Adherence in Global Airways - the Relationship Between Steroid Intake and the Impact on the Endocrine Axis, Bone Density, and Structure in Patients With Chronic Sinusitis and Asthma
Conditions: Chronic Rhinosinusitis Without Nasal Polyps, Asthma, Chronic Rhinosinusitis With Nasal Polyps, Steroid-Induced Osteopenia (Diagnosis), Steroid-Induced Diabetes, Steroid-Induced Hyperglycemia
Sponsor: Christiane Haase

 
 
Protocol Summary - Adherence in Global Airways – the relationship between steroid intake and the 
impact on the endocrine axis, bone density, and structure in patients with chronic sinusitis and asthma 
Trial Responsible Nurse 
Christiane Haase, Clinical Nurse Specialist and Ph.D. Student 
Department of Otorhinolaryngology and Audiology 
Inge Lehmanns Vej 8 
2100 Copenhagen Ø 
Phone: 35459565 
Christiane.holbaek.haase.01@regionh.dk 
Trial Responsible Physician 
Vibeke Backer, Professor and Chief Physician 
Department of Otorhinolaryngology and Audiology 
Inge Lehmanns Vej 8 
2100 Copenhagen Ø 
35 45 60 33 
Nina.vibeke.backer@regionh.dk 
Purpose: 
The purpose is to investigate the relationship between high total intake of systemic steroids in patients 
with upper and lower airway disease, low endogenous cortisol production, and reduced bone density and 
structure. Additionally, through an exploratory follow-up (pilot project) study, to investigate whether 
improved adherence to local steroid treatment and biologic medication would decrease the patient's 
endogenous cortisol production. 
Method, Design, and Investigation Procedures: 
Patients referred for evaluation at the LuftvejsklinikAirway clinic, Department of ENT, Rigshospitalet with 
possible chronic sinusitis with or without asthma are offered participation in the project. The project 
consists of 1) a cross-sectional study and 2) an exploratory follow-up (pilot project) after four months. The 
patient population includes all newly referred patients who are offered evaluation and assessment for CRS, 
without polyps (CRSnNP) or with polyps (CRSwNP), and possible concurrent asthma with regards to 
potential biological treatment. 
Inclusion/exclusion criteria for the cross-sectional study: 
Inclusion criteria: 
• Diagnosed with CRS and possible asthma 
• Aged over 18 years 

 
 
Exclusion criteria: 
• Unable to read or speak Danish 
• Serious psychiatric comorbidities 
• Patients who have never taken systemic steroids 
• Not able to participate or fulfill local treatment according to the investigator's assessment 
• Does not give permission for access to FMK-online 
Inclusion/exclusion criteria for the exploratory study - 4-month follow-up (pilot project): 
Inclusion criteria: 
• Diagnosed with CRS and possible asthma 
• Aged over 18 years 
• Low adherence: Foster score, i.e. number of treatments taken compared to prescribed <80% (4 weeks out 
of 16 weeks) and/or measured on MARS-5 L/N ≤35 at first visit (corresponding to under 80%). If the patient 
does not have asthma, it is MARS-5N ≤19. 
• If asthma: ACQ ≥1.2 or ACT≤17 (partially uncontrolled asthma) 
• SNOT-22 score ≥35 (partially uncontrolled CRS) 
• Participation in the cross-sectional study at the initial visit to the Airways Clinic 
Exclusion criteria: 
• Adherence: Foster score >80% and/or MARS-5-L/N >35 points at the first visit 
• Unable to read or speak Danish 
• Serious psychiatric comorbidities 
• Patients who have never taken systemic steroids 
• Not able to participate or fulfill local treatment according to the investigator's assessment 
• Does not give permission for access to FMK-online 
 
Side effects, risks, and disadvantages: 
Synacthen test: There are no serious side effects or risks associated with undergoing a synacthen test. 
When injecting Synacthen (ACTH), one may experience short-term side effects such as a feeling of warmth, 
and in rare cases, transient nausea. In rare cases (0.01-0.1%), there may be reactions to ACTH, which can 
manifest as an allergic swelling of the face, mouth, and larynx, and in extremely rare cases (0.001-0.1%), 
this can progress to an anaphylactic reaction. Safety precautions are taken for each test, including the 
presence of a doctor on call with emergency contact information for treating an allergic or anaphylactic 
reaction. The test is performed in accordance with the recommendations from the endocrinology 
department at Rigshospitalet, where training also takes place. Safety measures are taken for each test, and 

