AU2019101555A4

AU2019101555A4 - Compositions and methods for treating certain gastrointestinal disorders

Info

Publication number: AU2019101555A4
Application number: AU2019101555A
Authority: AU
Inventors: Karin Ried
Original assignee: Nutrition Care Pharmaceuticals Pty Ltd; AUSNUTRIA DAIRY CHINA CO Ltd
Current assignee: Nutrition Care Pharmaceuticals Pty Ltd; Ausnutria Dairy China Co Ltd
Priority date: 2019-09-17
Filing date: 2019-12-11
Publication date: 2020-01-30
Anticipated expiration: 2027-12-11
Also published as: CN112274612A; AU2019279974A1

Abstract

Abstract The present invention provides Medications which are useful in treating or ameliorating the symptoms or adverse effects associated with a functional or a biochemical gastrointestinal disorder in an animal subject. The subject may be a human or a non-human 5 animal. The Medications of the invention comprise therapeutically active ingredients of natural origin, and include one or more of the following: (a) Curcumin; (b) L-Glutamine; .0 (c) Quercetin; (d) Glucosamine; (e) Aloe vera; (f) An edible essential oil; (g) Powder derived from the inner bark of Slippery Elm (Umus rubra); .5 (h) Guar Gum; and (i) Pectin. Methods of preparing and using the Medications in order to treat various functional and/or biochemical disorders of the gastrointestinal tract and associated symptoms in animal subjects, are also disclosed. Also disclosed are methods of improving the concentration of 20 beneficial bacteria in the gastrointestinal tract in an afflicted subject, by treating the subject with a Medication according to the invention.

Description

Title of Invention: 'Compositions and methods for treating certain gastrointestinal disorders'

The following is a full description of this invention, including the best method known to the Applicants of performing the invention:

2019101555 11 Dec 2019

Compositions and methods for treating certain gastrointestinal disorders

Field of the Invention

The present invention relates to the treatment of certain gastrointestinal disorders in animals. It has particular, although not exclusive, application to the treatment of gastrointestinal disorders in mammalian subjects, and especially, in humans. Accordingly, and while not detracting from the scope of the numerous ι applications to which the invention may be put, the background to the invention will be discussed by way of background in the following comments with particular reference to its application to mammals (and especially, to humans).

Background to the Invention

In many animals (and most notably, in mammals, and especially humans), the : gastrointestinal tract is essentially a hollow muscular tube which communicates between the subject’s mouth and the anus. In most such animals, the gastrointestinal tract serves two primary functions. First, in many species, it serves as an animal’s means of ingesting, digesting and absorbing nutrients. Secondly, and at the same time, the gastrointestinal tract expels waste materials left over from the digestive process.

i Maintaining good gastrointestinal health throughout life is therefore essential. If either of these basic functions of a subject’s gastrointestinal function is disturbed, the resultant consequences for the subject’s wellbeing can be serious.

There are several major categories of disorders which can adversely impact on gastrointestinal function. Gastrointestinal disorders can be characterized broadly as:

(a) Structural disorders;

(b) Biochemical disorders; and (c) Functional disorders.

Structural disorders - as their name implies - are caused by structural or anatomical irregularities of the gastrointestinal tract. The present invention is not concerned however with treating this category of such disorders. Rather, the invention is concerned instead with the treatment of certain functional or biochemical disorders of the gut.

2019101555 11 Dec 2019

Biochemical disorders of the gastrointestinal tract are those where abnormal function of the tract can be attributed to a specific biochemical stimulus, such as (for example) an allergen, or intolerance to a substance contained in food, such as lactose.

Functional disorders of the gastrointestinal tract are a group of idiopathic : disorders of normal tract function. They are characterised by gastrointestinal symptoms related to any combination of the following features:

(a) motility disturbance (b) visceral hypersensitivity (c) altered mucosal and immune function i (d) altered gut microbiota, and (e) altered central nervous system processing.

(Reference: Parkman HP and Doma S. “Importance of gastrointestinal motility disorders”, Practical Gastroenterology, September 2006).

In this context, the use of the term “functional” refers to impairment of one or : more of the following:

(1) normal motility of the gastrointestinal tract;

(2) sensitivity of nerves in the gastrointestinal tract; or (3) the ways in which the central nervous system controls (1) or (2).

(Reference: Dalton, Christine: “What is a functional Gl disorder?” (2017) a i publication of the University of North Carolina Center for Functional Gl & Motility

Disorders, University of North Carolina School of Medicine, published at https://www.med.unc.edu/ibs/files/2017/10/What-ls-Functional-GI.pdf)

The impairment to normal function observed in afflicted subjects is typically chronic or recurrent.

Motility for this purpose may be defined as the muscular activity of the gastrointestinal tract. In normal subjects, gut motility is characterised by a process known as peristalsis, which is an orderly and coordinated sequence of contractions of the muscular structures that form key parts of the gastrointestinal tract, in a direction from the “upper” regions of the tract (ie, those closest to the subject’s mouth) to the “lower” regions (ie, those at or near the anus). In normal subjects, the process of peristalsis therefore operates to move substances which the subject ingests orally, to lower regions of the tract, so that digestive metabolic processes may be performed on those substances via specific anatomical structures located along the tract, and so that

2019101555 11 Dec 2019 in turn, the subject may absorb desired nutrients, and at the same time, process waste materials for removal from its body.

In subjects who suffer from a functional gastrointestinal tract disorder, these processes are typically disrupted. The degree of the disruption is typically such that : instead of there being an orderly co-ordinated sequence of muscular contractions, an afflicted individual instead suffers from spasms of the gut musculature. The spasms can be very rapid, very slow and/or disorganised. Such spasms typically cause the subject to suffer discomfort, and (not uncommonly) pain.

In some affected individuals, one or more of the subject’s nerves that innervate i or supply a part of the gastrointestinal tract may be abnormally sensitised to stimuli (including for example, even normal stimuli such as the presence of food in the tract).

In some such subjects, even normal muscular contractions of the tract can trigger discomfort or pain through actuation of signalling in abnormally sensitised nerves.

In yet other afflicted subjects, the normal processes of communication between : the gut and the brain are impaired. The communications between the brain and the gut that regulate normal gut function are known to be bi-directional (this is called the “braingut axis”). Disturbances observed in functional gastrointestinal disorders in the normal bi-directional neuronal communications of the tract are sometimes referred to collectively as “brain-gut dysfunction”. This condition causes or contributes to the i symptoms of discomfort and pain that afflicted subjects experience.

In a given subject, the underlying cause of a functional gastrointestinal disorder may be any one of the three mechanisms mentioned earlier, or combinations or two or more of them. As indicated earlier, functional gastrointestinal disorders are generally regarded as being idiopathic conditions. Hence, in many instances, in view of the current state of medical science, the ultimate cause of the particular condition is not readily discernible, and the condition presents as having developed spontaneously. Much about the pathophysiology of these orders presently remains unknown. Taken together, these considerations mean that diagnosing and treating afflicted individuals can present particular challenges to clinicians. The risk of misdiagnosis is high, and the consequences of misdiagnosis or inappropriate treatment can therefore be serious.

Functional gastrointestinal disorders are characterised by symptoms which cannot be explained by reference to identifiable structural or biochemical markers. Traditionally then, they have been diagnosed by reference solely or predominantly to

2019101555 11 Dec 2019 the symptoms of dysfunction which prevail in the afflicted individual. Accordingly, functional gastrointestinal disorders have generally considered to be diagnoses of exclusion, meaning that they could only be diagnosed after objectively identifiable diseases or conditions were ruled out However, in 1988, a group of clinicians and < researchers met in order to clarify and establish stricter criteria for the diagnosis of these disorders. The criteria (known as the “Rome Criteria”) are now in their fourth revision (as of 2016).

According to the Rome IV criteria, there are approximately 20 conditions which currently are recognized as being functional gastrointestinal disorders. These i conditions affect millions of people of all ages around the world. One of the most commonly encountered of these conditions is Irritable Bowel Syndrome (or “IBS”). IBS is characterised by symptoms which can include:

• bloating • cramping : · diarrhea • constipation (often alternating with diarrhea) • intolerance to certain foods, • fatigue and difficulty sleeping, and • anxiety and depression.

_j IBS often impacts severely on the lives of afflicted sufferers. The symptoms associated with IBS and other functional gastrointestinal disorders can cause discomfort, ranging from inconvenience to physical pain, as well as personal distress. For those with severe IBS symptoms the disorder can be debilitating, leaving them unable to participate fully in life activities and work.

IBS is particularly prevalent in many communities around the world. A meta review published in 2012 estimated that the pooled prevalence of IBS across the 82 studies reviewed (and covering a total of 260,960 subjects) was 11.2% of the total populations surveyed (Reference: Lovell, RM and Ford, AC “Global Prevalence of and Risk Factors for Irritable Bowel Syndrome: A Meta-analysis” Clinical Gastroenterology and Hepatology (2012) Volume 10, Issue 7, pp 712-721 [July 2012]). More recent studies on the prevalence of the condition estimate that IBS may affect between 16

2019101555 11 Dec 2019 and 26% of the population (Reference: Drossman, D “Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features, and Rome IV” Gastroenterology (2016) Volume 160, Issue 6, pp 1282 to 1279). It has also been estimated in the past that the human health care cost of IBS to the United States alone lies in the realm of i billions of Dollars per annum. For example, in a paper published as far back as in 1995 (Talley et al, Gastroenterology 109, pp 1736-1741 (1995)), it was estimated that the health care cost of IBS in the human population the United States was then US$8 Billion per year.

Given that of the known gastrointestinal disorders, IBS alone is so prevalent, i that the condition can impact so adversely on the life of an afflicted sufferer, and that it imposes such significant health care (and indeed, consequential) costs on modern society, it would be highly desirable to have effective treatments for such disorders. Modification of an individual’s lifestyle and diet are amongst the tools available to modern medicine in the quest to treat such disorders, but many sufferers find it difficult < to comply with prescribed lifestyle or dietary modifications, especially over an extended period. The known treatments also include medications, but for the most part, the known medications used are often synthetic pharmaceuticals whose efficacy can vary significantly from one patient to the next. In addition, in modern society, some of the compliance problems associated with the use of traditional medications may be i attributable to a sector of the patient population preferring to avoid taking synthetic pharmaceuticals, especially over an extended time frame.

In order to ensure greater effectiveness of treatment, there is hence a need for a method of treating functional or biochemical gastrointestinal disorders which involves administering medications that comprise therapeutically active ingredients of natural origin as the active agents. There is thus correspondingly a need for medications that are useful in treating such disorders, and which comprise therapeutically active ingredients of natural origin as active agents, as well as methods by which such medications can be manufactured, especially in large quantities. The present invention therefore aims to address these needs.

2019101555 11 Dec 2019

Summary of the Invention

The present therefore invention generally provides Medications which are useful in treating or ameliorating the symptoms or adverse effects associated with a functional : or a biochemical gastrointestinal disorder in an animal subject.

The animal subjects that may be treated in accordance with the present invention include:

(a) mammals;

(b) birds;

i (c) fish;

(d) reptiles; and (e) amphibians.

In some embodiments of the invention, the animal subject is a mammal. In particular embodiments, the animal subject is a human. In other embodiments : however, the subject may be any other non-human animal that has a gastrointestinal tract. The invention therefore can generally be used in both human and veterinary medicine in order to treat functional or biochemical gastrointestinal disorders in animal subjects of all the kinds mentioned earlier.

The invention may be used generally to treat either adult or immature animal i subjects. Accordingly, the invention may be used in order to treat not only adult subjects, but also to treat young and old subjects. The invention can therefore be used in, amongst other applications, neonatal and geriatric care.

It is to be understood that wherever appearing in this specification, the terms “subject”, “animal subject” and “patient” are used interchangeably, and mean the same thing.

The functional or a biochemical gastrointestinal disorders that may be treated by using Medications according to the invention include the following:

(a) any functional gastrointestinal disorder as defined in the Rome IV Classification as published in 2016 (the text and content of which is expressly incorporated into this specification by reference, as if set expressly set out in it); and (b) any biochemical gastrointestinal disorder.

2019101555 11 Dec 2019

In either case, the disorders may be of either the upper or the lower region of the gastrointestinal tract.

