Conditions: Non-allergic Rhinitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
Chronic rhinitis is affecting more than 200 million people worldwide. Its prevalence is estimated to be as high as 30% of the Western population. Rhinitis is defined as symptomatic inflammation of the inner lining of the nose and is characterized by the following symptoms: rhinorrhea, nasal blockage, nasal itching and/or sneezing. The cut-off point for defining rhinitis as chronic rhinitis is considered to be persisting symptoms for over more than twelve weeks Chronic rhinitis can be divided into three major subgroups; based on the knowledge of the major etiological factor: infectious rhinitis, allergic rhinitis and non-allergic, non-infectious rhinitis, in literature also referred to as nonallergic rhinitis. Non-inferiority in efficacy of the two novel treatment regimes i.e. capsaicin nasal spray 0,01mM (2puffs/nostril/day) during 4 weeks and capsaicin nasal spray 0,001mM (2puffs/nostril/day) during 4 weeks compared to the current treatment of capsaicin nasal spray 0,1mM (5/day administered on a single day) with regard to the change from baseline in VAS for major nasal symptom on week 4.

(Estimated placebo effect is 25%.)

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: Capsaicin intervention 2: placebo
Intervention descriptions: intervention 1: via nasal spray intervention 2: via nasal spray

Protocol document:
Prot_SAP_001.pdf: 
Version 3, 09-12-2015 
 
 
1 
 
 
December 2014 
  
 
 
 
 
 
 
 
 
ELABORATION OF A PATIENT-FRIENDLY 
TREATMENT STRATEGY WITH CAPSAICIN 
NASAL SPRAY IN PATIENTS WITH IDIOPATHIC 
RHINITIS 
 
 
 
ACADEMIC MONOCENTER CLINICAL STUDY 
 
 
 
Sofie Mees, PhD fellow 1,2  
Emily Dekimpe, CTA 2,3 
Brecht Steelant, PhD fellow 1,2 
Inge Kortekaas, PhD fellow 1,2 
Ina Callebaut, PhD, CTA 2 
Dr. Laura Van Gerven, MD, PhD 2 
Prof. Dr. Jan Ceuppens, MD, PhD 1,3 
Prof. Dr. Karel Talavera, PhD 4 
Prof. Dr. Peter Hellings, MD, PhD 1,2 
 
 
1Laboratory of Clinical Immunology, Catholic University of Leuven, Belgium 
2Dpt. of Experimental Oto-rino-laryngology, University Hospitals Leuven, Belgium 
3Dpt. of Allergology, University Hospitals Leuven, Belgium 
4Laboratory of Ion Channel Research, Catholic University of Leuven, Belgium 


Version 3, 09-12-2015 
 
 
2 
Introduction 
 
 
A. Chronic rhinitis 
 
Chronic rhinitis is affecting more than 200 million people worldwide. Its prevalence 
is estimated to be as high as 30% of the Western population. Rhinitis is defined as 
symptomatic inflammation of the inner lining of the nose and is characterized by the 
following symptoms: rhinorrhea, nasal blockage, nasal itching and/or sneezing. The 
cut-off point for defining rhinitis as chronic rhinitis is considered to be persisting 
symptoms for over more than twelve weeks (1) (2) (3).  
Beside the classical symptoms, patients often suffer from nasal hyper reactivity 
(NHR) i.e. the induction of nasal symptoms by non-specific physical and chemical 
triggers such as temperature changes, smoke/scents, physical activity, emotional 
stress and changes in humidity (4) (5).  
 
Chronic rhinitis can be divided into three major subgroups (Figure 1); based on the 
knowledge of the major etiological factor: infectious rhinitis, allergic rhinitis and 
non-allergic, non-infectious rhinitis or NANIR, in literature also referred to as NAR.  
 
Figure 1: Visualization of the tree major subgroups within chronic rhinitis 
 
 
B. Non-allergic rhinitis (NAR) 
 
As we lack a uniform definition of NAR, epidemiology of NAR is difficult to 
accomplish. It is estimated that more than 50 million people in Europe suffer from 
NAR (2).  
The diagnosis of NAR is based on exclusion of clinical signs of infection as well as 
exclusion of sensitization to airborne allergens. 
As there are different phenotypes of NAR, good clinical history is the key to the right 
diagnosis. 
 
Subgroups of NAR are occupational rhinitis, elderly or senile rhinitis, gustatory 
rhinitis, hormonal rhinitis and drug-induced rhinitis (as a cause of adverse effects of 
systemic treatment or because of abuse of decongestive nasal therapy) (6). 
Up to 50% of the patients with NAR, are suffering from idiopathic rhinitis or IR (1), 
rhinitis of an unknown etiology. 