 
 
there is an agreement with the on-call ENT doctor. This includes calling a doctor for treatment of an allergic 
reaction (often with prednisolone Solucortef 40 mg and antihistamine (Tavegyl), as well as possible 
adrenaline inhalation) or an anaphylactic reaction (intramuscular adrenaline with 0.3 mg in an Epipen). 
Economic considerations: 
The mentioned research group has initiated the project. There is no increased financial consumption 
associated with the project, as it involves patients who are part of the clinical outpatient treatment at the 
LuftvejsklinikRespiratory Clinic, ENT, RH. Funding has been sought for extra work for a nurse at the Danish 
Lung Association, Rigshospitalet's research fund, and other small and large funds. A final response to these 
applications is awaited in the spring of 2023. Included patients and the Regional Ethics Committees will be 
informed of the name of the sponsor and the amount of support, if obtained. 
Recruitment of study participants: 
Patients are recruited at their initial visit to the LuftvejsklinikAirway Clinic. A nurse from the clinic will 
provide information about the project and ask if the patient is interested in participating. If the patient is 
interested, an information meeting with a researcher from the group will be arranged. If the patient wishes 
to participate, they will receive verbal and written information about the project. If the patient wishes to 
participate, they must complete a written consent form for participation in the project. 
Publication of trial results: 
All results, whether positive, negative, or inconclusive, will be published via www.clinicaltrials.gov. 
Scientific Ethical Statement: 
Participants have the right to self-determination to choose whether they want to participate in the project 
and a "no" will be respected. They will be adequately informed about the purpose of the project. They will 
be informed that their participation is voluntary, and they can withdraw from the project at any time 
without consequences for their future treatments and consultations in the healthcare system. They will 
receive verbal and written information about the project. They will also be made aware that they have at 
least 24 hours to consider before giving consent for participation. If they choose to participate, written 
informed consent will be obtained once they have decided. The project has been approved by the Capital 
Region's Data Protection Agency P-2022-493. The project is also being conducted on the basis that the 
research group has an expectation that the results will be useful for future treatments of this group of 
patients. For example, if they have a severely affected endocrine axis (low P-cortisol) and will need 
supportive steroids in, for example, cases of surgical treatment under general anesthesia. 
 
 

 
 
Protocol - Adherence in Global Airways – the relationship between steroid intake and the impact on the 
endocrine axis, bone density, and structure in patients with chronic sinusitis and asthma 
Research Group: 
Clinical Nurse Specialist, Cand. Cur, Christiane Haase (PI) 
Clinical Nurse Specialist, Cand. Cur, Ditte Gertz Mogensen 
Chief physician and Ph.D., Ear-Nose-Throat, Kasper Aanæs 
Professor and Chief physician, Endocrinology, Peter Schwarz 
Professor and Chief physician, Pulmonology, Vibeke Backer 
Introduction: 
There has been a significant focus on ensuring treatment of diseases in both upper and lower airways 
(global airways) simultaneously because they have the same inflammatory disease mechanism. 
Approximately 9% have chronic sinusitis (CRS), 4% of the Danish population is diagnosed with CRS with 
nasal polyps (CRSwNP)(1), and 7-10% have asthma. Over the years, some of these patients have been 
treated with systemic and/or locally acting steroids (glucocorticoids). These patients referred have 
moderate to severe disease with a significant disease burden, and therefore continue to be treated with 
steroids. The risk of developing secondary adrenal insufficiency is high with prolonged use of systemic high-
dose and potent glucocorticoids but can also occur with locally administered glucocorticoids (2). It has 
recently been demonstrated that treatment of eczema with steroid-containing creams has indications of 
side effects not only on the skin but also on the bones (3). Moreover, there is an additive effect, so that it is 
the total burden of steroid intake that is significant for the development of side effects, but whether it also 
affects cortisol response to ACTH is unknown (4). Treatment with steroids currently affects the endocrine 
axis (P-cortisol), increasing the risk of osteopenia, osteoporosis, and possibly diabetes. Our knowledge of 
which preparations, doses, and modes of administration cause these side effects is inadequate, and 
whether the total dose over time is significant is unknown. This gives rise to conducting a cross-sectional 
study to determine the significance of these side effects, followed by an exploratory follow-up study of 
patients with global airway diseases and high adherence (80%) to local treatment. 
Purpose: 
The purpose is to investigate the relationship between high total intake of systemic steroids in patients 
with upper and lower airway disease, low endogenous cortisol production, and reduced bone density and 
structure. Additionally, through an exploratory follow-up (pilot project) study, to investigate whether 
improved adherence to local steroid treatment and biologic medication would decrease the patient's 
endogenous cortisol production. 
Hypothesis/research question: 
Patients with CRS/CRSnNP/CRSwNP who have received systemic steroids have an impact on the adrenals 
with low basal P-cortisol (below 500nmol), abnormal response to stimulation with ACTH (synacthen test) 
measured at the final P-cortisol. Additionally, a reduced increase (delta value) in P-cortisol is expected in 
connection with a synacthen test. These patients also have an affected bone density and structure with a 
higher incidence of osteopenia and osteoporosis than expected for this age group. Patients with 
CRS/CRSnNP/CRSwNP who can improve their adherence to >80% have an increasing impact on P-cortisol. 

