Slide-Kit - jh-comm.eu · PDF filedifferential diagnosis such as peptic ulcer disease, achalasia, gastritis, ... aspects of the generic quality of life as seen in this slide. Moreover,

Slide-Kit

Alfa Wassermann and its subsidiaries are part of the Alfasigma Group

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Contents

Part 1. About GastroEsophageal Reflux Disease (GERD) Part 2. Management of GERD Part 3. ESOXX® ONE in management of GERD

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Part 1. About GastroEsophageal Reflux Disease (GERD)

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GastroEsophageal Reflux (GER) as physiological process, is an involuntary passage of gastric contents into the esophagus. Conversely, GastroEsophageal Reflux Disease (GERD) is defined as the manifestation of frequent, severe symptoms or complications which are sufficient to impair the individual’s health related quality of life.The scheme distinguished between individuals who report minor reflux induced symptoms and those in whom symptoms have significant impacts. The latter group makes up about 20% of total population.

Dent J, et al. Gut 2005;54:710-7.Fass R, et al. Am J Gastroenterol 2001;96:303-14. Boeckxstaens G, et al. Gut 2014;63:1185-93.

GastroEsophageal Reflux Disease

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1. Boeckxstaens G, et al. Gut 2014;63:1185-93. 2. Dent J, et al. Gut 2005;54:710-7. 3. Fass R, et al. Am J Gastroenterol 2001;96:303-14.

• Symptoms of GERD such as heartburn and regurgitation occur weekly in about 20% of the adult population3

Mild or infrequent

GERD Significant impact

GERD-like symptoms

Severe or frequent

NOT DISEASE Minor impact

• GastroEsophageal Reflux (GER) is an involuntary passage of gastric contents into the esophagus. It is a normal physiological process that occurs several time a day in all healthy individuals in the absence of symptoms.

• Conversely, as a pathological condition, GastroEsophageal Reflux Disease (GERD) is defined when symptoms or complications, associated with significant morbidity are present.1,2

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GERD can be classified as: Erosive Reflux Disease (ERD) by the presence of symptoms with erosions present at endoscopy or Non-Erosive Reflux Disease (NERD) by the presence of symptoms without esophageal erosions on endoscopic examination. NERD represents the more common phenotypic presentation of GERD and comprises patients who have typical symptoms without any mucosal breaks at endoscopy. However, these patients are markedly heterogeneous from a pathophysiological point of view and should be correctly classified by means of 24 h impedance-pH testing, which enables detection of both acid and weakly acidic reflux and correlation with symptoms. This technique is able to identify two subsets of NERD (that is, patients with an excess of acid or with a hypersensitive esophagus to both acid and weakly acidic reflux) and patients with functional heartburn (who do not have any kind of reflux underlying their symptoms).

Katz O, et al. Am J Gastroenterol 2013; 108:308-28.Savarino E, et al. Nat Rev Gastroenterol Hepatol 2013;10:371-80.

GastroEsophageal Reflux subgroups

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Savarino E, et al. Nat Rev Gastroenterol Hepatol 2013;10:371-80.

SAP, symptom association probability; SI, symptom index.

Erosive Reflux Disease (ERD)

Patients with mucosal breaks visible at endoscopy

Non-Erosive Reflux Disease (NERD)

True NERD Patients with negative upper endoscopy and abnormal esophageal acid exposure at impedance-pH monitoring

Acid hypersensitive esophagus

Patients with negative upper endoscopy; normal esophageal acid exposure and positive symptom association to acid reflux (SI>50%, SAP>95%) at impedance-pH monitoring

Non-acid hypersensitive esophagus

Patients with negative upper endoscopy; normal esophageal acid exposure and positive symptom association to non-acid reflux (SI>50%, SAP>95%) at impedance-pH monitoring

Functional heartburn

Patients with heartburn that does not respond to PPIs; negative upper endoscopy; normal esophageal acid exposure time; negative symptom association to any type of reflux (SI<50%, SAP <95%) at impedance-pH monitoring

SAP: Symptom Association Probability; SI: Symptom Index; PPIs: Proton Pump Inhibitors

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For many years, GERD was considered to be strictly correlated with the presence of acid reflux and Erosive Reflux Disease (ERD) has been considered the more common manifestation of GERD. However, in the past decade it has been realized, also with the demonstration of endoscopic and impedance-pH testing, that ERD represents the minority of patients with GERD (~35%), whereas the majority of them (~65%) are included in the Non-erosive Reflux Disease (NERD) phenotype, meaning the absence of macroscopic alteration of esophageal mucosa.


Patients with Erosive and Non-Erosive Reflux Disease

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35%

65%

0%

10%

20%

30%

40%

50%

60%

70%

ERD NERD

Patie

nts (

%)

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Endoscopic and impedance–pH testing can be used to classify patients with GERD. Using this technique, 65% of patients with typical reflux symptoms do not have any esophageal mucosal lesion visible at endoscopy. Of these patients, 40% have true Non-Esophageal Reflux Disease (NERD); 20% have a hypersensitive esophagus to acid; 15% have a hypersensitive esophagus to non-acid and 25% have functional heartburn. 35% of patients with reflux symptoms have Erosive Reflux Disease (ERD) of which 5% have complicated GERD, including Barrett’s esophagus.


Endoscopic and impedance-pH testing categorisation of patients with GERD

Endoscopic and impedance-pH testing can be used to classify patients with GERD

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95% ERD

5% Complicated GERD

40% True NERD

20% Acid hypersensitive

esophagus

15% Non-acid hypersensitive

esophagus

25% Functional

heartburning

65% Endoscopy-negative

35% Endoscopy-positive

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To establish the true prevalence of GERD, a symptom threshold must be defined that adequately selects patients whose quality of life is impaired as a result of their disease. Experience of heartburn at least twice weekly is thought to be sufficient to result in impaired quality of life. Notwithstanding, it is clear that the worldwide incidence of GERD and its complications is increasing along with the exponentially increasing problem of obesity. First evident of GERD as dominant clinical problem appears in Western societies, this trend is now extending worldwide.

Boeckxstaens G, et al. Gut 2014;63:1185-93.

Epidemiology of GERD

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• Over the past 40 years, GERD has risen from relative obscurity to one of the dominant clinical problems encountered in gastroenterology

• The worldwide incidence of GERD and its complications is increasing along with the exponentially increasing problem of obesity

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Data from studies on the prevalence of GERD (defined by typical symptoms at least once weekly) indicate estimates of 18.1-27.8% in North America, 8.8-25.9% in Europe, 2.5-7.8% in East Asia, 8.7-33.1% in the Middle East, 11.6% in Australia, and 23.0% in South America.


Global variations in the prevalence of GERD

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GERD: typical symptoms at least once weekly

18.1

8.8

2.5

8.7

11.6

23

0 5 10 15 20 25 30 35

North America

Europe

East Asia

Middle East

Australia

South America

27.8

25.9

7.8

33.1

Prevalence of GERD (%)

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The symptoms of GERD can be subdivided into typical and atypical. Typical gastroesophageal symptoms include heartburn and regurgitation which have high specificity but low sensitivity for GERD. Atypical symptoms can be distinguished in gastroesophageal and extra-esophageal manifestations. Atypical gastroesophageal symptoms such as epigastric pain, dyspepsia, nausea, bloating, and belching may be suggestive of GERD but may overlap with other conditions in the differential diagnosis such as peptic ulcer disease, achalasia, gastritis, dyspepsia and gastroparesis. Atypical extra-esophageal symptoms include chronic cough, bronchospasm, wheezing, hoarseness, sore throat, asthma, laryngitis, dental erosions, globus and sleep disturbance.

Badillo R, Francis D. World J Gastrointest Pharmacol Ther 2014;5:105-12.

Symptoms of GERD

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TYPICAL SYMPTOMS

Gastro-esophageal symptoms

Regurgitation, heartburn

ATYPICAL SYMPTOMS

Gastro-esophageal symptoms

Epigastric fullness, epigastric pressure,

epigastric pain, dyspepsia, nausea,

bloating, belching

Extra-esophageal symptoms

Chronic cough, bronchospasm,

wheezing, hoarseness, sore throat, asthma,

laryngitis, dental erosions, globus, sleep disturbance

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GERD symptoms have a profound impact on health-related quality of life and affect a wide range of aspects of the generic quality of life as seen in this slide. Moreover, the presence of NERD is associated with increased anxiety and depression indicating that psychological factors further negatively impact the quality of life. It is therefore important to recognize, diagnose and properly treat patients with GERD in order to avoid detrimental effects on quality of life as well as numerous complications.