In embodiments of the invention, the functional gastrointestinal disorders which may be treated include the following:

(1) esophageal disorders;

(2) gastroduodenal disorders;

(3) bowel disorders;

(4) centrally mediated disorders of gastrointestinal pain;

(5) childhood functional gastrointestinal disorders (neonatal/toddler);

(6) childhood functional gastrointestinal disorders (child / adolescent); (7) anorectal disorders;

(8) functional abdominal pain disorders; and (9) gallbladder and Sphincter of Oddi disorders.

In particular embodiments of the invention, the functional gastrointestinal disorders amenable to treatment in accordance with the invention include:

(A) Reflux hypersensitivity;

(B) Irritable Bowel Syndrome;

(C) Functional; dyspepsia;

(D) Gastro Esophageal Reflux Disorder (“GERD”);

(E) Belching, nausea and vomiting disorders;

(F) Functional chest pain and heartburn;

(G) Functional constipation;

(H) Functional diarrhea;

(I) Functional abdominal bloating/distension;

(J) Centrally mediated abdominal pain syndrome;

(K) Faecal incontinence;

(L) Infant Colic;

(M) Enteritis (inflammation of the small intestine);

2019101555 11 Dec 2019 (N) Gastritis (inflammation of the lining of the stomach); and (O) Leaky Gut Syndrome.

Biochemical gastrointestinal disorders that may be treated in accordance with the invention include:

: (a) intolerance to specific substances contained in foods; and (b) intolerance to orally administered medications.

Such disorders include lactose intolerance, and intolerance to specific orally ingested allergens.

The symptoms of gastrointestinal disorders which may be treated in accordance i with the present invention include the following:

(a) chest pain;

(b) heartburn;

(c) reflux and reflux hypersensitivity;

(d) indigestion and impaired digestion;

: (e) bloating;

(f) abdominal distension;

(g) belching;

(h) nausea;

(i) vomiting;

(j) flatulence;

(k) constipation;

(l) diarrhea;

(m) fecal incontinence;

(n) urgent need to defecate; and (o) abdominal discomfort or pain.

In accordance with the present invention, Medications suitable for treating the disorders and conditions previously mentioned include one or more therapeutically active ingredients of natural origin, optionally formulated in combination with one or

2019101555 11 Dec 2019 more conventional formulation ingredients. Examples of conventional formulation ingredients include, but are not limited to, carriers, gelling agents, stabilizers, solvents, excipients, solubilisers, binders, buffers, preservatives, emulsification agents, bulking agents, lubricants, suspending agents, disintegrating agents, flavours, sweeteners, i antioxidants, isotonic agents, and combinations thereof.

In embodiments of the invention, the therapeutically active ingredients of natural origin include one or more of the following:

(a) Curcumin;

(b) L-Glutamine;

i (c) Quercetin;

(d) Glucosamine;

(e) Aloe vera(f) An edible essential oil;

(g) Powder derived from the inner bark of Slippery Elm (Ulmus rubra/, : (h) Guar Gum; and (i) Pectin.

Preferably, the Curcumin is derived from Turmeric (Cucurma longa).

Quercetin is a plant flavonol of the flavonoid group of polyphenols. It is found in numerous fruits, vegetables, leaves, and grains. Common foods that contain this substance in appreciable quantities include red onions and kale. The substance as used in the Medications according to the invention is preferably derived from the dried flower buds of the Japanese Pagoda Tree (Sophora japonica).

Preferably, Glucosamine (an amino-sugar) as used in Medications made in accordance with the invention, is derived from shellfish or crustaceans, such as lobster, ίο

2019101555 11 Dec 2019 crab, prawns and/or shrimp. In some preferred forms of Medications made in accordance with the invention, Glucosamine is present as Glucosamine Hydrochloride.

Preferably, the Aloe vera component of such Medications takes the form of, or is derived from Aloe vera fresh leaf. It is particularly preferred that the fresh leaf used is at : least substantially devoid of Aloe plant material derived from latex or rind.

Preferably, the edible essential oil is a Peppermint Oil, being the essential oil derived from Peppermint (Mentha piperita).

Preferably, the Guar Gum as used in Medications made in accordance with the invention, is obtained by grinding the endosperms of seeds of the Cluster Bean plant i (Cyamopsis tetragonolobus (L.) Taub).

Pectins are a family of complex polysaccharides that contain 1,4-linked a-Dgalactosyluronic acid residues. They provide prebiotic fibres in formulations of the Medication. Pectins suitable for making Medications according to the present invention, are found in many plants and fruits. The pectins used in Medications made in < accordance with the invention are preferably derived from citrus fruits. In particularly preferred embodiments, they are derived from dilute acid extracts of the inner portion of the rind of citrus fruits.

In preferred forms of this aspect of the invention, a pharmaceutically acceptable preparation or formulation for treating a functional or biochemical gastrointestinal disorder would contain a combination containing all of the therapeutically active ingredients (a) to (j) listed above. In some preferred forms, the pharmaceutically acceptable preparation or formulation optionally also includes Sodium Diphosphate.

Medications made in accordance with the present invention may be prepared or formulated in any of a number of different ways so as to be suitable for administration to the subject. In embodiments of the present invention, such Medications could take the form of edible powders, capsules, tablets, liquids or gels containing one or more of the therapeutically active ingredients (a) to (j) listed above, as well as, optionally - in some embodiments - Sodium Diphosphate.

2019101555 11 Dec 2019

In one generally preferred form of this aspect of the invention, a Medication made in accordance with the present invention would be formulated as an edible powder containing one or more of the therapeutically active ingredients (a) to (j) listed above. Such an edible powder could either be ingested directly by the subject (for i example, by eating a quantity of the powder), or incorporated into another food (for example, by dissolving it in a beverage or by including it in the batter for a baked foodstuff). In particularly preferred versions of these embodiments of the invention, such a powdered formulation would contain all of the therapeutically active ingredients (a) to (j). In one preferred version of that embodiment, such a formulation would i contain all of the therapeutically active ingredients (a) to (j), as well as Sodium Diphosphate in about the following amounts per (or in each) kilogram of the finished product:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

i (c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g;

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin -20 g; and (k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In some preferred forms of the invention, a Medication made in accordance with the present invention would be formulated such as to deliver a daily dose of the following therapeutically active ingredients to the patient:

(1) L-Glutamine - 0.3 to 30 grams;

2019101555 11 Dec 2019 (2) Quercetin - 0.06 to 1.5 grams; and (3) Glucosamine Hydrochloride - 0.5 to 2.0 grams.

The invention further generally provides a substance that comprises one or more of the following therapeutically active ingredients:

(a) Curcumin;

(b) L-Glutamine;

(c) Quercetin;

(d) Glucosamine;

(e) Aloe vera;

(f) An edible essential oil;

(g) Powder derived from the inner bark of Slippery Elm (Ulmus rubra);

(h) Guar Gum; and (i) Pectin.

for or when used in the manufacture of a medicament for the treatment of a 15 functional or biochemical gastrointestinal disorder of the kinds previously described.

Preferably, in this aspect of the invention, the Aloe vera component of such a medicament takes the form of, or is derived from Aloe vera fresh leaf.

Preferably, in the medicament, the edible essential oil is a Peppermint Oil, being the essential oil derived from Peppermint (Mentha piperita).

In some preferred forms, substances in accordance with the invention also include Sodium Diphosphate.

In one generally preferred form of this aspect of the invention, the substance would contain all of the therapeutically active ingredients (a) to (j). In a particularly

2019101555 11 Dec 2019 preferred version of that embodiment, the substance would contain all of the therapeutically active ingredients (a) to (j) in about the following amounts per (or in each) kilogram of the finished medicament:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g (e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; as well as:

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

The present invention further generally provides a method of treating a functional or biochemical gastrointestinal disorder of the kinds previously described, the method comprising the step of administering to a patient in need of such treatment, a Medication that comprises an effective dose of one or more of the following therapeutically active ingredients:

(a) Curcumin;

(b) L-Glutamine;

(c) Quercetin;

(d) Glucosamine;

(e) Aloe vera;

2019101555 11 Dec 2019 (f) An edible essential oil;

(g) Powder derived from the inner bark of Slippery Elm (Ulmus rubra)', (h) Guar Gum; and (i) Pectin.

Preferably, in the method of this aspect of the invention, the patient is a human being.

In some preferred forms of this aspect of the invention, the Medications administered to the patient also include Sodium Diphosphate.

In one generally preferred form of this aspect of the invention, the Medication would contain all of the therapeutically active ingredients (a) to (j). In a particularly preferred version of that embodiment, the Medication would contain all of the therapeutically active ingredients (a) to (j) in about the following amounts per (or in each) kilogram of the finished Medication:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g (e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; as well as:

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

2019101555 11 Dec 2019

In another generally preferred form of this aspect of the invention, the method would comprise administering to the patient, a Medication formulated as an edible powder containing one or more of the therapeutically active ingredients (a) to (j) listed above. As previously described, such an edible powder could either be ingested directly by the subject (for example, by eating a quantity of the powder), or incorporated into another food (for example, by dissolving it in a beverage or by including it in the batter for a baked foodstuff). In other preferred embodiments of the invention, the Medication could be administered by incorporating a suitable quantity or dose of the Medication in another pharmaceutically acceptable delivery vehicle, such as a tablet, a capsule or caplet, a chewable tablet, gel, capsule or caplet, a rapidly dissolving tablet, gel, capsule or caplet, or a sustained or delayed release version of any of these delivery devices. Ordinary persons of skill in the field of pharmaceutical formulation would readily appreciate that in practice, Medications in accordance with the invention could be formulated for administration to intended animal subjects in these or in many other ways, and that all such modes of administration are specifically included within the scope of the present invention.

In particularly preferred versions of these embodiments of the invention, such a powdered formulation would contain all of the therapeutically active ingredients (a) to (j). In a particularly preferred version of that embodiment, such a formulation would contain all of the therapeutically active ingredients (a) to (k) in about the following amounts per (or in each) kilogram of the finished product:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g;

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

2019101555 11 Dec 2019 (h) Guar Gum - 20 g;

(i) Pectin -20 g; and (k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In this method of treatment aspect of the invention, a Medication formulated as : such an edible powder would be administered to a human patient as a 5 gram dose. In any period of 24 hours, an adult patient would be administered a maximum dose of no more than 15 grams of the powdered formulation.

Where the patient is not an adult, the dosage per day is preferably as follows:

(a) For a patient aged 12 years or older - up to the recommended daily i prescribed dose (although of course, desirably, the dose for a given patient will be recommended by a health care professional);

(b) For a patient aged between 5 and 12 years - up to one-half of the recommended and maximum adult daily dose;

(c) For a patient aged between 2 and 5 years - up to one-third of the recommended and maximum adult daily dose; and (d) In the case of a child aged under 2 years, as directed by a physician or other health care professional.

Preferably, the method of treatment optionally involves co-administering a probiotic substance to the patient. Preferred probiotic substances for this purpose include preparations or formulations that contain bacterial species selected from the Bacteroides genus and/or the phylum Firmicutes. Particularly preferred probiotic bacterial species for this purpose include Bifidobacteria and Lactobacillus bacterial species. In some preferred forms of this aspect of the invention, the step of coadministering the probiotic substance to the patient is commenced before the step of administering the Medication to the patient.

The present invention further generally provides a method of increasing the concentration of one or more beneficial bacterial species in the gastrointestinal tract of

2019101555 11 Dec 2019 a patient afflicted by a functional or biochemical gastrointestinal disorder of the kinds previously described, the method comprising the step of administering to the patient, a Medication that comprises an effective dose of one or more of the following therapeutically active ingredients:

(a) Curcumin;

(b) L-Glutamine;

(c) Quercetin;

(d) Glucosamine;bifo (e) Aloe vera(f) An edible essential oil;

(g) Powder derived from the inner bark of Slippery Elm (Ulmus rubra)-, (h) Guar Gum; and (i) Pectin.