 
 
Primary outcome: 
The primary outcome is to investigate whether newly referred patients with upper and possible lower 
respiratory tract diseases have an impact on their own cortisol production after prolonged use of systemic 
steroids. That is, the baseline level of plasma cortisol is <500 nmol, and a correlation with lifelong use of 
systemic steroids can be demonstrated. 
Secondary outcomes: 
Cross-sectional study: 
1: After a stimulation test, plasma cortisol is not above 500 nmol. 
2: The increase in plasma cortisol is associated with the intake of systemic steroids. 
3: Demonstration of the correlation between lifelong use of systemic steroids and the degree of osteopenia 
and osteoporosis (T-score). T-score from DEXA scanning is used to measure bone density and structure. An 
affected T-score is defined as follows: T-score between -1.0 and -2.5 = osteopenia and score ≤ -2.5 = 
osteoporosis. 
4: The number of patients with osteoporosis/penia of the spine and femur is increased compared to 
expected findings in age-matched individuals. 
Exploratory follow-up at 4 months (pilot project): 
5: Patients with CRSwNP/CRSsNP/CRS with and without asthma who have shown low adherence <80% after 
the cross-sectional study and who have achieved adherence over 80% at follow-up have also developed 
adrenal function impairment with a reduction in plasma cortisol of at least 8% (exploratory study). 
Study design (brief description): 
The study design is a cross-sectional study of newly referred patients to the Luftvejsklinik, ENT, RH for 
investigation and treatment of CRS and possibly asthma. And an exploratory follow-up (pilot project) study 
of patients who attend 4-month control. 
Background: 
Chronic rhinosinusitis (CRS) is a condition with chronic inflammation in the nose and sinuses. CRS can be 
with both nasal polyps (CRSwNP) and without polyps (CRSsNP) (5). 9% of the Danish population is affected 
by CRS, and about 4% are estimated to be diagnosed with CRSwNP (1). The diagnosis is based on the 
patient's symptoms and objective signs of inflammation in the nose and sinuses. The symptoms are a 
blocked nose or nasal secretion, reduced airflow, reduced sense of smell, pain/pressure around the nose, 
forehead, or eyes. The above symptoms must have been present for more than 12 weeks, and one of the 
symptoms must be secretion or reduced airflow through the nose to make a diagnosis (6). About 40% of 
CRS patients in primary care have asthma, whereas 65% referred for treatment at the hospital have asthma 
(7). CRSwNP that is not satisfactorily controlled particularly affects quality of life (8). It is often 
characterized by type-2 inflammation, i.e., an increased number of eosinophils in the mucous membranes 
in the sinuses and nasal polyps - as well as comorbidities such as asthma, ASA/NSAID intolerance (N-ERD), 
and allergies (5). CRS can be treated both surgically and medically. The basic medical treatment of CRS 
includes daily saline irrigation and use of nasal steroids. If there is a lot of secretion, antibiotic treatment 
can also be added to the basic treatment. In the case of nasal polyps, systemic corticosteroid treatment 
(prednisolone tablets/injection betamethasone) can also be added (5,6). If the medical treatment is not 