Yang XJ, et al. World J Gastroenterol 2015;21:4302-9.Badillo R, Francis D. World J Gastrointest Pharmacol Ther 2014;5:105-12.

GERD negatively impacts the quality of life

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Adapted from: Yang XJ, et al. World J Gastroenterol 2015;21:4302-9.

Quality of life in healthy controls and in individuals with ERD and Non-Erosive Reflux Disease (NERD)

GERD affects a wide range of aspects of the quality of life

60

30

120

90

150

Physical function

Role-physical

Role-emotional

Social functioning

Bodly pain General health

Mental health

Vitality

a p<0.05, b p<0.01. RE: Reflux Esophagitis; NERD: Non-Erosive Reflux Disease.

Scor

e (S

F-36

)

ERD

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An observational study in Europe held across six countries (Germany, Greece, Norway, Spain, Sweden and the UK) including over 370,000 subjects also concluded that GERD places a significant burden on primary care patients, in terms of work absenteeism and presenteeism and in daily life. GERD was associated with substantially reduced work productivity.

Gisbert JP, et al. Health Qual Life Outcomes 2009;7:90.

GERD affects work productivity

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Mean percent productivity lost due to GERD, measured using the Work Productivity and Impairment questionnaire for patients with GERD

GERD has significant burden in terms of work absenteeism and presenteeism

0

5

10

15

20

25

30

Germany Greece Norway Spain Sweden UK

Work time missed due to GERD Reduced productivity while working Reduced productivity in daily activities

Tim

e lo

st (%

)

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In the same European observational study, the average monetary impact of GERD-related work absenteeism and presenteeism were substantial in all countries (from €55/week per employed patient in the UK to €273/patient in Sweden).


GERD is associated with economic losses

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Mean monetary losses related to work absenteeism and reduced productivity while working (presenteeism) due to GERD

The average monetary impact of GERD-related work absenteeism and presenteeism is substantial

0

50

100

150

200

250

300

Germany Greece Norway Spain Sweden UK

Hours absent Work hours lost due to reduced productivity working

Cost

per

wee

k pe

r em

ploy

ed p

atie

nt

(Eur

o)

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While a number of potential risk factors for GERD have been identified by reviewing epidemiological data, all of the positive associations have rather small odds ratios, leaving their clinical implications in doubt. Obesity and possibly increasing age are more well established risk factors. However, the relationship with age has been difficult to establish, given that older patients may underreport reflux symptoms. The relationship with obesity has been confirmed in longitudinal studies. It is reasonable to expect that, although behaviour such as alcohol consumption, smoking and diet may contribute to development of the disease, a subject would also be likely to adapt their behaviour in response to the experience of life impairing symptoms. Tobacco smoking, age, female sex and lower education have also been associated with new-onset symptoms of gastrointestinal reflux. Given the above, weight loss and tobacco smoking cessation should be recommended to GERD patients.

Dent J, et al. Gut 2005;54:710-7.Hallan A, et al. Am J Gastroenterol 2015;110:393-400.

Risk factors for GERD

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• Most notably risk factor is the obesity

• A relationship with age has been difficult to establish, given that older patients may underreport reflux symptoms

• Tobacco smoking, age, female sex and lower education have also been associated with new-onset symptoms of gastrointestinal reflux

Dent J, et al. Gut 2005;54:710-7. Hallan A, et al. Am J Gastroenterol 2015;110:393-400.

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Historically, GERD has been considered as strictly and almost exclusively correlated to the presence of acid reflux, while several evidence have more recently demonstrated that it has a multifactorial aetiology, that implies esophageal, gastric and duodenal dysfunctions, such as delayed gastric emptying, pepsin and bile salts (synergistic with acid, particularly in complicated esophagitis and Barrett’s esophagus).

Cram M, de Caestecker J. Medicine 2010;39:132-6.

Summary of factors involved in GERD

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MULTIFACTORIAL AETIOLOGY

ESOPHAGUS

POOR VOLUME CLEARANCE • Primary and secondary esophagus peristalsis • Ineffective esophageal motility impairs clearance (common in severe esophagitis) POOR ACID NEUTRALISATION • Low salivary bicarbonate • Low esophageal glands secretion (mucus, bicarbonate)

ESOPHAGEAL MUCOSAL DAMAGE • DIS • Na+/H+ exchange pump

FAIL OF BARRIER FUNCTION • Intrinsic LES tone • TLESRs • Extrinsic sphincter (diaphragmatic crus) tone • Hiatal hernia

STOMACH

• Gastric acid output • H. pylori infection • Pepsin presence (mainly active at pH<4) • Delayed gastric emptying (increased TLESRs)

DUODENUM • Duodenogastric reflux (bile salts, acids and trypsin presence - synergistic with gastric acid at acid pH)

LES: Lower Esophageal Sphincter; TLESR: Transient Lower Esophageal Sphincter Relaxation; DIS: Dilated Intercellular Spaces

Esophagus

Stomach

Duodenum

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Dilation of Intercellular Spaces (DIS) appear to play a relevant role in heartburn. Because sensory neurons in the esophageal epithelium reside within the intercellular spaces, the increase in paracellular permeability may explain heartburn symptoms during esophageal acid exposure in patients with NERD. Heartburn may result from contact of refluxed gastric content with nociceptors within the esophageal mucosa and transmission of this peripheral signal to the central nervous system for cognition.

Orlando RC. Best Pract Res Clin Gastroenterol 2010;24:873-82. Arul P, et al. Malays J Pathol 2014;36:181-8.

Dilation of Intercellular Spaces (DIS)

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Orlando RC. Best Pract Res Clin Gastroenterol 2010;24:873-82. Arul P, et al. Malays J Pathol 2014;36:181-8. Orlando LA, Orlando RC. Curr Gastroenterol Rep 2009;11:190-4

• The cells of the inner layer, the stratum corneum, initially provide defence of esophageal mucosa in the form of a permeability barrier comprised of apical cell membranes and Apical Junctional Complexes (AJC) that prevent the diffusion of luminal acid

• Acid initially injures the esophageal epithelium by altering the AJC, causing an early increase in paracellular permeability and a morphologic lesion known as dilated intercellular spaces

• Dilation of intercellular spaces (DIS) is found in 65-80% of cases of NERD

Dilation of intercellular spaces are important for diagnosis of GERD and also play a role in associated heartburn symptoms

Normal intercellular spaces

Dilated Intercellular Spaces (DIS)

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The anti-reflux barrier comprises an intrinsic Lower Esophageal Sphincter (LES) and an external sphincter formed by the crural diaphragm. The LES is about 4 cm long with the right crural diaphragm encircling the proximal 2 cm. Therefore, the LES is part intra-abdominal, allowing a ‘flap valve’ mechanism to operate (raised intra-abdominal pressure closes the intra-abdominal segment). The anatomical superimposition of both sphincters forms the barrier to reflux.


The normal anti-reflux barrier

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Mullassery D, Jones MO. Surgery 2013;31:614-7. Cram M, de Caestecker J. Medicine 2010;39:132-6.

Anatomy of normal anti-reflux barrier at the lower esophagus

• The anti-reflux barrier comprises an intrinsic Lower Esophageal Sphincter (LES) and an external sphincter formed by the crural diaphragm

• The LES is part intra-abdominal, allowing a ‘flap valve’ mechanism to operate (raised intra-abdominal pressure closes the intra-abdominal segment)

• The anatomical superimposition of both sphincters forms the barrier to reflux.

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GERD-related complications include peptic stricture and ulceration, Barrett’s esophagus, esophageal adenocarcinoma and pulmonary disease. Peptic esophageal erosions and ulcerations are excavated defects in esophageal mucosa that result when epithelial cells succumb to the caustic effects if refluxed of acid and pepsin. Since DIS is a reflection of a break in barrier function, this supports the concept that these three forms of GERD (NERD, ERD and Barrett’s esophagus) share a common pathogenesis.

Malfertheiner P, Hallerbäck B. Int J Clin Pract. 2005;59(3):346-55. Orlando RC. Best Pract Res Clin Gastroenterol 2010;24:873-82.

Physiological consequences of GERD

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Malfertheiner P, Hallerbäck B. Int J Clin Pract. 2005;59(3):346-55. Orlando RC. Best Pract Res Clin Gastroenterol 2010;24:873-82.