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g (e) Aloe vera fresh leaf - 100 g;

2019101555 11 Dec 2019 (f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; as well as:

: (k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In another generally preferred form of this aspect of the invention, the method would comprise administering to the patient, a Medication formulated as an edible powder containing one or more of the therapeutically active ingredients (a) to (k) listed above. As previously described, such an edible powder could either be ingested i directly by the subject (for example, by eating a quantity of the powder), or incorporated into another food (for example, by dissolving it in a beverage or by including it in the batter for a baked foodstuff). In particularly preferred versions of these embodiments of the invention, such a powdered formulation would contain all of the therapeutically active ingredients (a) to (k). In a particularly preferred version of that : embodiment, such a formulation would contain all of the therapeutically active ingredients (a) to (k) in about the following amounts per (or in each) kilogram of the finished product:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g;

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

2019101555 11 Dec 2019 (i) Pectin -20 g; and (k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In another preferred embodiment of this aspect of the invention, the method comprises the additional step of administering a further probiotic substance to the : patient. In one particularly preferred embodiment of this aspect of the invention, the step of administering the probiotic substance to the patient is commenced before commencing the step of administering the Medication to the patient.

In an alternative preferred embodiment of this aspect of the invention, the method the step of administering the probiotic substance to the patient is commenced i on or after commencing the step of administering the Medication to the patient.

For the purposes of the present invention, a “probiotic” is any substance which stimulates or promotes the growth of any beneficial microorganism (and especially, bacterial) species of the gastrointestinal flora. Preferred probiotic substances for this purpose include preparations or formulations that contain bacterial species selected ; from the Bacteroides genus and/or the phylum Firmicutes. Particularly preferred probiotic bacterial species for this purpose include Bifidobacteria and Lactobacillus bacterial species.

Preferably, in this aspect of the invention, a Medication formulated as such an edible powder would be administered to a human patient as a 5 gram dose. In any period of 24 hours, the patient would be administered a maximum dose of no more than 15 grams of the powdered formulation.

It is also to be understood that wherever appearing in this specification, the terms “Medication” and “medicament” are used interchangeably, and mean the same thing.

Detailed description of exemplary embodiments of the Invention

Exemplary embodiments of the Invention will now be described by way of example only in the comments that follow, and with reference to the drawings and tables provided.

2019101555 11 Dec 2019

Overview of a study performed on adult human patients with gastrointestinal symptoms

The following comments and information describe and report the results of a study : conducted in Melbourne, Australia, of the impact of a Medication formulated by or on behalf of the Applicant, on certain gastrointestinal symptoms in a sample population of 50 adult volunteer subjects. The study was conducted on behalf of the Applicant by National Institute of Integrative Medicine Ltd (Australian Company Number 095 139 209) (the latter entity having assigned all the intellectual property rights in the conduct of i and the results of the study to the Applicant).

Volunteers for the study were recruited by advertisements, through the use of social media, and via the National Institute of Integrative Medicine’s web site.

The Medication

The Medication administered to participants in the study was manufactured in Australia : or on behalf of the Applicant, and each 5 gram sachet of the medication contained the following ingredients:

Ingredient	Quantity present

Curcuma longa rhizome as Cumerone®	30.37 mg
Containing curcuminoids	6.074 mg
Containing curcumin	4.25 mg
Glutamine	2.5 g
Quercetin	200 mg
Glucosamine hydrochloride (from Shellfish)#	500 mg
(Equivalent to Glucosamine):	415.05 mg
Aloe vera (inner leaf / gel without latex & rind) Equivalent to Aloe vera leaf fresh	500 mg
Equivalent to Aloe polysaccharides	187.5 mg
Equivalent to Aloin (as barbaloin)	0.02 meg

Ulmus rubra (Slippery Elm) Bark Powder	500 mg
Guar Gum	100 mg
Pectin	100 mg
Peppermint oil	3 mg
Sodium phosphate	250 mg

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On a per kilogram basis, the Medication therefore had the following composition (a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g (e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; and (k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

The Medication was provided to patients in powdered form in sachets containing 15 5 grams of the Medication. At the inception of the study, participants were given guidance on how to take the Medication. It was suggested that a preferred form was to take the Medication with warm water. Other methods of oral administration (eg, to take the medication with food or with beverages other than water, were also options available to the participants.

2019101555 11 Dec 2019

Participants

A total of 50 adult participants with gastrointestinal symptoms were enrolled to take part in the study, after an initial 66 to 100 volunteers were screened. The participants enrolled had either upper or lower gastrointestinal tract symptoms (or both).

Some of the key characteristics of the participants are summarised in the following comments.

The mean age of the enrolled participants was 50yrs (female 76%).

The participants were grouped into those that manifested with upper gastrointestinal tract (Gl) issues (n=32, 74%) and lower Gl issues (n=42, 97%), with most participants (n = 31, 72%) experiencing both.

Preliminary evaluation of the participants at recruitment revealed the following:

Table 1

Gl Symptoms: Bloating (76%) Other symptoms: Fatigue (60%)

Heartburn/reflux (50%) Anxiety (54%)

Constipation (52%) Bad-breath

Diarrhea (48%) Mouth-ulcers

Nausea (48%) Rashes (30%)

Key aspects of these data are represented graphically in Fig 1.

Study Methodology

After enrolment, the study involved assessing certain parameters of the gastrointestinal health of the enrolled participants over a period of approximately 16 weeks. The assessments were performed at 4 stages, as follows:

(1) At a first visit (Visit 1) at the commencement of the study;

(2) At a second visit (Visit 2), that took place at 3-4 weeks after Visit 1;

(3) At a third visit (Visit 3) that took place 4 weeks after Visit 2;

(4) At a fourth visit (Visit 4) that took place 4 weeks after Visit 3.

2019101555 11 Dec 2019

After this schedule was completed, the data obtained from the study were compiled and analysed.

The key events that took place at each stage were as follows:

Stage	Key events

Visit 1 (Commencement and “run-in” stage)	Certain baseline gastrointestinal health data for each participant were collected, in the manner explained below under “Data Collection”. The data included the collection of stool samples from each patient, for laboratory analysis.
Visit 2 (3-4 weeks after Visit 1)	The participants were divided into 2 “Groups” (namely, “Group 1” and “Group 2”). Participants were asked to take 5 grams of the Medication daily during this stage. The Medication was taken each evening over the duration of this stage. Data for the stage were collected from each participant.
Visit 3 (4 weeks after Visit 2)	Participants in each Group were asked to take 10 grams of the Medication daily during this stage. The Medication was taken each evening over the duration of this stage. Data for the stage were collected from each participant.
Visit 4 (4 weeks after Visit 3)	Participants in each Group were asked to take 0, 5 or 10 grams of the Medication daily during this stage, according to individual patient preference. Data for the stage were collected from each participant. This included the collection of stool samples from each participant at the commencement of this stage. Blood and urine samples were collected from participants at the end of the stage, for laboratory analysis.

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Data Collection

Data were collected from the study in two ways:

(a) Assessments of certain patient gastrointestinal health indicators were collected via individual patient answers to a series of questions contained in clinical questionnaires aimed at addressing the frequency and severity of certain key gastrointestinal symptoms.

The clinical questionnaires used were:

(1) the Leeds Dyspepsia Short Form Questionnaire;

(2) the Bristol-Stool-Chart;

(3) the GERD-Questionnaire, and (4) the Birmingham-IBS-Symptom- Questionnaire.

Although these questionnaires would be familiar to persons of skill in the field of the invention, for the sake of ensuring full disclosure, exemplary details of the questionnaires can be found either in this specification, and/or at the following web sites:

(1) the Leeds Dyspepsia Short Form Questionnaire - at the address; https://onlinelibrary.wiley.com/doi/full/10.1111/j. 1365-2036.2006.03233.x (2) the Bristol-Stool-Chart; https://www.continence.com.au (3) the GERD-Questionnaire, and http://www.journalofmas.eom/articles/2018/14/3/images/JMinAccessSurg_2018 _14_3_213 214880_sm7.pdf (4) the Birmingham-IBS-Symptom- Questionnaire:

https://bmcgastroenterol.biomedcentral.eom/articles/10.1186/1471-230X-8-30

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Full details of each of these exemplary source materials are incorporated into this specification by reference, as if they were specifically set out in this document.

(b) Furthermore, gut microbiota, intestinal permeability, inflammatory markers, and H- pylori infection were assessed by using standard laboratory techniques, the nature of which would readily be apprehended by persons of skill in the field of the invention.

Statistical analysis of data collected

Where required, data collected from the study were subjected to statistical analysis in accordance with accepted and conventional biostatistical methodologies. These included the use of the Paired T-Test and the Chi-squared test. (Fort an example of a reference, see: Colquhoun, D, Lectures on Biostatistics (Oxford University Press, 1971). The Birmingham-IBS-Symptom Questionnaire Data were analysed using the methodology outlined in Roalfe (2008) (Reference: Roalfe, AK, Roberts, LM, and Wilson “Evaluation of the Birmingham-IBS-Symptom-Questionnaire”, BMC Gastroenterol (2008) Jul 23 8:30). Certain other data (for example, the data tabulated at Table 33 and shown in Figure 20) were analysed using Fisher’s Exact Test (Reference: http://mathworld.wolfram.com/FishersExactTest.html).

Results

Extent of participation by the participants

As previously indicated, at the commencement of the trail, there were 50 participants enrolled.

Of these:

• 7 participants (14%) withdrew after Visit 1;

• 43 participants completed the trial;

• Of the participants that completed the trial:

• 42 completed the intestinal permeability testing at start and end of study (n=1 failed to complete this test at the end of the study); and • 37 completed the stool testing.

2019101555 11 Dec 2019

Comparison of the prevalence or severity of certain symptoms observed at four time points in the study

Fig 2 summarises some of the key results observed from the study as a whole, when assessed across the four major time points during the duration of the study.

As can be seen from Fig 2, reductions were observed in all the key symptoms assessed over the duration of the study. In particular, the following reductions were observed:

• Abdominal boating reduced by 55%;

• Diarrhea reduced by 75%;

• Heartburn/reflux reduced by 78%; and • Fatigue reduced by 32%.

Palatability of the Medication to the participants

Table 2 (below) summarises feedback received from the participants about the palatability of the Medication.

Table 2: Participants' perceptions of Palatability

Response to taste	n	%

Liked a lot	5	11.6
Liked	19	44.2
Neutral	16	37.2
Disliked	3	7
Totals	43	100

The majority of participants therefore either responded positively or were neutral to the taste of the Medication.

2019101555 11 Dec 2019

Table 3 (below) sets out data concerning the methods preferred by participants for taking the Medication.

Table 3: Participants' preferred method of taking the Medication

As shown in Table 3, some 83.7% of the participants chose to take the formula with warm water, as recommended at the commencement of the study.

The participants’ preferred dosage regimes

As previously indicated, during the Visit 3 and Visit 4 stages of the study, the participants were asked to take up to 10 grams of the Medication daily.

Table 4 (below) summarises the results of the acceptability of the 10 gram per day dosage to the participant group.

Table 4

Acceptability of 1 sachet (5g) and 2 sachets (1 Og)	1 sachet (5g)	2 sachets (1 Og)
	n	%	n	%

Very Easy	19	44.2	12	27.9.
Easy	21	48.8	16	37.2.
Sometimes easy, sometimes hard	3	7	10	23.3
Hard	0	0	4	9.3
Very Hard	0	0	1	2.3
Totals	43	100	43	100

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As will be apparent from Table 4:

• Almost all participants found taking 1 sachet either “easy” or “very easy”; and • The acceptability of 2 sachets ranged from very easy to very hard - with the highest number of participants scoring this in the “easy” category.

[The next page is page 29].

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Compliance by the participants with the study’s dosage regimes

This parameter is summarised in Table 5 (shown below).

Table 5: Compliance (%) amongst the total participants with dosage regimes

Study stage and dose	n	Percentage of participants complying with the dose in the month (%)	Other observations

Visit 2 (5 grams)	43	90.8
Visit 3 (10 grams)	39	89.5	3 participants took 5 grams; 1 participant took 0 grams
Visit 4

5 grams	13
10 grams	28
0 grams	2

Table 6:

The choice of dosage regime adopted by Participants at Visit 4, and their reasons for doing so

The results for these parameters are summarised in table 6 (below).

