Clinical trial NCT03193216
Conditions: Barretts Esophagus With Dysplasia
Keywords: Barrett's GERD reflux alginate solution proton pump inhibitor
Sponsor: Medical University of South Carolina
Start date: 2017-08-25; Completion date: 2022-01-01
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates the addition of an alginate based solution to twice daily proton pump inhibitor therapy (PPI) in patients undergoing ablative therapy for dysplastic Barrett's esophagus. The investigators hypothesize that the addition of this medication will help to achieve complete remission of Barrett's over a shorter period of time.

Detailed description:
Barrett's esophagus (BE) is a pre-cancerous condition in the esophagus that results from constant acid exposure and is a precursor to esophageal adenocarcinoma (EAC). Surprisingly, EAC rates continue to rise despite efforts aimed at addressing BE. Patients with dysplastic BE are at increased risk for developing EAC and in high grade dysplasia (HGD), this risk can be as high as 6% per year. For these reasons, these patients are candidates for ablation therapy, either with cryotherapy, endoscopic mucosal resection (EMR), and/or radiofrequency ablation (RFA). In patients receiving ablative therapy, 3-5 treatments are typically required before there is resolution of all Barrett's epithelium while patients remain on twice daily proton pump therapy.

A recent case study by the current authors demonstrated initial failed response of BE with HGD to RFA and subsequently cryotherapy. Only after initiation of a liquid alginate solution (Gaviscon Advance - UK formulation) was there a subsequent rapid and complete response to therapy. This case suggests that liquid alginate provided additional esophageal protection allowing mucosal healing and an overall enhanced response to treatment. This finding is mechanistically plausible given existing evidence demonstrating the carcinogenic properties of bile acids and injurious activity of pepsin in non-acid refluxate, and liquid alginate's unique ability to control these components and inhibit acid reflux. The investigators feel further investigation is warranted in studying the role of adjunct liquid alginate solution in patients undergoing treatment for BE.

The ingredient of interest in is alginic acid (alginate), a polysaccharide found in the cell walls of brown algae. Alginates are unique in their ability to form a protective layer above gastric contents upon exposure to gastric acid, thus limiting exposure of esophageal epithelium to gastric acid, bile acid, pepsin, and other parts of the gastric contents. Concurrently, the bicarbonate in alginate-based solutions forms carbon dioxide in the presence of gastric acid, which converts the gel into foam which floats to the surface of the gastric contents. Hence, alginate solutions form "rafts" which provide a physical barrier to acid reflux, as well as a pH-neutral substitute which refluxes preferentially over gastric acid.

Arms: arm 1: Patients in this group will be taking the study medication -- alginate solution in addition to standard of care twice daily proton pump inhibitor therapy
Interventions: intervention 1: Alginates
Intervention descriptions: intervention 1: Liquid Alginate therapy will be added to twice daily PPI regimen. Patients will be asked to take the alginate solution four times daily (following meals and at bedtime) at 10ml/dose.

Protocol documents:
Prot_SAP_000.pdf: 
 
ELIAS 15 
 
 
The Impact of Adjuvant Liquid Alginate on Endoscopic Ablation Therapy of Complicated Barrett’s 
Esophagus: A Pilot Study  
NCT03193216 
Document Date: 12/05/2018 
 


 
ELIAS 16 
 
RESEARCH PLAN 
 
PROTOCOL TITLE:  
 
The Impact of Adjuvant Liquid Alginate on Endoscopic Ablation Therapy of Complicated Barrett’s 
Esophagus: A Pilot Study  
 
PRINCIPAL INVESTIGATOR:  
• 
Puja Elias, MD, MPH 
 
CO-INVESTIGATORS:  
• 
Mark M. Brodie, MD, Kevin Batte, MD, Brenda Hoffman, MD, Donald O. Castell, MD, B. Joseph 
Elmunzer, MD 
  
COLLABORATORS: 
 
