Taste and Smell Dysfunction in Patients More Than Two Years After Start of Immune Checkpoint Inhibitor Therapy
Conditions: Melanoma, Non-small Cell Lung Cancer (NSCLC), Urogenital Cancers
Sponsor: University Medical Center Groningen

 
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Taste and smell dysfunction in patients more 
than two years after start of immune 
checkpoint inhibitor therapy 
(November 2023) 
 
 
 
NCT06495008

 
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PROTOCOL TITLE: Taste and smell dysfunction in patients more than two years after start 
of immune checkpoint inhibitor therapy 
 
Protocol ID 
11303 
Short title 
Taste-SPICIER 
EudraCT number  
Not applicable 
Version 
3 
Date 
21-11-2023 
Coordinating 
investigator/project leader 
 
Dr. J.J. de Haan 
Department of Medical Oncology 
University Medical Center Groningen 
Hanzeplein 1, 9713 GZ Groningen 
Phone: +31 50 361 28 21 
Email: j.j.de.haan@umcg.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
Dr. J.J. de Haan 
Department of Medical Oncology 
University Medical Center Groningen 
Hanzeplein 1, 9713 GZ Groningen 
Phone: +31 50 361 28 21 
Email: j.j.de.haan@umcg.nl 
Co-investigators 
Department of Medical Oncology 
Dr. Janine Nuver 
Prof. dr. Anna K.L. Reyners 
Department of Oral and Maxillofacial Surgery 
 
Dr. Harriët Jager-Wittenaar 
 
 

 
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Sponsor (in Dutch: 
verrichter/opdrachtgever) 
University Medical Center Groningen 
Hanzeplein 1 
PO Box 30.001 
9700 RB Groningen 
 
 
Subsidising party 
Not applicable 
Independent expert (s) 
Dr. J.H. Maduro 
Radiotherapy  
University Medical Center Groningen 
Hanzeplein 1, 9713 GZ Groningen 
Phone: +31 50 361 61 61 (49375) 
Email: j.h.maduro@umcg.nl 
Laboratory sites  
Not applicable 
 
 
Pharmacy  
Not applicable 
 
 

 
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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. dr. J.A. Gietema, MD PhD 
Department of Medical Oncology 
 
 
 
Principal Investigator: 
Dr. J.J. de Haan, MD PhD 
Department of Medical Oncology 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 9 
2. 
OBJECTIVES ................................................................................................................11 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................13 
4.1 
Population (base) ...................................................................................................13 
4.2 
Inclusion criteria .....................................................................................................13 
4.3 
Exclusion criteria ....................................................................................................14 
4.4 
Sample size calculation ..........................................................................................14 
5. 
TREATMENT OF SUBJECTS .......................................................................................14 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................14 
7. 
INVESTIGATIONAL PRODUCT ....................................................................................14 
8. 
METHODS ....................................................................................................................15 
8.1 
Study parameters/endpoints ...................................................................................15 
8.1.1 
Main study parameter/endpoint .......................................................................15 
8.1.2 
Secondary study parameters/endpoints ..........................................................15 
8.2 
Study procedures ...................................................................................................15 
8.3 
Withdrawal of individual subjects ............................................................................16 
8.3.1 
Specific criteria for withdrawal .........................................................................16 
8.4 
Follow-up of subjects withdrawn from treatment .....................................................16 
9. 
SAFETY REPORTING ..................................................................................................17 
9.1 
Temporary halt for reasons of subject safety ..........................................................17 
9.2 
AEs, SAEs and SUSARs ........................................................................................17 
9.2.1 
Adverse events (AEs) ......................................................................................17 
9.2.2 
Serious adverse events (SAEs) .......................................................................17 
9.3 
Follow-up of adverse events ...................................................................................18 
10. 
STATISTICAL ANALYSIS ..........................................................................................19 
10.1 
Primary study parameter(s) ....................................................................................19 
10.2 
Secondary study parameter(s) ...............................................................................19 
11. 
ETHICAL CONSIDERATIONS ...................................................................................20 
11.1 
Regulation statement .............................................................................................20 
11.2 
Recruitment and consent........................................................................................20 
11.3 
Objection by minors or incapacitated subjects ........................................................20 
11.4 
Benefits and risks assessment, group relatedness .................................................20 
11.5 
Compensation for injury .........................................................................................20 
11.6 
Incentives ...............................................................................................................20 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................21 
12.1 
Handling and storage of data and documents ........................................................21 
12.2 
Monitoring and Quality Assurance ..........................................................................21 
12.3 
Amendments ..........................................................................................................21 
12.4 
Annual progress report ...........................................................................................21 
12.5 
Temporary halt and (prematurely) end of study report ............................................21 