GERD-related complications include peptic stricture and ulceration, Barrett’s esophagus and esophageal adenocarcinoma

Proposed means by which injury to esophageal epithelium leads to the three common endoscopic types of GERD

GERD-related complications

Gastric reflux

NERD

DIS

Inflammation

ERD

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Part 2. Management of GERD

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Heartburn and regurgitation are the typical symptoms of the disease. Heartburn describes the sensation of discomfort or burning behind the sternum rising up to the neck, whereas regurgitation is the effortless return of stomach contents into the pharynx. Patients often use the term heartburn to refer to other upper gastrointestinal symptoms such as epigastric pain, so it is important to clarify this. Furthermore, in most languages there is not a direct translation for the word ‘heartburn’. Symptoms often occur in clusters, and it can be difficult for the patient to define a predominant symptom. Atypical symptoms such as dysphagia, odynophagia, globus (lump in the throat), sore throat, laryngitis, water brash, and cough are other possible symptoms of the disease, but their diagnostic utility is uncertain. In addition, there is a significant association between disturbed sleep and GERD, which may be bidirectional. Night-time reflux can lead to sleep disturbance and sleep disturbance may further aggravate GERD. This may facilitate the occurrence of complicated GERD and decreased quality of life.

Moayyedi P, Talley NJ. Lancet 2006;367:2086-100. Jung HK, et al. J Neurogastroenterol Motil 2010;16:22-9.

Assessing the symptoms of GERD

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Moayyedi P, Talley NJ. Lancet 2006;367:2086-100.

• Heartburn and regurgitation are the typical symptoms of GERD − Heartburn describes the sensation of discomfort or burning behind the sternum

rising up to the neck, whereas regurgitation is the effortless return of stomach contents into the pharynx

− Patients often use the term heartburn to refer to other upper gastrointestinal symptoms such as epigastric pain, so it is important to clarify this

• Symptoms often occur in clusters and it can be difficult for the patient to define a predominant symptom

• Atypical symptoms such as dysphagia, odynophagia, globus (lump in the throat), sore throat, laryngitis, water brash and cough are other possible symptoms of the disease, but their diagnostic utility is uncertain

• There is a significant association between disturbed sleep and GERD. Night-time reflux can lead to sleep disturbance and may further aggravate GERD

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The diagnosis of GERD is typically made by a combination of clinical symptoms, response to acid suppression, as well as objective testing with upper endoscopy and esophageal pH monitoring. For example, the combination of moderate to severe typical symptoms and endoscopic changes (erosions of the esophageal mucosa or Barrett’s esophagus) are highly specific (97%) for GERD (confirmed with pH testing). However, a well-taken history alone can prove very valuable in diagnosis, especially in the setting of heartburn and regurgitation which have a very high specificity (89% and 95%, respectively), albeit low sensitivity (38% and 6%) for GERD.


Diagnosis of GERD

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• Diagnosis of GERD is typically made by a combination of clinical symptoms, response to acid suppression, as well as objective testing with upper endoscopy and esophageal pH monitoring

- The combination of moderate to severe typical symptoms and endoscopic changes (erosions of the esophageal mucosa or Barrett’s esophagus) are highly specific (97%) for GERD (confirmed with pH testing)

• However, a well-taken history alone can prove very valuable in diagnosis, especially in the setting of heartburn and regurgitation which have a very high specificity (89% and 95%, respectively), albeit low sensitivity (38% and 6%) for GERD

• In evaluating patients with GERD, it is important to define the type of gastroesophageal reflux (acid, non acid,…) and the presence of microscopic lesions in endoscopically normal mucosa

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This table shows some of the indications for diagnostic testing in GERD.


Indications for diagnostic testing of GERD

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DIAGNOSTIC TEST INDICATION

PPI trial Typical GERD symptoms with no alarm symptoms

Esophageal pH monitoring

Refractory symptoms where GERD diagnosis is in question. Pre-operative evaluation for anti-reflux surgery

Upper endoscopy

Alarm symptoms (e.g., dysphagia), PPI unresponsive patients, high risk for Barrett’s esophagus

Barium esophagram

Evaluation of dysphagia, otherwise not recommended for GERD evaluation

Esophageal manometry Prior to anti-reflux surgery to rule out esophageal dysmotility (e.g., achalasia, scleroderma), otherwise not recommended for GERD evaluation

GERD: Gastroesophageal Reflux Disease; PPI: Proton Pump Inhibitor.

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A large number of methods are available for evaluation of GERD as detailed in this slide.

Falk GL, et al. World J Gastroenterol. 2015;21(12):3619-27.Ricci G, et al. Obes Surg. 2011;21(1):48-53. Badillo R, Francis D. World J Gastrointest Pharmacol Ther 2014;5:105-12.Hayat JO, et al. Gut 2015;64:373-80.

Diagnostic tests for GERD

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Falk GL, et al. World J Gastroenterol. 2015;21(12):3619-27. Ricci G, et al. Obes Surg. 2011;21(1):48-53. Badillo R, Francis D. World J Gastrointest Pharmacol Ther 2014;5:105-12. Hayat JO, et al. Gut 2015;64:373-80.

TEST COMMENTS Contrast radiography Low-cost, easy-to-perform, but not appropriate for diagnosis

Gastroesophageal scintigraphy Assesses only immediate postprandial GER

pH monitoring Evaluate the patient under more physiological conditions and for longer periods

Esophageal multichannel intraluminal impedance

Detects retrograde movement of fluids, solids and air in the esophagus

24-h pH-metry + multichannel intraluminal impedance

Allows simultaneous assessment of chemical and physical properties of esophageal refluxes

Empirical therapeutic test with acid suppression

Trial for four weeks with a PPI, which can be extended to 12 weeks if there is clinical improvement

Esophageal manometry Assesses the motility of the esophagus; not recommended for GERD diagnosis

Upper gastrointestinal endoscopy with biopsy

Allows direct visual examination of the esophageal mucosa and collection of samples for histopathological analysis, however there are limitations in its use for GERD diagnosis

Salivary pepsin test Uses pepsin as a surrogate marker for gastroesophageal reflux

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Erosions of the esophageal mucosa (esophagitis) occurs in less than half of patients with typical reflux symptoms, particularly those seen in primary care and in patients with atypical symptoms. The presence and severity of erosions at endoscopy was prone to significant inter observer error, but this problem has been improved by the Los Angeles classification, which defines the disease by the occurrence of mucosal breaks.

Cram M, de Caestecker J. Medicine 2010;39:132-6.Moayyedi P, Talley NJ. Lancet 2006;367:2086-100.

Grading of Erosive Reflux Disease (ERD)

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Los Angeles classification of ERD

Moayyedi P, Talley NJ. Lancet 2006;367:2086-100. Cram M, de Caestecker J. Medicine 2010;39:132-6.

One [or more] mucosal breaks no longer than 5 mm, not extending between the tops of two mucosal folds

One [or more] mucosal breaks more than 5 mm long, not extending between the tops of two mucosal folds

One [or more] mucosal breaks continuous between the tops of two or more mucosal folds but which involve less than 75% of the esophageal circumference

One [or more] mucosal breaks involving at least 75% of esophageal circumference

LA grade A

LA grade D LA grade C

LA grade B

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The major therapeutic goals of GERD are listed in this slide.


Therapeutic goals in GERD

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The goals of treatment are: • control of symptoms • healing of complications • maintenance of remission

For most patients, the aim is symptom control using the minimum effective treatment

For those with complications, the aim is to keep erosions healed

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The mainstay of treatment is medical, with surgical treatment for non-responders or by patient choice. A ‘step-up’ approach concentrates on lifestyle modification and antacid before acid suppression is prescribed. It is suitable for uncomplicated patients with infrequent symptoms. A ‘step-down’ approach focuses on rapid symptom control with full-dose PPIs, and subsequent dose reduction or introduction of less effective agents. It is the favoured approach for all except those with complications who are best treated with full-dose PPI in the long term.