Table 6

	10 grams	5 grams	0 grams	5 grams	0 grams

Number of participants	28	10	1	3	1
Reasons given for adopting the dose	• Significant improveme nt in upper Gl symptoms • Loose and	• Improvement s in upper Gl symptoms • Harder stools, straining to	• Disliked taste and texture	• Harder stools, straining to pass stools, feeling constipated, less regular	• Disliked taste and texture • Looser bowel motions

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mushy stools were firming up • More frequent and regular bowel motions

pass stools, feeling constipated, less regular bowel motions

bowel motions, abdominal bloating • Disliked taste and texture

Table 7: Incidence of unwanted effects

The results for this parameter are summarised in Table 7 (below).

Table 7

Exacerbation of symptoms	Month and Dose
Type	Month 1 (Visit 2)	Month 2 (Visit 3)	Month 3 (Visit 4)
Daily dose	5 gram dose	10 gram dose	Dose of 0, 5 or 10 grams
None	21	21	35
Bloating	5	1	1
Incomplete evacuation/ Harder stools / Constipation	6	14	3
Urgent 1 Loose / Diarrhea	5	2	2
Reflux/lndigestion	4	1	0
Other	2	4	2

As will be apparent from reading Table 7:

• The number of participants experiencing side effects declined from Month 1 to Month 3; and · The number of participants who experienced harder stools, incomplete evacuation and constipation increased in Month 2 at the higher dose of 10 grams.

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Table 8: Incidence of unwanted effects in the participant group with both upper and lower Gl symptoms

The results for these parameters are shown in Table 8 (below):

Table 8

Unwanted effects: Upper Gl & Lower Gl participants (n = 32)

Unwanted effect	Month 1 (Visit 2)	Month 2 (Visit 3)	Month 3 (Visit 4)
Daily dose	5 grams	10 grams	0, 5 or 10 grams
None	16	19	25
Bloating	3	0	1
Incomplete/Harder/Constipation	5	11	3
Urgent/Loose/Diarrhea	3	0	1
Reflux/indigestion	4	0	0
Other	1	2	2

As will be evident from Table 8:

• Unwanted effects in participants experiencing both upper and lower symptoms reduced significantly from Month 1 to Month 3 of the study;

io · At the daily dose of 10 grams in Month 2, the number of participants experiencing harder stools, incomplete evacuation or constipation increased; and • No reflux/indigestion side effects were observed in Months 2 or 3.

Table 9: Incidence of unwanted effects in the participant group with both 20 upper and lower Gl symptoms, by the dose chosen in Month 3 of the Study

The results for these parameters are shown in Table 9 (below):

Table 9

Unwanted effects: Upper & Lower participants (n = 32) in Month 3 by choice of dosage
Unwanted effects	0g	5g	10g
None	0	6	19

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Bloating	0	1
Incomplete/Harder/Constipation	1	2
Urgent/Loose/Diarrhea	0	1
Reflux/indigestion	0	0
Other	1	1

By way of summary:

• These results show that In general, more participants with both upper and lower symptoms chose the 10 gram dosage; and • No reflux/indigestion side effects were observed in Month 3.

Table 10: Unwanted effects in participants with lower Gl issues

For all intents and purposes, virtually all participants (97% of the sample population studied) had experienced lower Gl issues at the commencement of the study.

Table 10 (below) summarises the impact of the Medication on those issues throughout the duration of the study.

Table 10

Unwanted effects in the lower Gl participant population

Baseline stool consistency		Month 1: 5g (n=43)	Month 2: lOg (n=39)	Month 3: Choice Og (n=2)	Month 3: Choice 5g (n=13)	Month 3: Choice 10g (n=28)
Normal stool	None	6	5	0	2	0
	Bloating	0	0	0	0	6
	Incomplete/Harder/Constipation	2	3	0	0	2
	Urgent/Loose/Diarrhea	0	0	0	0	0
	Reflux/indigestion	1	0	0	0	0
	Other	1	2	0	0	0

Soft	None	5	5	1	3	5
	Bloating	0	0	0	0	1
	Incomplete/Harder/Constipation	2	3	0	0	0
	Urgent/Loose/Diarrhea	4	1	1	0	0
	Reflux/indigestion	1	0	0	0	0
	Other	0	1	0	0	1

Hard	None	10	11	0	6	12
	Bloating	5	0	0	0	0
	Incomplete/Harder/Constipation	2	6	0	1	0
	Urgent/Loose/Diarrhea	1	0	0	0	1
	Reflux/indigestion	2	1	0	0	0
	Other	1	1	0	1	0

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Other general observations reported by participants or which emerged from the study

The following additional observations or comments emerged from the study:

• The Medication was generally well tolerated by participants;

• The impact of the Medication on upper gastrointestinal symptoms was observed generally to be more rapid than with lower Gl symptoms;

• A number of the participants reported that during the study, they were able to reduce the extent of their use of other medications (in particular, anti-reflux medication and laxatives);

• A number of participants reported that after taking the Medication, they found that they were able to introduce foods into their diet which had previously been triggers for gastrointestinal symptoms. The food triggers that participants had been able to introduce into their diet included gluten, carbohydrates, FODMAPs (namely, fermentable oligo-, di-, mono-saccharides and polyols), and acidic/spicy foods. Some participants found that they either had less severe symptoms in response to such food triggers than before the study, and in some instances, participants found that they had no symptoms; and • The 10g/day dose of the Medication was generally found to be more likely to induce constipation than 5g/day. This is a useful finding for subjects who suffer from loose stools, but conversely, the dose of the medication administered may need to be taken into account in relation to subjects suffering from constipation/ hard stools.

The impact of the Medication on participants’ responses to food triggers

Table 11 (which appears in Fig 3 of the accompanying drawings) sets out data showing the impact of the Medication on food triggers in the participants.

In summary, the data in Table 11 show:

· An overall improvement of between 18 to 57% in participants’ ability to tolerate trigger foods;

2019101555 11 Dec 2019 • A 52% improvement in the ability of participants who had tolerance issues to this food, in tolerating it;

• A significant improvement (>40%) in the tolerance of participants to foods that cause GERD (notably, these are citrus foods, acidic foods, caffeine and spicy foods; and • A significant improvement (47%) in the tolerance of patients who previously had issues tolerating casein.

The impact of the Medication on the tolerance of participants with upper Gl symptoms

Table 12 (which appears in Fig 4 of the accompanying drawings) sets out the impact of the Medication on the tolerance of participants with upper Gl symptoms, to the food triggers studied. It is to be noted that all but one of the participants also had lower Gl symptoms.

In summary, the data in Table 12 show:

• A 16 to 50% improvement amongst participants, in their tolerance to FODMAP trigger foods; and • An improvement of >40% in the response of participants to trigger foods for GERD.

[The next page is page 35].

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Changes observed in participants’ tolerance levels to food triggers, based on the dose of the Medication

Table 13 (which appears in Fig 5 of the accompanying drawings) sets out the results > observed when assessing this parameter.

In summary:

• The dose of 10 grams per day was found to be more effective overall; and • The 10 grams per day dose of the Medication was more effective in participants who had issues with acidic foods, fatty foods, caffeine, spicy foods or alcohol.

)

Impact of the Medication on the use of other medicines or supplements to relieve upper or lower Gl symptoms

The data for this aspect of the study are set out in Table 14.1 (which in turn, appears as i Fig 6 of the accompanying drawings).

Details of the changes in the medicines or supplements used to relieve upper Gl symptoms )

The data for this aspect of the study are set out in Table 14.2 (which in turn, appears as Fig 7 of the accompanying drawings).

In summary, these data show that by the end of the study, there had been a reduction of 40% in the number of participants who used other medicines or supplements to relieve > their upper Gl symptoms.

Table 14.3: Details of the changes in the medicines or supplements used to relieve lower Gl symptoms

The data for this aspect of the study are set out in Table 14.3 (which in turn, appears as 30 Fig 8 of the accompanying drawings).

The laxatives used included Soda bicarb, Nomacol fibre granules, Colozone (Mg laxative), Herbalax, Metamucil fibre capsules, Nulax, Celery juice, Coloxil, Intestinal Movement Formula.

In summary: No change was found in the number of participants with lower Gl symptoms 35 taking medicines or supplements to relieve those symptoms.

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Results from Questionnaires

LEEDs Dyspepsia Questionnaire (upper Gl symptoms) > Total participants with upper gastrointestinal symptoms: N=32

Method of analysis: Within subject comparison of LEEDs Questionnaire answers, by repeated measure t-test.

) Table 15.1 - LEEDs 1. Baseline vs Control (run-in-phase)

The data for this aspect of the study are set out in Table 15.1 (which in turn, appears as Fig 9 of the accompanying drawings).

Table 15 .2 - LEEDs 2. Baseline vs 12 weeks = Change after treatment with the 5 Medication

The data for this aspect of the study are set out in Table 15.2 (which in turn, appears as Fig 10 of the accompanying drawings).

) In summary:

• The Medication significantly reduced upper Gl symptoms (including indigestion, heartburn, regurgitation and nausea) (p<0.001)

Figure 11: Graphical representation of Leeds Questionnaire Scores

The data for this aspect of the study are represented graphically in Fig 11 of the accompanying drawings).

Figure 12: Sample of a LEEDs Questionnaire

A sample of the LEEDs Questionnaire used in the study is depicted in Fig 12 of the accompanying drawings.

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GERD Questionnaire - (upper Gl symptoms) Frequency of upper Gl symptoms

As indicated earlier, a sample of this Questionnaire can be found on the Internet, at the following World Wide Web address:

i http://www.journalofmas.eom/articles/2018/14/3/images/JMinAccessSurg_2018_14_3_213 214880_sm7.pdf.

Total participants with upper gastrointestinal symptoms: N=32.

)

Method of analysis: Within subject comparison of answers to the GERD Questionnaire by repeated t-test.

Table 16.1 - GERD 1. Baseline vs Control (run-in-phase)

The results for this aspect of the study are set out in Table 16.1, (which in turn, i appears as Fig 13 of the accompanying drawings).

Table 16.2 - GERD 2. Baseline vs 12 weeks = Change after treatment with the Medication

The results for this aspect of the study are set out in Table 16.2, (which in turn, appears as ) Fig 14 of the accompanying drawings).

In summary:

• The Medication significantly reduced the frequency and severity of upper Gl symptoms, • including indigestion, heartburn, regurgitation, nausea and associated quality of sleep issues (p<0.001).

GERD frequency and days measurements

These data are set out in Fig 15 of the accompanying drawings, which includes (and depicts as “Table 1” in Fig 15, a sample GERDQ Questionnaire).

[The next page is page No 38].

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GERD Quality of Life (QoL) Questionnaire and GERD HQoL - (Upper Gl Symptoms)

The results for this aspect of the study are set out in Table 17.1 (below):

Table 17.1 - GERD QoL 1. Baseline vs Control (run-in-phase)

Questionnaire	Measure	N	Control Mean ± SE	Baseline Mean ±SE	Difference Mean ± SE	p-value
GERD QoL	Daily activity	32	47.07 ±5.06	42.77 ±4.81	4.30 ±2.81	p = 0.138
Treatment Effect (Subgroup on PPI)	11	63.63 ±9.61	56.06 ± 11.01	7.58 ±8.66	p = 0.402
Diet	32	48.95 ±6.71	52.08 ±5.70	3.13 ±5.06	p = 0.54
Psych Wellbeing	32	56.25 ±6.35	47.65 ±6.31	8.59 ±4.68	p = 0.076
Overall score (subgroup on PPI)	11	62.74 ±7.50	76.04 ± 10.07	13.30 ±9.98	p = 0.21
Adjusted Overall Score*	32	50.76 ±5.44	47.50 ±4.90	3.25 ±3.38	p = 0.34
Gerd HQoL	Total Score	32	20.19 ±2.72	18.50 ±2.25	1.69 ±1.59	P = 0.30

Notes to Table 17.1:

Total participants with upper gastrointestinal symptoms: N=32;

> Subgroup: Participants on meds (PPI) only (n=11) - GERD QoL - Treatment effect;

Method of analysis: Within subject comparison of the answers to the GERDQoL and GERD HQoL Questionnaires by repeated measure t-test.