 
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12.6 
Public disclosure and publication policy ..................................................................22 
13. 
STRUCTURED RISK ANALYSIS...............................................................................22 
14. 
REFERENCES ..........................................................................................................23 

 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; 
in Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-
formulier) 
AE 
Adverse Event 
AR 
CSQ 
Adverse Reaction 
ChemoSensory Questionnaire 
CiTAS 
Chemotherapy-induced Taste Alteration Scale 
CTLA-4 
Cytotoxic T-lymphocyte antigen-4 
CV 
Curriculum Vitae 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IC 
ICIs 
Informed Consent 
Immune checkpoint inhibitors 
METC  
 
NSCLC 
PD-1 
PDL-1 
QoL 
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
Non-small cell lung cancer 
Programmed death 1 
PD ligand 1 
Quality of life 
RCC 
Renal cell carcinoma 
RODI 
Regional Oral Dryness Inventory 
(S)AE 
(Serious) Adverse Event  
Sponsor The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; 
in Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
XI 
Xerostomia Inventory 

 
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SUMMARY 
 
Rationale:  Immune checkpoint inhibitors (ICIs) are widely used as treatment for multiple 
cancer types and the number of patients with long-term disease control after ICIs is increasing. 
However, the use of ICIs is associated with adverse events (AEs) which can have a negative 
impact on quality of life (QoL). These AEs include oral manifestations, like alterations in taste 
and smell, xerostomia, and oral mucosal disorders, and could lead to unwanted weight loss. 
However, the characteristics of taste and smell dysfunction and xerostomia after treatment 
with ICIs are unknown. More insight in this phenomenon should be gained to make health care 
professionals aware of this problem to help patients cope with these AEs. 
Objective:  To determine the prevalence of taste and smell dysfunction in patients more than 
two years after start of ICI therapy - compared with a control group of caregivers. Secondary 
objective: to assess the association between taste and smell dysfunction, and saliva secretion 
rate, saliva composition (pH, electrolyte and protein composition) and subjective feeling of a 
dry mouth (xerostomia) in patients more than two years after start of ICI therapy - compared 
with a control group of caregivers. 
Study design: Observational cross-sectional study.  
Study population: Patients (aged ≥18 years) with melanoma, non-small cell lung cancer 
(NSCLC) or urogenital cancers who have started treatment with an ICI (CTLA-4 inhibitor, PD-
(L)1 inhibitor, or both) ≥2 years ago, and their caregivers. 
Main study parameters/endpoints: Taste and smell dysfunction, measured using taste strips 
and Sniffin’ Sticks. Secondary parameters are salivary flow rate, salivary pH. proteins and 
electrolytes, xerostomia and perceived taste and smell dysfunction.  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Participation in the study will include one study visit of approximately 1,5 
hour. If possible, the study visit will be combined with a regular follow-up visit. In this study, no 
invasive procedures will be performed. The results of the full study group will be used to guide 
future interventions and support for cancer patients treated with ICIs. 

 
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1. INTRODUCTION AND RATIONALE 
Immune checkpoint inhibitors (ICIs) are widely used as treatment for multiple cancer types, 
including renal cell carcinoma (RCC), melanoma and non-small cell lung cancer (NSCLC)(1). 
It is estimated that 44% of the patients with cancer may derive benefit from ICIs and 13% would 
have a response to the ICIs(2). ICIs block the immune inhibitory signals of the tumour, so T 
cells can target cancer cells and exert an anti-tumour effect(3). Effective specific targets of ICIs 
are the immune-regulatory checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4), 
Programmed death 1 (PD-1) and PD ligand 1 (PD-L1)(4).  
 
