Efficacy of GUM Hydral Mouthwashes on Symptoms of Radiotherapy-induced Xerostomia: a Randomized, Double-blind, Crossover Study.
Phase: NA
Conditions: Xerostomia, Xerostomia Following Radiotherapy
Sponsor: Catholic University of the Sacred Heart

 
 
 
 
 
 
Study Code: SSHNC-1  
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Study Code (CTC):  SSHNC-1 
 
 
 
PROTOCOL TITLE 
 
Efficacy of GUM Hydral mouthwashes on symptoms of radiotherapy-induced xerostomia: a 
randomized, double-blind, crossover study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Firma del PI 

 
 
 
 
 
 
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1.  INTRODUCTION 
 
 
1.1 
BACKGROUND INFORMATION  
 
Head and neck squamous cell carcinoma (HNSCC) accounts for more than 750,000 new cases per 
year (1) and its prognosis is still poor in terms of mortality and of morbidity and it causes 
approximately 350,000 deaths annually worldwide (2). The prognosis and therapy of this cancer are 
mainly related to the TNM stage and stage seems to be one of the most important prognostic features. 
Therefore, although advanced surgical techniques have increased the prognosis, it is still poor, with 
a survival rate which approximately varies between 25% and 45% in stages III and IV (3) (4) (5). 
Radiotherapy (RT) is an established treatment modality for HNSCC and other H&N tumors, either 
for treatment alone or as adjuvant (6) (7). Unfortunately, high-dose RT has significant adverse 
effects on the oral and maxillofacial tissues, both hard and soft, and dental management of these 
patients is based largely on individual and expert opinion, as few prospective studies have been 
performed to determine risk factors for adverse oral sequelae (8). In particular, when salivary glands 
are within the irradiated field, irreversible salivary glands damage occurs in 63–93% of the patients. 
Salivary gland damage typically manifests as reduced saliva secretion, which in turn can translate 
into a subjective sensation of dry mouth (xerostomia), oral discomfort, altered taste, difficulty with 
speaking, swallowing, chewing, and increased risk of dental disease. Overall hyposalivation and 
related xerostomia can cause a substantial reduction in quality-of-life (QoL). However there is 
currently little robust evidence to inform the management of hyposalivation and xerostomia in this 
population (9) (10). Although the treatment of xerostomia is very individual, a first-line medication 
is to ameliorate the dehydration in the mouth by substituting for the secretion of saliva. (11) 
 
 
 
 
 
 
 
1.2 
MEDICAL DEVICE DESCRIPTION 
 
 
 
GUM Hydral (GUM Hydral: Sunstar Italiana SRL. Corso Italia 13 21047 Saronno, VA, Italy) is a 
product based on hyaluronic acid and sodium citrate. It helps in rehydrating and protecting the oral 
tissues, by forming a film on those tissues. It may be helpful in reducing the xerostomia symptoms. 
 
 
1.3 
FEATURES OF THE MEDICAL DEVICE 
The device is a high-density liquid and it is used as a mouthwash. In this trial, the aim is to investigate 
if its efficacy in reducing the xerostomia symptoms is higher than placebo. 
The placebo will be made of water with xylitol in addition. Xylitol is a is a sugar alcohol used as a 
sugar substitute, which does not increase the risk of tooth decay. In this formulation, its only role is 
to give a slight sweet flavor to water. 
Water added with xylitol, in fact, may reduce, to a certain extent, the xerostomia symptoms, so it 
may be considered as a suitable comparator. 
The device used for the clinical trial will be identified with visible marking stating “Exclusively for 
clinical investigations SSHNC-1 only”. 

