fatty acid compositions have not been diagnosed with NAFLD or NASH.

In the above aspects (compositions, uses and methods) conveniently the omega-3 fatty acid composition is in the form of an oil and is formulated in one or more capsules, such as hard or soft gelatin capsules as described hereinbefore, and at a dosage level known in the art, for example, about 1 to 4 g, particularly 2 to 4g, of omega-3 fatty acid composition. Conveniently, the omega-3 fatty acid composition is formulated into capsules each of which contain approximately one gram of active ingredient, so that multiple capsules are administered to obtain the required dose.

The validation and increased use of faecal elastase-1 (FE-1) concentration (FEC) measured by pancreatic elastase-1 tests have allowed recent studies in larger populations to investigate the prevalence of pancreatic exocrine insufficiency (PEI). Faecal elastase-1 is a very stable protein secreted from the exocrine pancreas and found intact in faeces. The FE- 1 test has a high predictive value and high sensitivity for PEI. A good correlation has been observed between FEC mass and duodenal lipase (r=0.84; p<0.001), amylase, trypsin, volume and bicarbonate output. It has been suggested that a FEC value of <100 μg/g or <200 μg/g is a sign of PEI. Therefore, reference herein to "a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency" may be understood to mean a human who has been thus diagnosed on the basis of a test such as the FEC test described above and further described in the Examples and References herein. In one aspect a human being is described as being diagnosed with PEI if their FEC value is <100 μ^. In another aspect a human being is described as being diagnosed with PEI if their FEC value is <200 μ^.

Further diagnostic tests are described in Lindqvist et al (World Journal of

Gastroenterology, 19 (42), 2013, p7260) and include:

• Clinical symptoms including foul smelling and loose stools, weight loss, muscle wasting, flatulence and steatorrhea

• Malnutrition (PEI essentially precluded if the patient presents with a normal panel of serum nutritional values) • Pancreatic imaging (eg endoscopic ultrasound)

• Fecal fat quantification

13

• C mixed triglyceride breath test, which measures degradation of triglycerides

• Direct pancreatic function tests.

Existing treatments for PEI are known, for example pancreatic enzyme replacement therapy. The methods contemplated herein may be in addition such existing treatments.

As stated above, humans suffering from PEI are expected to have lower serum levels of omega-3 fatty acids because the condition makes it more difficult to absorb dietary fatty acids. Increasing plasma levels of EPA and DHA is a potential treatment goal independently of the resultant effect on plasma triglycerides. The PRECISE study described in the Examples hereinafter is designed to any beneficial effect of Epanova® over Lovaza® in increasing plasma EPA and DHA. Specifically, it is designed to define a threshold elastase level at which the uptake of DHA and EPA is 2-fold better after dosing with Epanova® compared to dosing with Lovaza®. Suitably, plasma levels of EPA and/or DHA are measured as area under a curve of plasma concentration over time, such as over 48 hours.

It will be understood by the skilled person that plasma levels of any specific omega-3 free fatty acid may only be raised if they are present in significant quantities in the omega-3 composition which is administered to the humans. Therefore, the aspects of the invention relating to raising of plasma EPA and/or DHA will be understood to refer only to raising of EPA if the omega-3 composition is MAT9001, which is understood to contain minimal DHA.

In one aspect there is provided an omega-3 free fatty acid composition, wherein the omega-3 free fatty acids are substantially in free fatty acid form, for use as a medicament for raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided Epanova®, or a bio -equivalent version thereof, for use as a medicament for raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency. In another aspect, there is provided Epanova® for use as a medicament for raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In the above uses, suitably a human being has been diagnosed as suffering form pancreatic exocrine insufficiency on the basis of testing their fecal elastase 1 levels.

Therefore, in another aspect, there is provided Epanova® for use as a medicament for raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency with a measured FEC level of <200 μ^, such as <180 μg/g, such as <160 μ^, such as <140 μ^, such as <120 μg/g, such as <100 μg/g, such as <80 μ^.

In one aspect, there is provided a method of raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of an omega-3 fatty acid composition to said human being, wherein the omega-3 fatty acids are substantially in free fatty acid form.

In another aspect, there is provided a method of raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of Epanova®, or a bio-equivalent version thereof to said human being.

In another aspect, there is provided a method of raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of Epanova® to said human being.

Therefore, in another aspect, there is provided a method of raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency with a measured FEC level of <200 μ^, such as < 180 μg/g, such as < 160 μ^, such as < 140 μ^, such as < 120 μ^, such as < 100 μ^, such as <80 μ^, by administration of Epanova® to said human being.

manufacture of a medicament for raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency. In another aspect, there is provided the use of Epanova®, or a bio-equivalent version thereof, in the manufacture of a medicament for raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

In another aspect, there is provided the use of Epanova® in the manufacture of a medicament for raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency.

Therefore in another aspect, there is provided the use of Epanova® in the manufacture of a medicament for raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency with a measured FEC level of <200 μ^, such as <180 μ^, such as <160 μ^, such as <140 μ^, such as <120 μg/g, such as <100 μ^, such as <80 μ^.

Reference herein to a "bio-equivalent version" of a composition is intended to refer to a version of the composition which has, or could be, granted marketing authorization by a regulatory body on the basis of being bio-equivalent (ie having the same biological effect) to the composition.

Example

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

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

The following abbreviations and special terms are used in this Clinical Study Protocol

(CSP):

Abbreviation or special term Explanation

AE Adverse event

ALT Alanine transaminase

AST Aspartate transaminase AUC Area under plasma concentration-time curve from zero to infinity

AUCO-t Area under plasma concentration-time curve from time 0 to the last measurable concentration

CI Confidence interval

Cmax Maximum plasma drug concentration

CSA Clinical Study Agreement

CSP Clinical Study Protocol

CSR Clinical Study Report

CV Coefficient of variation

DMP Data Management Plan

DHA Docosahexaenoic acid

DPA Docosapentaenoic acid

EC Ethics Committee, synonymous to Institutional

Review Board (IRB) and Independent Ethics Committee (IEC)

eCRF Electronic case report form

EE Ethyl ester

EPA Eicosapentaenoic acid

FAS Full analysis set

FE-1 Faecal elastase-1

FEC Faecal elastase-1 concentration

FFA Free fatty acid

GCP Good Clinical Practice

GLP-1 Glucagon-like peptide- 1

GI Gastrointestinal

GMP Good Manufacturing Practice

GSRS Gastrointestinal Symptom Rating Scale

HbAlc Glycated haemoglobin

HDL High-density lipoprotein

IB Investigator's Brochure

ICF Informed Consent Form ICH International Conference on Harmonisation International Co-ordinating investigator

If a study is conducted in several countries the International Co-ordinating Investigator is the Investigator co-ordinating the investigators and/or activities internationally.