 
 
optimal, patients can be offered surgical treatment - endoscopic sinus surgery (ESS) (5). The goal is to aim 
for the removal of polyps in the nose and sinuses. 
Comorbidity: 
In patients with CRSwNP, one should also focus on comorbidity due to the interaction between the upper 
and lower airways. Patients with uncontrolled CRSwNP are often burdened with a high disease burden. 
CRSwNP and asthma often have a negative impact on each other. Therefore, patients should be evaluated 
for asthma. Patients with CRSwNP with type-2 inflammation (high eosinophil cell count in the blood or 
nasal mucosa) have more frequent recurrence of CRSwNP after surgery than patients with low eosinophil 
cell count (5). Patients with asthma may also experience faster recurrence of their polyps than patients 
who do not have asthma. 
Asthma: 
Asthma is a chronic respiratory disease characterized by chronic inflammation in the airways, airway 
hyperresponsiveness, and variable airflow obstruction (9). It is estimated that over 300 million people 
worldwide suffer from asthma, which has a significant impact on the economy (10). Symptoms of asthma 
include cough, wheezing, shortness of breath, and chest tightness, among others, and can vary in intensity. 
The diagnosis is based on the medical history, symptoms, and objective findings, such as spirometry, FeNO 
measurement, provocation tests, and peak flow test (9). 
Adherence: 
The term adherence describes the patient's adherence to the treatment strategy developed in consultation 
with a healthcare provider. The patient is considered an active participant in their treatment. Adherence 
can be measured both for pharmacological and non-pharmacological treatment. The WHO categorizes 
adherence measurements into subjective and objective measurements (11,12). Objective measurements 
include measurements such as pill counting, electronic monitoring (shared medical record), or biochemical 
measurements (e.g., blood tests) (11). Subjective measurements require an assessment by a healthcare 
professional or the patient themselves. Self-reporting by the patient or assessment by the healthcare 
provider is the most common method used to assess patient adherence. Foster's score and MARS-5 are 
subjective tools for measuring patient adherence. With Foster's score, the patient is asked a single 
question, "How many days out of seven do you take your medicine as recommended?" Starting at 0, the 
score is calculated as the number of days of taking the prescribed amount. Zero days are equal to 0% 
assessed adherence and taking the medication every day for seven days is equal to 100% assessed 
adherence (13). MARS-5 - developed by Professor Rob Horne (14,15). MARS-5 is a generic tool. It has been 
validated in many different clinical settings, including patients with asthma (16). 
Poor adherence is especially seen with prolonged treatments among chronically ill patients, underscoring 
the importance of focusing on sustained adherence in these patients (17). Some patients discontinue their 
treatment once they have symptom control, after which an exacerbation occurs. They resume their 
treatment with the feeling that "it does not help" because they experience worsening symptoms (18). WHO 
estimates that only 50% of patients receiving long-term pharmacological treatment for their chronic 
illnesses are adherent to their treatment (18,19). Adherence to asthma and COPD has been found to range 
from 22% to 78% (10,18). In connection with "usual care," patients with asthma receive information, 
education, and training in relation to their disease in many places. Adherence to pharmacological 
treatment depends on age, educational level, knowledge of asthma, how many times medication is to be 
taken, whether the medication is easy to take, and how their communication is with the healthcare 

 
 