Version 3, 09-12-2015 
 
 
3 
C. Idiopathic rhinitis (IR) 
 
Up to 20% of the adult population in Flanders suffer from IR. It is affecting a very 
heterogeneous group of patients. The diagnosis of IR is a diagnosis by exclusion. 
Allergy, infection, hormonally or drug induced rhinitis and other rare forms of 
rhinitis, such as elderly, gustatory, occupational or local allergic rhinitis have to be 
eliminated.  
 
Often IR patients suffer from NHR (4) which implies that one or more nasal 
symptoms are induced upon encounter of environmental stimuli, such as humidity 
changes, temperature changes, smoke, other scents, irritants or strong odors. 
Although the problem of NHR in clinical practice is significant and IR represents a 
nasal condition with major impact on the quality of life, it still is largely neglected. 
Maybe because the mechanisms underlying NHR are not well understood. Several 
studies point towards the involvement of a neural mechanism such as neurogenic 
inflammation (7) (8). 
 
In AR patients, NHR is associated with hyper innervation of the nasal mucosa with 
increased expression of calcitonin gene related peptide and Substance P in the nerve 
fibers, which is considered a sign of neuronal hyper reactivity. AR and IR patients 
show the same level of mucosal hyper innervation, suggesting a neuro-inflammatory 
involvement in both (8).  
 
 
D. Capsaicin  
 
In 1991, the Swiss research group of Lacroix et al., described for the first time that IR 
patients benefit from intranasal capsaicin spray (9). Their findings were confirmed 
by other researchers e.g. Riechelman et al. (10), Blom et al. (11) (12). In 1997, Blom 
et al. published the first placebo-controlled trial showing therapeutic efficacy (11).  
Van Rijswijk et al. demonstrated in 2003 that five nasal applications on one day is as 
effective as five applications spread over two weeks (13), what makes the new 
treatment protocol more attractive both for patient and medical staff. 
 
The research group of Prof. Dr. P.W. Hellings of the Department of Oto-rino-
laryngology of the University Hospitals Leuven has more then six years of clinical 
experience with capsaicin (Figure 2), in treatment of patients with IR who do not 
respond well to the available treatment (i.e. intranasal corticosteroids). 
 
 
 
Figure 2: Structural formula of capsaicin 
 


Version 3, 09-12-2015 
 
 
4 
In a very recent academic proof-of-concept study, major therapeutic effects have 
been shown on nasal symptoms and reduction of NHR in 14 patients with IR. That 
fact that confirms the work of several former investigators and a numerous amount 
of studies in which the therapeutic effect of capsaicin was already proven (9) (10) 
(11) (12) (13). 
 
E. TRP channels 
 
Since decades capsaicin (8-methyl-N-vanillyl-6-nonenamide), the natural extract of 
red, hot chili pepper, is used as an analgesic in topical preparations (14) (15). 
Prolonged exposure to capsaicin makes the afferent nerves insensitive not only to 
the pungent substance but also to other noxious stimuli. The process of 
defunctionalization of nociceptor fibers is the mechanism behind its analgesic 
properties (14) and its therapeutic properties are due to the effect of capsaicin on 
the transient receptor potential V1 (TRPV1) on the sensory C-fibers in the nasal 
mucosa (16).  
 
Activation of these peripheral sensory nerve endings can trigger the TRP channel 
family - a family of chemoreceptors present in the airway lining. 
Currently, a lot of research is devoted to these channels because there is a strong 
conviction that disturbances in afferent sensory mechanisms are very important in 
the pathogenesis of functional problems (17).  
 
Members of the mammalian TRP family that are of specific importance for our 
research are TRPA1 (Ankyrin 1), TRPM8 (Melastatin 8) and TRPV1 (Vanilloid 1).  
TRPA1 is very commonly expressed in the nasal mucosa and is functioning as a major 
irritant detector. Therefore it is believed to play a crucial role in occupational 
rhinitis.  
The TRPM8 channel itself is activated by cold temperatures (as well as TRPA1) and 
TRPM8 activation leads to a cold sensation. Its function is not yet completely 
understood.  
Interestingly, approximately nine months after capsaicin treatment, symptoms tend 
to recur. The underlying mechanism is still uncertain, but is currently being 
investigated by the fundamental research team of Prof. Dr. K. Talavera. 
 