 
 
 
 
 
 
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Funder will initiate the shipment of the medical device to the site upon the Principal Investigator 
received the Ethics Committee approval. Prior to any shipment, the site will be informed by the 
Funder/Sponsor on the upcoming shipment, expected arrival date and content of the shipment. The 
site should confirm receipt of the shipment. 
Funder will also be encharged of the manifacturing and biological stabilization of placebo, whose 
composition is described above.  
The placebo used for the clinical trial will be identified with visible marking stating “Exclusively 
for clinical investigations SSHNC-1 only”. 
Funder will also initiate the shipment of the placebo to the site upon the Principal Investigator 
received the Ethics Committee approval. Prior to any shipment, the site will be informed by the 
Funder/Sponsor on the upcoming shipment, expected arrival date and content of the shipment. The 
site should confirm receipt of the shipment. 
 
For the risk analysis please refer to the IfU (Instruction for Use).  
 
1.4 PURPOSES AND OBJECTIVES OF THE CLINICAL TRIAL 
The aim of this study is to describe the effect of the administration of Hydral on reducing patients’ 
xerostomia symptoms due to radiotherapy. (12)  
 
1.5 EXPERIMENTAL DESIGN 
The study will be conducted as a double-blind randomized clinical trial (RCT) and foresees a 
crossover design, so the population will be divided into two groups, receiving both the medical 
device and the placebo. The interventions will be described in paragraph 2.3. 
 
2 MATERIALS AND METHODS 
 
2.1 PATIENTS SELECTION 
 
 
Inclusion criteria: 
• Patients willing to sign the informed consent form 
• Patients older than 18 years 
• Patients with diagnosis of HNC, who had received local radiotherapy at least three months 
before the beginning of the study, involving the salivary glands, both for curative and palliative 
purpose, with or without chemotherapic treatment, reporting xerostomia symptoms 
• Patients with diagnosis of HNC, who had received local radiotherapy as an adjuvant to surgical 
resection at least three months before the beginning of the study, with or without chemotherapic 
treatment, reporting xerostomia symptoms- 
 
 
 
 

 
 
 
 
 
 
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Exclusion criteria: 
• Patients with documented contraindication to any of the components of GUM HYDRAL (there 
included eccipients) 
• Patients with any neurological and psychiatric condition having an influence on the ability to 
self-apply the treatment 
• Patients unwilling to complete the request diary card 
• Patients unable to attend the ambulatory visits scheduled by the protocol 
• Patients participating to other clinical studies 
• Patients who had received antitumoral treatment during the previous three months  
• Patients with concomitant Sjogren’s syndrome  
• Other causes of xerostomia (pharmacological treatment) 
 
2.2 WITHDRAWAL PROCEDURES 
 
 
The intervention will be stopped in any case of reported adverse event that can be attributed to GUM 
Hydral, or in case the patients will need a drug or a medication which could interfere with the 
xerostomia symptoms. 
In order to improve the adherence of the patients to the protocol interventions, all the patients will 
be asked to update a diary card reporting the usage of the product. 
During the duration of the treatment, the patients will be asked not to use any product analogue of 
Hydral. 
 
2.3 INTERVENTIONS 
 
The patients will be recruited in the Oral Medicine Department, in a 12 months period. 
 
Study design (see flow-chart)  
A baseline visit (T0) will be conducted three months after the end of RT.  
The investigational product GUM Hydral and the placebo will be each administered for a 30-days 
treatment period. 
The patients will be divided into two groups: at day 1 (baseline - T0), group A will receive treatment 
product, group B will receive a placebo.  
At day 15, the compliance of the patient and any adverse effect will be evaluated by a phone call. 
At day 30, the administration of the products will be stopped, and a 30 days washout phase will take 
part, followed by Phase 2 of the study. 
At day 61, each group will be treated with the alternative product. 
At day 75, the compliance of the patient and any adverse effect will be evaluated by a phone call. 
At day 90, the final questionnaire will be administrated, and the investigation of all endpoints will 
take place. 
 