IP Investigational Product

IVRS Interactive Voice Response System

IWRS Interactive Web Response System

λζ Elimination rate constant

LFT Liver function test

LPLV Last Patient Last Visit

Magnesium Mg2+

MedDRA Medical Dictionary for Regulatory Activities

OAD Oral antidiabetic drug

OM-3 Omega-3

OM-3 EE Omega-3 fatty acid ethyl esters

OM-3 FFA Omega-3 free fatty acids

PEI Pancreatic exocrine insufficiency

PI Principal Investigator

PK Pharmacokinetic

PRECISE The current study: 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 EP AN OVA® and OMACOR®

following a single oral dose in patients with different degrees of PEI

PRO Patient-Reported Outcome

SAE Serious adverse event

SD Standard deviation

tl/2 Terminal half-life

T2DM Type 2 diabetes mellitus

TG Triglyceride

TLC Therapeutic Lifestyle Changes

tmax Time of maximum concentration ULN Upper limit of normal

WBDC Web-Based Data Capture

STUDY DRUG (Epanova®) - Type A porcine soft gelatin capsules are prepared, each containing one gram (lg) of a PUFA composition comprising omega-3 PUFAs in free acid form. The capsules are coated with Eudragit NE 30-D (Evonik Industries AG).

This open-label, 2-part, non-therapeutic pharmacokinetic (PK) study has been designed to investigate the presence of PEI in patients with T2DM, using the FE-1 test as an indirect measure of exocrine pancreatic function. The study will also investigate PK variables of DHA and EPA from EPANOVA® and OMACOR® following a single oral dose in 3 groups of T2DM patients with different degrees of PEI (Normal, Intermediate, and Low FEC). The recruitment part of the study (Part A) will allow a better understanding of how fasting plasma TG levels are related to different degrees of PEI, as determined by FEC. Moreover, lipid-soluble vitamins (Vitamin D and Vitamin K) as well as DHA and EPA will be measured in the patients as PEI might result in lower levels as a consequence of reduced lipase activity.

Plasma levels of magnesium (Mg2+), retinol-binding protein, prealbumin and albumin will also be measured as these analytes have been associated with PEI in patients with chronic pancreatitis (Lindkvist et al 2012).

Part B is a single dose, 2-way cross-over, open-label design to investigate the PK of EPANOVA® and OMACOR® measured as total plasma levels of DHA and EPA. Part B will enable the understanding of the relationship between the degree of PEI and the plasma exposure of EPANOVA® and OMACOR®. The hypothesis is that reduced pancreatic exocrine function, reflected by a Low or Intermediate FEC value, influences OMACOR® bioavailability to a greater extent compared to EPANOVA®. An observed 2-fold difference in bioavailability of the sum of DHA and EPA (DHA+EPA) is considered clinically relevant.

The study will be conducted in Type 2 diabetics (aged 18 to 70 years). The inclusion and exclusion criteria (see Sections 3. land 3.2, respectively) are defined to select Type 2 diabetics who are known to be free from any significant illness. A study population of patients with T2DM is preferred as such patients often have hypertriglyceridaemia and PEI as determined by low FEC. All patients will be instructed to follow the total fat intake recommended by the Therapeutic Lifestyle Changes (TLC) diet, which allows standardisation of a moderate fat intake that is recommended for hypertriglyceridaemia and tolerated in patients with PEL

Blood samples for the determination of total plasma levels of DHA and EPA will be collected up to 48 hours post-dose to obtain accurate estimates of area under plasma concentration time curve from time 0 to the last measurable concentration (AUCo-t) and maximum plasma drug concentration (Cmax) for these analytes.

Study design

This study is a 2-part open-label, randomised, crossover, multicentre, 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.

Part A is an open-label recruitment part of the study to investigate plasma lipids, especially plasma triglycerides (TGs), and FEC levels in Type 2 diabetics, to assess the relationship between plasma TGs and degree of PEI.

A subset of the patients enrolled will be consecutively randomised into Part B of the study.

Part B is a randomised open-label 2-way crossover part of the study to investigate the PK of single doses of EPANOVA® 4 g and OMACOR®4 g in Type 2 diabetics with different

degrees of PEI, as determined by FEC.

Type 2 diabetic patients will be recruited to investigate the importance of different levels of FEC, grouped as:

• Low: FEC <100 μg/g;

• Intermediate: FEC >100 μg/g to <200 μg/g; and

• Normal: FEC >200 μg/g

for plasma TG levels (Part A), as well as to assess plasma exposure of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from EPANOVA® and OMACOR®, respectively, in patients with different levels of FEC (Part B). Following enrolment in Part A (Visit 2), patients will be asked to record their bowel habits and Bristol stool scale daily over a period of 6 to 7 days between Visits 2 and

3. They will also collect samples of their faeces for determination of FEC on 2 occasions between these visits. Blood samples will be taken to assess TG levels, and for analysis of plasma EPA and DHA.

At Visit 3, a Patient-Reported Outcome Gastrointestinal (GI) Symptom Rating Scale form regarding the past one week's GI history will be completed by the patient, in order to understand any possible relationship between GI symptoms and pancreatic exocrine dysfunction, as assessed by measuring FEC.

In Part B, a subset of the patients enrolled will be randomised to receive the crossover sequence AB (a single dose of EPANOVA® 4 g followed by a single dose of OMACOR® 4 g) or sequence BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g). Randomisation will be stratified by FEC classification in Part A. Patients not randomised into Part B will complete the study at Visit 3.

At Visit 4, study drug will be administered 30 minutes after the start of a

Therapeutic Lifestyle Changes diet-based breakfast (25% to 35% energy from fat). The breakfast should be completed in 30 minutes, ie, before study drug administration. The patient will stay at the study site for 10-hour blood sampling for PK. A 24-hour PK sample will be taken at Visit 5, and a 48-hour PK sample will be taken at Visit 6.

The washout period between completion of 48-hour PK sampling and the second administration of study drug (Visit 7) will be a minimum of 10 days, but no longer than 14 days. Visits 7, 8 and 9 will involve the same study procedures and assessments as Visits

4, 5, and 6. Visit 10 will be a telephone call for safety follow-up, which will occur around 5 weeks after enrolment and one week after the second administration of study drug, before study drug administration. The patient will stay at the study site for 10-hour blood sampling for PK. A 24-hour PK sample will be taken at Visit 5, and a 48-hour PK sample will be taken at Visit 6.