General considerations for treatment of GERD

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• The mainstay of treatment is medical, with surgical treatment for non-responders or by patient choice

• A “step-up” approach concentrates on lifestyle modification and antacid before acid suppression is prescribed − This is suitable for uncomplicated patients with infrequent

symptoms

• A “step-down” approach focuses on rapid symptom control with full-dose PPIs and subsequent dose reduction or introduction of less effective agents − Favoured approach for all except those with complications who

are best treated with full-dose PPI in the long term

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Lifestyle advice and antacid therapy is advocated as first-line treatment for GERD. Lifestyle factors are only weakly associated with reflux symptoms, so it is unlikely that these will have a major effect on the disease. Nevertheless, advice such as stopping smoking, reducing alcohol intake and weight loss in obese patients is likely to have wider benefits, even if the effect on reflux symptoms is small. Most patients will not respond adequately to these first-line measures and will need further treatment. The available alternatives include pharmacological, endoscopic and surgical treatment.

Moayyedi P, Talley NJ. Lancet 2006;367:2086-100.Cram M, de Caestecker J. Medicine 2010;39:132-6.

Lifestyle modifications for GERD

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Moayyedi P, Talley NJ. Lancet 2006;367:2086-100. Cram M, de Caestecker J. Medicine 2010;39:132-6.

Lifestyle advice and antacid therapy is

advocated as first-line treatment for GERD

Unlikely that it will have a

major effect on the disease

Stopping smoking, reducing alcohol intake

and weight loss in obese patients

Likely to have wider benefits

Most patients will not respond adequately to

these first-line measures

Will need further pharmacological, endoscopic and

surgical treatment

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The cornerstone of treatment of GERD is acid suppression which can be achieved with Histamine-receptor Antagonists (H2RAs) or Proton-pump Inhibitors (PPIs). H2RAs inhibit acid secretion by competitively and reversibly blocking parietal cell H2-receptors, one of the stimulants to acid production. The site of action of the PPIs is the gastric acid pump (H+/K+ ATPase), which is the final common pathway for acid secretion in the stomach. PPIs are a highly effective therapy for GERD and its complications and are the agents of choice for the suppression of gastric acid production.

Several publications and systematic reviews have highlighted that 20-40% of patients with GERD do not respond (either completely or partially) to proton pump inhibitors (PPIs), thus showing that acid is often not the only pathogenetic factor involved. Moreover, other systematic reviews and meta-analyses have documented that the clinical efficacy of PPIs is generally less than 50% in patients with NERD.

Moayyedi P, Talley NJ. Lancet 2006;367:2086-100.Cram M, de Caestecker J. Medicine 2010;39:132-6.Heidelbaugh JJ, et al. Am Fam Physician 2003;68:1311-8

Antisecretory agents for GERD

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The cornerstone of treatment of GERD is acid suppression with histamine-receptor antagonists or proton-pump inhibitors

Moayyedi P, Talley NJ. Lancet 2006;367:2086-100. Cram M, de Caestecker J. Medicine 2010;39:132-6. Heidelbaugh JJ, et al. Am Fam Physician 2003;68:1311-8.

*Available histamine H2 RAs and PPIs

AGENT* EQUIVALENT DOSAGES DOSAGE Histamine H2-receptor antagonists → have a more rapid onset of action

Cimetidine Famotidine Nizatidine Ranitidine

400 mg tid 20 mg tid

150 mg tid 150 mg tid

400-800 mg tid 20-40 mg tid 150 mg tid 150 mg tid

Proton-pump inhibitors → have a longer duration of action

Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole

40 mg od 30 mg od 20 mg od 40 mg od 20 mg od

20-40 mg od 15-30 mg od

20 mg od 40 mg od 20 mg od

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Antacids act locally to buffer gastric and esophageal contents, providing rapid, but relatively short-term symptom relief. Alginates are generally formulated in combination with an antacid, and form a viscous protective barrier on the top of the gastric contents, preventing acid contact with the esophagus. Although antacids and alginates may be useful in milder cases of GERD, over-the counter antacids provide effective symptom relief in only about 25% of patients with GERD. The necessity of frequent dosing and the inconvenience of liquid dosage forms also limit the usefulness of antacids and alginates. Drugs such as the H2-receptor antagonists and omeprazole, which have been introduced during the last 15-20 years, have to a great extent replaced antacids in the treatment of peptic ulcer. Antacids are best used ‘as required’ for relief of mild or infrequent symptoms. Alginates depend on the formation of a floating viscous raft on top of gastric contents creating a barrier to reflux, so are best taken after meals. They relieve symptoms, but do not heal esophagitis.

Pettit M. Pharm World Sci 2005;27:432-5.

Antacids and alginates

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• Antacids are alkalis such as aluminium hydroxide, magnesium salts, sodium bicarbonate and calcium hydroxide

• Generally formulated in combinations (e.g. magnesium hydroxide, aluminium hydroxide), often with other components, such as simethicone, alginates (anti-reflux agents) and hydrotalcite (another type of antacid)

• Antacids act locally to buffer gastric and esophageal contents, providing rapid, but relatively short-term symptom relief

• Alginates are generally formulated in combination with an antacid, and form a viscous protective barrier on the top of the gastric contents, preventing acid contact with the esophagus

• Over-the counter antacids provide effective symptom relief in only about 25% of patients with GERD


30

Slide Kit

Sucralfate also acts as a barrier to acid and pepsin, although, unlike alginates, it acts by binding to damaged epithelium. It may also assist healing of the damaged mucosa by binding epidermal and fibroblast growth factors. Sucralfate provides a similar level of symptomatic relief to that of H2RAs; however, studies evaluating sucralfate in the healing of GERD have produced inconsistent results, with reported healing rates varying from 17-67%.


Sucralfate

30

• Sucralfate acts as a barrier to acid and pepsin, although, unlike alginates, it acts by binding to damaged epithelium

• May assist healing of the damaged mucosa by binding epidermal and fibroblast growth factors

• Sucralfate provides a similar level of symptomatic relief to that of H2RAs − Studies evaluating sucralfate in the healing of GERD have produced

inconsistent results, with reported healing rates varying from 17-67%


31

Slide Kit

A simplified treatment algorithm for using prescription medications for GERD is shown in this slide.

Adapted from: Scarpignato C. Is there an Effective Medical Therapy for Extra-digestive GERD: Facts and Fictions. Proceeding of the conference “Extra-digestive GERD: what’s next?” Parma, April 16-18, 2015.

Algorithm of medical treatment in GERD

31

Add-on medication: antacids/alginates/sucralfate

Suspected GERD

Continue therapy or down titrate

PPI therapy (twice daily for 1-3 months)

Symptom improvement or relief Symptom persistence

Add-on medications

Symptom persistence

Functional investigation & endoscopy

Alternative diagnosis •Check compliance •Discuss surgery

Symptom improvement or relief

Continue therapy or down titrate

Normal Abnormal

Scarpignato C. Is there an Effective Medical Therapy for Extra-digestive GERD: Facts and Fictions. Proceeding of the conference “Extra-digestive GERD: what’s next?” Parma, April 16-18, 2015.

32

Slide Kit

Management of patients with symptoms (typical or atypical, which do not adequately respond to PPIs) requires a gradual approach, initially based on the use of add-on treatments in addition to antisecretory therapy.

Badillo R, Francis D. World J Gastrointest Pharmacol Ther 2014;5:105-12.Cram M, de Caestecker J. Medicine 2010;39:132-6.Katz PO, et al. Am J Gastroenterol 2013;108:308-28.

Algorithm for evaluation of refractory GERD

32

Badillo R, Francis D. World J Gastrointest Pharmacol Ther 2014;5:105-12. Cram M, de Caestecker J. Medicine 2010;39:132-6. Katz PO, et al. Am J Gastroenterol 2013;108:308-28

Referral to ENT**, pulmonary, allergy

Atypical symptoms

REFLUX MONITORING

Low pre test probability* of GERD

Test off medication with pH or impedance-pH

ABNORMAL (ENT, pulmonary or allergic

disorder)

High pre test probability* of GERD

Test on medication with impedance-pH

NORMAL

Exclude other etiologies

Upper endoscopy

ABNORMAL (eosinophilic

esophagitis, erosive esophagitis, other)

Specific treatment

No response

Specific treatment

REFRACTORY GERD

Typical symptoms

Optimize PPI therapy

* Pre test probability is based on GERD prevalence in patient population under question, clinician's impression and response to PPI trial

**ENT = Ears, nose and throat disease

33

Slide Kit

Patients with PPI-refractory GERD can be challenging to treat and are frequently referred to a gastroenterologist. First, compliance with medical therapy and proper dosing should be addressed. Given high rates of non-compliance, an accurate history is important to obtain in order to avoid escalating therapy unnecessarily. If symptoms are truly refractory to proper medical therapy, the dosing can be increased or an alternate PPI can be used. Both methods may lead to further symptom improvement and both appear to be equally effective. If a patient has predominantly night-time symptoms, more effective nocturnal acid suppression may be achieved with bid or night-time dosing of PPIs. If symptoms persist after attempts at maximising medical therapy, evaluation for non-GERD aetiologies should be undertaken.