provider (18,19). Adherence to inhalation medication is lower than with treatment with tablets taken orally 
or medication given by injection. The more complex and the more times the patient has to remember to 
take the medication, the more difficult it is to maintain optimal adherence (18,19). In a recent study, 
adherence was investigated in patients with asthma and pregnancy. The most interesting finding was that 
patients had a perception of being somewhat adherent. However, upon checking their electronic medical 
records, it turned out that patients did not buy as much medication as they thought. Thus, they were less 
adherent than they perceived themselves to be (20). 
CRSwNP is a chronic disease like asthma, where low adherence is often seen in mild to moderate cases of 
CRS compared to severe cases of CRSwNP (21). However, the clinical perception is that not all patients take 
all their daily doses, but few scientific studies have focused on this. The difficulty in treating CRS is that the 
patient must use nasal steroids 1-2 times daily and combine it with nasal saline irrigation at least once daily. 
Reduced adherence is accompanied by poor disease control. Therefore, it is important to support and 
strengthen patients' adherence in relation to CRS with or without asthma to achieve good disease control 
(21). 
Glucocorticoid-induced adrenal insufficiency and osteoporosis: 
The use of steroids is a part of medical treatment for CRSwNP and asthma, and systemic steroid use is often 
seen in moderate to severe cases. It can affect the body's own production of hormones, which at different 
doses can trigger adrenal insufficiency. The condition is divided into primary and secondary adrenal 
insufficiency (22). Primary adrenal insufficiency involves the body's reduced or complete lack of hormone-
producing cells in the adrenal cortex. Secondary adrenal insufficiency is caused by reduced production or 
effect of ACTH from the pituitary gland in the brain (2, 22, 23). The most common form of secondary 
adrenal insufficiency develops during external steroid treatment with pharmacological doses for a non-
endocrine disease, such as CRSwNP and asthma. About 25% of patients receiving long-term steroid 
treatment develop long-term adrenal insufficiency - the higher the dose and treatment duration, the 
greater the risk (2, 23). Adrenal insufficiency can also occur with locally administered steroids - for example, 
it has been shown that 8% of patients treated with inhaled steroids, 52% after intramuscular injection, and 
more than a third of patients in long-term low-dose steroid treatment develop insufficiency (23, 24). In 
addition, steroid creams have been shown to have systemic side effects in a previously unknown high 
number of patients (3). Reduced production of steroids from the adrenals is a situation that should be 
considered in connection with acute illness, but also surgery (22, 25). Many patients with CRSwNP are 
offered 1-3 injections of steroids annually, in addition to high doses of nCS. Surgical intervention is also 
performed in between these injections. Here, one could consider supplementing preoperatively with 
steroids as protection against the stress of surgery if the endocrine axis is affected. Systemic glucocorticoids 
are used as treatment for a wide range of diseases, such as inflammatory diseases like CRSwNP or asthma 
either as needed or chronically (26-28). Glucocorticoid-induced osteoporosis is the most common 
secondary cause of osteoporosis and is a global public health problem, where fractures contribute to 
significant morbidity and mortality (29). The frequency of secondary glucocorticoid-induced osteoporosis is 
unknown in patients with CRSwNP (26). Prevention of this and negative consequences should be a focus 
point for healthcare professionals in these patients due to long-term treatment with systemic 
glucocorticoids (28). 
Method: 
Regarding 1) In the cross-sectional study, patients will receive the standard investigation and treatment at 
the Luftvejsklinik. This includes investigation for airway disease and possible type-2 inflammation, 

 
 
treatment, etc. Measurement of their adherence and possible optimization of CRS and asthma treatment. 
The total amount of systemic steroids will be calculated and included in the study. 
Experimental intervention (synacthen test): To investigate how prolonged use of systemic steroids and 
adherence affect cortisol production, all patients who agree to participate in the project will undergo a 
synacthen test. A synacthen test is used to assess whether the body's adrenal glands produce cortisol 
satisfactorily (i.e., own production). Cortisol is a hormone produced in the adrenal glands and is therefore 
called adrenal cortex hormone. It has a few effects, including on muscles, supportive tissues and bones, and 
nutrient metabolism. Therefore, the adrenal glands' ability to produce hormones is important. Reduced or 
absent production of adrenal cortex hormones can be seen with prolonged treatment with systemic 
steroids (adrenal cortex hormones). A synacthen test will be performed twice in total on all patients. The 
first time is at the 1st visit (preliminary examination) and the second time at the 4-month follow-up. 
Ad 2) Exploratory investigation/4-month follow-up (pilot project): The experimental intervention in the 
follow-up involves measuring P-cortisol in patients who have now achieved high adherence (> 80%). 
Patients will receive standard follow-up/monitoring and treatment in the respiratory clinic. 
Study population: 
The study population consists of patients referred to the Luftvejsklinik, ENT, RH, for evaluation of 
CRS/CRSwNP/CRSnNP and with or without asthma for biological treatment. They are classified according to 
the type of inflammation they have (type-2 or non-type-2), whether they have CRSwNP or CRSsNP, their 
adherence, comorbidity with asthma, and finally the severity of the disease. All patients are given standard 
questionnaires to assess CRS/CRSwNP/CRSnNP and asthma (STARR-15, SNOT22, ACQ, ACT, MARS-5-L/N, 
Fosterscore - routine questionnaires for all patients in the Luftvejsklinik). 
Patients for the project are recruited at the initial visit to the LuftvejsklnikLuftvejsklinik. A nurse from the 
clinicc will inform about the project and ask if the patient is interested in participating. If the patient is 
interested, a meeting will be arranged with a researcher from the research group (see section on 
information). 
Inclusion/exclusion criteria for the cross-sectional study: 
Inclusion criteria: 
• Diagnosed with CRS and possibly asthma 
• Age over 18 years 
Exclusion criteria: 
• Do not read or speak Danish 
• Severe psychiatric comorbidities 
Patients who have never taken systemic steroids 
• According to investigators' experience, cannot participate or comply with local treatment. 
• Do not give permission to access FMK-online 
 
