Gut Guarding Gel for Endoscopic Resection to Treat Early Gastroenterological Tumor and Polyps (Evaluation of the Safety of Sodium Alginate Mixed With Calcium Lactate on Endoscopic Mucosal Resection / Endoscopic Submucosal Dissection)
Phase: NA
Conditions: Submucosal Tumor of Gastrointestinal Tract
Sponsor: National Cheng-Kung University Hospital

Clinical Trials of Medical Devices: Study Protocol 
Name 
EndoGel for endoscopic resection to treat early gastroenterological 
tumor and polyps 
Medical 
EndoGel 
Device 
Specification Gel-W Sodium Alginate 100mg (shortened to Vials of white powder) 
Gel-B Calcium Lactate 400mg (shortened to Vials of blue power) 
Manufacturer ITRI Active Pharmaceutical Ingredient Manufacturers/ Taiwan 
Contract 
National Cheng Kung Hospital 
Giver 
Project Investigator launched the clinical trials (IIT) 
Code 
July19th, 2017 
Number 
Wei Shou Shi Zi No.1060013298 
Author 
Project Investigator, Dr. Jiung-Wen Kang 
Internal Medicine, National Cheng Kung Hospital 
 
Performed in accordance with Clinical Investigation of Medical Devices for 
Human Subjects-Good Clinical Practice (ISO 14155-1, -2) 
 

Abstract 
 
Endoscopic Submucosal Dissection (ESD) or endoscopic mucosal resection aims 
at dissecting mucosal lesions completely, which can only be applied in suitable 
appropriate patients and lesions. The standard operation procedure of ESD includes 
the following steps: marking of the lesions, repeated submucosal injections, lesion 
resections, repeated submucosal dissections and removal of lesions. Making use of 
various endoscopic devices will facilitate submucosal dissection of lesions swiftly 
and safely. Endoscopic mucosal resection is a similar procedure, involving 
submucosal injection of suitable solution; then, using snares to remove the lesions at 
one or several times piece by piece. In both situations, an ideal mucosal elevation can 
help doctors remove lesions effectively and safely without damaging the surrounding 
normal tissue. For these purposes, the solutions in the submucosa should be able to 
provide a thick submucosal fluid cushion, remain in the submucosal area long enough 
to allow the treatment procedures successfully completed, ESD or EMR, and to 
preserve the tissue specimen for pathological examinations. 
 
Normal saline used to be the most widely-used solutions for submucosal 
injection. However, it can only sustain the submucosal cushion for a short period 
of time. To overcome the current limitations, more ideal solutions for submucosal 
injections are developed. Hyaluronic acid is now the most optimal solution for 
submucosal injection in Japan, but it is not covered by Health Insurance in many 
countries due to very expensive. As a result, we aim at developing a better solution 
for submucosal injection. 
 
We produced a kind of new solution for submucosal injection, named EndoGel, 
a Class II medical device. This clinical trial aims at recruiting patients who are 
diagnosed with polypoid lesions in their esophagus, stomach or intestines. In these 
patients endoscopic dissection or endoscopic mucosal resection is considered the 
most appropriate treatment for them. In our clinical trial, we intend to inject EndoGel 
in the submucosal area of the targeted lesion in patients’ esophagus, stomach or 
intestines to facilitate the performance of ESD. The purpose of this clinical trial is to 
 
 
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evaluate the safety and efficacy of using EndoGel in ESD and endoscopic 
dissection of superficial tumors. 
 
 
 
I. Introduction 
 
1.1 Background 
 
The westernization of Asian diets has increased the incidence of polyps and 
early cancers of gastrointestinal tract in Taiwanese people. Accordingly, there is a 
sharp surge in the number of people who undergo regular health screenings. Also, 
the number of patients doing esophago-gastro-duodenoscopy (EGD), polypectomy 
resection and endoscopic submucosal dissection (ESD) increases remarkably. As 
evidences show that effective polypectomy in GI tract can prevent future cancer 
evolving from the previous polyps, the device to facilitate the preemptive technology 
is important, we invent our EndoGel for this purpose. 
 
Normal saline is widely used as the solution for submucosal injection in 
endoscopic treatment. However, the fluid appears lost in the mists of time, and only 
maintains the submucosal cushion for a short period of time. The drawbacks make 
endoscopic surgeries more difficult, increasing the risks of harming deep mucosal 
tears while dissections. On the other hand, the loss of normal saline causes repeated 
injections and thus prolongs the time of endoscopic dissection. To overcome the 
current limitations, more ideal solutions for submucosal injection are developed. 
Hyaluronic acid is now the most optimal solution for submucosal injection, but it is 
not covered by Health Insurance and thus very expensive. As a result, it is not 
widely used by most countries around the world. 
 