Peter W. Dettmar Ph.D, Kent E. Armeson, MS 
 
Background 
 
Barrett’s esophagus (BE) is a pre-cancerous condition in the esophagus that results from constant acid 
exposure and is a precursor to esophageal adenocarcinoma (EAC). Surprisingly, EAC rates continue to 
rise despite efforts aimed at addressing BE. Patients with dysplastic BE are at increased risk for 
developing EAC and in high grade dysplasia (HGD), this risk can be as high as 6% per year. For these 
reasons, these patients are candidates for ablation therapy, either with cryotherapy, endoscopic mucosal 
resection (EMR), and/or radiofrequency ablation (RFA). In patients receiving ablative therapy, 3-5 
treatments are typically required before there is resolution of all Barrett’s epithelium while patients remain 
on twice daily proton pump therapy29. A recent case study by the current authors demonstrated initial 
failed response of BE with HGD to RFA and subsequently cryotherapy. Only after initiation of a liquid 
alginate solution (Gaviscon Advance - UK formulation) was there a subsequent rapid and complete 
response to therapy. This case suggests that liquid alginate provided additional esophageal protection 
allowing mucosal healing and an overall enhanced response to treatment.  This finding is mechanistically 
plausible given existing evidence demonstrating the carcinogenic properties of bile acids and injurious 
activity of pepsin in non-acid refluxate, and liquid alginate’s unique ability to control these components 
and inhibit acid reflux1,2,5,6,7,8,10,16,18,21,25,26,34.  We feel further investigation is warranted in studying the role 
of adjunct liquid alginate solution in patients undergoing treatment for BE. 
The ingredient of interest in is alginic acid (alginate), a polysaccharide found in the cell walls of brown 
algae. Alginates are unique in their ability to form a protective layer above gastric contents upon 
exposure to gastric acid, thus limiting exposure of esophageal epithelium to gastric acid, bile acid, 
pepsin, and other parts of the gastric contents. Concurrently, the bicarbonate in alginate-based solutions 
forms carbon dioxide in the presence of gastric acid, which converts the gel into foam which floats to the 
surface of the gastric contents. Hence, alginate solutions form “rafts” which provide a physical barrier to 
acid reflux, as well as a pH-neutral substitute which refluxes preferentially over gastric acid12,13,17. 
 
It is noteworthy that Gaviscon Advance, which is approved for over-the-counter use in Europe by the 
European Medicines Agency (EMA) but not FDA approved in the U.S., is qualitatively and quantitatively 
different from U.S. Gaviscon formulations in terms of alginate composition.  Gaviscon Advance, but not 
American Gaviscon, has demonstrated superiority to placebo, non-inferiority to proton pump inhibitors 
(PPIs), and efficacy as add-on therapy in patients already on PPI with regard to relieving symptoms of 
GERD4,15,22.  Furthermore, only the UK version of dual action antacid (antacid with alginate) has been 
shown to be superior to antacids alone in reducing post-prandial esophageal acid exposure in GERD 
patients19. Finally, as Dettmar et al. have demonstrated in a comparison of raft characteristics between a 
range of alginate/antacid formulations, Gaviscon Advance forms alginate rafts more quickly than other 


 
ELIAS 17 
 
formulations (most notably U.S. Gaviscon formulations), and these rafts are more coherent, have more 
complete flotation, and are of greater resiliency, weight, strength and volume than regular and extra 
strength Gaviscon (USA)30. 
 
Hypotheses & Specific Aims 
 
H1 (primary): Adjuvant treatment with liquid alginate solution in addition to proton pump inhibitor (PPI) 
therapy will result in complete endoscopic eradication of complicated Barrett’s esophagus (BE) more 
rapidly than endoscopic treatment on PPI therapy alone. 
 
H2 (secondary): Adjuvant treatment with liquid alginate solution in addition to PPI therapy will result in 
fewer endoscopic treatment sessions necessary to achieve complete eradication of complicated BE 
compared to treatment with PPI alone.  
  
SA 1 (primary): Eradication rate at one year will be compared between current recruits (i.e. study 
patients on adjuvant liquid alginate) and historical controls Patients will be matched by type of therapy, 
and to the best of our ability, length of Barrett’s. 
 
SA2 (secondary): To compare the duration of treatment required to achieve complete endoscopic 
eradication of BE in patients treated with the combination of PPI and liquid alginate solution vs. those 
treated with PPI alone.  
 
SA 3 (tertiary): To compare the number of treatment sessions required to achieve endoscopic 
eradication of BE in patients treated with the combination of PPI and liquid alginate solution vs. those 
treated with PPI alone.  
 
