Double Blind Study - Use of Gelronate Gel vs. Aloevera in Preventing/Minimizing Radiation-induced Dermatitis in Breast Cancer Patients
Phase: NA
Conditions: Radiation Dermatitis
Sponsor: Sheba Medical Center

 
 
Study Protocol V3   7.1.2019 
 
 
 
1 
 
 
7.1.2019 
 
Double blind  Study – Use of Gelronate Gel vs. Aloevera in Preventing / 
Minimizing Radiation-Induced Dermatitis in Breast Cancer Patients  
 
 
Principle Investigator: 
Dr. Merav A. Ben-David, Head, Breast Radiation unit,  
                                           Sheba Medical Center 
 
 
 
 
 
Study Number: 5652-18-SMC 
 
 
 
 
Aim: To evaluate the effect of Gelronate® gel, NaHA based product (medical device 
for topical application) vs. Aloevera Jell, in preventing or minimizing of radiation 
induced skin reaction in breast cancer patients. 
 
 
End Points:  
 
1. Primary – Development and degree of any skin reaction. 
a. Grading according to RTOG skin toxicity score (appendix1). 
b. Assessment of skin reaction by scoring of weekly digital photographs. 
c. Patient comfort assessed by weekly administrated questionnaire. 
 
2. Secondary – Skin reaction requiring conventional topical therapy (e.g. steroid 
cream etc.) as evaluated by clinical judgment of radiotherapy nurse/ radiation 
oncologist at OTV (on treatment view visits). 
 
 
Background 
One of the dose-limiting effect of radiotherapy is the acute reaction that ionizing 
radiation induces in normal tissues, i.e. skin. The severity of this acute reaction may 
link to different parameters, patient associated (BMI, diabetes) and radiation 
associated (dose per fraction and total dose). 
 
Hyaluronic acid (HA) is linear polysaccharide formed from repetitions of a disaccharide 
unit composed of one aminosugar and one uronic acid residue ([D-glucuronic acid (1-
-3) N-acetyl-D-glucosamine (1--4)]n) (Figure 1).  

 
 
Study Protocol V3   7.1.2019 
 
 
 
2 
 
Fig, 1. Disaccharide repeating unit of hyaluronic acid. 
 
 
The biopolymer is widespread in soft tissues (vitreous humour of the eye, joints, 
synovial fluid, skin and more). In vertebrates, HA has a wide variety of functions 
including maintenance of tissue hydration in the skin, sustaining tissue physical 
properties and induce rate changes in cell proliferation, cell migration and 
angiogenesis.  
 
There are two industrial methods for the production of HA: from rooster combs or from 
bacterial fermentation. Bio-Technology General (Israel) Ltd. developed and 
manufacture HA for ophthalmology and orthopedics purposes. BioLon and BioLon 
Prime are two products for operations in the interior chamber of the eye (cataract 
surgeries, cornea implantation etc.) and Euflexxa (Arthrease) syringes are for pain 
relief in patients suffers from osteoarthritis (OA). 
 
Due to its characteristics and biological properties including wound healing (Primavera 
et al. 2006, Moore et al 2005, Hanci et al 2015), HA may eliminate or reduce adverse 
events (AEs) like skin dermatitis. The purpose of this study is to evaluate the capability 
of 1% HA solution to eliminate or reduce skin reaction during radiation i.e. dermatitis. 
 
The tested product, Gelronate®, is gel composed of 1% high molecular weight 
pharmaceutical grade sodium hyaluronate and two types of commercial preservatives 
(Germal 115 and Phanochem/Salinip/Phenonip) dissolved in pharmaceutical grade 
purified water. Gelronate® supply in an airless pump bottle contain ~30ml gel. The aloe 
Vera 99.9% product is made by ESI, Israel, with no artificial coloring, in the same 
package with no identification. 
 
 
Study Plan 
120 female patients planned to receive whole breast radiation (+/- lymphatic drainage) 
in the radiotherapy unit at Sheba, who give written consent for participation, will be 
entered into the study and randomized. Based on statistical evaluation, 65 will receive 
the aloe Vera and 55 will receive the HA Gelronate® in blinded packages.  

 
 
Study Protocol V3   7.1.2019 
 
 
 
3 
 
 
Patients will undergo CT simulation with 3D treatment planning (as routinely done) 
and will receive 42.4 Gy in daily fraction of 2.65 Gy, five times per week to the whole 
breast according to the standard department protocol, with or without concomitant or 
subsequent lumpectomy cavity boost. Patient data including demographics, staging, 
systemic therapy, radiation details, other medications will be recorded in the attached 
forms (Appendix A, pages 7-9 below).  
 
BTG will provide sets of bottles sufficient for treatment of at least 120 patients, plus 
any extra gel bottles as needed for the participants to complete accrual and full 
treatment for 120 patients.  
  