In the United States, methylcellulose being the primary material, a new solution for 
submucosal injections is invented. This solution is now approved to be a Class II 
medical device by FDA. But it is neither registered nor clinically-used in Taiwan due to 
its high cost and weak promotion. In the past, most doctors in Taiwan used normal 
saline with higher concentration (3%) or glucose solutions (20%, 30%, 50%) for 
submucosal injection. These solutions are easy to access and comparatively cheaper; 
 
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moreover, they remain in the submucosal area longer than normal saline does. However, 
inflammatory reactions usually occur at the spots where physicians inject these 
solutions. Consequently, most Taiwanese endoscopists now use Glycerol (10%) or 
Hyaluronic acid at patients’ own expense as the solution for submucosal injection. But 
another problem rises; TFDA did not officially permit physicians to use these solutions 
in endoscopic surgeries. In other words, the cost of them is a grey area. 
 
By contrast, our medical device, EndoGel, is composed of calcium lactate and 
sodium alginate, both of which have been widely used clinically in Taiwan. TFDA 
has approved the use of 0.3% alginate in 500ml for intravenous injection. As a result, 
sodium alginate is considered safe and applicable. Further, the Handbook of 
pharmaceutical excipient explicitly lists it as a GRAS substance, with LD50 (cat, IP): 
0.25g/kg, LD50 (rabbit, IV): 0.1g/kg and LD50 (rat, IP): 0.25g/kg. Expectedly, we 
assume that the locally injected volume of alginate is below 50ml in single 
administration. If the patient is of 50 kg, the optimal dose of alginate for him/her is 
0.01g/kg. Furthermore, alginate leaks from the wound after therapy. 
 
Calcium lactate has also been used commonly in Taiwan for many years. It is 
used in the treatment of Hypocalcemia, Osteoporosis and Postmenopausal, and can be 
intravenously injected. Calcium lactate is also regarded as GRAS. Expectedly, we 
assume that the locally injected volume of alginate is below 50ml in single 
administration. If the patient is of 50 kg, the optimal dose of calcium lactate for 
him/her is 0.02g/kg. 
 
After we mix sodium alginate and calcium lactate, the viscosity of the mixed 
solution increases due to cross-linking. Thus, the solution can create an optimal height 
of submucosal cushion with its high viscosity. The results of pre-clinical trials also 
manifested that the effect of this solution in submucosal elevation is equivalently good 
as that of Hyaluronic acid, and even better than that of Glycerol! Animal body ESD also 
showed the feasibility of this solution in submucosal elevation. 
 
Consequently, we formally submitted an application for using this solution, named 
EndoGel, in submucosal injection; we also requested for the consent of TFDA 
 
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to conduct clinical trials for a class II medical device to investigate EndoGel. Besides, 
because EndoGel has been registered, we would change the name of the intervention 
as AceGel to prevent misunderstanding and other problems in the future. 
 
 
 
1.2 Clinical Trial Guidance 
 
This clinical trial is performed in accordance with Clinical Investigation of 
Medical Devices for Human Subjects-Good Clinical Practice (ISO 14155-1, -2). 
Before we recruited the patients, we had sent all the documents such as proposals 
and clinical trial informed consents to IRB of National Cheng Kung University and 
TFDA, and consequently they have approved this case. Afterwards, we started to 
recruit patients with all the procedures in conformance with what has instructed in 
Clinical Investigation of Medical Devices for Human Subjects-Good Clinical 
Practice. 
 
During the recruitment process, IRB at National Cheng Kung University 
audited the relevant documents on August 31st, 2018, and provided us with 
instructions and suggestions. 
 
 
 
II. Materials and Methods 
 
2.1 Description of Medical Devices 
 
EndoGel is a solution for submucosal injection. It can be used to lift gastric 
lesions when being injected into the submucosal areas during ESD or EMR. The 
submucosal cushions help endoscopists efficiently remove the lesions with 
electric probes or polypectomy snares, offering patients a less invasive option for 
gastrointestinal cancer treatment. 
 