 
Study Design 
 
This is a pilot prospective cohort study at a single tertiary care center.  Patients with BE and proven 
dysplasia (high or low grade) or risk of other abnormality presenting to our tertiary care center interested 
in endoscopic treatment will be asked to participate in the study. Participation will involve taking 10 mL of 
Gaviscon Advance four times daily along with twice daily PPI during the treatment duration.  The control 
group will be a historical cohort of Barrett’s esophagus patients treated in the last 5 years by the same 
endoscopists using similar approaches—these are patients who were prescribed twice daily PPI therapy 
alone during treatment.  
 
Eligibility Criteria 
 
Patients who are already scheduled for treatment of their dysplastic Barrett’s esophagus or risk of other 
abnormality who are planning to undergo EMR, or ablation therapy with cryotherapy (spray or balloon) 
and/or RFA (with or without EMR) will be eligible for enrollment.  
 
Inclusion criteria (all must be present): 
(1) Age ≥18 
(2) Patients already previously scheduled for treatment of complicated Barrett’s esophagus 
(3) Long Segment Barrett’s (>3cm) 
 
 
Exclusion criteria: 
(1) Moderate to severe renal impairment, as defined by eGFR< 60 for 2 consecutive readings 
(2) Lack of capacity for decision-making 
(3) Allergy to hydroxybenzoates   


 
ELIAS 18 
 
(4) Patients with uncontrolled hypertension or decompensated heart failure  
(5) Pregnancy- patients of child-bearing potential will be tested. 
(6)  Patients with elevated calcium or potassium on screening laboratory testing (labs completed within 
the last month) 
 
 
Enrollment 
 
Eligible patients who provide informed consent will be included in this prospective study and asked to 
take the alginate solution in addition to their twice daily PPI therapy.  If patients are on concurrent H2 
blocker therapy, this will be stopped after enrollment in the study. Subjects will be primarily recruited in 
the office setting, following decision to undergo ablation therapy.  Upon the start of ablation therapy, 
patients will start taking 10ml of Gaviscon Advance 30 minutes after every meal and at bedtime (4 daily 
doses, after breakfast, lunch, dinner and before bed).  This will begin on the day of the first endoscopy, 
after the ablation treatment. PPI therapy will continue as previously prescribed.  
 
Endoscopic treatment 
 
Standard guidelines will be followed for patients undergoing EMR, RFA or cryotherapy or RFA, up to 8-
10 cm can be treated during one session and sessions are scheduled every 10-12 weeks. For 
cryotherapy, approximately the same area can be treated (8-10cm) during one session, and sessions are 
scheduled every 8-10 weeks. When initial EMR is performed, follow-up endoscopic ablative therapy will 
be scheduled approximately 8 weeks later. The decision of which therapy to implement depends largely 
on anatomy and patient preference and will be determined by the endoscopists involved in the study—
Dr. Puja Elias (PI), Dr. Brenda Hoffman, or Dr. B. Joseph Elmunzer.  Furthermore, all decisions 
pertaining to the need for repeat procedures to address inadequate treatment or incomplete tissue 
sampling, or the decision to refer for the alternate procedure, will be dictated by the above endoscopists.  
As mentioned previously, number of sessions to achieve complete eradication of Barrett’s varies by 
length, but on average can take anywhere from 3-5 sessions, depending on initial length of BE as well as 
existence and size of hiatal hernia31.   
 
Follow-up Assessments 
 
All enrolled subjects will be followed until resolution of Barrett’s is achieved, as confirmed by biopsy and 
endoscopic visualization. A measurement system referred to as the Prague classification32 will be used 
to document areas of the esophagus with Barrett’s and to assess improvement from one endoscopy to 
another. This system allows the endoscopist to record the area of Barrett’s involved by describing the 
area involved that is circumferential in nature and the area that is patchy. Decrease in surface area 
involved will help guide the aim for the study. During treatment sessions, pertinent clinical and 
endoscopic data will be collected (see Appendix A). Immediately prior to each treatment visit, an office 
visit will take place at the MUSC Gastroenterology endoscopy/outpatient clinic with study personnel 
including the PI, research coordinator, and/or fellow/resident participating in the study, which will serve to 
collect data regarding blood pressure, surveillance serum chemistries, treatment experience, adverse 
events to the drug, or any other issues (see Appendix B).  Adherence to the medication regimen will be 
done by asking patients to bring in all used and unused bottles. IDS will assist in calculating how much 
drug has been taken and this data will be recorded at each visit.  
These data will then be entered into a coded RedCap database. At approximately six week intervals, the 
study research coordinator will call to verify medication regimen adherence as well as any adverse 
events associated with the study drug. 
 