Each Visit is described in the following flow-chart 
 
 
 

 
 
 
 
 
 
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Activities/Procedures 
Screening Visit  
(after 
3 
months 
from the end of the 
RT) 
From Day-3 to Day 0 
Baseline 
Visit 
Day 1 
DAY 15  
(± 2 gg) 
DAY 30 
(±  7 gg) 
 
 
DAY 31-60 
Washout 
phase 
 
 
 
DAY 61 
 
 
DAY 75 
 
 
DAY 90  
(End of Study Visit) 
(±  7 gg) 
 
PHASE A 
 
 
PHASE B 
Visit 
 
V1 
 
 
V2 
V3 
 V4 
 
V5  
(Note 2) 
 
 
 
 
V6 
 
V7 
Informed Consent signature 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
verification 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Medical and surgical history 
and underlying diseases 
X 
 
 
 
 
 
 
 
Previous 
and 
concomitant 
treatments 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Physical examinations 
X 
 
 
X 
 
X 
 
X 
Salivary flow measurement 
X 
 
 
X 
 
X 
 
X 
Oral 
swab 
for 
mycetes 
determination 
X 
 
 
 
 
X 
 
X 
Medical Device  administration 
and 
accountability 
(pts compliance to treatment is 
assessed at each protocol visit) 
(Note 3) 
 
 
X 
(Note 4) 
X 
X 
 
X  
(Note 5) 
 
X 
X 
Diary card dispensing and 
verification 
 
X 
X 
X 
 
X 
X 
X 
QoLs administration 
X (Note 6) 
 
X 
X 
 
 
X 
 
X 
 
X 
AEs monitoring 
X 
X 
X 
X 
X 
 
X 
X 

 
 
 
 
 
 
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Note1:     the screening visit might have a maximum duration of 1 day 
Note 2:   during the washout period a telephone contact will be conducted, in order to assess the safety profile of the patients, by specifically 
asking  to refer any AE occurred and relevant concomitant medications administered (if applicable)  
Note 3:    an instruction procedure to standardize the products administration will be finalized. Patients will be asked to rinse with 15 ml of 
product, three times a day.  
Note 4:    PHASE  A, Group A receives Hydral, Group B receives placebo 
Note 5:    PHASE B, Group A receives placebp, Group B receives Hydral 
Note 6:   this QoLS administration must be conducted after the ICF signature and before the first Medical Device administration  
 
 
 
 
 

 
 
 
 
 
 
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2.3.1 STUDY PROCEDURES 
 
VISIT SCHEDULING 
 
• Visit 1: DAY 1 
• Visit 2: DAY 15 
• Visit 3: DAY 30 
• Washout phase: DAY 31-60 
• Visit 4: DAY 61 
• Visit 5: DAY 75 
• Visit 6: DAY 90 
 
DESCRIPTION OF VISITS AND ASSESSMENTS 
 
VISIT 1: 
 
- Informed consent signature 
- Inclusion/Exclusion criteria verification 
- Medical and surgical history and underlying diseases will be verified 
- Previous and concomitant oral treatments will be checked out and proceed regularly, 
excluding any antitumoral therapy, both radio and chemotherapy 
- Physical examination 
- Oral swab for mycetes determination will be taken 
- Salivary flow, both basal and stimulated, will be measured 
- Three questionnaires for the assessment of xerostomia and of the quality of life will be 
administered: 
QLQ30 
QLQH&N35 
XQ questionnaire. In addition, one question by the Shortened Xerostomia Inventory (SXI-
D) scale score will be used 
- In addition, xerostomia will be assessed even through a NRS Scale 
- Further, the patient’s satisfaction in using each product will be evaluated by using a Likert 
scale 
- Drug Administration and accountability: participants will be instructed to rinse with the 
mouthwash five times per day, especially before going to bed.  
 