 


Version 3, 09-12-2015 
 
 
5 
Objectives 
 
 
A. Aims 
 
Our primary aim is: 
 To evaluate if two novel treatment modalities (explained more briefly on 
page 9 in paragraph ‘Study Onset’ of chapter ‘Methodology’) show non-
inferiority on subjective evaluations (symptom score on a Visual Analogue 
Scale (VAS), Therapeutic Response Evaluation (TRE) and Rhinitis Quality of 
Life Questionnaire (RQLQ)) compared to the current treatment modality of 
capsaicin nasal treatment in patients with IR. The gathered data of this single 
center trial can be used to guide the decision on the set-up and the design of 
a larger multi-center trial being powered to prove non-inferiority. 
 
Our secondary aims are: 
 To evaluate if the two novel treatment modalities show non-inferiority 
compared to the current treatment modality of capsaicin nasal treatment in 
patients with IR on objective evaluations (Peak Nasal Inspiratory Flow (PNIF) 
measurements before and after CDA challenge). 
 To evaluate the occurrence of adverse events at week 4, week 12 and week 
26 and recurrence of symptoms and NHR at week 26 in the different 
treatment groups. 
 
 
B. Hypothesis 
 
Non-inferiority in efficacy of the two novel treatment regimes i.e. capsaicin nasal 
spray 0,01mM (2puffs/nostril/day) during 4 weeks and capsaicin nasal spray 
0,001mM (2puffs/nostril/day) during 4 weeks compared to the current treatment of 
capsaicin nasal spray 0,1mM (5/day administered on a single day) with regard to the 
scores on week 4 (taking into account the baseline level). 
 
 
 
C. Outcome  
 
 VAS for major nasal symptom at week 4, week 12 and week 26. The region of 
equivalence is defined as a difference in VAS of less than 1.  
 VAS for total and individual nasal symptoms at week 4, week 12 and week 
26. The region of equivalence is defined as a difference in VAS of less than 1.  
 TRE (based on a scale from 1 to 5) at week 4, week 12 and week 26. The 
region of equivalence is defined as a difference in percentage for patients of 
less than 10% in all different TRE scoring groups. 


Version 3, 09-12-2015 
 
 
6 
 NHR (objectively measured by PNIF before and after CDA challenge) in all 
treatment modalities at week 4, week 12 and week 26. The region of 
equivalence is defined as a drop in PNIF of less than 10%. 
 Appearance of adverse events at week 4, week 12 and week 26. 
 Recurrence of symptoms (based on a scale of 1 to 5) at week 26. 
 
 
Study design 
 
 
A. Type of study 
 
This academic, mono center, randomized, double blind, double dummy, 
placebo controlled, parallel-group study will be carried out in the Department 
of Oto-rino-laryngology of the University Hospitals Leuven in 2014, and be 
running until March 2018. 
 
The following milestones will be outlined: 
 August 2014: Preparation of the logistics of the clinical trial. 
 September 2014: EudraCT number application and submission at CTC and 
MEC of the University Hospitals Leuven, without major expected problems in 
the light of the previous proof-of-concept study and reputation of the 
research team of Prof. Dr. Peter Hellings. 
 January 2015: First IR patient included in this trial. 
 July 2015: Last visit of first included patient. 
 October 2017: Last IR patient included in this trial. 
 April 2018: Last visit of last included patient, all ELISAs performed, and start 
of data analysis. 
 
 
 
Table 1: Visualization of the time management of the study 
2014	
2015	
2016	
2017	
2018	
Q3	
Q4	
Q1	
Q2	
Q3	
Q4	
Q1	
Q2	
Q3	
Q4	
Q1	
Q2	
Q3	
Q4	
Q1	
Q2	
Q3	
Prepara on	
First	pa ent	in	study	
Last	pa ent	in	study	
Study	
Data	analysis	


Version 3, 09-12-2015 
 
 
7 
Involved investigators: 
 Apr. Sofie Mees, PhD fellow (screening and clinical follow-up) 
(telephone number: +32 16 33 24 03)  
 CTA Emily Dekimpe 
 Brecht Steelant, PhD fellow 
 Inge Kortekaas Krohn, PhD fellow  
 CTA Ina Callebaut, PhD 
 Dr. Laura Van Gerven MD, PhD (recruitment, screening and clinical 
follow-up) 
 Prof. Dr. Peter Hellings (recruitment and screening and principal 
investigator) 
 