Inclusion/exclusion criteria for exploratory study - 4 months follow-up (pilot project): 

 
 
Inclusion criteria: 
• Diagnosed with CRS and possibly asthma 
• Age over 18 years 
• Low adherence: Foster score, i.e. number of treatments taken compared to prescribed <80% (4 weeks out 
of 16 weeks) and/or measured on MARS-5 L/N ≤35 at first visit (equivalent to less than 80%). If the patient 
does not have asthma, it is MARS-5N ≤ 19. 
• If asthma: ACQ ≥1.2 or ACT ≤17 (partially uncontrolled asthma) 
• SNOT-22 score ≥35 (partially uncontrolled CRS) 
• Participation in cross-sectional study at initial visit to Respiratory Clinic 
Exclusion criteria: 
• Adherence: Foster score> 80% and/or on MARS-5-L/N> 35 points at first visit 
• Cannot read or speak Danish 
• Severe psychiatric comorbidities 
• Patients who have never taken systemic steroids 
• According to investigators' experience, cannot participate or comply with local treatment 
• Do not give permission to access FMK-online 
Method of investigation: 
Demographic information: 
Height, age, gender, weight, lung function. 
Blood tests: 
Leukocytes and differential count, allergy blood tests with a package of specific allergens (routine). 
Research blood test plasma cortisol. 
Synacthen test: 
The Synacthen test is performed by inserting a venous catheter at time 0, and then a blood sample is taken 
to determine the plasma cortisol level. Subsequently, 0.25 mg of ACTH is injected into the venous catheter, 
and 5 ml of iso NaCl is flushed. After 30 minutes, a blood sample is taken to determine the plasma cortisol 
level. The first mL should be discarded before obtaining a new P- Cortisol is taken. The 0-sample and 30-
sample belong to the same Sampling Test Form (PTB). Scanned with PDA corresponding to the actual 
sampling time. The blood samples are sent together with their corresponding PTBs for analysis at the 
Clinical Biochemical Department, RH. Results will appear in the patient's medical record under laboratory 
results. The patient must not have ingested hydrocortisone or steroid inhalation at least 12 hours before 
the test and should not have received treatment with injection (i.m) steroid such as diprospan within the 
last three months (30). The entire procedure for the synacthen test takes approximately 1 hour and 15 
minutes, including preparation and completion. The test itself takes about 30 minutes. This applies to both 
the cross-sectional study and exploratory follow-up. 

 
 