Objectives

Primary Objective: Outcome Measure:

Part A:

To describe the distribution of plasma TGs in patients with T2DM by degree of PEI (Normal: FEC >200 μ g/g; Intermediate: FEC >100 μ g/g to <200 μ g/g; and Low: FEC <100 μ g/g)

Part A: Plasma TG levels at end of Part A (Day 7±2 days)

FEC at end of Part A (Day 7±2 days)

Part B:

To evaluate and compare the plasma exposure of DHA and EPA from EPANOVA® and OMACOR®, respectively, in patients with T2DM with different levels of FEC

Part B:

Baseline-corrected area under plasma concentration time curve from time 0 to the last measurable concentration (AUCo-t), area under plasma concentration-time curve from zero to infinity (AUC) and maximum plasma drug concentration (Cmax) of the sum of DHA+EPA, and EPA and DHA separately, during Part B

Safety Objective: Outcome Measure:

To evaluate the safety of EPANOVA® and OMACOR® when administered to patients with T2DM and different degrees of PEL

Vital signs (blood pressure and heart rate)

Adverse events (AEs)/Serious AEs (SAEs)

Exploratory Objectives: Outcome Measures:

Part A:

To assess high-density lipoprotein (HDL) and non-HDL cholesterol in the different levels of FEC

Part A:

Total cholesterol and HDL cholesterol plasma concentrations at end of Part A (Day 7±2 days)

Part A:

To assess plasma levels of Vitamins D and K, total DHA and EPA, and analytes that may correlate to PEI (eg, magnesium [Mg2+], albumin and prealbumin) in relation to plasma TGs and PEI degree (FEC levels) Part A:

Vitamin D, Vitamin K, Mg2+, retinol-binding protein, albumin, prealbumin, total DHA and total EPA concentrations at end of Part A (Day 7±2 days)

Part A:

To understand how GI symptoms including Bristol stool scale relates to FEC values Part A:

GI symptoms and bowel habits Target patient population

The study population will be clinically diagnosed Type 2 diabetics; adult male and female patients on stable oral anti-diabetic therapy (>3 months). Treatment with insulin or injectable glucagon-like peptide- 1 is not allowed. At Visit 1, the patient's glycated haemoglobin value should be 6.5% and <9.0%. The inclusion and exclusion criteria to be assessed at Visit 1 , are based on the more stringent criteria needed for Part B of the study.

Duration of treatment

In Part B, patients will be randomised to receive the crossover sequence AB (a single dose of EPANOVA®4 g followed by a single dose of OMACOR® 4 g) or sequence BA (a single dose of OMACOR® 4 g followed by a single dose of EPANOVA® 4 g).

The washout period between completion of 48-hour PK sampling and the second administration of study drug (Visit 7) will be a minimum of 10 days, but no longer than 14 days.

Investigational product (IP), dosage and mode of administration

Omega-3 carboxylic acids (EPANOVA®), single dose, 4 x 1 g oral capsule.

Omega-3-acid ethyl esters (OMACOR®), single dose, 4 x 1 g oral capsule.

Statistical methods

The analysis of data will be conducted by study part (Part A and Part B) based on different subsets according to the purpose of analysis, ie, Full analysis set (FAS) for Part A or Safety analysis set and PK analysis set in Part B.

In general, continuous variables will be summarised using descriptive statistics (n, mean [geometric mean for PK parameters], standard deviation [SD], minimum [min], median, maximum [max]). Categorical variables will be summarised in frequency tables (frequency and proportion).

Part A

The distribution of plasma TG levels by the degree of PEI will be summarised using descriptive statistics as well as graphical displays.

Plasma levels of cholesterol, HDL, Vitamin D and Vitamin K, Mg2+, albumin, retinol- binding protein and prealbumin will be summarised and graphically displayed by degree of

PEI. In addition, Mg2+, albumin, retinol-binding protein and prealbumin will be plotted against plasma TGs (different symbols will be used for different degree of PEI).

The relationship between GI symptoms and bowel habits will be assessed, as well as their relationship to degree of PEI.

Part B

Global Hypothesis:

While there is no formal hypothesis testing, the global hypothesis of exploratory interest in Part B is:

1. Let μ represent the generic label for the population geometric mean for a particular parameter (eg, AUCEPA+DHA, AUCEPA, AUCDHA, etc).

2. Let the geometric means (of a parameter of interest, eg, AUCEPA+DHA, AUCEPA, AUCDHA, etc) for EPANOVA® and OMACOR® be μ Ep and μ Om, respectively. Then the Global generic Hypothesis on the particular parameter of interest (AUCEPA, for instance) is:

μ Ep μ Ep

HO: = 1; vs Ha : ≠\ .

μ Om μ Om

Main Analysis:

The main analysis of each PK parameter will be carried out on the entire PK analysis set based on a General Linear Mixed Model on log-transformed data; with FEC classification, treatment and period as fixed effects, and measurements within each patient as random effects. Model-based geometric mean-ratios, and 90% confidence intervals (CIs) will be reported. Additionally, relative treatment effects will be estimated between the 3 levels of the stratification factor, using FEC (Low) as the reference, also based on the above Mixed Model.

Other Analyses:

The exposure of a single dose of EPANOVA® 4 g relative to OMACOR® 4 g will be estimated by degree of PEI using general linear models applied to log-transformed data (baseline corrected sum of total EPA+DHA, total EPA and DHA Cmax, AUCo-t, and AUC) with treatment and period as fixed effects, and measurements within each patient as random effects. Point estimates and 90% CIs for differences on the log scale will be exponentiated to obtain estimates for ratios of geometric means on the original scale.

EPANOVA® 4 g will serve as the reference in the comparisons and no adjustments will be made for multiple comparisons.

Pharmacokinetic parameters (both corrected and uncorrected Cmax, time of maximum concentration [tmax], AUCo-t, AUC, elimination rate constant [ λ z], and terminal half-life [ti/2]) on the sum of total EPA+DPA, total EPA and total DHA, will be summarised using descriptive statistics and graphically displayed by treatment and degree of PEI. In addition to the default summary statistics, the coefficient of variation and the standard error of the mean will also be summarised.

All safety data will be summarised by treatment and degree of PEI, and will be presented in data listings.

The validation and increased use of faecal elastase-1 (FE-1) concentration (FEC) measured by pancreatic elastase-1 tests have allowed recent studies in larger populations to investigate the prevalence of pancreatic exocrine insufficiency (PEI). Faecal elastase-1 is a very stable protein secreted from the exocrine pancreas and found intact in faeces. The FE- 1 test has a high predictive value and high sensitivity for PEI. A good correlation has been observed between FEC mass and duodenal lipase (r=0.84; p<0.001), amylase, trypsin, volume and bicarbonate output (Stevens et al 2004). It has been suggested that a FEC value of <100 μg/g or <200 μ g/g is a sign of PEI.