B. Inclusion criteria 
 
The following criteria will be administered for the screening of a patient in order to 
obtain inclusion of the patient in our study: 
 IR patients with at least 2 persistent (> 12w) rhinological symptoms (nasal 
discharge, sneezing, nasal congestion) for an average of at least 1 h per day, 
 IR patients with a total nasal symptoms score (TNS) of 5 or more on a visual 
analogue scale (VAS).  
 Age > 18 and < 60 years. 
 Written informed consent. 
 Willingness to adhere to visit schedules. 
 Adequate contraceptive precautions in female patients with childbearing 
potential. ** 
 
 
C. Exclusion criteria 
 
Patients meeting the following criteria will be excluded out of the study: 
 Patients with concomitant allergic rhinitis, demonstrated by positive skin 
prick test (Hal reagents) and/or IgE in blood. *  
 Patients with structural abnormalities: nasal polyps, severe septal deviation 
(septum reaching concha inferior or lateral nasal wall), septal perforation, 
hypertrophy of the inferior turbinates. 
 Patients with local allergic rhinitis (LAR) or entopy. 
 Systemic steroid treatment less than 4 weeks before the inclusion in the 
study, nasal steroid spray less than 4 weeks before the inclusion, oral 
leukotriene antagonists or long-acting antihistamines less than 2 weeks 
before the inclusion. 
 Inability of the patient to stop taking medication affecting nasal function like 
ß-blockers. 
 History of prolonged use or abuse of decongestant nasal spray like 
xylometazoline spray and/or use or abuse of decongestive oral medication. 
 Evidence of infectious rhinitis/rhinosinusitis or common cold within 4 weeks 
prior to inclusion. 


Version 3, 09-12-2015 
 
 
8 
 Pregnancy or lactation. ** 
 Any disorder of which might compromise the ability of a patient to give truly 
informed consent for participation in this study.  
 Enrollment in other investigational drug trial(s) or receiving other 
investigational agent(s) for any other medical condition. 
 Contra-indications for the use of local anesthesia (cocaine 5%). 
 Smoking or occupational exposure to irritants (like hypochlorite, persulfates, 
isocyanates). 
 Nasal malignancies or severe comorbidity like granulomatosis or vasculitis. 
 
 
Note *: 
Patients with underlying allergic disease are defined by positive skin prick test for 
the 18 most prevalent inhalant allergens (house dust mite, timothy grass, smooth 
meadow grass, orchard grass, nettle, plantago, oxeye daisy, mugwort, alder, birch, 
hazel, horse, cat, dog, rabbit, Alternaria, Aspergillus and Cladosporium  - HAL Allergy, 
Leiden, The Netherlands) and/or positive IgE analysis in the blood. 
Note **: 
Female patients with childbearing potential will be offered a pregnancy test at the 
screening. 
 
 
D. Possible hurdles 
 
Based on the former studies in which the therapeutic effect of capsaicin is proven 
(9) (10) (11) (12) (13) (18) and given the fact that capsaicin is well tolerated and side 
effects are minimal, it is very unlikely to be subject of foreseen or unforeseen 
obstacles in the elaboration of this study protocol. Beside minor inconveniences 
such as rhinorrhea, sneezing and watery eyes, there are no other known side 
effects.  
 
With regard to the safety of all individuals, the study will immediately be abrogated 
and the treatment protocol we will un-blinded at once, in case of any allergic 
reaction or any other adverse event. 


Version 3, 09-12-2015 
 
 
9 
Methodology 
 
 
A. Study onset 
 
This study will include 4 parallel arms of equal sample size. 
120 IR patients will be included in this four-arm study (n=30 patients per treatment 
arm). 
Group I Caps/Plac will receive capsaicin nasal spray at similar dose (0,1mM) as in the 
previous studies, followed by daily application of 2 puffs of placebo spray in each 
nasal cavity (n=30). 
Group II Plac/Caps high will receive placebo at visit 3, followed by capsaicin nasal 
spray at 0,01mM (2 puffs in each nostril) per day for 4 weeks (n=30). 
Group III Plac/Caps low will receive placebo at visit 3, followed by capsaicin nasal 
spray at 0,001mM (2 puffs in each nostril) per day for 4 weeks (n=30). 
Group IV Plac/Plac will receive placebo nasal spray at visit 3, followed by placebo 
nasal spray (2 puffs in each nostril) per day for 4 weeks (n=30). 
 
The study protocol is illustrated in the picture below. 
 
 
Figure 3: Visualization of the study protocol with four treatment arms 
 
 
B. Product preparation 
 
Mrs. Apr. Els Ampe of the Laboratory of Clinical Pharmacology and Pharmacotherapy 
at the Department of Pharmaceutical and Pharmacological Sciences of the Catholic 
University of Leuven will prepare all nasal solutions. 
 