DEXA scan: 
Patients with CRS/CRSsNP/CRSwNP receive a DEXA scan as part of their clinical evaluation. This group has 
received larger amounts of nasal steroid for often more than 10 years, as well as 1-3 times systemic steroid 
annually over several years. Therefore, it is good clinical practice to refer to a DEXA scan to examine bone 
density and structure and any need for treatment with calcium and vitamin D. These investigations are 
included in the project. 
Questionnaires: 
Patients are required to complete the following questionnaires as part of the standard treatment in the 
Respiratory Clinic: 
• STARR-15 
• SNOT-22: 
• ACQ 
• ACT 
• MARS 5-L/N: 
• Foster score 
Data processing: 
Data will be entered into REDCap (Research Electronic Data Capture), which is a secure web application for 
building and managing databases and online questionnaires. The system was developed at Vanderbilt 
University, which released the first version in 2008 (31). The use of REDCap is a requirement from Region 
Hovedstaden. 
Statistical analysis: 
Statistical analysis of the data will be performed using IBM SPSS Statistics. Results will be presented as 
mean, SD, median, range, and 95% CI. Parametric data will be compared using paired tests, and non-
parametric data using Mann-Whitney Test. Categorical variables will be tested using the chi-square test. 
Power calculation for cross-sectional study and exploratory follow-up at 4 months (pilot project): 
Rationale: In a recent study on severe asthma, patients received daily tablet prednisolone (>5 mg) for 3 
months. 60% of the patients had adrenal insufficiency, 33% had total insufficiency, and 27% had partial 
insufficiency (32). Patients with CRS are often treated with steroid injections in Denmark, receiving an 
average of three steroid injections per year (clinical observation, REDCap, Global airways incl. biological 
treatment). Some receive up to six injections per year, with an effect lasting approximately 6-8 weeks per 
injection. This means that patients with CRS are only covered for about 6 months out of 12 months per 
year. This is different from severe asthma with daily treatment. Therefore, we estimate that we can detect 
half of the findings from the asthma study (32). We therefore expect that half of the 60% who develop 
insufficiency in the asthma study = 30% of the CRS patients will have adrenal insufficiency. As some will 
have received steroid injections several months ago, a slight reduction is estimated to 25%. But no less than 
25%, as many receive high-dose nasal steroids, which, like steroid cream, may cause adrenal insufficiency 
(3). The 25% is our best estimate. It may be higher but not lower. The literature has documented that 8% of 
a population have adrenal insufficiency without having received supplemental steroids before the test. To 

 
 
demonstrate a difference between the background population and our population with 25% adrenal 
insufficiency, we will need to investigate 72 patients with an alpha value of p <0.05 and a power of 80%, 
and with a dropout rate of 10%, we will need to test around 80 patients (cross-sectional study). 
In the exploratory follow-up at 4 months (pilot project), we will investigate whether good adherence 
(>80%) to nasal steroids versus continued poor adherence (<80%) changes in P-cortisol compared to 
measurement of P-cortisol from the cross-sectional study. It is not known whether good adherence (>80%) 
changes adrenal function. This pilot project will be used for a possible future study, where the effect of 
adherence will be the primary focus. Therefore, we will include all 80 patients from the cross-sectional 
study and divide their results into good and poor adherence. 
Extraction of biological material: 
A maximum of 14 ml of blood is extracted during each Synacthen test (minimum 0.5-3.5 ml maximum split 
tube x 2-, and 3.5-ml maximum x 2 for the first blood sample for P-cortisol baseline and for the second 
blood sample for P-cortisol determination). The first blood sample is collected for P-cortisol measurement 
before the IV injection of ACTH and a minimum of 0.5 ml and a maximum of 3.5 ml of blood is extracted. 
The second blood sample is collected after 30 minutes following the IV injection of ACTH, and a minimum 
of 0.5 ml and a maximum of 3.5 ml of blood is extracted. The material is destroyed after analysis. 
Therefore, no research biobank will be established. 
Information from patient records: 
Patient information will be collected during the participant's visit to the Luftvejsklinik. Information about 
the participant, such as medical history, examinations, and medication use, will be obtained from the 
medical records. The information will only be used to screen whether the participant can participate in the 
project. Journal information used in the project before the participant has given consent will be disclosed 
to the researcher, as the researcher does not have access to obtain the information from the journal before 
consent. Once the participant has given consent, the responsible trial sponsor and any regulatory authority 
will have direct access to obtain information about the participant's medical records to see information 
about the participant's health conditions that may be necessary for the implementation of the project. 
Additionally, this is also for monitoring purposes, including self-monitoring, quality control, and monitoring 
that they are obligated to perform. If the participant has undergone blood tests and DEXA scans before the 
initial pre-examination and signing of the consent form, this data will be obtained from the patient's 
medical records if the participant wishes to participate in the project. Thus, unnecessary examinations will 
not be performed when data already exists. Data obtained from patient records after consent will be used 
in the project. This includes medical history, age, height, weight, objective clinical examinations, DEXA 
scans, blood test results, lung function values, and data from patient-completed questionnaires. The same 
data will be used in the exploratory follow-up study. 
Treatment of personal information and information: 
The project will be carried out in submission with the General Data Protection Regulation and the Data 
Protection Act. The researcher will ensure that the information meeting takes place in an undisturbed 
location in the department. They will be informed that participation is voluntary and that they will have at 
least 24 hours to consider their decision. Participants will also be made aware that they have the right to 
have a support person present during the information meeting to ensure that the participant feels safe, or 
to assist with relevant questions, keeping track of what was said and decided during the meeting. However, 
participants can also sign the consent form on their own request before the meeting. They will also be 