Table 17.2 - GERD QoL 2. Baseline vs 12 weeks = Change after treatment with the Medication

Questionnaire	Measure	N	Control Mean ± SE	Baseline Mean ±SE	Difference Mean ± SE	p-value
GERD QoL	Daily activity	32	42.77 ±4.81	17.68 ±3.60	25.09 ±3.72	p < 0.001
Treatment Effect (Subgroup on PPI)	11	56.06 ± 11.01	41.67 ±8.84	14.39 ±8.71	p = 0.129*
Diet	32	52.08 ±5.70	33.07 ±6.27	19.01 ±4.27	p < 0.001
Psych Wellbeing	32	47.65 ±6.31	19.14 ±5.14	28.51 ±5.62	p <0.001

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	Overall score (subgroup on PPI)	11	76.04 ± 10.07	32.59 ±6.60	43.44 ±7.74	p < 0.001 ^#
Adjusted Overall Score*	32	47.50 ±4.90	23.29 ±4.45	24.21 ±3.64	p < 0.001
Gerd HQoL	Total Score	32	18.50 ±2.25	8.63 ±1.62	9.88 ±1.85	p < 0.001

Legend to Tables 17.1 and 17.2.

Bold p-values are indicative of statistical significance (p < 0.05). Treatment effect (TE) was only analysed for participants taking medication (n=11, PPI). The Overall Score as per GERD QoL original i questionnaire was calculated for (n=11 on PPI) = DA+TE +DI +PW) / 4 * The adjusted overall score was calculated for all participants with upper symptoms (n=32) (DA+DI+PW) / 3 # 8/11 took PPI daily/regularly before the study, 3/11 occasionally; 60% (n=5 out of 8) of participants taking PPI’s daily at the start of the study, reported no longer requiring daily PPIs after the Medication ) intervention.

The data from Tables 17.1 and 17.2 are depicted graphically in Fig 16 of the accompanying drawings.

In summary:

i · The Medication significantly improved the Quality of Life in participants with upper symptoms, including daily activities, diet, and psychological wellbeing (p<0.001), and associated Health Related Quality of Life (GERD- HQoL, p<0.001).

Fig 7: Examples of the GERD QoL and GERD HQoL Questionnaires

Examples of these are depicted in Fig 17 of the accompanying drawings.

Birmingham - Irritable Bowel Syndrome (IBS) - Q (Lower Gl Symptoms)

Total participants with lower gastrointestinal symptoms: N=42

Note: One participant was excluded from this analysis, as the participant concerned had only upper Gl symptoms.

Method of analysis: Within subject comparison of the results of the Birmingham IBS Q by repeated measure t-test.

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Table 18.1: Birmingham IBS 1. Baseline vs Control (run-in-phase) n=42 (Analysis as per Roalfe (2008)) i The results for this aspect of the study are set out in Fig 18.1 of the accompanying drawings.

Note: Most patients reporting constipation (N=7) at visit 1 were taking laxatives/herbs during the run- in =control phase, thus reducing the number reporting constipation at baseline (v2) to n=3.

Table 18.2: Birmingham IBS Symptom - Score: Baseline vs Control (run-in-phase) n=42 (Analysis as per Roalfe (2008))

The results for this aspect of the study are set out in Fig 18.2 of the accompanying drawings.

Note: Most patients reporting constipation (N=7) at visit 1 were taking laxatives ) during the run- in =control phase, thus reducing the number reporting constipation at baseline (v2) to n=3.

> Table 18.3: Birmingham IBS Symptom - Number of Days: Baseline vs 12 weeks = Change after treatment with the Medication

The results for this aspect of the study are set out in Fig 18.3 of the accompanying drawings.

Bold p-values shown in Table 18.3 are indicative of statistical significance (p < 0.05).

)

Table 18.4: Birmingham IBS Symptom Score: Baseline vs 12 weeks = Change after treatment with the Medication

The results for this aspect of the study are set out in Fig 18.4 of the accompanying 35 drawings.

In summary:

The Medication significantly improved frequency (days) and severity (score) of

2019101555 11 Dec 2019 lower Gl symptoms, including diarrhea, and overall pain (p<0.001).

• Constipation improved in a small number of patients (n=3) reporting constipation at baseline (p=0.047).

> Figure 19 - Birmingham Day Differences

These data are represented graphically in Fig 19 of the accompanying drawings.

) Figure 20 - Birmingham Scores Questionnaire

These data are represented graphically in Fig 20 of the accompanying drawings.

Birmingham lower Gl Symptoms Questionnaire i

These data analyse the results obtained from various subgroups in the study. Each subgroup includes solely participants with the particular symptom.

Table 19: Birmingham Days: Control vs Baseline

Questionnaire	Measure	N	Control Mean ± SE	Baseline Mean ± SE	Difference Mean ± SE	p-value
Birmingham days	Constipation	34	6.44 ±0.69	4.24 ±0.75	2.19 ±0.66	p = 0.02
Diarrhea	37	6.02 ±0.86	5.94 ±0.84	0.087 ± 0.60	p = 0.89
Abdominal pain	39	7.53 ±0.86	7.94 ±0.88	0.42 ±0.70	p = 0.56
Troublesome Flatulence	34	4.60 ±0.45	4.94 ±0.37	0.35 ±0.41	p = 0.41

Table 20: Birmingham Days: Baseline vs 12 weeks

Questionnaire	Measure	N	Control Mean ± SE	Baseline Mean ± SE	Difference Mean ± SE	p-value
Birmingham days	Constipation	34	4.24 ±0.75	2.97 ±0.76	1.28 ±0.60	p = 0.04
Diarrhea	37	5.94 ±0.84	2.31 ±0.47	3.62 ±0.81	p < 0.001
Abdominal pain	39	7.94 ± 0.88	2.14 ±0.49	5.79 ±0.79	p < 0.001
Troublesome Flatulence	34	4.94 ±0.37	1.38 ±0.36	3.57 ±0.52	p < 0.001

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Table 21: Birmingham Score: Control v Baseline

Questionnaire	Measure	N	Control Mean ± SE	Baseline Mean ± SE	Difference Mean ± SE	p-value
Birmingham days	Constipation	34	7.82 ±0.70	6.88 ±0.59	0.94 ±0.51	p = 0.07
Diarrhea	37	8.16 ±0.73	7.78 ±0.72	0.38 ±0.60	p = 0.53
Abdominal pain	39	8.12 ±0.57	7.97 ±0.51	0.15 ±0.51	p = 0.76
Troublesome Flatulence	34	4.09 ±0.18	4.24 ±0.13	0.147 ±0.18	p= 0.42

> Table 22: Birmingham Score: Baseline v 12 weeks

Questionnaire	Measure	N	Baseline Mean ± SE	12 wks Mean ± SE	Difference Mean ± SE	% Change reduction	p-value
Birmingham days	Constipation	34	6.88 ±0.59	4.12 ±0.70	2.76 ±0.66	-40%	P< 0.001
Diarrhea	37	7.78 ±0.72	4.43 ± 0.60	3.35 ±0.62	-43%	P< 0.001
Abdominal P	39	7.97 ±0.51	3.05 ± 0.46	4.92 ±0.51	-62%	P< 0.001
Troubleso me Flatul	34	4.24 ±0.13	1.79 ±0.30	2.44 ± 0.35	-58%	P< 0.001

) Figure 21: Birmingham Scores Questionnaire

Fig 21 depicts graphically, analysis of the results obtained from four participant subgroups.

[The next page is page No 43].

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Figure 22: Birmingham Score Subgroup Analysis

Fig 22 depicts graphically, analysis of the Birmingham Score results across four : participant subgroups.

In summary:

• Three-quarters of the participants experienced a combination of specific Gl ι symptoms.

• 77% (n=33 out of 42) suffered constipation and abdominal pain at baseline.

• 83% (n=35) suffered diarrhea and abdominal pain at baseline.

• 71% (n=30) suffered constipation and flatulence at baseline.

• 76% (n=32) suffered diarrhea and flatulence at baseline.

: · The Medication significantly reduced the frequency and severity by 40-60% of lower Gl symptoms, such as constipation (40%), diarrhea (43%), abdominal pain (62%), and troublesome flatulence (58%) in participants with these symptoms at beginning of the study (p<0.0001).

Figure 23: Example of Birmingham IBS Questionnaire

Fig 23 depicts an example of a Birmingham Score Questionnaire for IBS.

Reference: Roalfe AK, Roberts LM, Wilson S. Evaluation of the Birmingham IBS symptom 25 questionnaire. BMC Gastroenterology 2008;8:30.

[The next page is page No 44],

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Irritable Bowel Syndrome - Quality of Life (IBS-QoL) (Lower Gl Symptoms)

Total participants with lower gastrointestinal symptoms: N=42

Note: 1 participant was excluded from the analyses of lower Gl symptoms as that participant had only upper symptoms.

Method of analysis: Within subjects comparison of Irritable Bowel Syndrome QoL by repeated measure t-test.

Table 23: IBS-QoL 1. Baseline vs Control (run-in-phase)

Table 23

Questionnaire	Measure	N	Control Mean ± SE	Baseline Mean ± SE	Difference Mean ± SE	p-value
IBS QoL	Emotional	42	9.62 ±0.88	9.41 ±1.00	0.21 ±0.49	p = 0.67
Mental Health	42	8.81 ±0.83	9.07 ±0.96	0.26 ±0.49	p = 0.60
Sleep	42	4.98 ±0.71	4.09 ±0.644	0.88 ±0.64	p = 0.17
Energy	42	5.74 ±0.52	5.90 ±0.55	0.17 ±0.33	p = 0.62
Physical Function	42	4.90 ±0.76	4.21 ±0.74	0.69 ±0.76	p = 0.37
Diet	42	7.31 ±0.54	7.52 ±0.64	0.21 ±0.43	p =0.62
Social Role	42	8.74 ±0.72	7.97 ±0.76	0.76 ±0.40	p = 0.06
Physical Role	42	6.81 ±0.99	6.50 ±1.00	0.31 ±0.53	p = 0.56
Total Score	42	56.90 ±4.60	51.95 ±4.68	4.95 ±1.87	p = 0.012

Bold p-values are indicative of statistical significance (p < 0.05).

[The next page is page No 45].

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Table 24: Baseline vs 12 weeks = Change after intervention

Table 24

Questionnaire	Measure	N	Baseline Mean ± SE	Week 12 Mean + SE	Difference Mean + SE	p-value
IBSQoL	Emotional	42	9.41 ± 1.00	3.00 + 0.78	6.40 + 0.85	p < 0.001
Mental Health	42	9.0710.96	2.48 + 0.74	6.60 + 0.81	P < 0.001
Sleep	42	4.0910.644	0.74 + 0.33	3.36 + 0.60	p < 0.001
Energy	42	5.90 + 0.55	1.79 + 0.43	4.11 + 0.53	p < 0.001
Physical Function	42	4.21 + 0.74	1.38 + 0.47	2.83 + 0.73	p < 0.001
Diet	42	7.52 + 0.64	3.64 + 0.56	3.88 + 0.63	p < 0.001
Social Role	42	7.97 + 0.76	3.40 + 0.68	4.57 + 0.67	p < 0.001
Physical Role	42	6.50 + 1.00	2.00 + 0.63	4.50 + 0.79	p < 0.001
Total Score	42	51.95 + 4.68	18.43 + 4.13	33.52 ±3.86	p < 0.001

Note: Bold p-values are indicative of statistical significance (p < 0.05).

In summary:

i · The Medication significantly improved lower symptoms associated Quality of Life, including emotional and mental health and wellbeing, sleep, energy, physical functioning, diet and social interactions (p<0.001).

Figure 24: IBS Qol Score Difference

The data for this aspect of the study are represented graphically in Fig 24 of the accompanying drawings.

Figure 25: Example of Revised IBSQoL

An example of this appears at Fig 25 of the accompanying drawings.

[The next page is page 46].

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Bristol Stool Chart

Table 25: Bristol Stool Chart 1: Number of participants with each stool type (n=43)

Table 25

	Type 1: Hard Lumps	Type 2: Sausag e- shaped	Type 3: Like a sausage with cracks	Type 4: Like a sausage or snake	Type 5: Soft blobs with clear cut edges	Type 6: Fluffy pieces with ragged	Type 7: Watery, no solid pieces
Control	3	4	14	10	4	8	0
Baseline	1	2	15	13	5	7	0
12 Weeks	1	10	12	18	1	1	0

Figure 26: Bristol Stool Chart 1: Number of participants with each stool type (n=43)

The data set out in Table 25 are represented graphically in Fig 26 of the accompanying drawings.