The FEC measurements indicated the presence of PEI in 22.9% (FEC <100 μ^) or 59.3%) (FEC <100 μg/g or FEC <200 μg/g, respectively) in a mixed population of Type 1 and Type 2 diabetics (Hardt et al 2003a). Pancreatic insufficiency was more frequent among Type 1 diabetics and correlated with early onset of disease, long diabetes duration and insulin treatment. However, a correlation between clinical gastrointestinal (GI) symptoms and FEC has not been reported. Therefore, the large majority of patients with FEC <200 μg/g are not expected to have GI problems or malabsorption symptoms.

The gold standard for estimation of PEI is measurement of faecal fat excretion (Lindkvist 2013). In a smaller study of 101 Type 1 and Type 2 diabetics, mean faecal fat excretion was 9.2 g and 59.4% had a fat excretion >7 g/day, which is regarded as abnormal. In 39.6% of the patients, the fat excretion was >10 g/day (Hardt et al 2003b).

In the study of 544 Type 2 diabetic patients and 544 healthy controls, the association between levels of FEC and T2DM was investigated (Rathmann et al 2001). This study is unique for 2 reasons; it is the largest study investigating the prevalence of PEI in T2DM and, moreover, all patients were also investigated with respect to plasma levels of TGs. Non-fasting plasma TG levels were 2.2±1.9 mmol/L (mean±standard deviation [SD]) in the diabetics and 1.6±1.8 mmol/L in the controls. Results showed that FEC was lower in Type 2 diabetics than in controls. Moreover, low FEC levels (<100 μ^) were found in 11.9% of the diabetics, and FEC levels <200 μg/g were found in 30.3% of the diabetics. Therefore, this study indicates that in a population of Type 2 diabetics a substantial proportion will have a disturbed exocrine pancreatic function.

The recruitment part of the current study (Part A) is based on the assumption at least -10% of patients with T2DM will have FEC levels <100 μg/g and 20% of patients with T2DM will have FEC levels of 100 μ g/g to 200 μ^.

Plasma TG levels are often higher than >1.7 mmol/L in Type 2 diabetics.

Therefore, Type 2 diabetics often have hypertriglyceridaemia and require TG-lowering therapy. A large proportion of Type 2 diabetics have reduced FEC levels indicating a reduced exocrine pancreatic function. It is not known if reduced pancreatic exocrine function as determined by FEC is influencing fasting plasma TG levels in Type 2 diabetics.

The study will also investigate how the degree of pancreatic exocrine dysfunction will affect the plasma exposure of EPA and DHA originating from EPANOVA® and OMACOR® (Part B). Inclusion criteria

For inclusion in the study, patients should fulfil the following criteria:

1. Provision of signed and dated written informed consent prior to any study specific procedures.

2. Male or female aged 18 years and <70 years, with suitable veins for cannulation or repeated venipuncture.

3. Clinically diagnosed Type 2 diabetics (American Diabetes Association guidelines; American Diabetes Association 2014), on OAD use 3 months and HbAlc value >6.5% and <9.0% at Visit 1.

4. Have a body mass index 18 kg/rm and <40 kg/rm and weigh at least 50 kg.

5. Be willing to maintain current activity level.

6. For patients on treatment for hypertriglyceridaemia: be willing to stop treatment with fibrates, niacin and OM-3 at Visit 1 and for the duration of the entire study.

7. Be willing to adhere to the total fat intake recommended by the TLC diet during screening and washout periods.

8. Be willing to avoid consuming fish, seafood and fish products from Visit 2 and for the remainder of the study.

Exclusion criteria

Patients should not enter the study if any of the following exclusion criteria are fulfilled:

1. Involvement in the planning and/or conduct of the study (applies to both

AstraZeneca or representative staff and/or staff at the study site).

2. Previous enrolment in the present study.

3. Participation in another clinical study with an investigational product (IP) during the last 28 days.

4. History of, or presence of (as found at Visit 1) any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study.

5. Any clinically significant illness, medical or surgical procedure or trauma within 4 weeks of the first administration of IP. 6. Intolerance to OM-3 fatty acids, EEs or fish.

7. On insulin therapy or treated with injectable GLP-1.

8. Treated with bile acid sequestrants.

9. Use of fish oil, other EPA or DHA-containing supplements, or EPA and/or DHA-fortified foods within 4 weeks of Visit 2, or during the study.

10. Use of flaxseed, perilla seed, hemp, spirulina, or blackcurrant oils within 7 days of Visit 2, and during the remainder of the study.

11. Any clinically significant abnormalities in clinical chemistry, haematology or urinalysis results as judged by the Investigator, found at Visit 1.

12. Plasma levels of TGs >10 mmol/L at any time during the study:

- Plasma levels of TGs will be checked at enrolment (Visit 2). Results should be available prior to any further study-related procedures being performed.

13. Smokers who cannot abstain from smoking during the clinic visits.

14. Recent history (past 12 months) of drug abuse or alcohol abuse, as judged by the Investigator.

15. Women who are pregnant, lactating, or planning to become pregnant during the study period, or women of childbearing potential who are not using acceptable contraceptive methods. A woman is considered of childbearing potential if she is not surgically sterile or is <1 year since last menstrual period.

16. Any other condition the Investigator believes would interfere with the patient's ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the patient at undue risk.

17. Plasma donation within one month of screening or any blood donation/blood loss >500 mL during the 3 months prior to Visit 2 or during the study.

18. Ongoing substitution therapy with pancreatic enzymes.

The following restrictions apply:

1. Patients must eat and drink only the meals and drinks provided during the residential period in the unit and adhere to the specified fasting periods and meal times required in the study.

2. Overnight fasting (>8 hours) should be applied before fasting samples are taken in the morning. 3. Patients must abstain from consuming alcohol from 72 hours before the ward visits (Visits 4 and 7), during the residential period and until the last PK samples have been obtained (Visits 6 and 9).

4. Treatment with statins should not be started during the study. Patients already receiving statin treatment should remain on the same dose of statin(s) for the entire study.

5. If any medication is necessary during the residential period, it should be prescribed by the Investigator and the AstraZeneca or representative Study Team Physician should be informed.

6. Patients must abstain from consuming fish, seafood and fish products from Visit 2 and for the remainder of the study.

7. Patients must abstain from consuming flaxseed, perilla seed, hemp, spirulina and blackcurrant oils from 7 days before the first dose of study drug (Visit 4) until PK sampling has been completed.

Discontinuation of investigational product

Patients may be discontinued from IP in the following situations:

• Patient decision. The patient is at any time free to discontinue treatment, without prejudice to further treatment

• Adverse event

• Severe non-compliance with the study protocol

• Development of any study specific criteria for discontinuation.