From the time of biopsy proven remission, patient medical records will be reviewed for up to 2 years to 
evaluate recurrences rates.  
Outcomes 


 
ELIAS 19 
 
 
Eradication rate of intestinal metaplasia (complete remission of intestinal metaplasia – CRIM) at one year 
will be the primary outcome. The length of time to eradication and the number of endoscopic procedures 
required for CRIM will be the secondary and tertiary outcomes.  CRIM will be defined as visual 
endoscopic evidence of neo-squamous epithelium occupying previous area of Barrett’s epithelium 
combined with biopsies showing normal squamous esophageal epithelium without intestinal metaplasia. 
 
When endoscopic eradication is observed, tissue biopsies of the GEJ and previously treated epithelium 
will be taken according to the Seattle protocol which recommends biopsies in a four quadrant fashion 
every 1 cm for a history of high grade dysplasia and ever 2 cm for a history of low grade dysplasia33. For 
areas of mucosal irregularity, targeted biopsies will also be taken.  Patients who have achieved 
eradication but on subsequent biopsies have recurrence of Barrett’s will undergo ablation treatment 
again until eradication is once again achieved.  The presence of dysplasia on any one specimen will 
prohibit a claim of eradication.  
 
The endoscopic footage from each study procedure will be video recorded. After quality assurance of the 
footage and removal of all identifiers, videos may be reviewed by a blinded and independent panel to 
confirm potentially subjective outcomes, such as the presence and extent of residual Barrett’s epithelium. 
De-identified videos may be distributed to reviewers electronically, or may be reviewed during in-person 
sessions.  
 
Adverse events related to the study drug will be defined according to standard consensus guideline 
documents published in the gastroenterology literature. 
 
 
Sample Size Calculation and Statistical Consideration 
We will compare the time to complete BE eradication/resolution (CRIM) between the prospective and 
historical cohorts using Kaplan-Meier time-to-event (time-to-CR) curves. The historical data maintained 
by the PI have n= 32 patients treated under similar conditions (e.g. facility, physicians) as the study 
patients who will be prospectively treated. As the purpose of this pilot study is to estimate the time to 
CRIM with the addition of liquid alginate for approximately 20 enrolled patients, no hypothesis testing will 
be performed to compare the distributions (hence, no power calculation). Comparisons will be descriptive 
only. Time-to-CR is assumed to be exponentially distributed and we will use the maximum likelihood 
estimate to estimate the rate parameter each cohort. Patients who do not reach CR by the end of the 
study will be censored at that time. The difference in the rate parameter between cohorts will be 
calculated with a 95% confidence interval. Median time to CR will be estimated based on these 
parameters. Median time to CR under current treatments is about 22 months 27. If median time to CR with 
liquid alginate solution is sufficiently improved (e.g. to < 18 months), we will have high-quality pilot data 
with which to estimate a sample size for a more definitive randomized trial. Additionally, we will tabulate 
the number of treatments required to achieve CR and compare descriptively between cohorts as a 
secondary endpoint. Analyses above will also be stratified according to important covariates, such as 
disease grade and type of treatment (RFA or Cryotherapy).   
 
Data Collection, Management, and Quality Control Procedures 
 
Data entry will occur through RedCap, which will allow for study data to be directly entered into the 
database by the site via a secure internet connection. In addition to use of passwords and other security 
measures, all documents containing identifying information on individuals or physicians are considered 
confidential materials and will be safeguarded to the greatest possible extent.  No information identifying 
a specific person, hospital, or physician will be released to or discussed with anyone other than study 
staff members. Appendix C shows the data points that will be collected from both the clinical and 
endoscopic visits. 
 


 
ELIAS 20 
 
Study Sites and Timeline 
 
This is a single center study which will be conducted solely at MUSC Patients will be monitored with a 
telephone call every six weeks as mentioned above and they will be provided with information to get in 
touch with the study team if they have problems between their visits..  Enrollment will be ongoing until an 
adequate number of subjects have been recruited.  Thus, we anticipate that the study can be completed 
within 2 years. 
 