EndoGel is composed of calcium lactate and sodium alginate, both of which are 
considered “Generally recognized as safe” (GRAS). After mixing the two substances, 
the viscosity of the solution increases due to cross-linking. Hence, the solution can 
 
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serve as the submucosal injective solution used for treatments of early 
gastrointestinal cancer, and can effectively prevent surgical complications such as 
bleeding and perforation. Ideally, the suggested mixing ratio is 1:1, but ratios ranging 
from 0.5:1 to 2:1 can still successfully trigger gelation of the mixed solution. Besides, 
we dye calcium lactate blue to help endoscopists to mark the lesions to be removed. 
As a result, we suggest that the injection of Calcium lactate (the blue one) precedes 
the injection of Sodium alginate (the white one) during ESD or EMR. Or 
alternatively, endoscopists can use a double diameter syringe to inject the two 
solutions simultaneously to the targeted lesion. 
 
During the trials, the physicians who performed ESD and EMR with EndoGel 
pointed out a pivotal drawback; they found that due to the repeated injections of 
EndoGel, the pressure in syringes was so high that the duration of surgery was 
extended. To overcome this problem, we adjusted the concentration and ratio of the 
components in EndoGel to create the desired proportion which meets the 
physicians’ need. The adjustment is shown in the following table; 
  
EndoGel After Adjustment 
 
Component 
Volume 
Sodium alginate 
100mg 
Calcium lactate 
400mg 
 
EndoGel is a product used for endoscopic therapy. We suggest that physicians 
inject calcium lactate (the vial with blue powder) first and sodium alginate (the vial 
with white powder) later. 
 
How to dilute sodium alginate: 
 
First, infuse the sodium alginate powder with 10-20mL sterile water or normal 
saline. Second, shake the vial for 30 to 60 seconds until the solution is clear 
without floating particles on the surface. Afterwards, draw the solution to fill a 
3mL syringe with a needle. The purpose of using a 3mL syringe is to reduce the 
resistance while injecting. 
 
 
 
 
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How to dilute calcium lactate: 
 
First, infuse the calcium lactate powder with 10-20mL sterile water or normal 
saline. Second, shake the vial well and draw the solution out with a 10mL 
syringe with a needle. 
 
How to use EndoGel: 
 
Fill the endoscopic aspiration syringes with calcium lactate and sodium alginate, 
and inject them respectively to the submucosal area of targeted lesions. Before 
injecting the second solution, fill the syringe with sterile water or normal saline to 
wash the residue solution within it away. If not, the remnant of calcium lactate is 
likely to become gel which obstructs the syringe when mixing with alginate. 
 
 
 
 
2.2 Abstract of the clinical trial 
 
Endoscopic Submucosal Dissection (ESD) is an endoscopic technique which 
aims at dissecting mucosal lesions completely. Speaking of ESD, it is of importance 
to select the appropriate patients and lesions. The standard operation procedure 
includes the following steps: marking of the lesions, repeated submucosal injections, 
lesion resections, repeated submucosal dissections and removal of lesions. Making 
use of various endoscopic devices will facilitate submucosal dissection of lesions 
swiftly and safely. Furthermore, an ideal mucosal elevation can also help doctors 
dissect lesions effectively. A suitable solution for submucosal injection can provide 
a thick submucosal fluid cushion, remain in the submucosal area long enough to 
securely allow ESD and preserve the tissue specimen which allows for pathological 
examinations. 
 
Normal saline used to be one of the most widely-used solutions for submucosal 
injection. However, it can only maintain the submucosal cushion for a short period 
of time. To overcome the current limitations, more ideal solutions for submucosal 
injections are developed. Hyaluronic acid is now the most optimal solution for 
submucosal injection, but it is not covered by Health Insurance and thus very 
 
 
 
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expensive. As a result, our project aims at developing a better solution 
for submucosal injection. 
 
Our project produced a kind of new solution for submucosal injection, named 
EndoGel. We have conducted in vitro and in vivo assays of pigs with EndoGel. 
The results showed no serious complications occurring to the pigs in vivo. 
 
 
 
2.2.1 Goal of the clinical trial 
 
The primary goal of this clinical trial is to evaluate the safety and efficacy of 
using EndoGel in ESD and endoscopic dissection of superficial tumors clinically. 
 
 
 
2.2.2 Design of the clinical trial 
 
2.2.2.1 Experiment design 
 
We aim at recruiting 12 patients who are diagnosed with 
gastrointestinal superficial tumors to conduct clinical trial therapies. 
EndoGel is the solution used for submucosal injection for all candidates. The 
usage of EndoGel is listed below; 
 
1. Infuse 10-20mL normal saline into the vial with blue powder of 
calcium lactate. Shake the vial well and then draw the solution out with 
a 10mL syringe with a needle. 
 