Criteria for withdrawal

Reasons for withdrawal from the study include:

1. Significant protocol violation on part of the Investigator or patient

2. Significant noncompliance on the part of the patient as determined by the

Investigator in consultation with the Medical Monitor

3. Patient withdrawal of consent

4. During the study, the patient required medications, supplements, ingredients or herbal therapies that were excluded

5. Occurrence of any AE or condition that could, in the Investigator^'s opinion, interfere with the evaluation of the treatment effect or put the patient at undue risk, eg, plasma TG levels >10 mmol/L.

Screen failures

Screening failures are patients who do not fulfil the eligibility criteria for the study, and therefore must not be enrolled. These patients should have the reason for study withdrawal recorded as 'Incorrect Enrolment' (ie, patient does not meet the required

inclusion/exclusion criteria). This reason for study withdrawal is only valid for screen failures (not randomised patients).

Withdrawal of the informed consent

Patients are free to withdraw from the study at any time (ie, from taking IP and

assessments), without prejudice to further treatment.

A patient who withdraws consent will always be asked about the reason(s) and the presence of any AEs. Any AEs that are unresolved at the patient's last AE assessment in the study will be followed up by the Investigator for as long as medically indicated, but without further recording in the electronic case report form (eCRF).

If a patient withdraws from participation in the study, his/her enrolment/randomisation code cannot be reused. Withdrawn patients will not be replaced.

Discontinuation of the study

Patients not randomised into Part B will complete the study at Visit 3.

The study may be stopped if, in the judgment of AstraZeneca or representative, patients are placed at undue risk because of clinically significant findings that:

• Meet individual stopping criteria or are otherwise considered significant

• Are assessed as causally related to study drug

• Are not considered to be consistent with continuation of the study.

Regardless of the reason for termination, all data available for the patient at the time of discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of treatment must be documented.

In terminating the study, the Sponsor will ensure that adequate consideration is given to the protection of the patients' interests. STUDY PLAN AND TIMING OF PROCEDURES

Enrolment/screening period

Procedures will be performed according to the study plan.

At screening and enrolment, consenting patients will be assessed to ensure that they meet eligibility criteria. Patients who do not meet these criteria must not be enrolled in the study.

Screening (Visit 1)

Study procedures carried out during screening (Visit 1) will include:

• Inclusion/exclusion criteria.

• Demographics.

• Medical/surgical history.

• Physical examination.

• Measurement of height, weight and waist circumference.

• Measurement of blood pressure and heart rate.

• Concomitant medications.

• Blood samples for laboratory screening.

• Urinalysis.

• Blood samples to assess TG levels.

• Blood sample for HbAlc. (HbAlc value at Visit 1 should be 6.5% and

<9.0%, for inclusion in the study.

• Dietary counselling for the TLC diet, including instructions regarding

fish diet restrictions.

Visit 1 2 3 4 5

Enrol Randomise 1 d after visit 4

Part A Part B

Day -7 to 42^b 0 7 ± 2 21 ± 5 22 ± 5

Written informed consent X

Inclusion / exclusion criteria X X

Demographic data X

Medical history X

PRO GSRS form^c X

Physical exam, height, weight, X x (weight

waist circumference¹¹ only)

Vital signs X X

Dietary counselling (TLC)^e inc X X

fish restriction

Adverse events X X X X

Concomitant medications X X X

Bristol stool scale assessments X X

during 1 week

Stool collection kits for FE-1 X

testing provided to patient⁸

Stool collection kits collected X

from patient

Blood samples TG, cholesterol X X X X

Blood samples EPA, DHA^h X X X X

Blood sample PEI, lab screen X X

Blood sample LFTs

Exploratory markers blood X

samples'

Urinalysis X X

Study drug admin^k X Visit 6 7 8 9 10

Id after Ward Id after Id after Safety visit 4 lOh visit 7 visit 8 follow up^a

Part B

Day 23 ±5 26-40* 27 - 41 28 - 42 35 - 49**

Written informed consent

Inclusion / exclusion criteria

Demographic data

Medical history

PRO GSRS form^c

Physical exam, height, weight, x (weight

waist circumference¹¹ only)

Vital signs X

Dietary counselling (TLC)^e

Adverse events X X X X X

Concomitant medications X

Bristol stool scale assessments

during 1 week

Stool collection kits for FE-1

testing provided to patient⁸

Stool collection kits collected

from patient

Blood samples TG, cholesterol X

Blood samples EPA, DHA^h X X X X

Blood sample PEI, lab screen

Blood sample LFTs X X

Exploratory markers

Urinalysis

Study drug admin^k X * Visit 7, minimum lOd and maximum 14d after visit 4

** Visit 10, minimum 5d after visit 9

a - visit 10 will be a telephone call for safety follow up

b - time interval between visit 1 and visit 2 depends on number of days required for washout of TG-lowering therapies. If no washout is required, the interval is -7 days; if washout period is required, the interval is a minimum of -28 days and maximum of -42 days.

c - the PRO GSRS form should be completed by the patient alone, upon arrival at the site, in a private situation

d - height and waist circumference will only be measured at visit 1

e - fibrate, niacin and OM-3 treatment should be stopped 4 weeks before any samples are taken.

f - the patient will be asked to record their bowel habits and Bristol stool scale daily over a period of 6 to 7 days between visits 2 and 3

g - two stool collection kits for FE-1 testing will be used to collect faeces samples on 2 occasions between visits 2 and 3.

h - at visits 2 and 3, single samples for analysis of EPA and DHA in plasma will be taken. At visits 4 and 7, blood samples for analysis of EPA and DHA in plasma will be taken as 3 samples before study drug dose administration at -1, -0.5 and -0.05 hours pre-dose, to be used as baseline, and 9 post-dose samples at 1, 2, 3, 4, 5, 6, 7, 8 and 10 hours after dosing. At visits 5 and 6, one blood sample for analysis of EPA and DHA in plasma will be taken at 24 hours post-dose and 48 hours post-dose, respectively. At visits 8 and 9, one blood samples for analysis of EPA and DHA in plasma will be taken at 24 hours post-dose and 48 hours post-dose, respectively. One blood sample will be taken for each timepoint; the sample will then be split into 2 plasma samples, one primary sample and one back-up sample.

i - blood samples for laboratory screening (Table 3) and HbAlc only from Table 5.

j - one additional blood sample will be collected at visit 2 and stored at a central laboratory for up to 12 monts after study completion, for possible future analysis of exploratory biomarkers. k - study drug will be administered 30 minutes after the start of a TLC diet-based breakfast (25% to 35%) energy from fat). The breakfast should be completed in 30 minutes, ie before study drug administration.

GSRS: gastrointestinal symptom rating scale

LFT : liver function test

HbAlc: glycated haemoglobin

PRO - patient reported outcome

TLC - therapeutic lifestyle changes.