The use of ICIs is associated with adverse events (AEs), mostly due to immune system 
activation. The AEs have various characteristics: they can be mild or life-threatening, can have 
a short or long onset and can develop in different organ systems(5). The most common 
affected systems are the gastrointestinal tract, skin, endocrine glands, and liver(6).  
 
Oral manifestations have also been described(7,8). Xerostomia (the feeling of a dry mouth) 
was reported in 69% of patients with cancer using ICIs, oral mucosal disorders in 33%, and 
dysgeusia (altered taste) in 24%(9). However, these previous studies did not report whether 
these patients were surveyed for these oral side effects or the numbers were based on 
problems spontaneously reported by patients. Oral side effects are often neglected by both 
patients and health care professionals, and therefore are easily underreported if not structurally 
surveyed among patients(10).  
 
Due to long-term survival, patients have to cope with continuing side-effects for a longer 
period of time(11). Chronic AEs have been found in more than 40% of the patients, mostly 
endocrinopathies and rheumatological toxicities(12).  
 
Also changes in taste and smell have been found in long-term responders using ICIs. A 
patient with remaining taste changes three years after immunotherapy discontinuation has 
been described by our group(13). Furthermore, a study which investigated the initiation of oral 
AEs in patients using ICIs found that these AEs mostly develop in the first 100 days, but can 
also develop after two years(9). However, these oral AEs were mentioned spontaneously and 
an objective determination of taste and smell dysfunction and their prevalence after treatment 
with ICIs is still lacking. 
 
As mentioned previously, a phenomenon that has been found in patients treated with ICIs 
is xerostomia. Possibly due to T cell-meditated inflammation, the salivary gland is affected(14). 
It has been hypothesized that oral dryness could be a chronic AE of ICI treatment: the salivary 
gland can be irreversibly damaged, which would lead to diminished saliva production and 
secretion(12). The reduced saliva secretion (hyposalivation) is often associated with the 
subjective feeling of a dry mouth (xerostomia). Oral dryness can contribute to taste 
disturbances, as saliva dissolves foods and makes it possible that taste molecules bind to 
gustatory receptor cells. Furthermore, hyposalivation is a risk factor for oral diseases, including 
dental caries.  
 
Saliva consists of multiple electrolytes and proteins. The electrolytes include sodium, 
potassium, chloride, magnesium, calcium, bicarbonate and phosphate(15). The proteins in 
saliva have many biological activities, including antibacterial and antifungal activity, food 
digestion and promoting wound healing. Therefore alterations in salivary electrolytes and  
proteins can lead to oral diseases and taste problems, as they make the dissolving of food and 

 
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thereby taste possible(16). The ion concentration and pH of the saliva will mostly be altered if 
the salivary flow rate is low(16). It could therefore be possible that the electrolyte composition 
of saliva is altered in patients with cancer treated with ICIs suffering from hyposalivation. 
However, electrolyte and protein analysis of saliva has not been performed in patients treated 
with ICIs. 
 
Alterations in taste and smell, xerostomia, and oral mucosal disorders can have impact on 
quality of life (QoL) and could lead to unwanted weight loss(17,18). Moreover, distribution of 
household roles and social functioning have also been found to be associated with taste and 
smell dysfunction(19,20). More insight in the prevalence and impact of taste and smell 
alterations, and xerostomia should be gained to make health care professionals aware of this 
problem and to help patients cope with these AEs.  
 
A cohort with melanoma, NSCLC and urogenital cancer patients treated with ICIs and their 
caregivers has already been built up. In this cohort, we will determine the prevalence and 
characteristics of taste and smell dysfunction of patients surviving more than two years after 
starting immune checkpoint inhibitor therapy. Furthermore, the association of taste and smell 
dysfunction to pH, saliva secretion rate, saliva composition and xerostomia will be assessed. 