PPI-refractory GERD

33

Patients with PPI-refractory GERD can be challenging to treat and are frequently referred to a gastroenterologist


Address compliance with medical therapy

and proper dosing

If symptoms are truly refractory

to proper medical therapy, increase the dose

or use an alternate PPI, use

add-on treatments

If symptoms are predominantly night-time, try

bid or night-time dosing of PPIs,

use add-on treatments

If symptoms persist after maximising

medical therapy, evaluate for non-GERD aetiologies

34

Slide Kit

The most common indication for laparoscopic anti-reflux surgery is informed patient choice. Patients responding well to medical therapy also do best with surgery. Other indications include:Failed medical treatment (e.g. persisting heartburn or ‘volume’ reflux despite heartburn control, resulting in nocturnal regurgitation). Careful investigation is required to ensure symptoms are due to reflux.Refractory complications (e.g. non-healing esophageal ulcer, recurrent benign stricture).Non-compliance with treatment: a difficult decision and therefore hard to generalize about appropriateness of surgery.The primary surgical intervention for the treatment of GERD is laparoscopic fundoplication, a procedure where the fundus of the stomach is wrapped around the esophagus to create a new cardiac valve-equivalent at the gastroesophageal junction. Short-term reflux control is achieved in more than 90% of patients. Failure rates, however, increase with time. In general, laparoscopic surgical intervention is effective compared to maintenance PPI.

Badillo R, Francis D. World J Gastrointest Pharmacol Ther 2014;5:105-12.Cram M, de Caestecker J. Medicine 2010;39:132-6.

Surgical management of GERD

34

• The most common indication for laparoscopic anti-reflux surgery is informed patient choice

• The primary surgical intervention for the treatment of GERD is laparoscopic fundoplication, a procedure where the fundus of the stomach is wrapped around the esophagus to create a new cardiac valve-equivalent at the gastroesophageal junction

Badillo R, Francis D. World J Gastrointest Pharmacol Ther 2014;5:105-12. Cram M, de Caestecker J. Medicine 2010;39:132-6.

Indications for anti-reflux surgery

Unwillingness to remain on lifelong medical therapy

Intolerance of medical therapy

Medically refractory symptoms with objective evidence of GERD

GERD in the setting of a large hiatal hernia

Medically refractory GERD in the setting of morbid obesity

35

Slide Kit

Proton-pump inhibitors have profoundly revolutionized the treatment of GERD. However, several areas of unmet need persist despite marked improvements in the therapeutic management of GERD. These include the advanced grades of ERD, NERD, maintenance treatment of ERD, refractory GERD, postprandial heartburn, atypical gastroesophageal and extra-esophageal manifestations of GERD, Barrett’s esophagus, chronic PPI treatment, post-bariatric surgery GERD and targeted esophagus treatment. Patients with NERD often fail to respond adequately to PPI treatment. It has been estimated, in fact, that failure to control symptoms occurs in up to 40% of patients treated with a PPI. Consequently, any future development of novel therapeutic modalities for GERD (medical, endoscopic, or surgical), would likely focus on the aforementioned areas of unmet need.

Dickman R, et al. J Neurogastroenterol Motil 2015;21:309-19. Katz PO, et al. Am J Gastroenterol 2013;108:308-28.

Unmet needs in GERD

35

Dickman R, et al. J Neurogastroenterol Motil 2015;21:309-19.

Healing and symptom’s response in advanced ERD

NERD

Post-prandial heartburn

Night-time heartburn

Maintenance treatment in ERD

On-demand/intermittent therapy

Refractory GERD

Atypical gastroesophageal and extra-esophageal manifestations of GERD

Dependency on food for efficacy

Chronic PPI treatment

Barrett’s esophagus

Post-bariatric surgery GERD

Targeted esophagus treatment

36

Slide Kit

Current medical therapies target only the stomach. However, troublesome symptoms, esophageal injury and/or complications are due to reflux of stomach contents into the esophagus.

Subramanian CR, Triadafilopoulos G. Gastroenterol Rep 2015;3(1):41-53.

36

• PPIs • H2-RA • Antacids • Alginates • Prokinetics

• Baclofen

All symptoms are generated by the

esophagus

Subramanian CR, Triadafilopoulos G. Gastroenterol Rep 2015;3(1):41-53.

Medical therapies act only on the stomach

• Current medical therapies act on the stomach • However, troublesome symptoms and/or complications are due to

esophageal injury

37

Slide Kit

The advent of impedance-pH monitoring has allowed to better define and subdivide the heterogeneous subgroups of patients traditionally comprised within the group of NERD. There are studies in the literature reporting that over 50% of patients presenting with reflux symptoms in primary care settings have negative endoscopy (absence of visible mucosal breaks). Stimuli other than acid can evoke typical reflux symptoms. In fact, differences in response to medical therapy confirms that GERD is a heterogeneous condition that is not strictly dependent on symptoms related to acid reflux.

Giacchino M, et al. Annals of Gastroenterology 2013;26:283-289. Savarino E, et al. Nat Rev Gastroenterol Hepatol 2013;10:371-80.

Medical treatment – final remarks

37

• Thanks to the application of esophageal impedance-pH testing with the possibility to detect all kind of refluxes and to correlate symptoms to them, GERD has been discovered to be a heterogeneous condition

• Stimuli other than acid can evoke typical reflux symptoms

• In fact, differences in response to medical therapy confirms that GERD is a pathology that is not strictly dependent on symptoms related to acid reflux

Giacchino M, et al. Annals of Gastroenterology 2013;26:283-289. Savarino E, et al. Nat Rev Gastroenterol Hepatol 2013;10:371-80.

38

Slide Kit

Part 3. ESOXX® ONE in management of GERD

38

39

Slide Kit

ESOXX® ONE is a medical device for the topical treatment of the symptoms of GastroEsophageal Reflux Disease (GERD). It is based on a synergistic mixture of three main components:• Hyaluronic Acid (HA)• Chondroitin Sulphate (CS)• Poloxamer 407, a bioadhesive carrier

ESOXX® ONE acts as a long lasting protective shield on esophageal mucosa. For its unique characteristics, ESOXX® ONE has been studied as a protective topical agent towards esophageal and gastric lesions. It is the only therapy that directly targets the esophagus.

Di Simone MP, et al. Clin Exp Gastroenterol 2012;5:103-7.Palmieri B, et al. Eur Rev Med Pharmacol Sci 2013;17:3272-8.

ESOXX® ONE

39

• ESOXX® ONE is a medical device for the topical treatment of the symptoms of GastroEsophageal Reflux Disease (GERD)

• It is based on a synergistic mixture of three main components: − Hyaluronic Acid (HA) − Chondroitin Sulphate (CS) − Poloxamer 407, a bioadhesive carrier

• ESOXX® ONE acts as a long lasting protective shield on esophageal mucosa

• ESOXX® ONE is the only GERD therapy that acts directly on the esophagus

Di Simone MP, et al. Clin Exp Gastroenterol 2012;5:103-7. Palmieri B, et al. Eur Rev Med Pharmacol Sci 2013;17:3272-8.

40

Slide Kit

Hyaluronic Acid (hyaluronan; HA) is a glycosaminoglycan made up of glucuronic acid and N-acetylglucosamine disaccharide units. HA is mainly present in the extracellular matrix of soft connective tissues and is involved in several key processes, including cell signaling, wound repair and regeneration, morphogenesis, matrix organization and pathobiology. HA also provides two very important functions in wound healing as part of cell proliferation and migration. First, HA provides a temporary structure in the early stages of the wound. This structure helps facilitate the diffusion of nutritional supplies and helps rid the wound of waste products from cell metabolism. Second, and most importantly, HA is closely involved in keratinocyte (cell type of the epidermis or outermost layer of the skin) proliferation and migration. Clinically, it is largely used for the treatment of several diseases. Topical HA preparations are applied in the management of recurrent aphthous ulceration, with immediate reduction of symptoms due to its barrier effect. Moreover, topical HA has recently been recognised as adjuvant treatment in chronic inflammatory disease of the upper aerodigestive tract.