 
 

 
 
 
 
 
 
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VISIT 2: 
 
- 
Drug Administration and accountability: the compliance of the patient will be evaluated 
- 
AEs monitoring 
 
 
VISIT 3: 
 
- 
Previous and concomitant oral treatments will be checked out and proceed regularly 
- 
Physical examination 
- 
Salivary flow measurement (both basal and stimulated) 
- 
Drug Administration and accountability: the compliance of the patient will be evaluated 
- 
Three questionnaires for the assessment of xerostomia and of the quality of life will be 
administered: 
QLQ 
30 
QLQ 
H&N35 
XQ questionnaire. In addition, one question by the Shortened Xerostomia Inventory 
(SXI-D) scale score will be used  
- 
In addition, xerostomia will be assessed even through a NRS Scale 
- 
Further, the patient’s satisfaction in using each product will be evaluated by using a 
Likert scale 
- 
AEs monitoring 
 
VISIT 4: 
 
- 
Previous and concomitant oral treatments will be checked out and proceed regularly 
- 
Physical examination 
- 
Drug Administration and accountability: the compliance of the patient will be evaluated 
- 
Three questionnaires for the assessment of xerostomia and of the quality of life will be 
administered: 
QLQ 
30 
QLQ 
H&N35 
XQ questionnaire. In addition, one question by the Shortened Xerostomia Inventory 
(SXI-D) scale score will be used 
- 
In addition, xerostomia will be assessed even through a NRS Scale 
- 
Further, the patient’s satisfaction in using each product will be evaluated by using a 
Likert scale 

 
 
 
 
 
 
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- 
Drug Administration and accountability: every patient will receive the product 
alternative to the one he used during the first phase of the trial 
- 
Oral swab for mycetes determination will be taken 
- 
AEs monitoring 
 
VISIT 5: 
 
- 
Drug Administration and accountability: the compliance of the patient will be evaluated 
- 
AEs monitoring 
 
VISIT 6: 
 
- 
Previous and concomitant oral treatments will be checked out and proceed regularly 
- 
Physical examination 
- 
Salivary flow measurement (both basal and stimulated) 
- 
Drug Administration and accountability: the compliance of the patient will be evaluated 
- 
Three questionnaires for the assessment of xerostomia and of the quality of life will be 
administered: 
QLQ 
30 
QLQ 
H&N35 
XQ questionnaire. In addition, one question by the Shortened Xerostomia Inventory 
(SXI-D) scale score will be used 
- 
In addition, xerostomia will be assessed even through a NRS Scale 
- 
Further, the patient’s satisfaction in using each product will be evaluated by using a 
Likert scale 
 
 
 

 
 
 
 
 
 
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2.4 STUDY OBJECTIVES 
 
The measurement of xerostomia is problematic. In contrast to hyposalivation, which can be 
objectively evaluated by using sialometry, xerostomia is comprised of a set of symptoms, and 
therefore can be assessed only by directly questioning individuals. 
The questionnaire which will be used to this evaluation are Xerostomia Questionnaire (13) (14). To 
the XQ questionnaire, 1 further question was added from Xerostomia Inventory (XI) scale score 
(15). 
The QLQ-C30 provides 30 questions, globally assessing patients’ quality of life. The QLQ-H&N35 
includes 35 questions, and addresses symptoms associated with specific tumor location, side effects 
associated with the oncologic treatment and additional QoL aspects modified by the disease or its 
treatment. The answers will be converted into a linear scoring scale, with values between 0 and 100, 
(16) (17) as per advocated by EORTC.  
The modified XQ provides a measure of the severity of radiation -induced xerostomia that affects 
the patients' QoL. This questionnaire consists of 10 questions, associated with patient-reported 
dryness. Moreover, a general question “how dry is your mouth?” has been added to the questionnaire. 
The modified XQ is a self-administered tool and patients will be asked to rate each symptom on a 
10-point NRS scale of 0-10, with higher scores indicating more severe dryness or discomfort due to 
dryness. Each item score is added, and the sum is linearly transformed to produce the final summary 
score ranging from 0 to 100, with higher scores representing higher levels of xerostomia. 
Patients’ compliance will be evaluated by the use of a diary card, in order to notice the amount of 
product used.  
2.4.1 PRIMARY OBJECTIVE 
To describe the results of the five questionnaires (listed below) at all the timepoints: 
QLQ 30 (18) 
QLQ H&N35 (19) 
Xerostomia Inventory (XI) scale score (20) (21) 
VAS scale 
Xerostomia Questionnaire (22) 
 
 

 
 
 
 
 
 
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2.4.2 SECONDARY OBJECTIVES 
- 
Evaluate Hydral treatment efficacy in reducing xerostomia’s symptoms; 
- 
Describe all the adverse events occurred during the study. 
 