The study nurses will provide each patient with the bottle and will ensure that the 
patient understands how to apply according to protocol. The gel will be applied as a 
thin lotion twice a day, immediately after radiotherapy treatment and once more in the 
evening/morning. The therapy should continue for 10 days following the end of 
radiation therapy.  
 
The study nurses will examine each patient weekly during treatment and 7-10 days 
after completion of radiotherapy. At each visit skin reaction based on RTOG toxicity 
score will be recorded and the patient will complete a short questionnaire regarding 
subjective and objective skin reaction. The patient's skin will be photographed (no face 
in the picture) on fraction 10-11, 15-16 and at the follow-up visit, days 9-10 after the 
end of radiation. This will be done with a digital camera and the electronic image will 
be stored for later evaluation. The images will be stored anonymously except for the 
patient's study number. 
 
Any patient developing moist desquamation or other grade 3 skin reaction during the 
radiation will stop treatment and will receive topical therapy as clinically indicated. 
 
Eligibility: 
 
Inclusion Criteria: 
 
1. Female patients aged at least 18 years with unilateral breast cancer following 
lumpectomy +/- chemotherapy. 
2. Planned to receive 42.4 Gy whole breast irradiation +/- boost to tumor bed. 
3. ECOG performance status 0-2. 
4. Capable of giving written informed consent. 
5. No co-morbidities known to affect radiotherapy reactions. 
6. No co-existing acute or chronic skin disease. 
7. No evidence of infection or inflammation of breast to be treated. 

 
 
Study Protocol V3   7.1.2019 
 
 
 
4 
 
8. Not receiving chemotherapy during radiotherapy course. Biological therapy 
(e.g. Herceptin) or hormone therapy will be allowed during the study. 
 
 

 
 
Study Protocol V3   7.1.2019 
 
 
 
5 
 
Exclusion Criteria: 
 
1. Chemotherapy within 4 weeks prior to planned start of radiation or 
chemotherapy planned during radiation. 
2. Prior radiotherapy to the chest wall. 
3. Collagen vascular disease. 
4. Participation in other clinical study. 
Statistical Considerations: 
 
Based on published data and previous experience we expect around 90% of patients 
to develop some degree of skin reaction and about 20% would require medical 
intervention due to grade 2-3 skin reactions. (Ben-David et al 2016, Fenig et al., 
Kodiyan et al. 2015, Olsen et al 2001).    
 
The relative large number of patients in the study was chosen in order to be able to 
have sufficient amount of data on large variety of patients (different age, BMI, skin 
color, origin, smokers/non-smokers etc.). Participation in this study will be offered and 
available to all radiation treated patient in the institute, therefore large variety of 
patients are expected to participate in this study. As a result, the data that will be 
obtained in the study may be used by any irradiation institute in the world.   
 
In addition to the weekly nurse/patient evaluation of skin toxicity (see appendix A), at 
the completion of the study the patient photographs will be evaluated blindly by a panel 
of 3 radiotherapy staff. The digital photo with the worst reaction of each patient will be 
scored.  
 
 
References 
 
Ben-David M.A., Elkayam R., Gelernter and Pfeffer R.M., Melatonin for prevention of 
breast radiation dermatitis: A Phase III, prospective, double-blind randomized trial. 
Israel Medical Association Journal 2016; 18(March-April):188-192. 
 
Fenig E., Brener B., Katz A., Sulkes J., Lapidot M., Schachter J., Malik H., Sulkes A. 
and Gutman H. Topical Biofine and Lipiderm for the prevention of radiation dermatitis: 
A randomized prospective trial. Oncology Reports 2001; 8:305-309. 
 
Hanci, D., Altun H., Effectiveness of hyaluronic acid in post-tonsillectomy pain relief 
and wound healing: A prospective, double-blind, controlled clinical study. International 
Journal of Pediatric Otorhinolaryngology 2015; 79:1388-1392. 
 
Kodiya J. and Amber K.T., A review of the use of topical Calandula in the prevention 
and treatment of radiotherapy-induved skin reaction. Antioxidants 2015; 4:293-303 
 
Moore K., Haas M.L. and Lloyd K.P., Patients undergoing radiation treatment were 
clinically evaluated for skin integrity, pain and itching in a preliminary trial using 

 
 
Study Protocol V3   7.1.2019 
 
 
 
6 
 
RadiaPlexRx containing 0.2% hyaluronic acid. Oncology Nursing Forum 2005; 
32(2):479-482. 
 
Olsen D.L., Raub W. JR, Bradley C., Johnson M., Love V. and Markoe A. The effect 
of aloe vera gel/mild soap versus mild soap alone in preventing skin reactions in 
patients undergoing radiation therapy. Oncology Nursing Forum 2001; 28(3):543-547. 
 