 
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2. OBJECTIVES 
 
Primary Objective:  
• 
To determine the prevalence of taste and smell dysfunction in patients more than two 
years after start of ICI therapy - compared with a control group of caregivers. 
 
Secondary Objective(s):  
• 
To assess the association between taste and smell dysfunction, and saliva secretion 
rate, saliva composition (pH, electrolyte and protein composition) and subjective feeling 
of a dry mouth (xerostomia) in patients more than two years after start of ICI therapy - 
compared with a control group of caregivers. 
• 
To assess the impact of taste and smell dysfunction in patients more than two years 
after start of ICI therapy. 
 

 
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3. STUDY DESIGN 
In this cross-sectional study, patients with melanoma, NSCLC or urogenital cancer ≥ 2 years 
following ICI therapy and their caregivers will be included. We will include patients who have 
previously participated in the study “Quality of life, cognitive function, and physical fitness of 
patients surviving more than 2 years after immune checkpoint inhibitor therapy” (METc 
2018/158, clinicaltrials.gov NCT03946007) and additional patients who are under control at 
the departments of Medical Oncology and Pulmonary Disease and did not participate in this 
previous studyA patient cohort of 70-120 patients and 70-120 of their caregivers has already 
been built and patients who have given permission to be approached for future research again 
will be invited for our study.  
 
Patients can be approached in two ways: 1) Patients will be asked during an outpatient 
clinic appointment by their clinical doctor if they can be approached afterwards by the 
investigator. When permission is given, the investigator will explain the study design and give 
the patient and the caregiver both a letter. These letters explains the study design and includes 
an informed consent form, 2) Patients who do not have an outpatient clinic appointment in the 
near future will be sent the letter with the study design and the informed consent form. In this 
letter, we will also ask each participant to invite their caregiver to participate in this study. For 
this, a separate letter directed at the caregiver will be sent to the participant. Patients and 
caregivers are asked to contact the investigator team if they are willing to participate. If the 
patient consents, a single appointment will be made during a regular follow-up visit to the 
outpatient clinic. If the caregiver consents too, we will make an appointment with both 
participants at the same time, if possible. Patients can participate alone if the caregiver is not 
willing to participate, and vice versa. 
 
During this visit, if patients and caregivers have no questions regarding the study or the 
study information that was sent, they are first asked to sign the informed consent. Next, saliva 
will be collected, and taste, smell and dry mouth will be subjectively and objectively be 
measured. Afterwards, characteristics will be taken from the patients’ electronic file, including 
age, gender, medical history and medication use. As the caregivers do not have a medical file, 
they are asked for these characteristics. 
 
 
 
 

 
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4. STUDY POPULATION 
4.1 Population (base)  
The participants in this study will be derived from an existing cohort of 70-120 patients who 
have undergone ICI treatment and have not received other systemic treatment (METc 
2018/158, clinicaltrials.gov NCT03946007). These patients have been previously included in 
a cross-sectional study in which health-related quality of life, neurocognitive function, 
endocrine function, cardiovascular risk, physical fitness, mood disorders, sexual problems, and 
work participation were investigated. Patients have survived two years or more after the first 
cycle of an immune checkpoint inhibitor for melanoma, NSCLC, or urogenital cancer. 
Furthermore, the quality of life of the caregivers of these patients was studied. 
 
The participants of this previously performed study who have given permission to be 
approached again, will be asked to participate in this study. In addition, to complete the 
required number of participants, additional patients from the departments of Medical Oncology 
and Pulmonary Disease, who were not included in the previously mentioned cohort, but who 
meet the criteria for this study, will be invited to participate in the study. Furthermore, a part of 
the caregivers of these patients have also been included in this previously mentioned cohort 
and has given permission to be approached again. The caregivers will act as control group for 
practical purposes, as they often accompany the patient on the hospital appointments. 
Furthermore, caregivers tend to have the same basic characteristics as the patients, and 
therefore, these characteristics will be distributed more equally in both groups. If a patient has 
a new caregiver, this new caregiver can also be asked to participate in this study instead of 
the previously included caregiver. Patients can also participate if they don’t have a caregiver. 
The caregivers of the additional patients will also be invited. 
  