The solution of the first treatment arm (Group I Caps/Plac) containing capsaicin 
0,1mM is prepared using the formula previously reported by Van Rijswijk et al. (13). 
In brief, the solution contained capsaicin at 0,1mM with 30,3mg pelargonic acid 


Version 3, 09-12-2015 
 
 
10 
vanillylamide (= synthetic capsaicin powder) dissolved in 3,3mL Ethanol 96° and 
diluted in a buffered 1L NaCl solution 0,9% with benzalkonium as preservative. 
 
The solution of the second treatment arm (Group II Plac/Caps high) with capsaicin 
0,01mM is a ten-time dilution of the first solution. 
 
The solution of the third treatment arm (Group III Plac/Caps low) with Capsaicin 
0,001mM is a hundred-time dilution of the original solution. 
 
The placebo solution contained the same buffer, but no pelargonic acid 
vanillylamide (= synthetic capsaicin powder).  
 
 
C. Sample size and setting 
 
The current study is not designed to prove non-inferiority, but serves as a pilot study 
to evaluate if non-inferiority is observed for the two novel treatment regimes 
compared to the current treatment regime. As many as possible IR patients 
matching the inclusion criteria (see above) will be recruited during the recruitment 
period. Based on previous experience in the center, the expected total number of IR 
patients equals 120 taking into account a recruitment period of three years. If it is 
possible to include 120 patients before the time frame of three years has finished, 
recruitment will be stopped earlier. If by any unforeseen circumstances, after three 
years still not enough patients are included in the study, recruitment will be running 
until a total number of 120 patients will be obtained.  
 
Note: 
A drop out rate of 10% due to concomitant infection, loss of follow-up or non-
related adverse events is possible during the setting. 
 
 
D. Statistics 
 
A linear model for longitudinal measures (More specifically, a direct likelihood approach is 
adopted using an unstructured covariance matrix (Molenberghs and Kenward, 2007, Section 
14.4)1.) will be used to compare the evolution of VAS, RQLQ and drop in PNIF 
between the four groups, with the baseline value as a covariate. A transformation of 
the outcome will be considered when needed to handle skewness in the distribution 
of the model residuals.  Differences between the groups will be compared with the 
a- priori defined regions of equivalence (see section Outcomes). 95% confidence 
intervals for differences at specific time points will be reported. Note again that the 
aim of this pilot study is to describe the pattern of the differences, and not to prove 
non-inferiority based on these confidence intervals. For the evaluation of the TRE, a 
                                                        
1 G. Molenberghs and M.G. Kenward. Missing Data in Clinical Studies. Hoboken, NJ : John Wiley & 
Sons, 2007. 


Version 3, 09-12-2015 
 
 
11 
logistic regression model using generalized estimating equations (GEE)2 will be used 
to compare the evolution in proportion patients free of complaints (TRE score 5), 
with the baseline TRE score as covariate. 
 
 
E. Patient recruitment 
 
Patients will be enrolled by four different strategies: 
 Patients with a new diagnosis of IR who visit the ENT department at the 
University Hospital of Leuven will be offered the possibility to take part in 
this study and will be screened for in- and exclusion criteria. 
 An announcement at the University website will be placed, explaining the 
aims and a short study protocol. 
 An announcement ‘ad valvas’ in the University Hospitals of Leuven will be 
placed, explaining the aims and a short study protocol. 
 ENT doctors will be contacted in order to provide them the possibility to 
offer their IR patients without AR with at least one nasal symptoms 
(rhinorrhea, nasal blockage, nasal itching and/or sneezing (1)) and/or NHR 
symptoms induced upon encounter of certain stimuli (humidity changes, 
temperature changes, smoke other scents, physical activity and emotional 
stress (5)) with capsaicin nasal spray. 
 An advertisement will be placed in local newspapers such as Metro, 
Randkrant, …  
 
Prior to any study-related measure, patients will be informed both verbally and in 
writing about the aim and nature of the study, the anticipated benefits and risks, the 
discomfort to which they may be exposed, and also about their right to withdraw 
from participation in the study at any time after their own free will. After given 
informed consent, patients will be offered a screening visit with Prof. Dr. Peter 
Hellings, Dr. Laura Van Gerven at week -3. CTA Emily Dekimpe and Apr. Sofie Mees 
will plan all visits. 
All eligible patients will be invited to return after three weeks for randomization and 
start of the study.  
 