Hyaluronic acid

40

• Hyaluronic Acid (HA) is a glycosaminoglycan made up of glucuronic acid and N-acetylglucosamine disaccharide units

• HA is mainly present in the extracellular matrix of soft connective tissues and is involved in several key processes, including cell signaling, wound repair and regeneration, morphogenesis, matrix organization and pathobiology


41

Slide Kit

Chondroitin Sulphate (CS) is a natural glycosaminoglycan present in the extracellular matrix and is formed by the 1-3 linkage of D-glucuronic acid to N-acetylgalactosamine. The mechanism of action of CS explains its beneficial effect on the cartilage, synovial membrane and subchondral bone. CS may also be of benefit in diseases where inflammation is an essential marker. In fact, many clinical studies have demonstrated the therapeutic effects of orally administered CS against diseases with inflammation. Furthermore, these reports suggest that CS plays an important role in the protection of the base of ulcers and has indirect anti-inflammatory activity.


Chondroitin sulphate

41

• Chondroitin Sulphate (CS) is a natural glycosaminoglycan present in the extracellular matrix and is formed by the 1–3 linkage of D-glucuronic acid to N-acetylgalactosamine

• CS plays an important role in the protection of the base of ulcers and has indirect anti-inflammatory activity


42

Slide Kit

Poloxamer 407 acts as a buffering agent to form a barrier for the acidity of the gastric fluid and to prolong the action on the esophageal mucosa in coating the esophageal epithelium as long as possible. Poloxamer 407 is a compound with specific thermoreversible bioadhesive properties; it is able to form a macromolecular complex with CS and HA, exerting a prolonged barrier activity on the esophageal mucosa. The phenomenon of thermogelling is perfectly reversible and is characterised by a sol/gel transition temperature. Below this temperature, the sample remains fluid, though above it the solution becomes semi-solid. Adhesive properties of Poloxamer 407 have already been used to lengthen the residence time of agents in the gastrointestinal tract. Good adhesion of Poloxamer 407 to the esophageal mucosa was observed in the mouse using an optical fiber spectrofluorimetric method.

Poloxamer 407

42

• Poloxamer 407 acts as a buffering agent to form a barrier for the acidity of the gastric fluid

• Poloxamer 407 is able to form a macromolecular complex with CS and HA, exerting a prolonged barrier activity on the esophageal mucosa

43

Slide Kit

This slide summarises the rational and properties of ESOXX® ONE , detailing the benefits of each component.

Reduces the damage of the mucosa induced by acid and pepsin gastric content Potential anti-inflammatory activity.

Hyaluronic acid (HA)

Key role in the extracellular matrix process (wound repair,

regeneration, morphogenesis

Bioadhesive carrier

(Poloxamer 407)

Summary of rationale and properties of ESOXX® ONE

43

• ESOXX® ONE has a protective barrier effect and its mode of action is not pharmacological, metabolic or any other systemic effect

Chondroitin sulfate (CS)

Prolonged

protective

and healing

properties

on

esophageal

mucosa With CS and HA forms a

macromolecular complex with a barrier activity

44

Slide Kit

This slide summarises the rational and properties of ESOXX® ONE , detailing the benefits of each component.

Reduce damage of mucosa induced by acid and pepsin gastric content. Potential anti-inflammatory activity

Summary of rationale and properties of ESOXX® ONE

44

• ESOXX® ONE has a protective barrier effect and its mode of action is not pharmacological, metabolic or any other systemic effect

Prolonged protective and healing properties on esophageal mucosa

With CS and HA forms macromolecular complex with barrier activity

Bioadhesive carrier

(Poloxamer 407)

Hyaluronic Acid (HA)

Chondroitin Sulfate (CS)

Key role in extracellular matrix process (favors wound repair, regeneration, morphogenesis)

45

Slide Kit

ESOXX® ONE: preclinical experience

45

46

Slide Kit

The barrier effect of ESOXX® ONE on esophageal mucosal damage has been studied in an experimental ex-vivo swine model. Perfusion of ESOXX® ONE after damaging acid solution for 90 min and pepsin solution for 60 min was able to completely prevent the EB staining in all the mucosal samples examined. This effect of ESOXX® ONE was not reversed by a short period of saline perfusion. Perfusion with ESOXX® ONE was able to reduce the permeability of the injured mucosa, even after saline washing of the swine oesophagus. These results were viewed as positive support for further clinical studies of ESOXX® ONE in the topical treatment of gastroesophageal reflux symptoms.

Di Simone MP, et al. Clin Exp Gastroenterol 2012;5:103-7.

ESOXX® ONE reduces permeability of injured mucosa in swine esophagus

46

No stain; undamaged mucosa + EB

Weak stain; damaged mucosa (acid solution 90 min) + EB

Strong stain; damaged mucosa (pepsin solution 60

min) + EB

No stain; damaged mucosa (acid solution 90 min) + ESOXX ® ONE + EB.

Cross-sections of esophageal mucosa after Evans Blue (EB) perfusion

EB: Evans Blue

Perfusion of ESOXX® ONE after damaging acid solution for 90 min and pepsin solution for 60 min was able to completely prevent EB staining

Di Simone MP, et al. Clin Exp Gastroenterol 2012;5:103-7.

47

Slide Kit

ESOXX® ONE: clinical experience

47

48

Slide Kit

In 2009, a preliminary clinical investigation was carried out on 40 patients with esophageal and gastric symptoms, 10 of whom were affected with reflux disease. This was a double-blind crossover study vs. placebo that enrolled 16 females and 24 males aged between 6 and 87 years (main 55-85), with esophagitis and gastritis symptoms characterised by heartburn, epigastric pain, dyspepsia, meteorism and belching. The compounds were blindly administered with the following schedule: one spoon (10 ml) every 8 hours (far from meals) and two spoons at bed time for two weeks. This was followed by a one week interval without administration. Next, two weeks of treatment were carried out by switching placebo and putative active principle in the groups.

Palmieri B, et al. Trends Med 2009;9:241-7.

Study design

48


• Double-blind crossover study vs. placebo that enrolled 16 females and 24 males aged between 6 and 87 years (main 55-85), with esophageal and gastric symptoms characterised by heartburn, epigastric pain, dyspepsia, meteorism and belching

• ESOXX® and placebo were blindly administered with the following schedule: one spoon (about 10 ml) every 8 hours (far from meals) and two spoons at bed time for two weeks, followed by a one week interval without administration

• Two weeks of treatment were then carried out by switching placebo and putative active principle in the groups

• Symptoms were scored daily

49

Slide Kit

Pre- and post- treatment endoscopic investigations showed improvement of inflammation and healing of the mucosa in patients with either esophageal or gastroduodenal pathologies.


Pre and Post treatment endoscopy

49

Adapted from: Palmieri B, et al. Trends Med 2009;9:241-7.

Pre and Post treatment endoscopy showed improvement of inflammation and healing of the mucosa in patients with both esophageal and gastroduodenal pathologies

Mucosal erosions of the esophagus (esophagitis)

Esophagitis after therapy

Pyloric ulcer

Pyloric ulcer after therapy

50

Slide Kit

Preliminary clinical experience showed that ESOXX® has favorable effects on the symptoms related to GERD.In the group starting on ESOXX® there was significant improvement vs. placebo. Pre-post treatment endoscopic investigations showed improvement of inflammation and healing of the mucosa in patients with either esophageal or gastroduodenal pathologies.There were no adverse events during the trial. Palmieri B, et al. Trends Med 2009;9:241-7.

Conclusions

50


• Preliminary clinical experience showed that ESOXX® has favorable effects on the symptoms related to GERD

• In the group starting on ESOXX® there was significant improvement of symptoms scores vs. placebo

• Pre-post treatment endoscopic investigations showed improvement of inflammation and healing of the mucosa in patients with either esophageal or gastroduodenal pathologies

• There were no adverse events during the trial

51

Slide Kit

In 2013, Palmieri and colleagues carried out a randomised double-blind, crossover, placebo-controlled study in 20 patients who had experienced heartburn and/or acid regurgitation for at least 3 days during a 7 day run-in period, without endoscopic mucosal breaks. Patients received four daily doses of ESOXX® ONE or placebo for a period of 14 days in addition to PPI standard therapy. After a washout period of 7 days, patients were then crossed over to receive ESOXX® ONE or placebo for an additional 14 days. PPIs, at a constant dose in past weeks, were maintained at the same dosage during the entire the study period. Patients were evaluated at baseline, after switching treatment and at the end of the study. Intensity of heartburn and acid regurgitation at awakening and/or at bedtime, were recorded daily by patients, using a 4-point rating scale as follows (0 = absence of symptom, 1 = minimal awareness of symptom, easily tolerated, 2 = awareness of symptom which is bothersome but tolerable without impairment of sleep or daily living, possible use of antacids, 3 = symptom hard to be tolerated interfering with daily activities and/or sleeping, recurrent use of antacids). The primary efficacy variables were the Sum of Symptoms Score Intensity (SSSI) over the 14-day treatment period, also expressed as Sum of Symptoms Intensity Difference (SSID), the difference obtained by subtracting SSSI at each time point from baseline value.