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a patient must meet all of the following criteria: 
1. Patient with melanoma, NSCLC or urogenital cancers ≥ 2 years since treatment with at 
least one cycle of immune checkpoint inhibitor (CTLA-4 inhibitor, PD-(L)1 inhibitor, or both) 
within the Department of Medical Oncology or Pulmonary Oncology of the UMCG. 
2. Age ≥18 years at time of immune checkpoint inhibitor treatment 
3. Understand or abide to the study procedures 
4. Have given informed consent 
 
A caregiver must meet all of the following criteria: 
1. Age ≥18 years 
2. Understand or abide to the study procedures 
3. Have given informed consent 
 
The inclusion criteria of the earlier study with this cohort have been adapted to this study. 
 

 
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4.3 Exclusion criteria 
A patient or caregiver who meets any of the following criteria will be excluded from participation 
in this study: 
1. As previous or subsequent therapies, only surgery and palliative radiotherapy is allowed 
(excluding radiotherapy in the head-neck and brain region) 
2. Previous treatment in the past ten years for malignancy other than melanoma (excluding 
non-melanoma skin cancer, cervical intra-epithelial neoplasia or carcinoma in situ of 
breast) (for patients: other than current malignancy) 
3. History of ear-nose-throat disease or auto-immune disorder affecting taste, smell, mouth 
mucosa, or saliva production (for patients: before start ICI) 
4. As previous or subsequent therapies, palliative radiotherapy for bone metastasis in the 
brain and head-and-neck region 
 
The exclusion criteria of earlier studies with this cohort have been adapted to this study. 
 
4.4 Sample size calculation 
It is expected that long-term taste and smell dysfunction are prevalent in 25% of the patients. 
As described in the introduction, taste changes were found in 24% of patients using 
immunotherapy(9). In this study, however, it is not reported whether these changes were 
reported spontaneously or were actively asked. It is therefore possible that the percentage of 
24% will be even higher. From earlier studies in patients years after treatment of testis 
carcinoma or childhood cancer, it is know that about 25% of these (former) patients have long-
term taste and smell changes(21,22). Based on this information, the percentage of 25% was 
determined.  
As caregivers with a history of disorders affecting taste and smell will be excluded, it is 
expected that these dysfunctions are present in 5% of the caregivers. If so, the differences 
between the patient and control group of caregivers can be assessed in a cohort of in total 
49+49=98 patients and caregivers with a 95% confidence level and a power of 80%.  
 
 
5. TREATMENT OF SUBJECTS 
Not applicable 
 
6. INVESTIGATIONAL PRODUCT  
Not applicable. 
 
7. INVESTIGATIONAL PRODUCT  
Not applicable. 
 
 
 
 

 
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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
Taste and smell dysfunction measured using taste strips and Sniffin’ Sticks in patients 
compared to caregivers.  
8.1.2 Secondary study parameters/endpoints 
- 
Salivary flow rate 
- 
Salivary pH 
- 
Salivary electrolytes and protein concentrations 
- 
Perceived taste and smell dysfunction 
- 
Perceived xerostomia (XI-scores and RODI-scores) 
 
8.2 Study procedures 
Both patients and caregivers are asked not to smoke, brush teeth, eat, or drink anything 
except water one hour before the tests. Then, unstimulated and chewing-stimulated 
saliva will be collected, the salivary flow rate will be measured using standardized 
procedures, and patients and caregivers will fill in two questionnaires regarding 
perceived taste and smell dysfunction. Taste and smell dysfunction will be assessed 
with taste strips and Sniffin’ Sticks. To assess subjective taste and smell perception, 
and the impact of taste and smell dysfunction, the Chemotherapy-induced Taste 
Alteration Scale (CiTAS) questionnaire, the Patient-Generated Subjective Global 
Assessment (PG-SGA) questionnaire, the Appetite, Hunger and Sensory Perception 
(AHSP) and the Questionnaire of Olfactory Disorders (QOD) will be used. Subjective 
xerostomia will be assessed with the Dutch versions of the  Xerostomia Inventory (XI) 
and the Regional Oral Dryness Inventory (RODI). The results of the patients will be 
compared with the caregivers. Salivary flow rate and pH will be measured immediately 
after collection, and subsequently the saliva will be stored at -800C until biochemical 
analysis. Below, the tests and examinations are explained in more detail.  
 