Patients will receive a financial compensation for transportation and participation in 
agreement with the current standards of the local Medical Ethical Committee of the 
University Hospitals of Leuven (see Informed Consent Form). 
 
 
F. Randomization 
 
Mrs. Ellen Dilissen will provide a randomization list.  
                                                        
 
2 G. Molenberghs and G. Verbeke (2005). Models for discrete longitudinal data, Springer-
Verlag, New-York 
 


Version 3, 09-12-2015 
 
 
12 
For tracking purposes and for double-blinded randomization, all patients will be 
allocated a study number starting with Caps001 until Caps120.  
Patients will be allocated on a one to one base to receive either capsaicin nasal 
spray or placebo.  
For each patient, an envelope with the study code will be kept in a locker at the 
office of the CTA Emily Dekimpe (+32 16 3 40757) of the Outpatient clinic of the 
Department of Otorhinolaryngology, Kapucijnenvoer 33i, 3000 Leuven, in case of 
urgent need to un-blind the study in case of any adverse event. 
 
As this study will include four parallel arms of equal sample size, the 120 included IR 
patients will be randomized in four equal groups of each 30 patients (n=30 patients 
per treatment arm). A block randomization with varying block sizes will be used. 
 
 
G. Demographic and clinical information 
 
Patient’s demographic information as well as general medical history will be 
gathered from medical records and verified during the screening visit to the 
Outpatient clinic. 
Demographic data of importance are: age, gender, smoking, occupation, exposure 
to agents during professional or recreational activity, concomitant bronchial disease 
(asthma, COPD), aspirin intolerance and current medication use.  
The respective information is gathered in case report forms (CRFs) and will be 
analyzed by GraphPad Prism 6. 
 
 
H. Time schedule and visit table 
 
 
 
 
 
Table 2: Schematic visualization of the timeframe and visit table 
October	
	2014	
	
October		
2014	
Baseline	Visit	
Week	-1	
Screening	
Week	-3	
	
January	
	2015	
Follow-up	Visit	2	
Week	12			
April		
2015	
Follow-up	Visit	3	
Week	26	
Treatment	
Week	0	
October		
2014	
Follow-up	Visit	1	
Week	4	
November		
2014	


Version 3, 09-12-2015 
 
 
13 
 
 
As demonstrated in table 1, the included patients will visit the ENT Department of 
UZ Leuven at six occasions. 
 
 
 Screening visit (week -3) 
Explanation of study, study protocol and treatment. 
Inclusion in study after signing the informed consent form. 
Evaluation of inclusion and exclusion criteria. 
Pregnancy test for women with childbearing potential. 
Skin prick test for common aero-allergens if not yet performed. 
Blood tests for total and/or specific IgE. 
Nasal endoscopy for exclusion of anatomic deformities, rhinosinusitis or nasal 
polyps. 
Symptom evaluation using VAS scores for individual and total nasal symptoms. 
Quality of life evaluation using the rhinitis quality of life questionnaire (RQLQ).  
 
 Baseline visit (week -1):  
Re-evaluation of the inclusion and exclusion criteria. 
Clinical nasal examination including nasal endoscopy. 
NHR challenge (by CDA provocation and/or hyperosmolar discs). 
Nasal fluid collection before and after NHR challenge. 
Evaluation of nasal airflow by peak nasal inspiratory flow (PNIF) device before and 
after NHR provocation. 
Symptom evaluation using VAS scores for individual and total nasal symptoms. 
Quality of life evaluation using the rhinitis quality of life questionnaire (RQLQ).  
 
 Randomization and start of treatment (week 0):  
Explanation treatment i.e. five applications of capsaicin/placebo nasal spray with a 
one-hour interval, followed by handing over the capsaicin nasal spray or placebo for 
the following four weeks. 
Brief nasal examination. 
Evaluation of adverse events. 
Two weeks after treatment, patients will be contacted by telephone in order to 
evaluate adverse events, check adherence and evaluate therapeutic response.  
 
 Follow-up visit 1 (week 4):  
Nasal examination including nasal endoscopy. 
NHR measurements by CDA and/or hyperosmolar discs. 
Nasal fluid collection by Merocell (both nostrils) for measurement of 
neuromediators before and after NHR measurements. 
Measurement of PNIF before and after NHR measurements. 
Evaluation of the therapeutic response (TRE) on a scale from 1 (= no relief of 
symptoms) to 5 (= total relief of symptoms). 
Symptom evaluation (VAS) for INS and TNS. 
Quality of life evaluation using the RQLQ. 