Therapeutic Lifestyle Changes diet

In this study, the dietary counselling for the TLC diet will be mainly to reduce the amount of total dietary fat to 25% to 35%, if necessary. The TLC diet will be used as guidance to achieve this. The dietary counselling in this study is not for weight reduction.

The TLC diet is recommended by various health organisations, including the US National Cholesterol Education Program (NCEP) (NCEP 2002). The TLC diet component emphasises reducing dietary cholesterol (<200 mg/day), saturated fats (<7% of total calories), and trans fats (lower intake). In the TLC diet, total fat comprises 25% to 35% of total calories, with up to 20% coming from monounsaturated fats and 10% from

polyunsaturated fats. The recommended ranges of intake for specific dietary components are listed in Table 2.

Table 2 Nutrient composition of the Therapeutic Lifestyle Changes diet

Nutrient Recommended Intake

Total fat 25% to 35% of total calories

Saturated fatty acids <7% of total calories

Monounsaturated fatty acids Up to 20% of total calories

Polyunsaturated fatty acids Up to 10% of total calories

Carbohydrates 50% to 60% of total calories

Fibre 20 g to 30 g per day

Protein Approximately 15% of total calories

Cholesterol <200 mg per day Total calories Balance energy intake and expenditure to maintain desirable body weight/prevent weight gain or loss.

For this study, patients will be instructed to restrict the intake of fish (particularly fatty fish including salmon, herring, mackerel and tuna), seafood and fish products.

Enrolment (Visit 2)

Study procedures at enrolment (Visit 2) will include:

• Inclusion/exclusion criteria.

• AEs.

• Concomitant medications.

• Blood samples for laboratory screening.

• Urinalysis.

• Blood samples to assess TG levels. Results should be available prior to any further study related procedures being performed, as patients with plasma levels of >10 mmol/L will be excluded from the study.

• One blood sample for analysis of plasma EPA and DHA.

• Blood samples for determination of analytes that may correlate to the degree of PEL

• One additional blood sample for possible future analysis of exploratory biomarkers.

• Bristol stool scale assessment information.

• Provision of stool collection kits for FE-1 testing.

Two stool collection kits for FE-1 testing will be used to collect faeces samples on 2 occasions between Visit 2 and Visit 3. The patient will also be asked to record his/her bowel habits and Bristol stool scale daily over a period of 6 to 7 days between Visits 2 and 3.

Visit 3

Study procedures at Visit 3 will include:

• Completion of a PRO GSRS form.

• Dietary counselling for the TLC diet, including instructions regarding fish diet restrictions.

•AEs.

• Bristol stool scale assessment information.

• Collection of stool collection kits for FE-1 testing. • Blood samples to assess TG levels.

• One blood sample for analysis of plasma EPA and DHA.

Patients not randomised into Part B will complete the study at Visit 3.

Treatment period

Procedures will be performed according to the study plan.

Study drug will be administered at Visit 4 and at Visit 7.

A single dose of study drug will be administered 30 minutes after the start of a TLC diet- based breakfast (25% to 35% of energy from fat). The breakfast should have been completed in 30 minutes, ie, before study drug administration.

Lunch and dinner should be eaten according to the patient's usual schedule. The times of eating lunch, dinner, snacks, and drinking coffee will be recorded.

Visits 4 and 7

Study procedures at Visits 4 will include:

• Measurement of weight.

• Measurement of blood pressure and heart rate.

• AEs.

• Concomitant medications.

• Blood samples to assess TG levels

• Blood samples for analysis of plasma EPA and DHA, to be taken as 3 samples before study drug dose administration at -1, -0.5, and -0.05 hours pre-dose, to be used as baseline, and 9 post-dose samples at 1, 2, 3, 4, 5, 6, 7, 8, and 10 hours after dosing.

Study procedures at Visit 7 will be the same as at Visit 4.

Visits 5 and 8

Study procedures at Visit 5 will include:

•AEs.

• A 24-hour post-dose blood sample for analysis of plasma EPA and DHA

Study procedures at Visit 8 will be the same as at Visit 5. Visits 6 and 9

Study procedures at Visit 6 will include:

• AEs.

• A 48-hour post-dose blood sample for analysis of plasma EPA and DHA.

• A blood sample for liver function tests (LFTs)

Study procedures at Visit 9 will be the same as at Visit 6.

Follow-up period: Visit 10

Visit 10 will be a telephone call for safety follow-up. The patient will be asked about any AEs.

STUDY ASSESSMENTS

The Inform Web-Based Data Capture (WBDC) system will be used for data collection and query handling. The Investigator will ensure that data are recorded on the eCRFs as specified in the CSP and in accordance with the instructions provided.

Safety assessments

Laboratory screening

Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis will be taken at Visits 1 and 2, as indicated in the study plan.

The laboratory variables shown in Table 3 will be measured:

Table 3 Laboratory screening variables

Haematology/Haemostasis (whole blood) Clinical Chemistry (serum or plasma)

Haemoglobin Creatinine

Leukocyte count Bilirubin, total

Leukocyte differential count (absolute count) Alkaline phosphatase

Platelet count Aspartate transaminase (AST)

Alanine transaminase (ALT)

Urinalysis (dipstick) Gamma-glutamyl transferase

Hb/Erythrocytes/Blood Potassium

Leucocytes Calcium, total Glucose Sodium

Protein/ Albumin Thyroxine

Ketones Thyroid stimulating hormone

Liver function tests

Blood samples for LFTs will be taken at Visits 6 and 9, as indicated in the study plan. Levels of ALT, AST and total bilirubin will be measured.

Physical examination

A physical examination will be performed at the times indicated in the study plan.

The physical examination at Visit 1 will include an assessment of the following: general appearance, respiratory, cardiovascular, and abdomen. Weight will be measured at Visits 1 , 4, and 7. Height and waist circumference will be measured at Visit 1 only.

Vital signs

Blood pressure and heart rate will be measured at Visits 1, 4 and 7.

Other assessments

Laboratory assessments

Plasma triglyceride and cholesterol levels

Blood samples for determination of plasma TG and cholesterol levels will be taken at the times indicated in the study plan. The laboratory variables shown in Table 4 will be measured:

Table 4 Laboratory variables to determine plasma TG and cholesterol levels

Laboratory assessment

Triglycerides

Total cholesterol

HDL-cholesterol

Glucose

Non-esterified fatty acid

HDL: High density lipoprotein. Plasma levels of analytes that may correlate with PEI

Blood samples for determination of analytes that may correlate to the degree of PEI will be taken at the times indicated in the study plan

The laboratory variables shown in Table 5 will be measured:

Table 5 Laboratory variables that may correlate with PEI

Laboratory assessment

Blood HbAlc (mmol/mol)

Vitamin D

Vitamin K

Magnesium

Retinol-binding protein

Albumin

Prealbumin

Cytokeratin 18 fragments (M30, M65)

Amylase

Lipase

HbAlc: Glycated haemoglobin. Bristol stool scale

The patient will be asked to record his/her bowel habits and Bristol stool scale daily over a period of 6 to 7 days between Visits 2 and 3. The Bristol stool scale is a chart designed to classify the form of human faeces (stools) into 7 categories, allowing the patient to compare their stool(s) to the scale.