Palmieri B, et al. Eur Rev Med Pharmacol Sci 2013;17:3272-8.

Study design

51

• Randomised double-blind, crossover, placebo-controlled study in 20 patients (10 ESOXX® ONE group; 10 control) who had experienced heartburn and/or acid regurgitation for at least 3 days during a 7 day run-in period

• Patients received four daily doses of ESOXX® ONE or placebo for a period of 14 days in addition to PPI standard therapy

• After a washout period of 7 days, patients were then crossed over to receive ESOXX® ONE or placebo for an additional 14 days

• The primary efficacy variables were the Sum of Symptoms Score Intensity (SSSI) over the 14-day treatment period, also expressed as Sum of Symptoms Intensity Difference (SSID), the difference obtained by subtracting SSSI at each time point from baseline value


52

Slide Kit

All 20 patients, 17 males and 3 females, mean age 55 ± 18 years (range 37-74), mean BMI 28.3 ± 5 kg/m2 (20% BMI ≥30 kg/m2) completed both randomised treatment periods. Patients had suffered from GERD for a mean of 4.5 ± 3.4 years and most of them were currently on treatment with PPIs alone or PPIs plus antacids. Baseline clinical characteristics were similar and comparable at the start of each treatment phase. At endoscopy the patients do not present evidence of mucosal damage. At the end of each treatment period, all patients exhibited satisfactory compliance to the scheduled regimen, independently of the randomised sequence (96% for ESOXX® ONE , 92% for placebo).


Patient characteristics

52

• N=20 (17 males and 3 females)

• Mean age 55 ± 18 years (range 37-74)

• Mean BMI 28.3 ± 5 kg/m2 (20% BMI ≥30 kg/m2)

• Suffered from GERD for a mean of 4.5 ± 3.4 years

• Most were currently on treatment with PPIs alone or PPIs plus antacids

• Negative endoscopy


53

Slide Kit

A statistically significant SSID was observed (-2.7 ± 1.4 vs. -0.6 ± 2.1 p<0.01) as result of significant changes in heartburn intensity (-1.6 ± 0.92 vs. 0.5 ± 1.9, p<0.03) and acid regurgitation intensity (-1.1 ± 0.6 vs. -0.1 ± 1.1 p < 0.04), after ESOXX® ONE administration.


Symptoms score intensity difference (SSID)

53

A statistically significant SSID was in heartburn intensity and acid regurgitation intensity after ESOXX® ONE administration


SSID and heartburn and acid regurgitation score intensity difference after completion of randomised sequences

HA+CS: Hyaluronic Acid + Chondroitin Sulphate (ESOXX® ONE); SSID: Symptom Score Intensity Difference; SID: Symptom Intensity Difference

-2.7

-1.6

-1.1

-0.6 -0.5

-0.1

HA + CS

Placebo

*

**

*

*p < 0.03 ;**p < 0.01

Heartburn SID Acid

regurgitation SSID 0

-1.0

-0.5

-1.5

-2.5

-2.0

-3.0

Scor

e

54

Slide Kit

SSIDs in each of the treatment phase with weekly mean values, deriving from patient’s diaries are summarised in this slide. From the first week of treatment onward, SSID values were always higher compared to placebo and maximal after the second week of treatment whatever the randomised sequence.


SSIDs in each treatment phase

54

SSID values were always higher compared to placebo and maximal after the second week of treatment whatever the randomised sequence


Sum of SSID weekly values

HA + CS Placebo

Wash-out 0 7

0 14 21 28 35

-0.5

-1.5

-1

-3

-2

-2.5

Days

SSID

2nd period 1st period HA+CS: Hyaluronic Acid and Chondroitin Sulphate (ESOXX® ONE); SSID: Symptoms Score Intensity Difference.

55

Slide Kit

Complete disappearance of symptoms was higher after ESOXX® ONE treatment: 52% vs. 12%.


Complete symptom disappearance

55

Complete disappearance of symptoms was higher after ESOXX® ONE treatment: 52% vs. 12%


Percentage patients with complete symptom disappearance and reporting good speed of action (≤30 min)

HA+CS: Hyaluronic Acid and Chondroitin Sulphate (ESOXX ®ONE)

52% 60%

12%

30%

0%

10%

20%

30%

40%

50%

60%

70%

Complete symptom disappearance

Good speed of action

HA+CS Placebo

*p = 0.01; **p = 0.05

* **

Patie

nts (

%)

56

Slide Kit

The time to disappearance of symptoms in the ESOXX® ONE group was significantly shorter than placebo (median 38 min vs. 65 min; p<0.01) and ESOXX® ONE treatment was associated with a higher, statistically significant percentage of patients reporting good speed of action (≤30 min) compared to placebo (60% vs. 30% respectively; p=0.05).


Details on Speed of action

56


Speed of action distribution by treatment

ESOXX® ONE was associated with a significantly higher percentage of patients reporting good speed of action ( ≤30 min) compared to placebo

(60% vs. 30% respectively)

SPEED OF ACTION HA + CS N° of patients (%)

PLACEBO N° of patients (%) P value

≤ 15 min > 15 min and ≤ 30 min >30 min (max 90 min)

2 (10) 10 (50) 8 (40)

1 (5) 5 (25)

Total of ≤30 min 12 (60) 6 (30) 0.05

HA+CS: Hyaluronic Acid and Chondroitin Sulphate (ESOXX ®ONE)

57

Slide Kit

The study concluded that treatment with ESOXX® ONE produced a fast relief of GERD symptoms. Secondary analyses showed that significantly more patients receiving ESOXX® ONE achieved rapid disappearance of symptoms and a prolonged symptom-free period. ESOXX® ONE was considered to be a valid tool in addition to PPIs for the treatment of GERD symptoms in NERD patients.


Conclusions

57

• ESOXX® ONE produced a fast relief of GERD symptoms

• Significantly more patients receiving ESOXX® ONE achieved rapid disappearance of symptoms and a prolonged symptom-free period

• ESOXX® ONE was considered to be a valid tool in addition to PPIs for the treatment of GERD symptoms in NERD patients


58

Slide Kit

Savarino et al. carried out a multicentre, randomised, double-blind, placebo-controlled study investigating the use of ESOXX® ONE in 154 NERD patients (76 ESOXX® ONE; 78 control). Following the screening visit at which PPI treatment was temporary discontinued, patients underwent a 15 day washout period. At the randomisation visit, patients were assigned to ESOXX® ONE or placebo in addition to PPI therapy for 15 days which was followed by a final study visit.

Savarino V, et al. Under publication.

Study design

58

• Multicenter, randomised, double blind, placebo-controlled trial in 154 NERD patients (76 ESOXX® ONE group; 78 control)

• Screening visit (V1), start of a 15-day (± 2 days) run in/wash out period with temporary PPI discontinuation

• Randomisation Visit (V2): 10 mL (1 stick) ESOXX® ONE or Placebo QID (1 hour after meals and at bed-time) for a 15-day treatment period in addition to PPI therapy

• Visit (V3) after 15-days (± 2 days) of treatment or final visit


59

Slide Kit

Patients must have had a diagnosis of NERD, absence of esophageal lesions at an esophago-gastroscopy performed in the last 6 months and typical symptoms of GERD (pyrosis and/or regurgitation and/or retrosternal pain and/or acid taste) for at least 3 months and for at least 3 days per week in the month preceding the screening visit.