Taste dysfunction 
Taste dysfunction will be objectively measured with “Taste Strips” (Burghart, Wedel, 
Germany)(23). Strips with an impregnated taste solution will be placed on the 
participants’ tongue. The taste solutions contain the basic tastes bitter, sweet, sour and 
salty in four different concentrations, thus 16 tests will be performed. The strips will be 
randomly administered and participants are asked which taste they notice. A right 
answer gives one point and a total of 16 point can be obtained.  
 
Smell dysfunction  
Smell dysfunction will be objectively measured with “Sniffin’ Sticks” (Burghart, Wedel, 
Germany)(24). Pens filled with liquid odorants are presented to the participants’ nose. 
Participants will smell 16 different scents with an interval of minimal 30 seconds to 

 
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prevent desensitization. For each scent, participants will choose between four options 
from a multiple choice card. Smell threshold will be measured with “Sniffin’ Sticks” with 
different odor concentrations. 
 
Saliva (flow rate, pH and elektrolytes) 
Saliva flow will be measured, both stimulated and unstimulated(25). The pH of saliva 
will be determined immediately after collection using an electronic pH meter. The 
composition of the saliva is determined by measuring electrolyte concentration (Na, K, 
Cl, HCO3, Zn) and the enzyme activity/concentrations of chitinase, amylase, lysozyme, 
Mucin5B, total protein, and carbonic anhydrase. 
 
Questionnaires 
Dysfunction in taste will be subjectively measured with the validated Dutch version of 
the CiTAS questionnaire(26). The CiTAS questionnaire consists of 18 questions on a 
5-point Likert-scale and identifies the type and severity of taste dysfunction. The PG-
SGA assesses weight, food intake, symptoms, and activities and function in 8 
questions(27). The AHSP questionnaire consists of 29 multiple choice questions and 
assesses appetite, hunger and sensory perception(28). Impact on quality of life will be 
measured with the QOD questionnaire(29). Xerostomia will be quantified with the 
internationally validated XI (a questionnaire with 11 items on a 5-point Likert-scale) and 
the RODI(30,31). The RODI consists of a schematic representation of 9 intra-oral 
areas, and the patient can indicate the severity of the xerostomia at these areas on a 
5-point Likert scale. 
 
 
8.3 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
8.3.1 Specific criteria for withdrawal  
Occurrence of signs or symptoms of progressive disease during study visit (after 
informed consent was signed). 
 
8.4 Follow-up of subjects withdrawn from treatment 
 
Subjects withdrawn from the study will not be assessed at a later time.  
 
 

 
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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study 
if there is sufficient ground that continuation of the study will jeopardise subject health or 
safety. The sponsor will notify the accredited METC without undue delay of a temporary 
halt including the reason for such an action. The study will be suspended pending a further 
positive decision by the accredited METC. The investigator will take care that all subjects 
are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the study procedure. All adverse 
events reported spontaneously by the subject or observed by the investigator or his 
staff will be recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to complete the 
initial preliminary report. All other SAEs will be reported within a period of maximum 15 days 
after the sponsor has first knowledge of the serious adverse events. 
 

 
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9.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. SAEs need to be 
reported till end of study within the Netherlands, as defined in the protocol. 
  
 
 
 

 
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10. STATISTICAL ANALYSIS 
This study aims to investigate the prevalence of taste and smell dysfunction in a predefined 
cohort of melanoma, NSCLC and urogenital cancer patients. Results will be reported as mean 
(standard deviation) and median (range) for parametric and non-parametric continuous 
variables, respectively. Categorical data will be presented as N and percentages. 
 