 
 
informed that they can withdraw from the project at any time without a reason and with immediate effect. 
If they wish to participate, they must fill out a written consent form for participation. If the participant 
wishes to take part in the project, they will receive oral and written information. They will also be informed 
that the project manager may withdraw a participant from the project at any time, regardless of the 
reason. The participant will be informed that they may be withdrawn from the project if they have another 
significant illness, do not comply with the protocol, or have a lack of ability to read and understand Danish. 
Finance: 
The mentioned research group has initiated the project. There is no increased financial consumption 
associated with the project as it involves patients who are part of the clinical outpatient treatment process 
at the Respiratory ClinicLuftvejsklinik, ENT, RH. Funding has been sought for additional work for a nurse at 
the Lung Association, Rigshospitalet's research fund, and other small and large foundations. A final 
response is awaited in the spring of 2023. Included patients and the Regional Ethics Committee for the 
Capital Region will be informed of the name of the donor and the amount of support if support is obtained. 
Conflicts of Interest: 
There are no financial conflicts of interest to report related to this project. 
Publication of Results: 
All results, whether positive, negative, or inconclusive, will be published via www.clinicaltrials.gov. 
Scientific Ethical Considerations: 
The participant's right to self-determination to choose to participate in the project will be respected. They 
will be sufficiently informed about the purpose of the project. They will be informed that their participation 
is voluntary and that they can withdraw from the project at any time without it having consequences for 
their future treatments and consultations in the healthcare system. They will receive oral and written 
information about the project. They will also be informed that they have at least 24 hours to consider 
before giving consent or not to participate. If they wish to participate, written informed consent will be 
obtained when they have decided whether or not to participate. The project has been approved by the 
Capital Region Data Protection Center P-2022-493. The project is also being carried out based on the 
researcher group's expectation that the results will be useful for future treatments. 
Information on Compensation: 
The trial is covered by the hospital's patient compensation. 
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Informed consent for participation in a health science research project 
Research project title: Adherence in Global Airways – the relationship between steroid intake and the 
impact on the endocrine axis, bone density, and structure in patients with chronic sinusitis and asthma 
Trial participant declaration of consent: 
I have received written and oral information and I know enough about the purpose, the method, the 
advantages, and the disadvantages of the trial to give my consent to participate in the trial. 
I know that it is voluntary to participate and that I can withdraw my consent at any time without losing  
my present and future rights to receive treatment. I give my consent to participate in the research project 
and have received a copy of the declaration of  consent, as well as a copy of the written information about 
the project. 
Name of the trial participant: ________________________________________________________ 
Date: _________________________ Signature: _________________________________________ 
You will be informed if significant new information regarding your health is disclosed during the research 
project. If you request to not be informed about significant new information regarding your  
health that is being disclosed during the research project, please tick here: _______________________(x) 
Would you like to be informed about the results of the research project and any consequences it might  
have for you? 
Yes (x) __________ No (x) ____________ 
Would you like to receive text messages from Department of Otorhinolaryngology, Head and Neck Surgery 
& Audiology with reminders to take your medication and fill out and complete the diary? 
Yes (x) __________  No (x) __________ 
Declaration from the person providing information: 
I declare that the trial participant has received oral and written information about the trial. 
I believe that sufficient information has been provided in order to make a decision regarding participation 
in this trial. 
Name of the person providing information: ___________________________________________________ 
Date: __________ Signature: _______________________________________________________________