2. Infuse 10-20mL normal saline into the vial with white powder of sodium 
alginate. Shake the vial well until no floating particles can be seen on the 
surface. Draw the solution out with a 3 mL syringe with a needle. Mix 
the two solutions in conformance with the suggested mixing ratios given 
in section 2.1. 
 
3. Fill the endoscopic aspiration syringes with calcium lactate and sodium 
alginate, and inject them respectively to the submucosa beneath targeted 
 
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lesions. Before injecting the second solution, fill the syringe with sterile 
water or normal saline to wash the residue solution within it away. If not, 
the remnant of calcium lactate is likely to become gel which obstructs 
the syringe when mixing with alginate. 
 
4. After mixing the two substances, the viscosity of the solution increases 
due to cross-linking. EndoGel will create a submucosal cushion with an 
optimal height. Remove the lesions with electric probes or 
polypectomy snares by dissecting the elevated cushion. 
 
The administered dose and injection times of EndoGel can be 
determined based on the size of lesions and the height of submucosal 
cushions. Physicians will perform the endoscopy surgery in endo rooms or 
operation rooms after clinical assessment. The standard operation procedure 
includes the following steps; 
 
Endoscopic submucosal dissection (ESD): 
 
(1). Mark the perimeter of the lesion with cautery. 
 
(2). Inject the lifting agent to the submucosa around the perimeter of the 
lesion. In this trial, the lifting agent is the mixed solution of alginate 
and calcium lactate. 
 
(3). Incise the elevated submucosa and circumferentially cut the perimeter of 
the lesion with an electrosurgical knife. 
 
(4). Dissect the submucosa beneath the lesion by an electrosurgical knife 
until the lesion is completely resected. 
 
(5). Manage any complications such as intraprocedural bleedings 
and perforations. 
 
(6). Make sure there is no bleedings or perforations after the dissection of 
lesions. If so, do the appropriate management. If not, ESD is 
officially completed. 
 
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Endoscopic mucosal resection (EMR): 
 
(1). Formulate a resection strategy. Make sure the lesions could 
be successfully removed via snare excision. 
 
(2). Inject the lifting agent to the submucosa around the lesion. In this trial, 
the lifting agent is the mixed solution of alginate and calcium lactate. 
 
(3). Use polypectomy snares to excise the lesions. 
 
(4). Manage any complications such as intraprocedural bleedings and 
perforations. 
 
After the therapy, we will monitor the vital signs of the patients in 
wards or endo rooms. We carry out the medical observation in order to react 
promptly to any immediate adverse events occurring to the patients, such as 
delayed bleedings and perforations. We will also conduct long term follow-
up hematology tests to monitor the GOT and GPT of the patients. 
 
2.2.2.2 Indicator of end point 
 
1. Complete resection rate of the gastrointestinal superficial tumors. 
 
2. Follow-ups of wound-healing conditions. Evaluate whether the 
lifting agent causes any local tissue damage. 
 
3. The incidence of complication is lower than 5% within one month. 
 
 
 
 
2.2.3 Ethical considerations 
 
Patients’ willingness to participate in clinical trials is respected. They have the 
freedom to decide whether they want to join the trials or not. They are also entitled 
to withdraw the clinical trial agreement at any time during the trial with no specific 
reasons. In addition, physicians won’t be unpleasant and biased against the patients. 
Moreover, the project investigator and sponsors also have the right to terminate the 
clinical trials. 
 
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2.2.4 Data quality assurance 
 
Physicians will try their best to avoid anti-information drugs such as NSAID, 
which will mislead the interpretation of treatment effects on those who join this 
clinical trial during observation period. 
 
 
 
2.2.5 Patient Population 
 
2.2.5.1 Inclusion/exclusion criteria 
 
The inclusion criteria: 
 
A. patients over 20 years old 
 
B. patients who are diagnosed with superficial tumors or polyps via 
endoscopy 
 
C. patients with tumor/polyp size over 10mm 
 
D. patients who never undergo endoscopic therapy before 
 
E. patients with the polyps of no deep submucosal invasion or metastasis 
 
 
 
 
The exclusion criteria: 
 
A. patients with other advanced malignant neoplasm 
 
B. patients with low white blood cell count (WBC<2,000μL), or patients 
with low platelet count (platelet count < 50,000/μL) or abnormal blood 
coagulation 
 
C. patients who are currently using anticoagulant and can’t stop using 
the drug 
 
 
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D. patients whose major organ dysfunction and thus being 
considered inappropriate to participate the trial 
 
E. patients who are diagnosed with deep submucosal invasion or metastasis 
 
F. patients who fail to do follow-up endoscopy evaluations 
 
G. patients who are allergic to the compositions of our product 
(sodium alginate or calcium lactate) 
 
H. patients who don’t sign the consent form of participation of this trial 
 
 
 
 
2.2.5.2 Sample size 
 
Period: from the time when IRB approved this trial to December, 2018 
 
12 patients will be recruited. 
 