 
Monitoring 
 
All study data will be monitored routinely for completeness, timeliness, and consistency by the project 
manager. Data accuracy will be verified on a quarterly basis by the project manager and principal 
investigator.  Due to a relatively small “n”, all subjects’ data will be reviewed.  Discovered discrepancies 
between recorded study data and information found in medical records will be addressed through 
discussions between the PI and research coordinator.  Subjects may be withdrawn from the study if they 
are lost to follow up, or if they endorse lack of compliance with liquid alginate solution and/or PPI therapy. 
 
 
 
Safety 
 
Gaviscon Advance is considered a very safe medication with a very mild side effect profile. It is widely 
available in the UK but not available in the US. An FDA IND application has been filed for its use for this 
study. Gaviscon Advance will be purchased directly from the pharmaceutical company, Reckitt 
Benckiser. Each 10 mL oral suspension contains 1g sodium alginate and 200 mg potassium hydrogen 
carbonate (active ingredients).  The formulation also contains calcium carbonate, carbomer, sodium 
saccharin, sodium hydroxide, and so any patients who have been advised to restrict their diet from any of 
these substances should consult a doctor before taking Gaviscon Advance.  Patients who suffer for have 
suffered from significant kidney or heart disease should speak with a physician before taking Gaviscon.  
Finally, the formulation includes methyl and propyl para-hydroxybenzoates which may cause allergic 
reactions (less than 1 in 10,000 patients), including skin rash, itching, difficulty breathing, dizziness, or 
swelling.  Overdosing of the medication may cause bloating. Please see summary of product 
characteristics – Appendix D).   
 
Any adverse event, either related to Gaviscon Advance or not, will be recorded in pre-treatment clinic 
and/or treatment visits, and will be evaluated by a safety review committee (see below). 
 
Safety Review Committee 
 
A safety review committee will be assembled for this clinical study. This committee will be composed of 3 
persons who are not study investigators. The overall goals of the committee will include the following: 1) 
identify unacceptably slow rates of accrual, 2) identify high rates of ineligibility, 3) identify protocol 
violations that suggest clarification of changes to protocol are needed, 4) identify unexpectedly high 
dropout rates that threaten the trial’s ability to produce credible results, 5) ensure the credibility of the 
study, 6) ensure the validity of study results, and most importantly, 7) protect the safety of trial 
participants. The safety review committee will meet quarterly. If irregularities are identified in any of the 
goal areas listed above, the committee will propose changes to the protocol or study infrastructure in 
order to remedy the problem. In the event of a severe problem, the committee may advise termination of 
the study.  
 
 
 


 
ELIAS 21 
 
Potential Problems and Pitfalls 
 
There are several potential pitfalls that may affect this study.  However, if these are anticipated and 
managed appropriately, we believe they will not significantly impact the validity of the findings.   
 
 
We have been conservative with the estimate of the anticipated number of subjects during the funding 
period.  There are typically only several patients at MUSC’s GI clinic per month that present with 
dysplastic Barrett’s (or Barrett’s with IMC) who are naïve to treatment. Therefore, we are proposing a 
pilot study with a conservative initial enrollment goal of 20 patients. This number can be increased to 
compensate for subjects who are potentially withdrawn or LTFU. If this pilot study proves to be 
informative, a multicenter initiative would be the next step.  
 
Another challenge will be ensuring subject compliance with both PPI and liquid alginate therapy.  This is 
particularly salient in patients who experience improvement in symptoms, and feel that they don’t need to 
take medicine anymore, especially since the recommended dose of the study drug will be four times a 
day. We will contact the patients in between each 2-3 month visit, via telephone call and routinely 
reiterate the importance of medication compliance. We will also accurately record adherence, as 
mentioned above, by asking patients to bring in all bottles (used and unused) that were dispensed to 
them.  Moreover, in the cases that prompted this line of research, we observed benefit associated with 
only twice daily dosing of alginate, making it feasible that our hypotheses could be met even if half the 
recommended dose is taken 
Lastly, the small sample size will limit the validity and generalizability of our observations. The numbers 
may be further be limited as patients undergoing RFA and cryotherapy will be analyzed separately. As 
mentioned above, this is intended to be a hypothesis-generating study that may inform the design of a 
larger multi-center initiative.  
 
 
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ELIAS 22 
 
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ELIAS 23 
 
 
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