Version 3, 09-12-2015 
 
 
14 
Evaluation of adverse events and check of adherence. 
 
 Follow-up visit 2 (week 12): 
Identical to FU 1 
 
 Follow-up visit 3 (week 26): 
Nasal examination including nasal endoscopy. 
Evaluation of the therapeutic response (TRE) on a scale from 1 (= no relief of 
symptoms) to 5 (= total relief of symptoms). 
Symptom evaluation (VAS) for INS and TNS. 
Quality of life evaluation using the RQLQ. 
Evaluation of adverse events and check of adherence. 


Version 3, 09-12-2015 
 
 
15 
 
 
Screening  
week -3 
Baseline  
week -1 
Treatment 
week 0 
FU visit 1 
week 4 
FU visit 2 
week 12 
FU visit 3 
week 26 
Explanation study 
and protocol 
x 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
Evaluation in-and 
exclusion criteria 
x 
x 
 
 
 
 
Pregnancy test 
(If necessary) 
x 
 
 
 
 
 
SPT 
(If necessary) 
x 
 
 
 
 
 
Blood analysis 
x 
 
 
 
 
 
ENT exam with 
nasal endoscopy 
x 
x 
x 
x 
x 
x 
Nasal fluid 
collection 
 
x/x* 
 
x/x* 
x/x* 
 
Explanation R/ 
x 
 
x 
 
 
 
Start R/, handing 
over study 
medication and 
diary  
 
 
 
x 
 
 
 
 
NHR 
measurements 
 
x 
 
x 
x 
 
TRE 
 
 
 
x 
x 
x 
Symptom 
evaluation VAS 
x 
x 
 
x 
x 
x 
Symptom 
evaluation RQLQ 
x 
x 
 
x 
x 
x 
AEE and check 
adherence 
 
 
x 
x 
x 
x 
ENT: ear, nose, throat 
 
TRE: therapeutic Response Evaluation 
 
AEE: Adverse Events Evaluation 
*: x/x = before and after NHR measurements 
 
Table 3: Overview of registrations and sample collections that were performed at each visit 


Version 3, 09-12-2015 
 
 
16 
I. Variables 
 
 Clinical ENT exam: 
Nasal endoscopy will be performed by an experienced MD.  
 
 Skin Prick Test (SPT): 
SPT for the 18 most prevalent inhalant allergens (e.g. house dust mite, grass, 
mugwort, alder, birch, hazel, pet animals, Alternaria, Aspergillus) provided by HAL 
Allergy, will be performed by investigators Apr. Sofie Mees or CTA Emily Dekimpe. 
 
 Blood analysis: 
Blood samples will be taken by an MD. Total IgE will be measured in the serum and if 
according to anamnestic details and/or lack of uniformity of the SPT specific IgE of 
necessary allergens will be determined. 
 
 NHR challenge by Cold Dry Air (CDA) provocation (19): 
Patients will be asked to acclimatize to room temperature for 20 minutes prior to 
exposure to CDA.  
All provocations will be performed by Apr. Sofie Mees or CTA Emily Dekimpe. 
Through a transparent anesthesia mask, placed over nose and mouth of the patient, 
compressed dry air for medical use will be delivered for 15 minutes (25L/minute). 
Patients will be instructed to breathe through the nose only. The temperature of the 
air reaching the nose will be approximately -10°C and the relative humidity less than 
10-15%. 
 
 Peak Nasal Inspiratory Flow (PNIF) measurement: 
Nasal congestion will be evaluated by three consecutive measurements performed 
by Apr. Sofie Mees or CTA Emily Dekimpe using a PNIF device before and 
immediately after CDA provocation.  
Hereby, an anesthesia mask will be placed over nose and mouth of the patient. After 
expiration by mouth, patients will be instructed to carefully close their mouth and 
forcefully inspire air through the nose.  
 
 Collection of nasal secretions:  
Nasal fluid will be collected by Apr. Sofie Mees by placing a small nasal sponge 
(Merocell 4 cm) between the middle and inferior turbinate for five minutes. This 
technique is a-traumatic and painless for the patient, and allows a rapid collection of 
nasal secretions without the need for local anesthesia. The fluid obtained before will 
be stored at -20°C until analysis. 
 
 Processing of nasal secretions: 
The following mediators will be evaluated: total and/or specific IgE, Substance P 
(SP), VIP, Neurokinin A, CGRP, IL 4, IL 5, … 
Analysis will be made using ELISA and/or ImmunoCAP and/or CBA. 
Additionally, the functionality of the TRPV1 will be investigated by calcium-imaging 
experiments. 