In summary:

• The Medication improved stool consistency towards the ideal type 4, and harder stools (types 3 and 2);

• The number of participants with loose/ diarrhoea-like stools significantly reduced, due to the fibre ingredients, such as Pectin, in the Medication (p<0.001);

• The Medication significantly improved stool frequency and regularity towards the ideal 1-2 times per day; and • A daily dose of 10g/day of the Medication was more likely to induce constipation that a dose of 5g/day.

[The next page is page No 47],

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Table 26: Bristol Stool Chart 2: Number of participants and average frequency of passing stools (n=43)

Table 26

Number of Days	>2 times per day	1-2 times per day (Ideal)	Every second day	1-3 days per week
Control	6	25 (58%)	6	2
Baseline	4	33 (76%)	5	1
12 weeks	5	34 (79%)	3	1

) Figure 27

The data set out in Table 26 are represented graphically in Fig 27 of the accompanying drawings.

Figure 28: An Example of the Bristol Stool Chart

An example of this appears at Fig 28 of the accompanying drawings.

D

Reference: Lewis S, Heaton K. Stool form scale as a useful guide to intestinal transit time Scandinavian J Gastroenterology 1997;32:920-4

Analysis of the Bristol Stool Chart Results by Repeated Measures t-test

Table 27: Bristol Stool Chart by Stool Consistency: Control vs Baseline

Stool type	Visit	n	Mean ± SE	Mean Difference ± SE	p- value
Normal	Control	1	4.00 ± 0	0.50 ±0.37	p = 0.21
	Baseline	1	4.50 ±0.37
Soft	Control	1	5.67 ±0.14	0.917 ±0.26	p = 0.05
	baseline	1	4.75 ±0.31
Hard	control	2	2.52 ±0.16	0.667 ± 0.26	p = 0.019
	baseline	2	3.19 ±0.20

Legend to Table 27:

Normal, optimal value = 4

Values below 4 are indicative of harder stools.

Values over 4 are indicative of softer, waterier stools.

2019101555 11 Dec 2019

Table 28: Bristol Stool Chart by Stool Consistency Baseline vs Week 12

Stool type	Visit	n	Mean ± SE	Mean Difference ± SE	p-value
Normal	baseline	10	4.50 ±0.37	1.00 ±0.47	p = 0.063
	12 weeks	10	3.50 ±0.40
Soft	baseline	12	4.75 ±0.31	1.42 ±0.34	p = 0.001
	12 weeks	12	3.33 ±0.23
Hard	baseline	21	3.19 ±0.20	0.095 ±0.32	ns
	12 weeks	21	3.10 ±0.22

Legend to Table 28:

Normal, optimal value = 4

Values below 4 are indicative of harder stools.

D Values over 4 are indicative of softer, waterier stools.

In summary:

• The results show a significant change towards the normal stool type in the soft stool group;

• The Medication had the most beneficial impact on the soft stool group.

Analysis of pain experienced by the participants Pain Scales - VAS (n=43)

Method of analysis: Within-subject comparison of the Pain VAS by repeated measure t-test by group (upper Gl symptoms or lower Gl symptoms)

The impact of the Medication on pain experienced by the participants was measured by using a Visual Analog Scale (“VAS”) for pain measurement.

[The next page is page No 49].

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Table 28A: Analysis of pain experienced by the participants Pain Scales - VAS (n=43)

The data for this aspect of the study are set out in Table 28A (below).

Table 28A

Questionnaire	Measure	N	Baseline	12 week score	Difference	p-value
Pain VAS Upper group	Upper Gl Pain	13	5.08 ±0.69	2.62 ±0.95	2.46 ±1.33	p = 0.088
	Lower Gl pain	24	4.23 ±0.54	1.97 ±0.42	2.25 ±0.59	p = 0.001
Other Pain	24	5.08 ±0.39	2.49 ±0.43	2.59 ±0.64	p < 0.001

(Reference: McCormack, JM, Horne, DJ and Sheather, S, “Clinical applications of visual analogue scales: a critical review”

Psychol Med (1988): 18, 1007-1019).

Note: Only participants who experienced pain are included in the tables and figures. Some participants experienced several types of pain. Some participants did not report any pain.

The numbers of participants who experienced one or more types of pain were as follows:

N= 5 3 types of pain

N= 6 2 types of pain (upper & lower)

N = 13 1 type of pain [The next page is page No 50].

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Upper Gl Symptom Group (n=32):

Table 29: Pain VAS (Score 0-10): Baseline vs Control (run-in-phase, n=32)

The data for this aspect of the study are set out in Table 29 (below).

Table 29

Questionnaire	Measure	N	Control Mean ± SE	Baseline Mean ± SE	Difference Mean ± SE	p-value
Pain VAS Upper group	UpperGI Pain	13	6.81 ±0.58	5.08 ±0.69	1.73 ±0.74	p = 0.038
	Lower Gl pain	24	4.62 ±0.38	4.23 ±0.54	0.40 ±0.52	p = 0.45
	Other Pain	24	4.76 ±0.44	5.08 ±0.39	0.33 ±0.46	p = 0.49

Table 30: Pain VAS: Baseline vs 12 weeks = Change after Treatment with the Medication (n=32)

The data for this aspect of the study are set out in Table 30 (below).

Table 30

Figure 29: Pain Severity (Upper Gl Symptoms)

The data for this aspect of the study are represented graphically in Fig 29 of the accompanying drawings.

Summary:

• Participants who experienced upper Gl symptoms demonstrated a significant reduction in upper abdominal, lower abdominal and other pain following treatment with the Medication in the study.

2019101555 11 Dec 2019

Lower Gl Symptoms Group (n=42):

Table 31: Pain VAS: Baseline vs Control (run-in-phase) : The data for this aspect of the study are set out in Table 31 (below).

Table 31

Questionnaire	Measure	N	Control Mean ± SE	Baseline Mean 1 SE	Difference Mean + SE	p-value
Pain VAS lower group	UpperGI Pain	12	6.7110.62	5.08 + 0.75	1.73 + 0.74	p = 0.64
	Lower Gl pain	30	4.7110.35	4.38 + 0.49	0.33 + 0.49	p = 0.50
	Other Pain	31	4.72 + 0.36	4.75 + 0.39	0.03 + 0.47	p = 0.95

Table 32: Pain VAS: Baseline vs 12 weeks after the Medication

The data for this aspect of the study are set out in Table 32 (below).

Table 32

Questionnaire	Measure	N	Baseline Mean 1 SE	12 weeks Mean + SE	Difference Mean + SE	p-value
Pain VAS Lower group	Upper Gl Pain	12	5.08 + 0.75	2.25 + 0.95	1.80 + 0.79	p = 0.065*
	Lower Gl pain	30	4.38 + 0.49	1.58 + 0.36	2.80 + 0.56	p < 0.001 *
Other Pain	31	4.75 + 0.39	2.81 + 0.43	1.93 + 0.63	p = 0.004*

Legend to Table 32:

i * = Statistical significance • Upper pain: borderline significant difference between baseline and 12 weeks (0.065), likely due to small numbers (n=12).

Figure 30: Pain Severity (Lower Gl Symptom Group)

The data for this aspect of the study are represented graphically in Fig 30 of the accompanying drawings.

In Summary:

• Participants experiencing lower Gl symptoms demonstrated a significant reduction in upper abdominal, lower abdominal and other pain following treatment with the medication during the study.

• There were no significant reductions in pain severity between the control and baseline between any of the measures.

2019101555 11 Dec 2019

Other Symptoms (n=43) relevant to gastrointestinal disturbances

The data for certain other symptoms relevant to gastrointestinal disturbances experienced by the participants during the study are set out in Table 33, which : appears at Fig 31 of the accompanying drawings.

Figure 20: Change in Other Symptoms - Medical Treatment Trial

The data for this aspect of the study are represented graphically in Fig 32 of the accompanying drawings.

i As indicated in Fig 32:

* Statistical analysis methodologies applied: Chi-Square analysis and Fisher’s Exact Test with two-tailed p-values using www.graphpad.com; and * p<0.05 : In Summary;

* The Medication generally reduced the incidence of other Gl-related symptoms, such as mouth ulcers, bad breath and rashes, with a significant lesser number of participants feeling constantly tired, or nervous (p<0.05).

Intestinal Permeability - Leaky Gut Report

I

Table 34: Leaky Gut - Intestinal Permeability Test (urine) - Baseline Test

Table 34

	Participants (n)	Mean (SD)	Range	Comment
Lactulose Recovery	43	1.31 (0.67) %	Normal: 0 0.3%	All above normal range
Mannitol Recovery	43	35.04 (13.3) %	Normal: 9.5- 25%	N=8 (18.6%) in normal range N=35 (81.4%) above normal range
Lactulose/Mannitol	43	0.040 (0.02)	Normal: 0-0.035	N=21 (48.8%) in

2019101555 11 Dec 2019

Ratio (LMR)

normal range N= 22 (51.2%) above normal range

Leaky Gut: Baseline - summary:

• All participants (n=43) had intestinal permeability or • About 80% (n=35) had intestinal hyperpermeability (high Lactulose and Mannitol • About half of the participants had an elevated Lactulose/Mannitol Ratio which suggests size of the gut mucosa has increased, allowing larger, possibly antigenic molecules to enter the blood

Table 35: Leaky Gut Baseline (v1), 12 weeks (v5) and change

The data for this aspect of the study are set out in Table 35 (below).

Table 35

Descriptive Statistics

	N	Minimum	Maximum	Mean	Std. Deviation
vl Lactulose Recovery	42	.41	3.34	1.3288	.67106
vl Mannitol Recovery	42	12.51	77.59	34.9674	13.41417
vl LM ratio	42	.012	.111	.04114	.022725
v5 Lactulose Recovery	42	.22	1.57	.5869	.36022
v5 Mannitol Recovery	42	13.00	41.92	26.1179	7.46940
v5 LM ratio	42	.011	.054	.02202	.010522
v51 Lactulose change	42	-3.11	.82	-.7419	.73055
v51 Mannitol change	42	-43.41	16.49	-8.8495	13.16274
v5 l LMratio cha nge	42	-.08	.01	-.0191	.02306

Legend to Table 35:

Normal ranges:

Lactulose Recovery: 0-0.3 % - the lower the lactulose recovery, the better Mannitol Recovery: 9.5-25%

LM ratio: 0-0.035 - the lower the LM Ratio the better.

N=42 (Note: One participant did not perform the test at the end of study; n=31 lower symptoms)

2019101555 11 Dec 2019

Analysis:

• Lactulose Recovery: mean (v1->v5) = 1.33 % (above normal range) -> 0.59 % (slightly above normal) : · v51 mean change - 0.74 % (more than 50% change to the better) • Mannitol Recovery: mean (v1->v5) = 35% (above normal range) -> 26.1 % (slightly above normal) • v51 mean change - 8.8 %, change to the better, improvement • LM ratio: mean (v1->v5) = 0.04 (above normal range) -> 0.22 % (within normal) i · v51 mean change - 0.02, change to the better, improvement

Figure 33: lactulose recovery data

The data for this aspect of the study are represented graphically in Fig 33 of the accompanying drawings.

As indicated in Fig 33, the data shown were analysed using the Chi-square test: P= : 0.0258.

In Summary:

• Lactose recovery - all above normal at V1.

· v5 result: 6/42 (14%) achieved normal levels after Medical treatment [The next page is page No 55].

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Figures 34 and 35: Individual Lactulose levels & percentage change over time

The data for this aspect of the study are represented graphically in Fig 34 and Fig 35 of ι the accompanying drawings.