The 7 types of stool are:

• Type 1 : Separate hard lumps, like nuts (hard to pass)

• Type 2: Sausage-shaped, but lumpy

• Type 3 : Like a sausage but with cracks on its surface

• Type 4: Like a sausage or snake, smooth and soft

• Type 5 : Soft blobs with clear cut edges (passed easily)

• Type 6: Fluffy pieces with ragged edges, a mushy stool

• Type 7: Watery, no solid pieces. Entirely liquid. Faecal elastase-1 concentration

Faeces samples for determination of FEC will be taken on 2 occasions between Visit 2 and Visit 3, as indicated in the study plan. In cases where faeces are assessed as Bristol stool scale Type 5 to 6, the patient will be instructed to take samples from the more firm parts of the faeces. Watery faeces (Bristol stool scale Type 7) will not be used for FEC

determination.

Patient reported outcomes

Gastrointestinal symptom rating scale form

At Visit 3, a PRO GSRS form regarding the past one week's GI history will be completed bythe patient, in order to understand any possible relationship between GI symptoms and pancreatic exocrine dysfunction, as assessed by measuring FEC. The form should be completed by the patient alone, upon arrival to the site, in a private situation.

The validated GSRS form consists of 15 items designed to assess a range of GI symptoms including abdominal pain/discomfort, heartburn, acid reflux, nausea, constipation, diarrhoea,etc (Dimenas et al 1993, Dimenas et al 1995, Svedlund et al 1988). The 7- pointrating scale ranges from "no discomfort at all" to "very severe discomfort".

Pharmacokinetics

Collection of samples

Blood samples for determination of total levels (summary of free and esterified) of DHA and EPA in plasma will be taken at the times presented in the study plan.

At Visits 2 and 3, single blood samples for analysis of EPA and DHA in plasma will be taken.

At Visits 4 and 7, blood samples for analysis of EPA and DHA in plasma will be taken as 3 samples before study drug dose administration at -1, -0.5, and -0.05 hours pre-dose, to be used as baseline, and 9 post-dose samples at 1, 2, 3, 4, 5, 6, 7, 8, and 10 hours after dosing. At Visits 5 and 6, one blood sample for analysis of EPA and DHA in plasma will be taken at2 4-hours post-dose, and 48-hours post-dose, respectively.

At Visits 8 and 9, one blood sample for analysis of EPA and DHA in plasma will be taken at 24-hours post-dose, and 48-hours post-dose, respectively. One blood sample will be taken for each timepoint; the sample will then be split into 2 plasma samples: one primary sample and one back-up sample.

Biomarker analysis

The patient's consent to the use of donated biological samples is mandatory.

Analytes to be measured in the study that may correlate to the degree of PEI are shown in Table 5.

Dose and treatment regimens

At Visit 4 and Visit 7, a single dose of study drug will be administered 30 minutes after the start of a TLC diet-based breakfast (25% to 35% of energy from fat) at Visit 4 and Visit 7. The breakfast should have been completed in 30 minutes, ie, before study drug

administration.

Patients will be randomised via an IVRS/IWRS to receive either:

• 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, or:

• 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.

In general, continuous variables will be summarised using descriptive statistics (n, mean [geometric mean for PK parameters], SD, minimum [min], median, maximum [max]). Categorical variables will be summarised in frequency tables (frequency and proportion).

Global Hypothesis

2. Let the geometric means (of a parameter of interest, eg, AUCEPA+DHA, AUCEPA, AUCDHA, etc) for EPANOVA® and OMACOR® be μ E_p and μ Om, respectively. Then the Global generic Hypothesis on the particular parameter of interest (AUCEPA, for instance) is:

(a) μ Ep μ Ep

HO: = \; vs Ha : ≠l;

μ Om μ Om

(b) All PK parameters will be evaluated on the sum of DHA and EPA (EPA+DHA) concentrations, as well as, separately for concentration levels of EPA and DHA.

(c) Although there are several pairs of hypotheses of interest, this is not an inferential study and hence tests and confidence levels will not be adjusted for multiplicity.

Sample size estimate

The sample size for Part A is determined based on the number required to ensure enough patients in the 3 FEC groups of Part B. Type 2 diabetics with FEC <100 μg/g is anticipated to be the smallest group. Therefore, the total number of patients in the study will be determined by the number required to be recruited for the PK part (Part B) for this group (ie, Low FEC level). Assuming that 7% to 10% of the patients enrolled will be in the FEC <100 μg/g group, approximately 200 to 300 patients will be enrolled in Part A.

With respect to Total EPA and Total DHA, each, a sample size of 20 patients per sequence (in the 2-way crossover design in Part B), assuming a geometric standard deviation of 0.8468, will ensure a power >90% in order to detect a 2-fold increase in the PK parameters (AUCt and Cmax) in favour of EPANOVA® when compared with OMACOR®, based on a paired-t test ( a =0.05). In order to account for a 10% attrition rate in number of evaluable patients (in Part B), a total of 66 patients will be randomised (22 patients in each FEC group).

In Part B, the 22 patients in each FEC group will be randomised in a 1 :1 ratio to receive the crossover sequence AB or BA, where:

• AB = one dose of EPANOVA® 4 g followed by 10 to 14 days washout,

followed by one dose of OMACOR® 4 g.

• BA = one dose of OMACOR® 4 g followed by 10 to 14 days washout,

followed by one dose of EPANOVA® 4 g. Outcome measures for analyses

Degree of PEI

Patients with Type 2 diabetes will be classified into 3 strata by the degree of PEI (based on the mean of their 2 FEC measurements obtained between Visits 2 and 3, or the observed value if only 1 sample is collected), defined as:

^• Normal: FEC >200 μ g/g.

^• Intermediate: FEC >100 μ g/g to <200 μ g/g.

^• Low: FEC <100 μ g/g.

PK parameters

The primary aim for the PK analysis is to estimate the exposure of total amount of DHA and EPA, ie, the sum of free and esterified fatty acids. Blood samples for the PK analyses of EPA and DHA will be taken as 3 samples before each study drug dose administration (- 1 , -0.5, and -0.05 hours); the mean of these 3 samples will be used to define the baseline concentration.