Participants and their caregivers will be compared using Mann Whitney U test or 
independent T-test,  depending on data distribution. For ordinal data, Chi-square tests will be 
performed. Correlations between perceived and objective taste and smell dysfunction will be 
studied with Pearson’s rho or Spearman’s rho, depending on data distribution.  
 
10.1 Primary study parameter(s) 
Taste strip and Sniffin’ Stick scores will be presented as mean scores and standard 
deviations. A higher score corresponds to a higher level of taste and/or smell dysfunction. 
 
10.2 Secondary study parameter(s)  
Salivary flow rates, saliva electrolytes, salivary proteins, salivary enzyme activity and pH, 
perceived taste and smell dysfunction will be presented as mean scores and standard 
deviations. 
Relationships between taste and smell dysfunction and salivary flow rates, saliva 
electrolytes, salivary proteins, salivary enzyme activity and pH will be analyzed using 
Pearson or Spearman correlation tests.  
 
 

 
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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (64th 
WMA General Assembly, Fortaleza, Brazil, October 2013) and in accordance with section 
10, subsection 1, of the Medical Research Involving Human Subjects Act (WMO). The 
protocol will be approved by the local Medical Ethical Committee. 
 
11.2 Recruitment and consent 
A patient cohort with 70-120 patients and 70-120 caregivers is already built up and patients 
and caregivers have given permission to be approached again. Potential participants will 
receive written study information. A week later, they will be called to ask if they want to 
participate. If a potential participant is willing to participate, he/she/they will sign written 
informed consent. The investigator will co-sign the informed consent form. The investigator 
will make a single appointment during a regular follow-up visit to the outpatient clinic. 
 
11.3 Objection by minors or incapacitated subjects 
 
Minors or incapacitated subjects will not be included in this study.  
 
11.4 Benefits and risks assessment, group relatedness 
This is a study without risks. Participation in the study will include one study visit of 
approximately 1,5 hour. If possible, the study visit will be combined with a regular follow-up 
visit. In this study, no invasive procedures are performed. The results of the full study group 
will be used to guide future interventions and support for cancer patients treated with ICIs. 
The participants will not have benefit by participating in this study.  
 
11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  
The sponsor is in accordance with the legal requirements in the Netherlands (Article 7 
WMO). As this study carries no risks for the participant, exemption is requested for the 
WMO clinical trial participants insurance. 
 
11.6 Incentives 
Participants will receive travel allowance if the study visit is not combined with a regular 
follow-up visit. 

 
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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Data of patients will be handled confidentially and a coded identification number will be used 
to link the data to the specific patients. The patients’ code will contain the abbreviation of 
the short study title, ‘TS’, and a number, starting with ‘01’. The principal investigator and 
coordinating investigator safeguard the key to the code. The handling of personal data 
complies with the EU General Data Protection Regulation and the Dutch Act on 
Implementation of the General Data Protection Regulation. (in Dutch: Uitvoeringswet AVG, 
UAVG). All research data will be stored for 15 years after the data collection has been 
completed (i.e. last research assessment for the last patient has been performed) in 
accordance with the NFU guidelines for WMO-compliant research. The saliva will be stored 
for three years. 
 
12.2 Monitoring and Quality Assurance  
The current study is considered to hold negligible risk. Therefore, monitoring will consist of 
checking the most important study procedures and data in a patient sample once a year. 
 
12.3 Amendments  
Amendments are changes made to the research after a favorable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favorable 
opinion. Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s visit. The sponsor 
will notify the METC immediately of a temporary halt of the study, including the reason of 
such an action. In case the study is ended prematurely, the sponsor will notify the accredited 
METC within 15 days, including the reasons for the premature termination. 
Within one year after the end of the study, the investigator/sponsor will submit a final study 

 
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report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC.  
 
12.6 Public disclosure and publication policy 
The results of this study will be disclosed unreservedly after the end of the study, either by 
publication in a peer-reviewed scientific journal or by publication on trial registers or websites. 
The published results cannot be traced back to the participants. All manuscripts derived from 
this protocol will be reviewed by the investigating group before submission. 
 
 
13. STRUCTURED RISK ANALYSIS  
Not applicable.

 
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