 
2.5  STUDY POPULATION 
 
 
 
 
 
 
 
IDENTIFICATION PARAMETERS 
 
 
Each patient will be identified with a univocal code (SSHNC-1_n°), which will be known only by 
the principal investigator.  
2.6 RANDOMIZATION  
 
 
Patients will be randomized to treatment groups using sequentially numbered, opaque sealed 
envelopes (SNOSE). (23) 
 
The principal investigator will be encharged of generating the allocation sequence, of enrolling the 
participants and of assigning the interventions to the participants. 
The co-workers who will administrate the therapies and the patients themselves will be blinded 
about the selected product. 
Only in case of assessment of any adverse event, it will be possible for the P.I. to reveal the product 
used during the therapy.  
 
2.7 DATA MANAGEMENT 
 
The data will be collected by using a web based electronic Case Report Form (eCRF) which will be 
prepared on the basis of the flow chart included in Section 2.5. The data entry will be performed at 
site by the Investigator or a designee. The data will be cleared according to specific procedures by 
the Data Management team of the eCRF provider. The query flow will involve both the monitoring 
team and the Investigators. 
All the details relevant to the data management will be described in the Data Management Plan, 
which will be prepared by the Data Manager in charge of the study. 
 
 

 
 
 
 
 
 
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2.8 STATISTICAL CONSIDERATIONS 
 
2.8.1 SAMPLE SIZE 
 
In order to detect a 30% difference, in a cross-over design, between the proportion of improved 
patients in the two groups, with an alpha=0.05 and a power of 80%, a sample size of N=40 is 
required. 
 
2.8.2 DATA ANALYSIS 
The sample will be described in its clinical and demographic features using descriptive statistics 
techniques. Quantitative variables will be described using the following measures: minimum, 
maximum, range, mean and standard deviation. Qualitative variables will be summarized with 
absolute and percentage frequency tables. Normality of continuous variables will be checked using 
Kolmogorov-Smirnov test.  
The primary objective will be achieved using descriptive statistics techniques, summarizing 
questionnaires’ results at the planned timepoints. Efficacy will be investigated considering an 
ANOVA mixed model. Adverse events will be described numerically (absolute frequency by type) 
and qualitatively. Comparison between the two groups in terms of adverse events will be done with 
a Chi-square test. 
 
3. SAFETY AND TOLERABILITY EVALUATION 
 
 
3.1 
SAFETY AND TOLERABILITY PARAMETERS  
Since GUM Hydral is intended for topical use only and its constituents are based on natural products, 
an evaluation of the vital signs is not necessary. The adverse events will be evaluated. 
 
 
3.2 
LABS PARAMETERS.  
Oral swabs for mycetes will be taken in order to assess whether the presence of candida species can 
modify the perception of xerostomia.  
 
 
 
 
 
 
 
3.3 
VIGILANCE ACTIVITIES  
 
DEFINITIONS 
INCIDENT 
Any malfunction or deterioration in the characteristics and/or performance of a device, as well as 
any inadequacy in the labeling or the instructions for use which, directly or indirectly, might lead to 
or might have led to the death of a patient, or USER or of other persons or to a serious deterioration 
in their state of health. 

 
 
 
 
 
 
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FATAL INCIDENT 
Incident where the Medical Device (MD) determined (or contributed to determine) the patient death 
(or user death). Factors such as potential risks in use of MD, characteristics of MD, patient health 
condition, etc.  should be considered to assess the causality relationship between the MD and the 
death. The evaluation of the health professional who witnessed the fatal event should be also taken 
into account. 
 