 
 
 
2.2.6 Clinical management and settings of clinical treatments 
 
After the preparation and patient evaluation for a safe endoscopy, endoscopists 
will decide to perform ESD or EMR on the patients in accordance with their health 
condition. During the surgery, the administered dose of EndoGel can be 
determined based on the size of lesions and the height of submucosal cushions. 
 
After the therapy, we will monitor the vital signs of the patients in wards or 
endo rooms. We carry out the medical observation in order to react promptly to any 
immediate adverse events occurring to the patients, such as delayed bleedings and 
perforations. We will also conduct long term follow-up hematology tests to monitor 
the GOT and GPT of the patients. Patients can leave hospital in 7 days if they are 
well recovered. They should also do follow-up examinations to see if there are any 
complications or adverse events. 
 
All patients will receive the endoscopic follow-up examinations 4 weeks after the 
endoscopic surgery to evaluate the wound-healing conditions and to check if there is 
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local recurrence. Patients should go back to the outpatient clinic to do follow-
up examinations after the first week and the sixth week. 
 
 
 
2.2.7 Variance of this trial 
 
Compared to the traditional endoscopy without using EndoGel, use of EndoGel 
in endoscopy can still risk complications such as bleedings and perforations. 
Generally, we can stop bleeding by using hemostatic clips to close perforation. A 
few serious cases may need the help of interventional radiological or surgical 
physicians. Physicians should also pay attention to the potential complications in the 
follow-up examinations. 
 
Within the recommended dose of this product, it is still likely to cause allergies; 
however, no other serious side effects are known. 
 
 
 
2.2.8 Drug therapy/ Clinical management 
 
Patients will get preventative antibiotics before the endoscopy. If there is any 
complication such as perforation happening during endoscopy, physicians will stop 
bleeding by using hemostatic clips to close perforation. Patients are not allowed to 
eat for several days and will be given antibiotics and intravenous parental nutrition 
after endoscopy. They are fasted until they don’t have abdominal pain or fever. 
Further, if they don’t have any abnormal symptoms after eating, they can bring oral 
antibiotics home. On the other hand, if bleeding occurs during the treatment, 
endoscopic hemostats and hemostatic clips will be used to stop bleeding; if there is 
delayed bleeding, blood transfusion therapy, endoscopic hemostasis, transarterial 
embolization, or surgical intervention may be used depending on the severity. 
 
Endoscopic resection of the specimen will be sent to the pathological examination; if 
a cancer is discovered, physicians will decide whether the patient should undergo 
additional surgeries based on the relevant pathological features (such as tumor clearance, 
cell differentiation, submucosal invasion, and lymphatic invasion). 
 
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A Follow-up examination will be arranged 4 weeks after surgery. The examination 
will assess the condition of wound healing to see if there is any residual polyp 
tissue at the wound or other places. If so, it will be removed and sent for testing. 
 
 
 
2.2.9 Subsequent observation care 
 
Patients will come back to the outpatient clinic after the first week of surgery 
to see if there is any side effect. They will also do the follow-up endoscopy within 
4 weeks to check the wound-healing conditions and if there is any local recurrence. 
After the 6th week, patients will return again for their check-up. 
 
 
 
2.2.10 Statistical analysis 
 
2.2.10.1 Hypotheses 
 
This trial is designed to be a single-armed and non-contrast experiment. We 
aim to evaluate the safety of EnodGel in the clinical use. 
 
2.2.10.2 Sample size 
 
The purpose of the study is not to compare this new treatment with traditional 
ones, and thus there is no statistical test to calculate the appropriate number of 
samples as in the case of general clinical trials. Instead, a small number of 
samples have been evaluated to test the safety, which is like what researchers do 
in Phase I Study. Therefore, we recruited 12 patients in total. 
 
2.2.10.3 Methods for statistical analyses 
 
Descriptive statistics are used to analyze the data in this study. 
 
 
 
 
 
 
 
 
 
 
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