Version 3, 09-12-2015 
 
 
17 
 
Of note:  
Because research concerning immunological features is rapidly evolving, it is 
possible that other neuromediators/proteins are analyzed or other scientific 
techniques are tried and tested on available samples of nasal fluid and/or biopsy. 
In order to provide future patients better treatment options, excess of nasal 
secretions/biopsies will never be discarded. 
 
 Product application: 
On the day of the treatment, all IR patients will be treated by Prof. Dr. Peter 
Hellings, Dr. Laura Van Gerven, Apr. Sofie Mees or CTA Emily Dekimpe with a 
blinded nasal spray (capsaicin or placebo) five times with one-hour intervals as 
described by the treatment protocol of Van Rijswijk et al. (13). The nasal mucosa of 
all patients will be anaesthetized prior to the first three applications by 2 puffs of 
cocaine 5% nasal spray in each nostril. To ensure effective local anesthesia, an 
interval of 10 to 15 minutes was maintained. 
To protect the eyes of the patients against potential irritating particles of capsaicin, 
all individuals will be suggested to close their eyes during the application of 
capsaicin nasal spray. 
After finalizing the treatment protocol, the patient will be handed over a nasal spray 
containing capsaicin 0,01mM, capsaicin 0,001mM or placebo to take home and to 
use for the consecutive four weeks, labeled with his/her allocated study number 
(Caps001-Caps120) and the usage (2 puffs in each nasal cavity once daily). 
 
 Evaluation of nasal symptoms by VAS scores:  
All patients will be asked to mark the typical nasal symptoms on a visual analogue 
scale for individual (INS) and total nasal symptoms (TNS) before treatment and at 
week 4, 12 and 26. A visual analogue scale is a measurement of a patient’s 
subjective evaluation of symptom severity by indicating a position on a line between 
two endpoints, which represent a well-validated and easy technique of the 
evaluation of symptom severity. Indeed, VAS scores for TNS have recently been 
validated and proposed as a means of evaluation of symptom control in rhinitis (20).  
 
 Evaluation of quality of life by Rhinitis Quality of Life Questionnaire: 
Functional problems that are most troublesome to adults with rhinitis will be 
measured by the RQLQ by 28 questions in 7 domains (activity limitation, sleep 
problems, nose symptoms, eye symptoms, non-nose/eye symptoms, practical 
problems and emotional function). There are three ‘patient-specific’ questions in the 
activity domain, which allow patients to select three activities in which they are 
most limited by their rhinitis. Patients recall how bothered they have been by their 
rhinitis during the previous week and to respond to each question on a 7-point scale 
(0 = not impaired at all and 6 = severely impaired). The overall RQLQ score is the 
mean of all 28 responses and the individual domain scores are the means of the 
items in those domains. The RQLQ has excellent measurement properties and has 
been used extensively throughout the world both in clinical practice and clinical 
trials. The validation studies have shown that these properties are very similar to 


Version 3, 09-12-2015 
 
 
18 
those found for the Asthma Quality of Life Questionnaire (21). Patients will be asked 
to score RQLQ before treatment and at week 4, 12 and 26. 
 
 Adherence evaluation: 
Patients will be asked to bring their nasal spray with them on follow up visit 2 at 
week 4. Weighing the residual fluid on day 28 will objectively check adherence.  
All patients will be asked to write down their symptoms, adverse events and degree 
of sensitization/desensitization in a dairy (see addendum). The diary will be handed 
over to them at the day of the treatment. 
 
 Therapeutic Response Evaluation (TRE): 
TRE will be measured on a 1 to 5 scale. 
5 
klachten zijn volledig verdwenen = klachtenvrij 
4 
klachten zijn bijna volledig verdwenen 
3 
klachten zijn verminderd, doch nog aanwezig 
2 
klachten zijn licht verminderd, doch nog sterk aanwezig 
1 
klachten zijn onveranderd ten opzichte van vóór de behandeling 
Patients will be asked to score their symptom relief on week 4, week 12 and week 
26. 
 
 Evaluation of recurrence of symptoms: 
The recurrence of symptoms will be measured on a 1 to 5 scale. 
5 
klachten zijn volledig terug aanwezig 
4 
klachten zijn voor een aanzienlijk deel terug aanwezig 
3 
klachten zijn nog steeds duidelijk verminderd  
2 
klachten zijn licht verminderd, doch beginnen terug te keren 
1 
klachten zijn nog steeds volledig verdwenen 
Patients will be asked to score their recurrence of symptoms at week 26. 
 
 


Version 3, 09-12-2015 
 
 
19 
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