[The next page is page No 56].

jj

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Figure 36: Mannitol Recovery

The data for this aspect of the study are represented graphically in Fig 36 of the accompanying drawings.

i The following observations are made about the data:

• *Statistical analysis was performed via the Chi-square test: P= 0.0046;

• V1: N=7 (16%) within normal range -> v5: n=20 (48%, half) within normal range after treatment with the Medication;

i · N=35 (84%) above normal range -> v5: n=22 (42%) above the normal range;

• Comparison of the number of participants above the normal range at v1 vs v5 by Chi-square Test; and • There was a significantly larger number of participants in the normal range for Mannitol Recovery after the treatment with the Medication than before (p = ; 0.003), indicating healing of leaky gut and a healthier gut membrane after the treatment.

Figure 37: Individual Mannitol Levels & Percentage Change Over Time

The data for this aspect of the study are represented graphically in Fig 37 of the i accompanying drawings.

Lactulose-Mannitol (“LM”) Ratio

With reference to Fig 38, the following observations are made concerning the data 25 gathered from this aspect of the study:

• V1: normal n=21 (50%), above range n=21 (50%);

• V5: normal n=36 (86%), above n=6 (14%);

• V1 -> v5 normal 50-86%, 36% improved to normal.

[The next page is page No 57],

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Summary of individual changes in the LM Ratio:

: · The LM ratio improved for all but one participant, with high LM levels (above normal range, group 2, n=21) at baseline.

• The one participant in group 2 with an increase in LM ratio chose to have no medical treatment (Og) in month 3.; and

I • All participants with LM ratios in the normal range at baseline (group 1) remained in this category;

• Chi-square Test: P= 0.0009.

[The next page is page No 58].

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Figure 39: Individual LM Ratio percentage change 0-12 weeks by Group LM ratio

The data for this aspect of the study are represented graphically in Fig 39 of the i accompanying drawings.

Comparison of means for Leaky Gut Studies - paired t-Test

The comparisons are set out in Table 35A (below).

) Table 35A

Paired Samples Statistics

Mean N Std. Deviation Std. Error Mean

vl Lactulose Recovery	1.3288	42	.67106	.10355
v5 Lactulose Recovery	.5869	42	.36022	.05558
vl Mannitol Recovery	34.9674	42	13.41417	2.06985
v5 Mannitol Recovery	26.1179	42	7.46940	1.15255
vl LM ratio	.04114	42	.022725	.003507
v5 LM ratio	.02202	42	.010522	.001624

Table 36 (below) sets out data for certain Leaky Gut studies, showing the changes observed after medical treatment.

i

Table 36: Leaky Gut:

Baseline vs 12 weeks - Change after medical treatment ) excl n=2 (Og/day dosage)

Measure N Baseline Mean 12 Weeks Difference % change p-value

Lactulose Recover	40	1.33 ±0.11	0.55 ±0.05	0.78 ±0.11	59%	p < 0.001
Mannitol Recovery	40	35.4 ±2.14	26.0 ±1.17	9.43 ±2.0	27%	p < 0.001
LM Ratio	40	0.04 ± 0.004	0.03 ±0.001	0.02 ± 0.004	50%	p< 0.001

By dose

Dose/day	Measure	N	Baseline Mean ± SE	12 Weeks Mean ± SE	Difference Mean ± SE	% change	p-value
5g	Lactulose Recovery	13	1.27 ±0.16	0.54 ±0.28	0.72 ±0.16	57%	p = 0.001
10g		27	1.37 ±0.14	0.56 ±0.07	0.81 ±0.15	59%	p< 0.001
5g	Mannitol Recovery	13	37.8 ±4.93	27.4 ±2.14	10.39 ±4.45	28%	p = 0.038
10g		27	34.3 ±2.15	25.3 ±1.40	8.97 ±2.18	26%	p< 0.001
5g	LM Ratio	13	0.04 ± 0.007	0.02 ±0.002	0.02 ±0.007	50%	p = 0.02
10g		27	0.04 ± 0.004	0.02 ±0.002	0.02 ± 0.004	50%	p< 0.001

2019101555 11 Dec 2019

ByPPI

PPI yes/no	Measure	N	Baseline Mean ± SE	12 Weeks Mean ± SE	Difference Mean ± SE	% change	p-value
PPI use	Lactulose Recovery	11	1.21 ±0.16	0.56 ±0.11	0.65 ±0.19	54%	p = 0.007

PPI use	Mannitol Recovery	11	34.7 ±3.38	26.8 ±1.84	7.95 ±3.47	23%	p = 0.045

PPI use	LM Ratio	11	0.04 ±0.005	0.02 ±0.004	0.02 ±0.005	50%	p = 0.007

Notes: Normal ranges: Lactulose Recovery: 0-0.3 %; Mannitol Recovery: 9.5-25%; LM ratio: 0-0.035 i PPi = Proton Pump inhibitor

In Summary:

) · The Medication significantly improved intestinal permeability, including

Lactulose by 59%, Mannitol Recovery by 27%, and Lactulose/Mannitol Ratio by 50% (p<0.001).

• The dosage of the Medication did not change the outcome appreciably.

• Individuals on PPIs had a slightly smaller but still significantly positive i improvement in intestinal permeability, including Lactulose Recovery by

54%, Mannitol Recovery by 23%, and Lactulose/Mannitol Ratio by 50%.

[The next page is page No 60].

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Figures 40 (a) - (b): Leaky Gut by Dosage - Individual Graphs

Lactulose Recovery by Dosage

The data for this aspect of the study are represented graphically in Fig 40 (a) and (b) of the accompanying drawings.

Figures 41 (a) - (b): Mannitol Recovery by Dosage

The data for this aspect of the study are represented graphically in Figs 41 (a) and (b) of the accompanying drawings.

Figures 42 (a) - (b): LM ratio by dosage - Individual Graphs

The data for this aspect of the study are represented graphically in Figs 42 (a) and (b) of the accompanying drawings.

Figures 43 (a) - (c): Leaky Gut by PPI Intake - Individual Graphs

The data for this aspect of the study are represented graphically in Fig 43 (a) to (c) of the accompanying drawings.

Figures 44 and 45 - Leaky Gut Change by BASELINE Stool Consistency

The data for this aspect of the study are represented graphically in Fig 44 and 45 of the accompanying drawings.

In Summary:

Percentage change within group:

The Medication significantly improved Lactulose Recovery for 33% of participants with normal stools, and 14% of participants with hard stool/constipation-type (p=0.0001), while there was no change in the group with soft stool I diarrhea-type. Lactulose Recovery remained above the reference range for leaky gut for all participants with soft stools.

[The next page is page No 61].

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Figures 46 and 47 - Mannitol recovery change by stool consistency

The data for this aspect of the study are represented graphically in Fig 46 and Fig 47 of the accompanying drawings.

: In Summary:

• The Medication significantly improved Mannitol Recovery for 45% of participants with normal stools, and 43% of participants with hard stools/constipation-type (p=0.0001), while there was no change in the group i with soft stool/ diarrhea-type; and • A third of participants (33%) with soft stool had Mannitol Recovery values within the normal range at baseline and at 12 weeks.

Figures 48 and 49 - LM Ratio change by stool consistency

The data for this aspect of the study are represented graphically in Fig 48 and Fig 49 of the accompanying drawings.

In Summary:

I • The Medication significantly improved Lactulose/Mannitol Ratio for 44% of participants with normal stool, and 33% of participants with soft stool/ diarrhea-type, and 33% of participants with hard stool/constipation-type (all groups: p=0.0001);

· All participants (100%) with normal stool, 90% with hard stool, and 66% with soft stool had normal LM Ratio levels, indicating a recovery from leaky gut, after taking the Medication for 3 months.

2019101555 11 Dec 2019

Cytokine Report - Inflammatory Marker Levels

Some key parameters for this aspect of the study were:

: Total participants analysed: N=43

Time points: v1 = between enrolment and baseline; v4 = between 8 and 12 weeks (end of study) i Method of Analysis: Within-subject comparison of Cytokine levels measured by repeated measure t-test.

The data for this aspect of the study are set out in Table 37, which appears in Fig 50 of the accompanying drawings, and in Fig 51.

: Summary of some observations from the results of this aspect of the study:

• Inflammatory marker levels in all participants were within or close to normal range.

• No significant changes in IL1 β, IL6, and TNFa were observed.

> Interleukin 1b change: small reduction - 0.0674 - all (v1 and v4) within i normal range > IL6 change: small reduction -0.0140 - all (v1 and v4) within normal range > TNFa: v1 & v4 very similar - only slight increase, only slightly above range of 14 (highest 17); V1 n=3 above range -> 2/3 stayed above range, 1 reduced, 1 increased, 4 different people above range.

• Further investigations into the slightly larger but not significant changes in IL8 revealed several confounding factors. The exclusion of n=6 participants with elevated IL8 levels revealed a smaller non-significant change in IL8 levels.

IL8 (interleukin 8) Level measurements (Excluding n=6 (change increase to >40 pg/ml, above range))

Some observations from the results of this aspect of the study:

1) ID 50 v41 change = 85.20, v4 = 94: had vertigo at time of blood draw (possibly due to a viral influence); IL 8 is implicated in viral infections (Bosch, I et al, J ViroL 2002 Jun; 76 (11 ):5588-97):

2019101555 11 Dec 2019

2) ID 26: v41_change = 68.20, started body building training during trial, IL8 increase implicated after exercise (Frydelund-Larsen L, Penkowa M, Akerstrom T, Zankari A, Nielsen S, et al. (2007). “Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle”, Experimental Physiology Vol.

92, No. 1 (January 2007), pp. 233-40.);

3) ID 21: v41_IL8_change = 47.30, taken PPI proton pump inhibitors before blood test, PPI increase IL8 production from gastric cells (Handa, O et al, Inflamm Res. 2006 Nov; 55 (11 ):476-80);

4) ID 24: v41_IL8_change = 46.90, started food trigger challenges during trial, had a bad flare up for 4 days prior to blood test;

5) ID 22: v41_IL8_change = 44.00, had a UTI infection the month before blood test, just stopped antibiotics, IL8 early marker for bacterial infection (Hirao, Y et al., “Interleukin 8 - An early marker for bacterial infection”, Laboratory Medicine, Volume 31, Issue 1, January 2000, Pages 39-44);

6) ID 2: v41-IL8_change = 43.50, had angular chelates (mouth edge sores), IL8 increase implicated in inflammatory skin conditions, such as psoriasis (Kondo S et al, “IL-8 gene expression and production in human keratinocytes and their modulation by UVB” J Invest Dermatol. 1993 Nov; 101 (5):690-4).

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Table 38 - Cytokine Analysis by Group (Upper / Lower Gl Symptoms)

The data for this aspect of the study are set out in Table 38, which appears in Fig 52 of the accompanying drawings.

Summary:

• Cytokine analysis by group (upper/lower symptoms) and by dosage (results i not shown) (Og, 5g, 10g) did not reveal any significant differences between the groups.

• Other than IL8 changes (due to complicating factors), no meaningful changes were observed.

• Normal acute fluctuations of inflammatory markers were expected.

: · The Medication does not influence inflammatory markers (in either direction), meaning it is safe because it doesn’t cause inflammation.