INCIDENT THAT HAS CAUSED A SERIOUS DETERIORATION IN THE HEALTH 
CONDITION 
Incident in which the MD has caused a serious deterioration in the health condition of a patient or 
user or third person is to be intended as:  
• an illness or life-threatening injury;  
• an impairment of a body function;  
• a condition requiring medical or surgical intervention to prevent an impairment of a body 
function or impairment of a body structure;  
• a condition requiring hospitalization or prolongation of hospitalization. 
 
NEAR INCIDENT 
Near Incident is to be intended as: 
• the condition where any malfunction or deterioration in the characteristics or performances, 
as well as any inadequacy in the labeling or instructions for use could result, if the MD had 
been used, a worsening of health condition or death of the patient or user, or 
• the condition where any malfunction or deterioration in the characteristics or performances, 
as well as any inadequacy or in the labeling or instructions for use could cause during the 
procedure of use or following, if health personnel had not intervened, a worsening of health 
condition or death of the patient or user. 
 
COMPLAINT 
Health care professionals should report only to the manufacturer or authorized representative or 
distributor any non-compliance and / or events that are not listed above, concerning the use or pre-
use procedures, related to a MD. 
 
INVESTIGATOR REGULATORY OBLIGATIONS 
The Investigator should submit any Incident/Near Incident to the Regulatory Authority (Ministero 
della Salute, Ufficio VI della Direzione Generale dei Dispositivi Medici e del Servizio Farmaceutico, 
DGDMF, dgfdm@postacert.sanita.it), to the EC (by e-mail or fax) and to the manufacturer/ 
authorized representative/distributor following  the timelines indicated  in the table herebelow: 
REPORT 
DEADLINE* 

 
 
 
 
 
 
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* to be applied also for Follow-Up reports and for claims to be reported to manufacturer/ 
authorized   representative/distributor.  
 
This form must be filled in with all the available information, dated and signed. 
Upon request by the Regulatory Authorities, the Investigator must complete his/her report with all 
available follow-up information. 
 
 
SAFETY FOLLOW-UP 
The safety information will be recorded by the Investigator starting from the date of the Informed 
Consent signature and will end-up at the End of Study Visit.  
 
4. ETHICAL ISSUES  
 
This trial will be carried out in compliance with the protocol, designed to ensure adherence to Good 
Clinical Practice, as described in:  
1 ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 1996. Note for Guidance on 
Good Clinical Practice CPMP/ICH/135/95  
2 EU Directive 2001/20/EC, 2005/28/EC  
3 Declaration of Helsinki (1964, and its amendments and subsequent clarification 
4 UNI EN ISO 14155:2011 
 
The Principal Investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in it and thereby to adhere to the principles of Good Clinical Practice that it 
conforms to.  
 
4.1 
PROTOCOL AMENDEMENTS  
All significant deviations from the protocol will be documented. Any changes made after 
data analysis has begun will be documented as such and the rationale provided.  
 
 
 
 
 
 
 
 
Incident 
Within 10 calendar days from the date of  knowledge by the 
Investigator 
Near Incident 
Within 30 calendar days from the date of knowledge by the 
Investigator 

 
 
 
 
 
 
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5. ADMINISTRATIVE PROCEDURES 
 
 
 
 
 
 
5.1 
ARCHIVING  
The Principal Investigator will ensure the archiving of the essential documents of the study as 
specified by the GCP and in compliance with the applicable legislation. The Principal Investigator 
will adopt all the necessary measures to avoid accidental or premature destruction. 
At the end of the study, all documents relating to the study should be retained for the period required 
by the applicable local regulatory requirement(s) or longer, if needed by the Sponsor. 
 
 
 
 
6. INVESTIGATOR’S RESPONSIBILITY 
 
The Investigator is aware of his responsibility for all the actions delegated by him/her to other 
members of his/her staff assigned to the conduct of the study. Except where specifically required. 
The Investigator is obliged to conduct the study in compliance with the study protocol and in 
adherence to the Good Clinical Practice (ICH-E6-R1, UNI EN ISO 14155:2011 and with the 
principles of the Declaration of Helsinki (1964) and successive revisions as well as in respect of the 
applicable legislation. 
 
 
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