Primavera G., Carrera M., Beradesca E., Pinnaro P., Messina M. and Areangeli G.  A 
double-blind, vehicle-controlled clinical study to evaluate the efficacy of MAS065D 
(XClair™), a hyaluronic acid-based formulation, in the management of radiation-
induced dermatitis. Cutaneous and Toxicology 2006; 25:165-171. 
 
 
 
 
 
 
 
 

 
 
Study Protocol V3   7.1.2019 
 
 
 
7 
 
APPENDIX A (Translated from Hebrew to English) 
 
Gelronate Study, Weekly Data Collection
 
 
 
Number in study_____________ 
 
 
Filling date______________ 
 
 
Number of given fractions
 
  ______ Dose Gy________ 
 
 
Skin condition 
 
Status according to RTOG__________ : 
 
4
 
3
 
2
 
1
 
0
 
 
Ulceration, 
hemorrhage, 
necrosis 
Confluent, 
moist 
desquamation 
other than 
skin folds, 
pitting edema 
Tender or 
bright 
erythema, 
patchy moist 
desquamation
/moderate 
edema 
Follicular, faint 
or dull 
erythema/epil
ation/dry 
desquamation
/decreased 
sweating 
No change 
over baseline 
Skin
 
 
 
Clinical description 
__________________________________________________________ 
 
___________________________________________________________________
 
 
____________________________________
_______________________________
 
 
___________________________________________________________________
 
 
 
 
 
Photo taken Yes/No 
 
 

 
 
Study Protocol V3   7.1.2019 
 
 
 
8 
 
Dermatology Assessment 
 
 
1. Nothing
     
2
 .
A little
     
3
 .
Frequent
     
4
 .
Continuing 
 
1
 
2
 
3
 
4
 
Dryness
 
 
 
 
 
Erythema
 
 
 
 
 
Suntan
 
 
 
 
 
Swelling
 
 
 
 
 
Rash
 
 
 
 
 
Wound
 
 
 
 
 
Peeling
 
 
 
 
 
Bleeding
 
 
 
 
 
“Wet” 
peeling
 
 
 
 
 
“Dry” 
peeling
 
 
 
 
 
Cellulitis
 
 
 
 
 
Pigmentation 
changes
 
 
 
 
 
 
 
Treatment decision: Continue study/Stop the study 
 
 
 
 
Inspected by:_____________ Signature:____________ Date:______ 
 
 
 

 
 
Study Protocol V3   7.1.2019 
 
 
 
9 
 
Personal evaluation of status and filling in the skin 
 
Study Number
 
__________
 
 
 
 
 
Date:___________ 
 
 
Number of radiation until today:
 
___________  
 
 
Grade your fillings during last week on the treated breast- 
 
1. Nothing 2. Small parts of the breast 3. Most of breast area 4. All breast 
area 
 
1
 
2
 
3
 
4
 
Biting
 
 
 
 
 
Hurt
 
 
 
 
 
Burn
 
 
 
 
 
Rough
 
 
 
 
 
Prickly
 
 
 
 
 
Soft
 
 
 
 
 
Dry
 
 
 
 
 
Wet
 
 
 
 
 
Smooth
 
 
 
 
 
Strange
 
 
 
 
 
Tickling
 
 
 
 
 
 
Comments________________________________________________ 
 
 

 
 
Study Protocol V3   7.1.2019 
 
 
 
10 
 
 
 
Patient’s code_______________ 
 
Data collection  CRF 
 
1. Birth date:
 
_______________  
2. Clinical background: Blood pressure/Diabetes/Other _______________ 
3. Full list of taken medicines_________________________ 
4. Detailed smoking habits________________________________________________ 
5. Weight 
6. Hight                               Calculated BMI 
7. Size of bra 
8. Skin color 
9. Origin 
10. Right/left breast 
11. Surgery date of the radiated breast______________________ 
12. Histology______________ 
13. Stage in the disease:   In surgery T N M: 
T  N M before chemotherapy 
 
_______________  
14. T   N    M after chemotherapy (or without)________________   
15. Tumor’s location according to simulation? Upper external/upper internal/lower 
external/lower internal/ breast’s center 
16. SLNBX  / ALND / NONE 
17. Repeated surgery in the breast? Yes/No (date of repeated surgery_____________) 
18. Starting date of radiation___________ 
19. Boost?  Yes/No  (concomitant Yes/No) 
20. Type of boost? P/E  Dose in Gy
 
_______  
21. Radiation into supraclavicular? Yes/No 
22. Radiation to intramammary? Yes/No 
23. כTotal radiation to the breast in Gy (without boost)
 
________  
24. SEPARATION 
25. Received hormonal treatment? (anytime) Yes/No (What type? _______________)