Inclusion criteria

59

• Both sexes

• Age: ≥18 years old

• ReQuest questionnaire confirming NERD diagnosis

• Absence of esophageal lesions at an esophago-gastroscopy performed in the last 6 months

• Typical symptoms of GERD (pyrosis and/or regurgitation and/or retrosternal pain and/or acid taste) for at least 3 months and for at least 3 days per week in the month preceding the screening visit


60

Slide Kit

The primary endpoint was the percentage of patients with at least 3 points reduction in the GERD Symptoms Total Score collected through the patient’s ReQuest questionnaire at final visit. Secondary endpoints were defined as: rate of patients with 50% reduction of GERD Total Symptoms Score at final visit, rate of patients with reduction of GERD Total Symptoms Score at final visit, change of Total Symptoms Score absolute value at final visit, severity and frequency of each symptom: heartburn, retrosternal pain, acid regurgitation, acid taste in the mouth, at final visit, days with symptoms, quality of life evaluated by QOL- SF-36 questionnaire.


Endpoints

60

• Primary endpoint − Rate of patients with at least 3 points reduction of the GERD Symptoms Total

Score collected through the patient’s ReQuest questionnaire at final visit

• Secondary endpoints − Rate of patients with 50% reduction of GERD Total Symptoms Score at final visit − Rate of patients with reduction of GERD Total Symptoms Score at final visit − Change of Total Symptoms Score absolute value at final visit − Severity and frequency of each symptom: heartburn, retrosternal pain, acid

regurgitation, acid taste in the mouth, at final visit − Days with symptoms − QOL- SF-36


61

Slide Kit

Patient characteristics were well balanced at baseline.


Patients’ baseline characteristics

61

ESOXX® ONE (n= 76)

PLACEBO (n=78)

ALL (n=154)

Female N (%) 48 (63.2%) 46 (59.0%) 94 (61%)

Age (mean±SD) years Range (min-max)

45.5±15 18-81

45.5±13.4 24-75

45.5±14 18-81

BMI (kg/m2) 23.8±3.1 23.7±3.2 23.7±3.1

GERD Total Symptoms Score Rate of patients with ≥ 3 GERD symptoms Heartburn (%) Retrosternal pain (%) Acid regurgitation (%) Acid taste in mouth (%)

7.30±2.4 44% 84% 54% 70% 61%

7.29±2.1 41% 86% 50% 66% 60%

7.30±2.3 43% 85% 52% 68% 60%

Past treatment with PPIs (%) Past treatment with other anti-GERD therapies (%)

92% 29%

82% 26%

87% 27%


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Compliance to treatment was greater than 90% in both groups.


Compliance and exposition

62

Compliance (mean±SD) % sticks assumption

Exposition (mean±SD) Days of treatment

ESOXX® ONE (n=76) PLACEBO (n=71)

90.9 ± 22.9

90.2 ± 20.7

14.3 ± 3.5

14.1 ± 3.2

Compliance to treatment was greater than 90% in both groups


63

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The results of the primary endpoint are shown here. A significant higher percentage of patients with reductions of total symptoms score 3 points were seen in patients treated with ESOXX® ONE vs. placebo.


Primary endpoint

63

Percentage of patients with a reduction in total symptoms score of at least 3 points at final visit

Significant differences in symptom reduction vs. placebo


ITT population

52.6%

32.1%

0%

10%

20%

30%

40%

50%

60%

ESOXX ONE PLACEBO

* * p=0.010

Patie

nts (

%)

ESOXX® ONE + PPI vs. PPI alone → +64% of patients had symptoms improvement

ESOXX® ONE

64

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Considering the percentage of patients with a 50% reduction in total symptoms score at final visit, significant differences vs. placebo were observed in the ITT population.


Patients with at least 50% reduction in symptoms

64

Percentage patients with 50% reduction in total symptoms score at final visit

Significant differences vs. placebo were seen in the proportion of patients with at least 50% reduction in symptoms Savarino V, et al. Under publication.

38.2

23.1

0%

10%

20%

30%

40%

50%

ESOXX ONE PLACEBO

* * p=0.042

ITT population

Patie

nts (

%)

ESOXX® ONE vs. PPI alone → +65% of patients had symptoms improvement

65

Slide Kit

65

78,90%

56,40%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

ESOXX ONE PLACEBO

* * p=0.003

ITT population

Patie

nts (

%)

Percentage patients with any reduction in total symptoms score at final visit

Significant differences vs. placebo were seen in the proportion of patients with any reduction in total symptoms score at final visit

Secondary endpoint


66

Slide Kit

Significant differences between ESOXX® ONE and placebo were seen considering the percentage of patients with any reduction in total symptoms score at final visit (78.9% vs. 56.4%; p=0.003; ITT population). There was also a significant reduction in the number of days with symptoms with ESOXX® ONE vs. placebo (-6.07 vs. -3.96; p=0.0059; ITT population). The average reduction of total symptoms score with ESOXX® ONE at final visit was double than that seen in the placebo group (-3.1±3.1 vs. -1.5±3.0; p=0.002) Savarino V, et al. Under publication.

Secondary endpoints (2/3)

66

Significant reduction vs placebo in the number of days with symptoms


-6,07

-3,96

-7

-6

-5

-4

-3

-2

-1

0 ESOXX ONE PLACEBO

* * p=0.0059

Num

ber o

f day

s

Number of days with symptoms

ITT population

67

Slide Kit

Significant differences between ESOXX® ONE and placebo were seen considering the percentage of patients with any reduction in total symptoms score at final visit (78.9% vs. 56.4%; p=0.003; ITT population). There was also a significant reduction in the number of days with symptoms with ESOXX® ONE vs. placebo (-6.07 vs. -3.96; p=0.0059; ITT population). The average reduction of total symptoms score with ESOXX® ONE at final visit was double than that seen in the placebo group (-3.1±3.1 vs. -1.5±3.0; p=0.002). Savarino V, et al. Under publication.

Secondary endpoints (3/3)

67


-3,10

-1,50

-4

-3

-2

-1

0 ESOXX ONE PLACEBO

* * p=0.002

ITT population

Patie

nts (

%)

Average reduction of total symptoms score at final visit

The average reduction of total symptoms score with ESOXX® ONE at final visit was double than that seen in the placebo group

(-3.1 ± 3.1 vs. -1.5 ± 3.0; p=0.002)

68

Slide Kit

The patients’ quality of life, evaluated with the SF-36 questionnaire, showed statistically significant differences in favour of the ESOXX® ONE group for general health perception (difference between the adjusted means of the ESOXX® ONE and placebo groups: -4.8006; 95% CI: -8.4409 to -1.1603; p=0.0101) and social function (difference between the adjusted means of the ESOXX® ONE and placebo groups: -5.2620; 95% CI: -9.7049 to -0.8190; p=0.0206) in the ITT population.


Quality of life

68

• Patients’ quality of life, evaluated with SF-36 questionnaire, showed statistically significant differences in favour of the ESOXX® ONE group for:

− general health perception (difference between adjusted means of Esoxx® One and placebo groups: -4.8006; 95% CI: -8.4409 to -1.1603; p=0.0101)

− social function (difference between adjusted means of Esoxx® One and placebo groups: -5.2620; 95% CI: -9.7049 to -0.8190; p=0.0206)


69

Slide Kit

Considering the palatability of ESOXX® ONE, 90% of patients reported that administration was acceptable (excellent, good, indifferent), independently from meals or bedtime, vs. 92% with placebo. In this study, ESOXX® ONE was found to be more effective than placebo in controlling the symptoms of NERD. It was also considered to have a good safety profile, was well-tolerated and highly palatable.


Conclusions

69


• 90% of patients considered ESOXX® ONE administration acceptable (excellent, good, indifferent) in terms of palatability independently from meals or bedtime vs. 92% placebo

• ESOXX® ONE added to PPI treatment was more effective than PPI alone in controlling the symptoms of NERD

• ESOXX® ONE was considered to have a good safety profile and was well-tolerated

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ESOXX® ONE: summary of clinical studies

70

Palmieri B, et al. Trends Med 2009;9:241-7. Palmieri B, et al. Eur Rev Med Pharmacol Sci 2013;17:3272-8. Savarino V, et al. Under publication.

Clinical experiences showed that ESOXX® ONE has favourable effects on the symptoms related to GERD

• ESOXX® ONE is associated with fast and prolonged relief of GERD symptoms and has good palatability

• ESOXX® ONE combination to PPIs is more effective than PPIs alone in controlling the symptoms in NERD patients

• ESOXX® ONE has a good safety profile and is well-tolerated

Alfa Wassermann and its subsidiaries are part of the Alfasigma Group

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Slide-Kit - jh-comm.eu · PDF filedifferential diagnosis such as peptic ulcer disease, achalasia, gastritis, ... aspects of the generic quality of life as seen in this slide. Moreover,