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Microbial Analysis Report (all n = 37)

The data for this aspect of the study are set out in Tables 39 (a) and (b) and Tables 40 (a) and (b) (below), which set out the Relative Abundance CFU/g (colony-forming i units per gram) - change over baseline to 12 weeks (v4- v1):

Tables 39 (a) - (b)

Bacteroidetes Phylum

	N	Mean	Std. Deviation
v41_Bacl_change Bacterioides-Prevotella group	37	280189189.2	807513393.0
v41_Bac2_change Bacterioides vulgatus	37	494270270.3	4972303343.0
v41_Bac3_change Barnesiella spp	37	60978378.38	147075778.2
v41_Bac4_change Odoribacter spp	37	23502702.7	80202055.55
v41_Bac5_change Prevotella spp	37	1209189.189	8244917.08
V41_sumBac_change Total Bacterioidetes phylum	37	860149729.7	5455944081.0

Firmicutes Phylum
	N	Mean	Std. Deviation
v41_Firml_change Anaerotruncus colihominis	37	1646486.486	12721424.67
v41_Firm2_change Butyrivibrio crossotus	37	139027.020	518990.4054
v41_Firm3_change Clostridium spp	37	947378378.4	4520966940.0
v41_Firm4_change Coprococcus eutactus	37	4816216.216	20765675.92
v41_Firm5_change Faecalibacterium prausnitzii	37	816972973.0	3563494559.0
v41_Firm6_change Lactobacillus spp	37	215405405.4000	1827978672.0
v41_Firm7_change Pseudoflavonifractor spp	37	54078378.380	158809612.0
v41_Firm8_change Roseburia spp	37	505702702.700	1714215546.0

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v41_Firm9_change Ruminococcus spp	37	5632432.432	76946348.75
v41_Firml0_change Veillonella spp	37	4586216.216	14449033.1
v41_sumFirm_change Total Firmicute phylum	37	2556358216.0	9362021650.0

Tables 40 (a) - (c)

	Actinobacteria Phylum	Std. Deviation
N	Mean
v41_Actinol_change Bifidobacterium spp	37	-74324324.320	763879755.4
v41_Actino2_change Bifidobacterium longum	37	-2789189.1890	69444677.36
v41_Actino3_change Collinsella aerofaciens	37	106378378.4000	436467216.0
v41_sumActino_change Total Actinobacteria phylum	37	29264864.86	1140080357.0
	Proteobacteria Phylum N Mean	Std. Deviation
v41_Proteol_change Desulfovibrio piger	37	1966378.378	12664416.41
v41_Proteo2_change Escherichia coli	37	3333243.243	58902755.03
v41_Proteo3_change Oxalobacter formigenes	37	812972.973	13448609.98
v41_sumProteo_change	37	6112594.595	70628367.26

Total Proteobacteria phylum

Euryarchaeota, Fusabacteria, Verrucomicrobia Phylum
	N	Mean	Std. Deviation
v41_methanobrevi_change Methanobrevibacter smithii	37	6937567.568	59543865.22
v41_Fusobac_change Fusobacterium spp	37	22524.3243	47322.842
v41_Akkermansia_change	37	1119459.459	6976722.386

Akkermansia muciniphila

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Figure 53: Change in microbial profile after 12 week program with the Medication (n=37) i The data for this aspect of the study are represented graphically in Fig 53 of the accompanying drawings.

Summary - Microbiota Changes (n=37):

• Mean Bacteriodetes, Firmicutes and Proteobacteria bacterial mass (RA) ) increased over time.

• Mean Bifidobacteria bacterial mass (relative abundance) decreased over time.

• Bifidobacteria and Lactobacilli are standard probiotics. In this study, participants were asked to stop their probiotic intake before the commencement of treatment (so as to take the Medication) one month after i the baseline stool test.

Observations on the results depicted in Fig 53:

Bacterioides vulgatus:

• Unlike other colonic Bacteroides species, B. vulgatus is not a versatile ) utilizer of polysaccharides. The only types of polysaccharide that support rapid growth and high growth yields by all strains are the starches amylose and amylopectin.

• B.vulgatus is the only sequenced Bacteroidetes species that possesses a gene coding for a xylanase. It has the largest and most complete set of enzymes that target pectin.

http://bacmap.wishartlab.com/organisms/533 • Pectin is included in the Medication.

Clostridium spp:

• While Clostridium spp have a bad reputation (e.g. Clostridium difficile, Clostridium botulism), not all Clostridia bacteria are detrimental to gut health.

• The study by Stefka et al (2014) in mice, found that a common gut bacteria called Clostridia helps prevent sensitization to food allergens. In fact,

2019101555 11 Dec 2019 immune responses to food allergens were reversed once Clostridia bacteria were put back into the mice.

• Another common type of gut bacterium, Bacteroides, did not have this effect, suggesting Clostridia may have a unique role in this regard.

i · The study found, that Clostridia colonization activates innate immune genes in intestinal epithelial cells.

Reference: Stefka, Andrew T., et al. Commensal bacteria protect against food allergen sensitization. Proceedings of the National Academy of Sciences 111.36 (2014): 13145-13150.

) Faecalibacterium prausnitzii:

• Faecalibacterium prausnitzii might have been influenced by the fibre-rich cellulose in the placebo capsules. Cellulose, generally regarded as inert, may have been food for growth for bacterial species thriving on dietary fibre, such as the Firmicute Butyrivibria crossus.

i References:

Chung WSF, Walker AW, Louis P, Parkhill J, Vermeiren J, Bosscher D, etal. Modulation of the human gut microbiota by dietary fibres occurs at the species level. BMC Biology 2016; 14:3; and

Flint HJ, Scott KP, Duncan SH, Louis P, Forano E. Microbial degradation of complex carbohydrates in the gut. Gut Microbes 2012;3:289-306

Lactobacillus spp:

• Lactobacillus bacteria, increased by the prebiotic aged garlic extract, are generally regarded as beneficial.

Reference: Slavin J. Fiber and prebiotics: mechanisms and health benefits. 25 Nutrients 2013; 5:1417-35.

Roseburia spp:

• The genus Roseburia consists of obligate Gram-positive anaerobic bacteria that are slightly curved, rod-shaped and motile by means of multiple subterminal flagellae. It includes five species: Roseburia intestinalis, R. hominis, R. inulinivorans, R. faecis and R. cecicola.

2019101555 11 Dec 2019 • Gut Roseburia spp. metabolize dietary components that stimulate their proliferation and metabolic activities. They are part of commensal bacteria producing short-chain fatty acids, especially butyrates, affecting colonic motility, immunity maintenance and anti-inflammatory properties.

i References:

https://www.ncbi.nlm.nih.gov/pubmed/28139139Tamanai-Shacoori Z et al.

Roseburia spp.: a marker of health? Future Microbiol. 2017 Feb;12:157-170. ) doi: 10.2217/fmb-2016-0130.

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Subgroup Analysis: Microbial change in participants by reference to whether a probiotic was previously taken

Figure 54 of the accompanying drawings depicts the results of a test to determine the : gut flora profiles of participants from the Baseline Stool test performed before treatment with the Medication commenced. In the results shown, 19 of the participants had previously taken a probiotic, and 11 participants had not.

Summary - Probiotics:

I • Orange (Firm6 = Lactobacilli) + dark grey+black (Actino1+2 = Bifidobacteria) • Seem to increase in group previously taking probiotics • Slight decrease in group not having previously taken probiotics • Conclusion: The Medication promotes the growth of existing beneficial < bacteria introduced through previous intake of probiotics.

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Figure 55: Microbial change by Dosage at 12 weeks (end of study)

The data for this aspect of the study are represented graphically in Fig 55 of the accompanying drawings.

Main change in 5g subgroup (n=13):

Green:

Grey:

Dark green Orange: Light blue:

Bac2 - Bacterioides vulgatus - increase in CFU/g (not in lOg group)

Firm3 - Clostridium spp - increase

Firm5 - Faecalibacillus prausnitzii- increase

Firm6 - Lactobacillus spp - increase (not in lOg group)

Fusobac - Fusobacterium spp - increase (not in lOg group)

Main change in lOg subgroup (n=28):

Grey:

Dark green: GreyBlue:

Firm3 - Clostridium spp - increase (less than 5g group)

Firm5 - Faecalibacillus prausnitzii - increase (less than 5g group) Firm8 = Roseburio - increase (not in 5g group)

Conclusions about the impact of the dose of the Medication on promotion of gut flora growth i The optimum result appears to have been achieved by using the 5g/day dose.

More growth across a larger variety of species was observed at that dosage level, than at the other two levels tested.

Comparison in Gut Flora Profiles - Group-upper symptoms (reflux, upper abdominal pain, stomach) vs group-lower symptoms (lower abdominal symptoms, IBS).

Figure 56: Change in Flora Profile in Group Upper

The data for this aspect of the study are represented graphically and in tabular form in Fig 56 of the accompanying drawings.

Summary by Group (Upper vs Lower Gl):

• Three-quarters (77%; n=20/26) of the participants with upper & lower symptoms chose to take 10g of the Medication.

• A third (36%, n=4/11) of the participants with only lower symptoms chose to take 10g of the Medication, half (45%) chose 5g, and n=2 (20%) chose Og.

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Conclusions:

A dosage of 10g/day of the Medication would appear to be more beneficial for upper Gl symptoms, while 5g of the Medication appears to be sufficient to benefit i lower Gl symptoms.

Figure 57: Microbial Profile at Baseline by Consistency of Stool (Hard/Soft/Normal)

The data for this aspect of the study are represented graphically in Fig 57 of the ) accompanying drawings.

Figure 58: Microbial Change 0-12 Weeks by Stool Consistency at Baseline

The data for this aspect of the study are represented graphically in Fig 58 of the accompanying drawings, i Summary:

• The Microbial profile was similar at baseline across all 3 groups of stool consistency.

) Microbial change over time

Summary:

• While the Medication generally improved microbial profile by increasing relative abundance/bacterial number in participants with normal or hard stool consistency, bacterial number decreased over time in those participants experiencing soft/diarrhea-type stools.

• One possible explanation for this result is that in the group with soft stool, due to the shorter transit time of food and the medication, bacteria have less time to feed and grow/multiply.

· There is a marked difference specifically in the following groups of bacterial species:

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Figures 59 (a) - (b): Microbial Change by Stool Consistency & whether a Participant took a PPI Medicine

The data for this aspect of the study are represented graphically in Fig 59 (a) and (b) of the i accompanying drawings.

Summary:

• PPI use appears to influence bacterial growth.

• While the Medication generally improved microbial profile by increasing rekative abundance/bacterial number in participants not taking PPIs (group no PPI, n=32), ) bacterial number decreased over time in the group on PPI (n=11).

Overall conclusions

These data strongly support the conclusion that the Medication has a number of beneficial effects in subjects who are afflicted with any one or more of a broad variety of gastrointestinal problems, including those of idiopathic origin (such as Irritable Bowel i Syndrome). The Medication can therefore be used to treat many such symptoms, and a broad array of gastrointestinal conditions.

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Interpretation of this specification

It will therefore be understood that the invention could take many forms and be put to many different uses. All such forms and uses are embodied within the spirit and scope of the invention, which is to be understood as not being limited to the particular details of the embodiments discussed above, but which extends to each novel feature and combination of features disclosed in or evident from this specification. All of these different combinations constitute various alternative embodiments of the invention.

It will also be understood that the term “comprises” (or its grammatical variants), wherever used in this specification, is equivalent in meaning to the term “includes” and should not be taken as excluding the presence of other elements or features. Further, wherever used in this specification, the term “includes” is not a term of limitation, and is not be taken as excluding the presence of other elements or features.

It is further to be understood that any discussion in this specification of background or prior art documents, devices, acts, information, knowledge or use (‘Background Information’) is included solely to explain the context of the invention. Any discussion of any such Background Information is therefore not be taken as an admission in any jurisdiction that any such Background Information constitutes prior art, part of the prior art base or the common general knowledge in the field of the invention on or before the earliest priority date or any priority date which the present application claims.

It is also to be understood that wherever in this specification, reference is made to any external document or recorded source of information, then the entire content of that document or the information contained in the recorded source of information is expressly incorporated by reference into this specification verbatim, as if that information was specifically set out in it.

Claims

1. A pharmaceutical substance or formulation for treating or ameliorating the symptoms or adverse effects associated with a functional or a biochemical gastrointestinal disorder in an animal subject, the substance or formulation comprising:

(a) Curcumin:

(b) L-Glutamine;

(c) Quercetin:

(d) Glucosamine:

(e) Aloe vera;

(f) an edible essential oil;

2. A pharmaceutical substance or formulation as claimed in claim 1, in which the animal subject is:

(a) a mammal;

(b) a bird;

(c) a fish;

(d) a reptile; or (e) an amphibian.

3. A pharmaceutical substance or formulation as claimed in claim 2, in which the animal subject is a mammal.

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4. A pharmaceutical substance or formulation as claimed in claim 3, in which the mammal is a human.

5. A pharmaceutical substance or formulation as claimed in either of claim 1 or claim 2, in which the animal subject is:

(a) a mammal other than a human;

(b) a bird;

(c) a fish;

(d) a reptile; or (e) an amphibian.

6. A pharmaceutical substance or formulation as claimed in any one of claims 1 to 5, in which the functional or biochemical gastrointestinal disorder comprises:

(a) any functional gastrointestinal disorder as defined in the Rome IV Classification as published in 2016; or (b) any biochemical gastrointestinal disorder.