Post-dose samples will be taken at 1 , 2, 3, 4, 5, 6, 7, 8, 10, 24, and 48 hours after dosing. Both baseline corrected and uncorrected PK parameters (with the exception of AUC, λ _z and ti/2 that will only be calculated on baseline corrected data) will be determined.

The following DHA and EPA PK parameters will be estimated on the baseline corrected plasma concentration data by non-compartmental methods using actual time from dosing:

Cmax Maximum concentration in the sampled matrix obtained directly from the

observed concentration versus time data.

tmax Time of maximum concentration (h) in the sample matrix, obtained directly from the observed concentration versus time data.

AUCo t Area under the concentration-time curve in the sampled matrix from zero

(pre-dose) to time of last measurable concentration calculated by linear

up/log down trapezoidal summation.

AUC Area under the concentration-time curve in the sampled matrix from zero (pre-dose) extrapolated to infinite time calculated by linear up/log down trapezoidal summation and extrapolated to infinity by addition of the last quantifiable concentration (Ct) divided by the elimination rate constant ( λ z):

AUCo-t + Ct/ λ z. If the extrapolated area (Ciast/ λ z) is >20% of AUC, then

AUC will be listed but not included in any summary.

λ z Apparent terminal elimination rate constant (1/h), determined by linear

regression of the terminal points of the log-linear concentration-time curve.

Visual assessment will be used to identify the terminal linear phase of the

concentration-time profile. A minimum of 3 data points and a Rsq of

0.8 will be used for determination.

ti/2 Apparent terminal elimination half/life (h), determined as ln2/ λ z.

The following PK parameters will be calculated for diagnostic purposes and listed, but will not be summarised:

λ z Interval The time interval (h) of the log-linear regression to determine AUC and ti/2. λ z N Number of data points included in the log-linear regression analysis.

Rsq Goodness of fit statistic for calculation of λ z (Regression coefficient).

% AUC extrapolated Percentage of AUC obtained by extrapolation, calculated as

[(Clast/ λ z)/AUC] x 100.

For the calculation of the PK parameters, the following rules will be applied:

• Actual sampling times will be used.

• PK parameters should be calculated on baseline-subtracted plasma concentrations. This means that plasma concentrations used in the PK calculations may be negative; all concentrations (including negative) should be used in the PK parameter calculations.

Exploratory analysis

Part A

Plasma levels of cholesterol, HDL, Vitamin D and Vitamin K, Mg2+, albumin, retinol- binding protein and prealbumin will be summarised and graphically displayed by degree of PEL In addition, Mg2+, albumin, retinol-binding protein and prealbumin will be plotted against plasma TGs (different symbols will be used for different degree of PEI).

The relationship between GI symptoms and bowel habits will be assessed, as well as their relationship to degree of PEL

11. List of References

American Diabetes Association 2014

Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2014; 37: Supplement 1 S81 -S90 Davidson et al 2012

Davidson MH, Johnson J, Rooney MW, Kyle ML, Kling DF. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova compared to Lovaza in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol 2012; 6:573-84.

Dimenas et al 1993

Dimenas E, Glise H, Hallerback B, Hernqvist H, Svedlund J, Wiklund I. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol 1993; 28:681-7.

Dimenas et al 1995

Dimenas E, Glise H, Hallerback B, Hernqvist H, Svedlund J, Wiklund I. Well-being and gastrointestinal symptoms among patients referred to endoscopy owing to suspected duodenal ulcer. Scand J Gastroenterol 1995; 30: 1046-52.

Hardt et al 2000

Hardt PD, Krauss A, Bretz L, Porsch-Ozcurumez M, Schnell-Kretschmer H, Maser E, et al. Pancreatic exocrine function in patients with type 1 and type 2 iabtes mellitus. Acta Diabetol 2000; 37: 105-10.

Hardt et al 2003a

Hardt PD, Hauenschild A, Nalop J, Marzeion AM, Jaeger C, Teichmann J, et al. High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase 1 concentrations in 1,021 diabetic patients. Pancreatology. 2003; 3:395-402.

Hardt et al 2003b

Hardt PD, Hauenschild A, Jaeger C, Teichmann J, bretzel RG, Kloer HU. High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic

insufficiency according to low fecal elastase 1 concentrations: a prospective multicentre study. DigDisSci 2003; 48: 1688-92. Lindkvist et al 2012

Lindkvist B, Dominguez-Munoz JE, Luaces-Regueira M, Castineiras-Alvarino M, Nieto- Garcia L, Iglesias-Garica J. Serum nutritional markers for prediction of pancreatic exocrine insufficiency in chronic pancreatitis. Pancreatology 2012; 12: 305-10.

Lindvist 2013

Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol 2013; 19:7258-66.

Loser et al 1996.

Loser C, Mollgaard A, Folsch UR. Faecal elastase 1 : a novel, highly sensitive, and specific tubeless pancreatic function test. Gut 1996; 39:580-6.

NCEP 2002

Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult

Treatment Panel III) final report. Circulation 2002; 106:3143-421.

Rathmann et al 2001

Rathmann W, Haastert B, Icks A, Giani G, Hennings S, Mitchell J, et al. Low faecal elastase 1 concentrations in type 2 diabetes mellitus. Scan J Gastroenterol 2001; 36: 1056- 61.

Stevens et al 2004

Stevens T, Conwell D, Zuccaro G, Van Lente F, Khandwala F, Hanaway P, et al. Analysis of pancreatic elastase- 1 concentrations in dudodenal aspirates from healthy subjects and patients with chronic pancreatitis. DigDisSci 2004; 49: 1405-11.

Svedlund et al 1998

Svedlund J, Sjodin I, Dotevall G. GSRS - a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. DigDisSci 1988;33: 129-34.

Claims

WHAT IS CLAIMED IS:

1. A method of treating hypertriglyceridemia in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency, by administration of an omega-3 fatty acid composition to said human being, wherein the omega-3 fatty acids in the composition are substantially in free fatty acid form.

2. A method as claimed in claim 1 wherein the human being has plasma triglyceride concentrations of > 500 mg/dL.

3. A method as claimed in claim 1 wherein the human being has plasma triglyceride concentrations of 200 mg/dL - 500 mg/dL.

4. A method as claimed in any one of claims 1 to 3 wherein the omega-3 fatty acid composition is Epanova® or a bio-equivalent version thereof.

5. A method of raising plasma EPA and/or DHA concentration in a human being who has been diagnosed as suffering from pancreatic exocrine insufficiency by administration of Epanova® to said human being.

6. A method as claimed in any one of claims 1 to 5 wherein the diagnosis that the human being is suffering from pancreatic exocrine insufficiency is made on the basis of having said human having a fecal elastase 1 level of <200 μ^.

7. A method as claimed in any one of claims 1 to 6 wherein the human being has also been diagnosed with Type II diabetes.